Hl2 Flashcards
Why get neutropenia fever
In cancer patients taking chemo that induce myelosuppression and reduce the developmental integrity of the gi mucosa
What does myelosuppression cause
Can lead to a muted and blunted neutrophil-mediated inflammatory response, therefore a fever is the earliest ( and maybe the only) sign of infection
Definition neutropenia fever
Temperature above 38.5% with an absolute neutrophil count below 500 cells/microL
Death rate neutropenic fever
Risk of death approaches 3% per hour that the fever goes untreated
100% mortality rate if not treated in 3 days
Infections with neutropenic fever
Normal endogenous flora
Indwelling central venous catheter
S aureus, s epidermis, and klebsiella species are the most common
Fungal infections neutropenic fever
Candida is the most common pathogen by far
Aspergillus and other fungi may be involved
Pneumocystis and toxoplasma
-can cause fever, relatively unusual
Caution of neutropenic fever
No rectal exam if ANC<500 cells/microL
-microscopic tears in every patient and allow bacteria to enter the body, fulminant sepsis and death can occur within 24 hours of a rectal examination
Primary prophylaxis neutropenic fever
Antimicrobial drugs to prevent infection
Who are high risk patients for infection
<500 cells/microL for >7 days
What do antibacterial prophylaxis target
Pseudomonas aeruginosa and other gram negative bacilli
What fluoroquinolones for neutropenic fever
Levoflaxcin , ciprofloxacin
Caution with fluoroquinolone
Prolonged QT
Tendon rupture
Promoting antibiotic resistance
Increasing risk for c diffe infections
Antifungals for neutropenic fever
Fluconazole
What does fluconazole target
Candida prophylaxis
Advantages fluconazole
Oral and IV formulations
Good tolerability
Inexpensive generics
Less drug drug interactions versus other extended spectrum azoles
Cautions fluconazole
Narrower spectrum for candida
Fluconazole resistance
No activity with aspergillus
Alternative antifungal
Echinocandins like caspofungin, micafungin, anidulafungin
Advantages echinocandins
Broader spectrum than fluconazole, good safety profile
Cautions echinocandins
IV formulations, expensive
Secondary prophylaxis
Prophylactic antimicrobial drugs to prevent recurrent infection
For patients that have had a history of a prior fungal infection are at a higher risk for recurrent infection
Voriconazole
First line for aspergillus
Not given together with certain chemotherapeutics like cytarabine or fludarabine
Severe neurotoxicity with vincristine
Other secondary prophylaxis
Suspend the extended spectrum azole 1 week prior to chemotherapy (for clearance) and to start the azole again after the dosing regimen
-to continue an antifungal during chemotherapy, amphotericin B or an echinocandin can be used
Empiric therapy neutropenic fever
Antimicrobial agents when a suspected neutropenic fever is occurring
IV antibiotics for empiric therapy
Given until ANC is above 1000 cells/mL
After this, switch to oral antibiotics only if patient is afebrile and tolerating meals without emesis
Combination IV regimens are preferred to single agents
Inpatient empiric IV antibiotics for high risk patients
Piperacillin and tazobactam
A carbapenem (imipenem, meropenem, doripenem, ertapenem)
Ceftazidime
Cefepime
Adjust empiric IV antibiotics based off specific clinical data
Cellulitis or pneumonia give vancomycin or linezolid
Gram negative bacteremia add an aminoglycosides (gentamicin)
Abdominalsymptoms or suspected C dif. Give metronidazole
Outpatient oral regimens (low risk) give ciprofloxacin and amoxicillin/clavulanic acid
Empiric antifungal
Should be added if persistent or recurrent fever does not resolve after 5 days with antibiotics alone
Casofungin-candida spp most likely, echinocandins provide excellent coverage
Adequa-te hydration neutropenic fever
Important initial step in management
Lessens the risk of hypotensiona Nd complication of organ ischemia and damage
G-CSF
Filgrastim
Decreases te duration of fever and neutropenia
Shortens the length of hospitalization
Neutrophilic leukocytosis
Leukocytosis with elevated ANC (absolute neutrophil count )
Neutropenia
Neutrophilic
Mild neutrophilic
Increased cell production
Accelerated release of cells from the marrow into the blood
Shift within the circulation from the marginal to the circulating pool
Reduced egress of neutrophils fromt he blood tissues
Combination
How long does it take to shift between marginal and circulating pools
Few minutes
How long shift of neutrophils from marrow to bloo
Few hours
How long take increase production of neutrophils
Days
Usually cause of moderate or marked neutrophilia
Increased production
Primary marrow disorders of neutrophilia
CML
Myeloproliferative neoplasma
Neutrophilic leukemia
Sickle cell disease
Secondary disorders neutrophilia
Infection Inflammation Smoking Stress Asplenia Medications
Drugs that cause neutrophilia
Corticosteroids, lithium, and exogenous growth factors like GCSF
Rare dramatic neutrophilia
Granulocytes cCSF secreting tumros like bronchogenic carcinoma
Persistent neutrophilia
CML should be excluded
Other myeloproliferative that will also have erythrocytosis, thrombocytosis or ganomegaly and/or leukoerythroblassstic blood film
Polycythemia vera
Essential thrombocythemia
Myelofibrosis
Smokers and neutrophilia
Usually mild neutrophilia
Just treat with smoking cessation
Obese and neutrophilia
Get mild neutrophilic leukocytosis
You usually dont do marrow exam for neutrophilia during systemic infection or critical illness in icu except when
Rare instance where neutrophilia is felt to be the proximate illness
Acute neutrophilia
Demargination syndrome
Marrow storage pool shift
Physical0cold, heat , exercise, convulsions, pain, labor
Emotion-anger, panic, severe stress, sad
Infectoin*-localized or systemic, bacterial, mycotic, rickettsial, viral
Inflammation or tissue necrosis**-burns, electric shock, trauma, gout, vascultis
Drugs, hormones, toxins-lithium, epi, endotoxin, glucocorticoids, smoking vaccines, venoms
Demargination syndrome
Exercise ad acute physical and emotional stress can increase the number of blood neutrophils within a few minutes. The response is minced by infusion fo epi or catecholamines that increase HR and CO
What causes demargination
Shift of cells from the marginal to te circulating pool;
Where do neutrophils come from in demargination
Spleen, pulmonary capillaries
How tell demargination from infection, stress, glucocorticoid administration
Increase in lymphocytes, monocytes and neutrophilia from the response to infections, protracted stress, or glucocorticoid administration.
Neutrophil counts are elevated, but lymphocyte and monocyte counts generally are depressed
Marrow storage pool shift
For acute neutrophilia
In response to infection and inflammation and is usually bands and and segmented neutrophils
Metamyelocytes
Not released to the blood except under extreme circumstances.
How big is postmitotic marrow pool
10 times size of blood neutrophils
In neutrophil production disorders, chronic inflammatory diseases and malignancies and with cancer chemotherapy the size of this pool is reduced and the capacity to develop neutrophilia is __
Impaired
Exposure of blood to foreign surfaces, such as hemodialysis membranes, activates te complement system and causes what
Transient neutropenia, followed by neutrophilia resulting from release of marrow neutrophils
G cSF GMCSF
Can cause acute and chronic neutrophilia by mobilizing cells from the marrow reserves and stimulating neutrophil production
Chronic neutrophilia
Malignancy-gastric and bronchogenic
Asplenia
What do if have neutrophilia
Repeat counts
After repeat neutrophilia counts and they normalize or persistent
Normalized-no further avaluation
Persistent-examine smear: leukoerythroblastosis?
Positive leukoerythroblastic
Bone marrow examination morphology , cytogenics, culture
One of three options
Tumor granulomatous
ph1 or BCR ABL-CML
JAK2-non CML mpn ( p vera, myelofibrosis)
Not positive for leukoerythroblastic
Fever and signs of infection-evaluate and treat
No fever-serologic for AID, peripheral blood for BCR ABL and JAK2 Potential drugs(lithium and steroids), smoker——-all of these diagnose autoimmune dx, myeloproliferative dx, drug induced, smoking related , idiopathic
Primary lymphocytosis
CLL, ALL, hairy cell leukemia
Reactive lymphocytosis
Viral (mono), HIV, bacterial infection, smokers and autoimmune (RA)
CLL morphology
Coarse, clumped chromatin, suspicion raised for CLL
ALL morph
Lymphoblasts
Large granular lymphocytic leukemia morphology
Large granular lymphocytes, particularly in patient with autoimmune disease such as RA
Hairy cell leukemia morphology
Lymphocytes with villous projections might suggest splenic marginal zone lymphoma or hairy cell leukemia
Sezary syndrome
, and cells with cerebriform nuclei
Follicular lymphoma morphology
Larger lymphocytes with cleaved nuclei
Is cell exam important in neutrophilia and leukocytosis
Just leukocytosis
Eosinophilia : who are we looking at
> 1500 or end organ damage bc more likely pathology
History of patients with eosinophilia
B symptoms, rash, diarrhea, allergic symptoms, travel history, food intake
Undercooked meat, pork, increases chance parasitic infection with trichinella spiralis
Geographic. Lifestyle for parasite
Trichinells
Pork from abattoirs involved mixing of meat from large number of pods
Geography parasite helminthic
Underdeveloped
Churg Strauss
Eosinophilic granulomatosis with polyangiitis
Extreme eosinophilia symtpoms
Critically ill and nearly always require hospitalization bc of the high probability of malignancy or infection , in addition to risks for life threatening damage to the cardiac, respiratory, nervous and GI systems
Basophils
CML and PV
Unexplained monocytosis in old ppl with cytopenias
Myeloid malignancies such as MDS and chronic CMML and generally warranty examination of the marrow
Mild moderate severe neutropenia
1000-500
500-1000
<500
Three important historical details of neutropenia
Degree
Acuity of onset
Presence or absence of associated symptoms
Degree of neutropenia
Informative
Acuity of neutropenai
Acute onset-may inquire about recent infections and new medications
Drug induced neutropenia
Discontinue it
-cephalosporin, clindamycin, gentamicin, sulfonamides, tetracyclines, vancomycin, carbamazepine, mephenytoin, phenytoin, amitriptilina, ranitidine, allopurinol, chlorpromazine, hydrochlorothiazide, chlorothiazide, propranolol, captopril, hydralazine
Malignancy with cytopenias
Identify other concerning findings such as cytopenias, adenoathy, fever, organometallic or unintentional weight loss, neutropenia.
What chronic infections cause neutropenia bc of splenic sequesteration and marrow invasions and suppression
SplenomegALY
TB, brucellosis, typhoid fever, malaria, kala azar
Hypersplenism cytopenia of one or more types
Hypersplenism
Hypersplenism
Splenomegaly, cytopenia, normal or hyperplastic bone marrow, and a response to splenectomy .
Why cytopenia with hypersplenism
Increased destruction of the cellular elements secondary to reduced flow of blood through enlarged and congested cords (congestive splenomegaly) or to immune mediated mechanism
Morphology hypersplenism
Normal although rbc may be spherocytosis due to low of surface area during longer transithrough the enlarged spleen .
Reticulocytosis hypersplenism
Increased from icnreased marrow production but increased sequesteration of reticulocytes in spleen
Causes hypersplenism
Ok
Rheumatologist
Hypersplenism with neutropenia
Felty-RA
What do if have neutropenia
Fever localizing signs-no stop looking for drugs look for toxins
Fever0yes ANC<500/mL->admit for IV antibodies consider G-CSF
Neutropenia new or old
New-single lineage or multilineage cytopenia
No-FH+? Yes-cycle? Yes-ELANE mutation?
FH+ yes-ELANE mutation
ELANE mutation
Yes cyclic neutropenia
FH_ not elane
Appropriate ethnic group?
Yes-constitutional neutropenia-familial neutropenia
No-familial neutropenia
Single linear or multilineage cytopenia new neutropenia
Isolated neutropenia-bone marrow examination
Pancytopenia-low b12? Yes megaloblastic anemia
No-bone marrow exam
Autoimmune disease? Yes-immune cytopenia
No-bone marrow examination
Bone marrow examination
Abnormal cytogenics-Myelodysplasia
LGL by flow-LGL
All normal-idiopathic neutropenia
Lymphopenia
ALC less than 1500 cells/microL
How assess ALC
Evidence of splenomegaly, adenopathy, or evidence of fungal infection, such as oral candidiasis.
Inherited and acquired causes
HIV
Viral a bateria-
Glucocorticoids
Alcoholism
Inherited lymphopenia
Congenital immunodeficiency
Acquired lymphopenia
Aplastic anemia
Infectious diseases
Iatrogenic
Monoctopenia monocytopenia
Hairy cell leukemia
Hairy cell leukemia
Constitutional symtoms, splenomegaly, and the majority of patients are monocytopenia even without classic hairy ells on the blood film, it is worthwhile performing flow cytometry with attention to hairy cell markers, including CD11c and CD103
MonoMAC
Monoctopenia and mycobacteria infection syndrome that causes severe monocytopenia
Mutation os severe monocytopenia of MonoMAC
GATA-2 gene
Risk of MonoMAC
High risk of progressing to MDS or acute myelogenous leukemia
What do if have neutrophilia
- Repeat counts.
- Normal no further exam, not normal examine smearL is it leukoerythroblastic?
3/ yes-bone marrow exam for tumor granulomatous, Ph or BCR-ABL-CML, JAK2-nonCML, MPN
No-fever-yes evaluate and treat
Fever no-serologic for AIDS, peripheral blood for BCR-ABL and JAK2, potential drugs, smoker to get autoimmune , myeloproliferative , drug induced, smoking related , idiopathic
Infection
Lose bone marrow, gain circulating pool, marginatum pool, and tissue
Epinephrine
Increase circulating pool, lose marginal pool
Steroids
Lose bone marrow, increase circulating pool and marinated pool
Leukocyte adhesion defiency
Lose bone, gain circulating pool, decrease tissue, decrease marginatum pool?
What causes leukocytosis
Benign more than malignant
Inflammation and leukocytosis
YES anything that causes inflammation an cause leukocytosis
Big cause of leukocytosis
Drugs
Inpatients with neutrophilia who smoke
Smoking may be responsible
Elane
Gene coding for neutrophil elastase, seen in cyclic neutropenia
Cyclic neutropenia
ELANE
What do is neutropenia
- Fever, localizing signs? New or old ?
Fever with neutropenia yes vs no
No-stop potential drugs look for toxins
Yes -AMC<500-admit for IV antibodies consider G-CSF
Neutropenia new onset vs old
New-single or multilineage cytopenia
Not nes-FH+?
Single of multilineage cytopenia : isolated neutropenia vs pancytopenia
Isolated-bone marrow exam
Pancytopenia-low B12 folate megaloblastic
Or
Autoimmune disease -no do bone marrow examination
Yes autoimmune-do immune cytokines LGL by flow
Bone marrow exam
Abnormal cytogenetic -Myelodysplasia
LGL by flow-LGL
All normal-idiopathic neutropenia
FH+
No is it cyclic-ela é
Yes-ela é
Elane mutation
Cyclic neutropenia
FH+
Appropriate ethnic group-constitutional neutropenia and familial neutropenia
Not appropriate ethnic group-familial neutropenia
Neutropenia and meds, nutritional defines , or sequesteration
Responsible for neutropenia
What percentage of circulating erythrocytes must be replenished daily to maintain a normal hematocrit
1%
What need for hematopoiesis
Healthy bone marrow microenvironment, healthy and hematopoietic stem cells, ample endogenous growth factors, and ample and usable body stores of iron, folate and cobalamin
Why men have higher hemoglobin and hematocrit
Testosterone production in men and borderline iron stores in menstruating women
Pregnant women
Rbc mass rises, plasma volume increases greater so lower hematocrit
Anemia in men and women levels
Hemoglobin<13
Men<12
Hypochromic
Decrease Hgb per RBC and or HCT< including iron defiency, inflammatory block to iron utilization, thalassemia and sideroblastic causes
Hyperchromic
Increase Hgb per RBC and/or HCT, implying loss of RBC embrace in relation to RBC volume (hemolytic , certain hemoglobinopatias)
What if have also issues with leukocyte counts, platelet counts and leukocyte counts alongside erythrocyte measurements
Trilineage hematopoiesis
Reticulocytes counts
Whether or not bone marrow responses to anemia are adequate.
Appropriate increase in reticulocytes count
> 100,000
What is reticulocytes>100,000
Almost always reflect erythrocyte loss or response to appropriate therapy (iron, folate, b12)
Lower than normal reticulocytes count
Erythrocyte underproduction, including anemia due to deficient erythropoietin, nutritional defiencies
A Anthony três (erythrocytes with a small number of spicules of variable size and distribution
Liver
Bite cells
Oxidative hemolysis, which may be due to unstable hemoglobins or potent oxidants (with or without G6PD or pyruvate kinase defiency)
Echinocytes (erythrocytes with a small number of spicules of uniform size and distribution on the cell surface)
End stage kidney disease
Hypochromia, anisotyosis, poikilocytosis
Iron defiency anemia
Intraerthrocytic parasites (plasmodium, babesia)
Hemolytic anemia
Rouleaux formation
Monoclonal protein, cold agglutination, or increased fibrinogen (as in acute phase reaction)
Schistocytes
Fragmentation hemolysis, as in micro or macro angiopathy hemolytic anemia (DIC, TTP, )
Sickle cell
Sickle cell
Small target cells (erythrocytes with area of central density surrounded by pallor and then a rim for density), teardrop cells, basophils stippling
Thalassemia
Spherocytosis
Membrane loss without central Paulo
Teardrop cells, nucleated erythrocytes, and immature myeloid forms
Myelophthisic anemia (leukoerythroblastosis)
Absolute reticulocytes count
> 100000 signify erythropoietin and a shift in reticulocytes pool from bone marrow to peripheral blood; compatible with bleeding, hemolysis, or response to treatment
Serum folate and vitamin B12 levels
Used to assess possible folate or vitamin B12 defiency
Serum iron, TIBC and ferritin
Low serum TIBC -iron defiency without inflammation (low ferritin)
Low serum iron and low TIBC characterize anemia of inflammation (normal high ferritin)
Caveat: 20% of patients with anemia of inflammation have iron/TIBC<10%
Serum transferrin receptor concentration
Elevated in the setting of increased erythropoietin or iron defiency. If hemolysis or ineffective erythropoietin is exclusões, an elevated serum transferring receptor concentration suggests and block iron transport
Serum creatinine
High levels signify underproduction of erythropoietin, which is manufactured primarily by the kidneys
Erythropoietin
Should rise logarithmically above normal levels in relation to decreasing hematocrit. Levels>500mU/mL predict poor response to recombinant erythropoietin administration
TSH
Assess hypothyroidism which may cause anemia
Serum testosterone
Assess hypotestosteronism in men which may cause anemia
LDH, bilirubin, and haptoglobin
Haptoglobin <20 mg/dL indicate hemolysis, supported by elevated LDH and total bilirubin
Urine hemosiderin and hemoglobin
Presence supports intravascular hemolysis
SPEP, UPEP, and quantities immunoglobulins
Hypogammaglobulinemia, positive serum monoclonal proteins, and urine free kappa or lambda light chains suggest possible plasma cell myeloma or lymphoma
Wright giemsa stain
Peripheral blood smears, reticulocytes appear larger than more senescent erythrocytes and somewhat purple due to icnreased ribonucleoprotein and nuclei acid content from the extruded erythrocyte nucleus
What should absolute reticulocytes count be in patients with anemia
> 100000 increased
Corrected reticulocytes count
Reticulocytes percentage x (observed HCT/expected HCT)
Corrects for degree of anemia
Reticulocytes production index (RPI
Reticulocytes percentage /correction factor
Corrects for shortened reticulate maturation time as anemia worsens
Absolute reticulocytes count
Erythrocyte counts reticulocyte count/100, where erythrocyte count is expressed as nx10 to the 6
In steady state conditions, absolute reticulocytes count is 25000 to 74000
Over 75000 imply stress erythropiesis
What do if patient has anemia
Get reticulocytes count
High reticulocyte count
Are they bleeding? Yes blood loss
No get a smear
Smear
Ok
Schistocytes
Microangiopathy
Spherocytes
Warm antibodies or hereditary spherocytosis
Sickle cell
Sickle cell
Bite cells
G6pd
Target cells
Thalassemia
Inclusions
Malaria
Low or normal reticulocyte count with anemia
Get a peripheral blood smear
Microcytic on blood smear
Iron defiency
Thalassemia
Sideroblastic anemia
Normocytic on peripheral blood smear
Aplasia Marrow infiltration Renal disease Inflammation Chroni disease
Microcytic on peripheral blood smear
B12 Folate Myelodysplasia Drug toxicity Alcohol
Fast and slow anemia examples
Slow-underproduction
Fast-bleeding or hemolysis
Why family history with anemia
May be hereditary or acquired
What supplement H and P with anemia with
Erythrocyte size MCV
Morphology
What is not known after h and p and blood lab tests
Bone marrow aspiration for infiltration myelopathies from fibrosis, cancer, infection, disorders of myeloid maturation like leukemia’s or myelodysplastic syndromes or aplasia
Aplastic anemia
Usually autoimmune
Symptoms aplastic anemia
Pancytopenia, fatigue, dyspnea, bleeding, infection
Blood aplastic anemia
Anemia, thrombocytopenia, leukopenia; blasts or other immature small in number
What must exclude with aplastic
Twelve and folate
Drug induced marrow suppression
Switch to other biochemical class n
Bone marrow aplastic anemia
Hypocellularity with increased fatty deposits and distinguish it from myelodysplastic or acute leukemia which may present similarly
Allogenic HSCand aplastic anemia
Curative in most so give under 40 and healthy and have HLA compatible sibling
How treat aplastic anemia if no can get HSCT
Immunosuppressive therapy with antithymocyte globulin and cyclosporine, with long term survival expected in the majority of patients
Microcytic anemia
Decreased iron availability, globin chain production and or heme synthesis
Hypochromic
What reduced iron availability
Inflammation
Iron defiency
Sideroblastic
Decreased heme synthesis
Most common cause microcytic anemia
Iron defiency
Mensural or GI
Most commmon morphological sign of iron defiency
Hypochromic is number 1
Microcytic is numbe r2
Pagophagia
Craving for ice, iced drinks, freeezer frost is a form of pica symptom of iron defiency disappears with replacement
Postmenopausal and men with iron defiency anemia
Check GI
Premenopausal women iron defiency
Gynecological and GI
How UA help with iron defiency anemia
Chronic intravascular hemolysis with loss of iron in the urin is uncommon
Gastrectomy
Decreased production HCL and iron absorption
Celiac disease
Results in malabsorption of iron by the duodenum
Most. Useful test in diagnosing iron defiency
Serum ferritin
What is ferritin
Acute phase reactant so less helpful if infection or inflammation
Treat iron defiency
Oral iron preparation
Ferrous sulfate
Ascórbico acid enhance absorption
Calcium, inhibitors of gastric acid decrease absorption
How long trat
r 6 months to 1 year until hemoglobin levels and iron stores return to normal
Indications for parenteral iron therapy
(1) inability to tolerate oral iron compounds; (2) inability to absorb oral iron; (3) repeated failure to adhere to a regular schedule of oral iron administration; (4) circumstances when iron (blood) loss exceeds oral iron replacement and/or when oral iron exacerbates symptoms of the underlying disease (eg, inflammatory bowel disease); (5) autologous blood donation (in selected cases); and (6) hemodialysis
Microcytic anemia
Clinicians should first assess the reticulocyte count and rule out stress erythropoiesis (eg, from bleeding or hemolysis). Reticulocytes are larger than senescent erythrocytes; consequently, increased reticulocyte numbers elevate the MCV, but generally not to levels >110 to 115 fL. Macrocytic anemia may be megaloblastic or nonmegaloblastic (Table 6
Hemolysis anemia what look at
type (spherocytic or nonspherocytic), site (intramedullary or extramedullary, intravascular or extravascular), and mechanism (immune-mediated or nonimmune-mediated, intrinsic vs extrinsic to the erythrocyte
Spherocytes hemolytic anemia
For example, spherocytic hemolytic anemia implicates a membrane defect, either acquired (eg, warm autoimmune hemolytic anemia) or congenital (eg, hereditary spherocytosis
No spherocytes hemolytic anemia
Nonspherocytic hemolytic anemias include “bite cell” hemolysis (eg, oxidant stress) and fragmentation hemolysis (eg, thrombotic microangiopathy
Intramedullary hemolysis
hemolysis is seen in various disorders associated with ineffective erythropoiesis, including thalassemia
Extramedullary hemolysis
Extramedullary hemolysis may be extravascular (eg, hemolysis mediated by the spleen) or intravascular (eg, hemolysis associated with cold agglutinin disease or thrombotic microangiopathy
Immune mediated hemolysis
Immune-mediated hemolysis is distinguished by the presence of antibodies (detected by the antiglobulin [Coombs] test) directed against erythrocytes; these antiglobulins, also referred to a “agglutinins,” may be detected when bound to the surface of red blood cells (direct antiglobulin [Coombs] test) or circulating in serum (indirect antiglobulin [Coombs] test). hey may also be further characterized by the body temperature at which they react, with “warm agglutinins” (usually IgG antibodies) reacting at body temperature, and “cold agglutinins” (usually IgM antibodies) reacting at temperatures below core body temperature. Hemolytic disorders “intrinsic” to the erythrocyte include membrane defects, enzymopathies, and hemoglobinopathies
Folate defiency
Alcohol, diet, small bowel disease, celiac disease
B12 defiency
Folate defiency, loss of vibratio or position sense favors b12 defiency. However neurologic disease due to b12 defiency may occur without anemia or macrocytosis
Drug induced change in erythrocytes
Numerous drugs prescribed for cancer, HIV, psoriasis, SLE, RA, and posttransplantation immunosuppression cause microcytic and megaloblastic changes in erythrocytes. HISTORY
Myelodysplastic syndromes
Primary hematopoietic disorders with hypercellular bone marrow and peripheral blood cytopenias due to ineffective e myelopoiesis, abnormal maturation and intramedullary apoptosis of myeloid cells
Oxidant hemolysis
In oxidant hemolysis, a by-product is methemoglobin, which contains ferric ions. Methemoglobin has altered spectrophotometric properties from hemoglobin, which contains ferrous ions. As a consequence, patients with methemoglobinemia have arterial pO2 values (reflecting the total concentration of oxygen in blood) that appear higher than expected in relation to the percent oxygen saturation (which specifically reflects the percent of oxygen bound to hemoglobin
Membrane defect (spherocytosis, eliptocytosis)
In patients with a positive family history, splenomegaly, and spherocytes, or elliptocytes on blood smear. Diagnosis is confirmed by osmotic fragility and negative direct antiglobulin (coombs)
Enzymopathy 9g6pd, pyruvate inase_
Episodic moderate hemolysis, precipitated by oxidant drugs or infection. Variable blood smear findings include bite cells, spherocytes, fragments, and minimal abnormalities of erythrocytes other than polychromatic.
What drugs NOT for G6PD
Dapsone, methylene blue, nutrofurantoin, phenazopyridine, phenylhydrazine, primaquine, sulfamethoxazole, and sulfapyridne. Pyruvate kinase is rare and cause moderately severe anemia and acanthosis
Pyruvate
Rare and causes moderately severe anemia; blood smear show acanthocytess
Hemoglobinopatias (HS, HC< thalassemia,
Chronic or episodic hemolysis. HgB A1 level is increased with B thalassemia; Hgb F also may be increased. No structural Hgb abnormality is detectable with a thalassemia diagnosis based on hematocrit, MCV, blood smear, and family study, abnormal Hbg are uncommon. In US. Blood smear changes suggest certain hemoglobinopatias hbg electrophoresis reveals the abnormal Hgb
Autoimmune hemolytic anemia
Spherocytes on blood smear; erythrocyte agglutination is seen with cold agglutination disease. Diagnosis is confirmed by direct and indirect antiglobulin testes and cold agglutination titer; direct antiglobulin test is positive for C3 in cold agglutination disease. Most cases of warm antibody disease are drug induced or associated with an underlying disorder
Erythrocyte fragmentation
TPP HUS DIC
TPP usually presents as neurologic symptoms and severe fragmentationa nemia and thrombocytopenia. With HUS , kidney abnormalities predominate, and anemia ad thrombocytopenia are milder. In other causes of microangiopathic anemia (DIC, malignant HTN, scleroderma renal crisis0, the anemia and thrombocytopenia are usually mild. To moderate ; these disorders are diagnosed by peripheral blood smear in the proper clinical context
Infection (malaria, babesiosis)
Symptoms of infection, particularly fever, usually dominate. Splenomegaly is the rule with malaria; babesiosis usually produces a milder malaria like illness, unless patient are asplenia. Finding intraerythrocytic parasites on blood smear is diagnostic
Hypersplenism
Splenomegaly can cause hemolysis; hypersplenism may also decrease the number of leukocytes, platelets, or any combination of cell lines. Hypersplenism produces no erythrocyte morphologic changes in erythrocytes, but the blood smear may show changes related to the underlying cause
Megaloblastic macrocytosis
Macro-ovalocytes suggest megaloblastic maturation of erythrocytes; hypersegmented neutrophils may also be present
Causes megaloblastic
folate and/or vitamin B12 deficiency, drugs affecting folate metabolism and/or DNA synthesis, and acquired idiopathic causes of megaloblastic maturation (eg, myelodysplastic syndromes
Megaloblastic anemia blood finding
MCV >115 fL is almost always due to a megaloblastic cause. Because megaloblastic causes of anemia impact trilineage hematopoiesis, leukopenia and thrombocytopenia
32
may accompany anemia. The myelodysplastic syndromes are stem cell clonal disorders characterized by ineffective hematopoiesis and various peripheral cytopenias
What do is patient has microcytic anemia
Patients with macrocytic anemia or specific neurologic symptoms should be screened for vitamin B12 deficiency. However, the MCV should not be used as the only indication to exclude vitamin B12 deficiency, which can be present despite a normal MCV or may be present in combination with microcytic causes of anemia (eg, iron deficiency or thalassemia), thereby yielding a normal MCV
Iron and b12 defiency
oncomitant iron and vitamin B12 deficiencies can arise due to various causes, including celiac disease
Treat b12
aily oral vitamin B12 can be used to treat most vitamin B12-deficient patients. Timed-release formulations may not reliably release their vitamin B12 content and should be avoided
Nonmegaloblastic macrocytoss
Large target cells (MCV = 105-110 fL) and echinocytes (erythrocytes with a small number of spicules of uniform size and distribution on the cell surface) signify membrane changes associated with liver disease. Diminished spleen function (hyposplenism or asplenia) yields large target cells, acanthocytes (erythrocytes with a small number of spicules of variable size and distribution on the cell surface), Howell- Jolly bodies, and variable numbers of nucleated erythrocytes
Normochromic normocytic anemia
When the MCV is normal (80-100 fL), assessing whether it is declining or rising over time may provide clues to an evolving microcytic or macrocytic pathology
Causes normocytic
Other causes of normocytic anemia (Table 8) include underproduction of erythropoietin (eg, kidney failure), deficiency of other growth factors (eg, thyroid hormone or testosterone), inflammation, and marrow infiltrative myelopathies, which yield teardrop cells, nucleated erythrocytes, and immature leukocytes
Most commmon caus normocytic
With the exception of acute blood loss, the most common cause is the anemia of inflammation.
Aplastic anemia normocytic
Aplastic anemia, a rare cause of normocytic normochromic anemia, is usually accompanied by severe granulocytopenia and thrombocytopenia due to deficient hematopoietic stem cells
Acute blood loss
Anemia with variation in erythrocyte size if iron defiency is present. Reticulocyte count is usually increased leukocyte count and platelet count may be increased depending on rapidity of bleeding
Chronic kidney disease
Anemia with a low reticulocyte count due to impaired erythropoietin production. Renal endocrine function does not correlate with renal exocrine
Pure red cell aplasia
Anemia with severe reticulocytopenia. Diagnosis má-fé by examination of a bone marrow aspirate in which erythroblastosis will be absent or severely diminished. Red cell aplasia can be idiopathic or secondary to a thymoma, solid tumor, hematologic malignancy, collagen vascular disease, viral infection, or drug. Red cell aplasia may also occur in patients with hemolytic anemia from any cause
Malignant (solid tumor, lymphoma, myelofibrosis)
Anemia with a low reticulocyte count. With bone marrow involvement by tumor, leukoerythroblastosis and extramedullary hematopoiesis occur, and nucleated erythrocytes and myelocytic are seen in the peripheral blood. Peripheral blood smear may show rouleaux formation or teardrop shaped erythrocytes (if splenomegaly)
Alcoholic liver disease
Anemia with a low reticulocyte count. Target cells and acanthocytes Amy also be present. Leukocyte and platelet counts will be reduced if there is portal HTN with splenomegaly , although thrombocytopenia in liver disease is chiefly due to underproduction of theombopoietin by liver
Anemia of inflammation (chronic disease)
A normocytic anemia that occurs in association with another disease. The underlying disorder is usually infectious, inflammatory, or neoplastic and is characterized by distinct abnormalities or iron metabolism. Low serum iron and transferrin with reduced transferrin saturation, normal or elevated serum ferritin, and normal or increased bone marrow iron stores
Hemolytic anemia
Anemia with an elevated reticulocyte count and spherocytes, sickle cells, bite cells, or fragmented erythrocytes. There may be hemoglobinuria. If the reticulocyte count is sufficiently elevated, the MCV may be high . The serum haptoglobulin leve willl be low whether the hemolysis is intravascular or extravascular, and if the hemolysis is antibody mediated, ther direct antiglobulin test result will be positive. The essential lab test is ther peripheral blood smear, which can distinguish between the different types of hemolysis: spheroid hemolytic anemia, erythrocyte enzyme enzyme defect, erythrocyte fragmentation, cold agglutination disease, hemoglobinopatias, heavy metal intoxication, and PNH. Urine hemoglobin and urine hemosiderin measurements are useful for detecting intravascular hemolysis.
Anemia of inflammation
nflammatory cytokines impede erythropoiesis by decreasing erythropoietin production, decreasing responsiveness of maturing erythroid precursors to erythropoietin, and decreasing iron absorption by the gastrointestinal tract and iron release from storage pools (macrophages
Hepcidin
Hepcidin, an acute phase protein that rises in response to certain inflammatory cytokines, is chiefly responsible for the effects on iron by causing internalization and degradation of the iron export protein ferroportin
Inflammatory cytokines transferrin
Inflammatory cytokines also decrease transferrin production while increasing ferritin
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levels. Thus, the consequences of inflammation are lower serum iron and total iron- binding capacity levels (calculated from transferrin levels) and higher serum ferritin levels
Iron defiency absent inflammation
With iron deficiency absent inflammation, transferrin and calculated total iron- binding capacity levels rise while ferritin levels decline (reflecting diminished storage pools of iron
Cytokines
Cytokines disrupt this physiologic response to iron deficiency, thereby confounding diagnosis of iron deficiency when inflammation is present. However, since cytokines increase serum ferritin levels by as much as 3 fold, serum ferritin levels <100 ng/mL (100 μg/L) may reflect iron deficiency in patients with inflammatory states.
Reticulocyte counts
Reticulocyte counts are inappropriately low for the degree of anemia. Bone marrow biopsies are generally not indicated unless competing causes of anemia are suspected (eg, pure red cell aplasia, sideroblastic anemia, or other myelodysplastic syndromes
Manage anemia if inflammation
The management of anemia of inflammation is treatment of the underlying inflammatory condition. When symptomatic anemia persists despite treatment of the chronic condition (eg, rheumatoid arthritis), administration of recombinant human erythropoietin can improve anemia and diminish the need for erythrocyte transfusion
Treatment anemia
Appropriate treatment is dictated by the underlying cause or causes of anemia. In view of the diverse causes of anemia, each dictating specific strategies for optimal management, an in-depth review of anemia treatments is not possible here. However, a few overarching principles apply
Consideration therapy anemia
Clinicians should always ensure intact nutritional, mineral, and vitamin stores. When anemia is due to bleeding, the source of bleeding should be eliminated as best as possible. When anemia relates to hemolysis, the cause should be identified. If hemolysis is due to a congenital hemoglobinopathy, it should be managed accordingly (eg, supplemental folic acid, hydroxyurea for sickle cell disease). If hemolysis is acquired, the cause should be identified and managed accordingly (eg, immunosuppression for autoimmune hemolytic anemia, plasmapheresis for thrombotic thrombocytopenic purpura, elimination of drugs causing oxidant stress, treatment of malaria or babesiosis, treatment of the underlying cause of disseminated intravascular coagulation, or replacement of a deteriorating native or mechanical heart valve)
When anemia related to underproduction of erythropoietin treatment
When anemia relates to underproduction of erythropoietin (eg, in chronic or end- stage kidney disease), treatment with erythropoiesis-stimulating agents should be considered. In patients with primary hematopoietic disorders impacting normal bone marrow hematopoiesis (eg, aplastic anemia, myelodysplastic syndrome, leukemia, plasma cell myeloma, lymphoma, and myelofibrosis), clinicians should proceed with the most appropriate management of the underlying primary hematopoietic disorder. For management of anemia-associated symptoms (eg, fatigue, lethargy, and exertional dyspnea), supportive blood transfusions versus pharmacologic doses of erythropoiesis-stimulating agents should be considered. In some instances, allogeneic hematopoietic stem cell transplantation may be indicated
Sickle cell
The sickle mutation is a single base change (GAT → GTT) in the sixth codon of exon 1 of the β-globin gene, resulting in replacement of the normal glutamic acid with valine
at position 6 of the β-globin polypeptide. When both β-globin genes (homozygous) have this single amino acid substitution, deoxygenated hemoglobin S heterotetramers polymerize to form fibrils, causing erythrocytes to sickle and hemolyze. Sickle cells, forming in the relatively hypoxic regions of tissues, impede blood flow in the microvas- culature and promote vaso-occlusion, resulting in profound, often disabling complica- tions, including acute pain (crises), chronic pain, and organ dysfunction or failure. When only one copy of the β-globin gene has this defect and is inherited along with a normal β-globin gene, patients have sickle cell trait and are asymptomatic. The preva- lence of sickle cell trait varies widely worldwide and may be as high as 50% in certain regions, affecting individuals of African, Hispanic, Mediterranean, Asian, and Indian descent. Among persons of African ancestry, sickle cell disease is one of the most com- mon genetic diseases; about 10% are carriers of the sickle gene, and 1 in 600 newborn infants have sickle cell disease
Screening sickle cell
The goal of newborn screening is to identify infants with sickle cell disease and to treat these patients for 5 years with prophylactic penicillin (or a macrolide, if there is an al- lergy to penicillin); antibiotic therapy has been shown to reduce both mortality and morbidity from pneumococcal infections in infants with sickle cell disease and sickle cell–β-thalassemia. Abnormal hemoglobin may be identified in white individuals; most reports indicate that universal screening is more cost effective than targeted screening. For possible future primary prevention, counseling the family of an affected infant should include screening of other family members, especially the parents
Complications sickle celll
Sickle trait is a benign carrier condition that can also be detected at birth. While indi- viduals with sickle cell trait do not have an increased mortality rate compared with the general population, there are a number of complications associated with sickle trait that may arise, including increased risk of sudden death with intense physical activity
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and extreme exercise. Athletic and military groups may require mandatory testing for sickle trait with opt-out provisions. However, the American Society of Hematology op- poses such mandatory screening, favoring universal interventions to reduce exertion- related injuries and deaths, since this approach can be effective for all athletes irre- spective of sickle cell status
Diagnosis sickle cell
Sickle cell disease is inherited in an autosomal manner. If both parents carry sickle he- moglobin or another abnormal hemoglobin, there is a 25% risk that the fetus of each pregnancy will have sickle cell disease or another sickle cell syndrome. Prenatal diag- nosis is possible, and genetic counseling is important for affected families to fully un- derstand the diagnosis, its complications, and possible therapeutic interventions
Clincila manifestations sickle cell
Most patients with sickle cell disease experience clinical manifestations in childhood, even as early as age 6 months. Aspects of the medical history that support the possibil- ity of sickle cell disease or a related hemoglobinopathy include recurring episodes of acute pain, chronic pain, and symptoms and signs of anemia and its sequelae. The av- erage hemoglobin level in patients with sickle cell disease is 7 to 8 g/dL (70-80 g/L); the anemia is normocytic normochromic, with high reticulocyte counts from stress erythropoiesis and chronic hemolysis. Microcytic hypochromic indices suggest sickle cell–β-thalassemia or coinherited α-thalassemia. High platelet and leukocyte counts relate to functional asplenia because of destruction of the spleen due to sickling (auto- infarction
Hemoglobin electrophoresis
Hemoglobin electrophoresis distinguishes most structural variants of hemoglobin. High hemoglobin F levels are associated with less severe clinical disease. Elevated he- moglobin A2 levels signify the presence of β-thalassemia. Knowledge of the molecular lesion in a patient with sickle cell disease may predict severity, assist with family coun- seling and planning, and guide use of aggressive therapeutic modalities (eg, allogeneic bone marrow transplantation
Additional lab test documents
Additional laboratory testing documents organ dysfunction caused by sickle cell dis- ease. Urinalysis and serum creatinine level identify patients with proteinuria and kid- ney failure. In patients who have received multiple transfusions, indirect antibody test- ing detects alloantibodies relevant to future transfusions; liver enzymes, viral hepatitis serologies, and serum iron chemistries identify patients who have contracted viral hepatitis and/or developed iron overload. Pulmonary hypertension, correlating with
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older age and prior history of acute chest syndrome, is the most common abnormality on echocardiography, with electrocardiography demonstrating signs of right ventricu- lar hypertrophy or strain. Physical examination findings associated with sickle cell dis- ease are summarized in Table 2.
Temperature sickle cell
Acute painful episodes are often associated with low grade fever. If temperature over 38.3 rule out infection
Pulse SC
Anemia, infection and pain associated with tachycardia
Respiration rate SC
Respiration rate is 16-20/min in the steady state. A rate <10/min suggests opioid overdose
Bp SC
Blood pressure is usually low normal. HTN increases morbidity and mortality risk.
Cardiac examination
A systolic murmur due to anemia is common. The absence of a murmur is associated with mild anemia and no cardiomegaly. Findings associated with pulmonary HTN and right ventricular hypertrophy or strain include increased intensity of the pulmonic component of s2, right sided murmurs and gallops and a prominent a wave in the jugular venous pulses
Pulmonary examination
The lungs are usually clear in the steady state. Rhonchi may be heard in patients with a history of recurrent ACS. Decreased breath sounds and/or pulmonary crackles in a febrile patient suggest pneumonia or ACS
Abdominal examination
With age and repeated episodes of suckling, the spleen becomes small, fibroses and devoid of any function . However splenomegaly may persist into young adulthood, espicially in patients with hemoglobin SC, SC-B thalassemia, or sickle cell a thalassemia. Hepatomegaly could be a sign of iron overload or heart failure. Tender hepatomegaly suggests hepatic crisis
Skin exam SC
Leg ulcers develop in 5% ulcers are msot often located not he medical or lateral aspect of the ankle
Neurologic examination
Focal findings suggestive of stroke. Not all patients with a history of stroke have residual weakness
Therapy SC
Hydroxyurea augments levels of hemoglobin F, which inhibits intracellular polymeri- zation of hemoglobin S. Hydroxyurea decreases the incidence of acute painful epi- sodes by approximately 50% in responders; it also reduces the incidence of acute chest syndrome and the need for blood transfusion. Nine-year follow-up of adult patients taking hydroxyurea showed that hydroxyurea was associated with a 40% reduction in mortality. In addition to inducing fetal hemoglobin, other beneficial effects of hy- droxyurea in sickle cell disease include improved erythrocyte hydration, macrocytosis, and lower neutrophil and reticulocyte counts with decreased adhesiveness and im- proved flow (rheology) of circulating neutrophils and reticulocytes. Together, these beneficial effects reduce intracellular sickling and result in reduced hemolysis and im- proved hemoglobin levels. There is growing evidence that hydroxyurea therapy also of- fers multiple benefits in children. Beginning hydroxyurea in childhood or adolescence may help to prevent chronic and long-term end-organ damage, thereby supplanting the need for chronic management strategies such as exchange transfusion and chela- tion therapy
Exchange transfusions
Exchange transfusions, a technique that removes the patient’s blood while transfusing normal, crossmatched donor blood, should be considered to decrease hemoglobin S levels by <30% in managing specific acute complications, including cerebral infarc- tion, fat embolism, acute chest syndrome, unresponsive acute priapism, and nonheal- ing leg ulcers. Incidence of iron overload requiring chelation therapy, which increases morbidity and mortality, is less in patients receiving exchange transfusions compared with those on simple blood transfusion
ACE
Angiotensin-converting enzyme (ACE) inhibitors prevent progressive kidney disease by lowering intraglomerular pressures. In addition, ACE inhibitors can lower protein excretion and should be used in patients with sickle cell disease and albuminuria, even in the absence of hypertension. Recombinant erythropoietin stimulates erythropoiesis to achieve hemoglobin levels similar to steady-state values (ie, 7-9 g/dL [70-90 g/L]) in patients who have kidney failure or to limit blood transfusions in patients who are alloimmunized and for whom crossmatch-compatible blood is difficult to find
Supplemental folic acid
Supplemental folic acid prevents folate deficiency (arising from chronic hemolysis) and subsequent elevation of homocysteine levels, which may be a risk factor for stroke. Periodic retinal examinations are recommended for monitoring and managing (photocoagulation) progressive proliferative sickle retinopathy. Pneumococcal, Hae-
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mophilus influenzae type b, and influenza vaccines prevent infections. Relaxation and biofeedback methods, cognitive coping strategies, and self-hypnosis are techniques that reduce emergency department visits, hospital admissions, hospital days, and anal- gesic use. Goals of these interventions are to improve quality of life by increasing activ- ity and enhancing normal function and to decrease dependence on opioid analgesics.
Hospitalized SC
Patients are hospitalized when severe acute painful episodes (crises) do not resolve at home with oral analgesics after 1 to 2 days or do not resolve or improve significantly after a minimum of 4 to 6 hours of treatment with parenteral opioids. Effective pain relief is best achieved with combined use of acetaminophen, nonsteroidal anti- inflammatory drugs, opioid analgesics, and adjuvant therapies (antihistamines, antide- pressants, and anticonvulsants). Meperidine is not recommended as opioid therapy, because it is less effective than morphine or hydromorphone and is associated with more side effects (eg, seizures). Nonsteroidal anti-inflammatory drugs should be avoided in patients with kidney failure
Supplemental O Sc
In patients with sickle cell disease, supplemental oxygen should be used only in the presence of demonstrated hypoxia (oxygen saturation <92% or arterial PO 2 ≤70 mm Hg [9.3 kPa]). For severe symptomatic anemia or acute organ failure, blood/exchange transfusions improve blood oxygen-carrying capacity and microvascular perfusion by diluting circulating sickled erythrocytes. To avoid increased blood viscosity, transfu- sions should not yield hemoglobin levels >10 g/dL (100 g/L
Allogenic bone marrow transplant
Allogeneic bone marrow transplantation (in patients aged <16 years with severe com- plications) may cure sickle cell disease, but its success depends on the availability of donors and the severity of the disease of the patient in question. Recipients of HLA- matched donor marrow have 75% to 85% event-free survival, 15% graft rejection, and 10% mortality
Thrombocytopenia
Decreased platelet
Cause thrombocytopenia
Thrombocytopenia occurs through 1 of 2 mechanisms: decreased platelet production or accelerated platelet destruction (Table 1). Most disorders that produce thrombocy- topenia through inadequate bone marrow production also affect other marrow cell lines and cause additional cytopenias. Platelet production may be decreased due to bone marrow injury mediated by toxins (eg, alcohol) or idiosyncratic drug reaction, metastatic cancer, miliary tuberculosis or other infections, deficiency of vitamin B12 or folic acid, or bone marrow disease (eg, acute leukemia, myelodysplastic syndrome, or aplastic anemia). Accelerated peripheral platelet destruction occurs in patients with splenomegaly and hypersplenism or disseminated intravascular coagulation. This chapter focuses on 3 other causes of accelerated platelet destruction: immune throm- bocytopenic purpura (ITP), heparin-induced thrombocytopenia (HIT), and throm- botic thrombocytopenic purpura–hemolytic uremic syndrome (TTP-HUS
ITP
Although ITP was formerly known as idiopathic thrombocytopenic purpura, immune thrombocytopenic purpura is a more appropriate term. Thrombocytopenia in ITP oc- curs when antibodies targeting platelet antigens mediate accelerated destruction. Anti- bodies arise in 3 distinct clinical settings: in response to a drug, in association with a disease, and when neither an offending drug nor a related underlying disease process can be identified (idiopathic
Drug platelet targeted antibody production
Almost any drug can trigger platelet-targeted antibody production, but the syndrome is most often linked to quinine or quinidine. Although these drugs are used infre- quently, quinine-related compounds are found in diverse naturopathic or herbal prod- ucts. Other drugs that are less often linked to ITP include ranitidine, trimethoprim- sulfamethoxazole, rifampin, phenytoin, and gold compounds. The glycoprotein IIb/ IIIa platelet inhibitors, such as abciximab, have also been associated with an acute on- set and severe thrombocytopenia. A careful drug history, including a review of all pre- scriptions, vaccines, over-the-counter drugs, herbal products, and supplements, is im- portant to identify the offending agent. Stopping the drug hastens recovery from ITP
B12
Associated with pancytopenia, macrocytosis, macro ovalocytes, hypersegmented neutrophilss, and possibly neurologic signs with b12 defiency
Bone marrow disorder (acute leukemia, aplastic anemia, myelodysplastic syndrome)
Associated with pancytopenia, abnormal blood smear (nucleated erythrocytes, teardrop cells, immature leukocytes) and abnormal bone marrow examination
Toxin or drug related bone marrow injury
History of alcohol abuse, environmental or occupational exposures or drug use. Mechanism may also include accelerated destruction. Often associated with anemia or pancytopenia
Infection
Thrombocytopenia is seen in HIV infection, hepatitis B and C, EBV infection, rubella, dissseminatioed TB and other mechanism. May also include accelerated destruction
ITP
Isolated thrombocytopenia int he absence of systemic disease, or a causative drug defines the ITP.a associated with large platelets on peripheral smear and increased megakaryocytic on bone marrow evaluation. ITP may also be drug induced or associated with underlying disease such as HIV, SLE or CLL
Heparin induced thrombocytopenia
History of exposure to heparin. May be associated with modest thrombocytopenia and devastating arterial and venous thrombosis
Chronic liver disease
Portal HTN can lead to splenic sequesteration of platelets and thrombocytopenia. Liver disease may be associated with target cells. Liver disease may be occult
TTP-HUS
Syndromes associated with hemolytic anemia and theombocytopenia. HUS is characterized by more severe renal involvement, TPP by more frequent neurologic symptoms. Associated with elevated serum LDH level, decreased haptoglobin concentration, and schistocytes on peripheral. Blood smear
DIC
Coagulopathy that typically occurs int he setting of sepsis, metastatic cancer, or obstetric catastrophe. Associated with prolonged prothrombin time and activated partial theombophlebitis time, low fibrinogen level, and thrombocytopenia
HELLP syndrome
Late pregnancy complication of thrombocytopenia associated with microangiopathic hemolytic anemia, and elevate liver enzymes and HTN
Pseudothrombocytopenia
In vitro clumping of platelets caused by EDTA dependent agglutinate leads to falsely decreased platelet counts. Excluded by examination of a peripheral blood smear; no therapy is needed
Gestational thrombocytopenia
Mild, asymptomatic thrombocytopenia first noted late in pregnancy; resolves following delivery without therapy
HIV ITP
Immune thrombocytopenic purpura may be part of a broader disease affecting im- mune regulation, such as HIV infection, systemic lupus erythematosus, and, especially in older patients, lymphoproliferative malignancy. Patients infected with HIV may de- velop ITP before the infection has been diagnosed and immunosuppression and oppor- tunistic infections occur. Therefore, screening for HIV infection is warranted in all pa- tients with ITP
Helicobacter pylori ITP
Recent reports link ITP to Helicobacter pylori infection, although platelet count response to antibiotic therapy is unpredictable.
Presentation ITP
Patients with ITP commonly present with easy bruising or petechial rash. At times, as- ymptomatic thrombocytopenia is noted on routine blood tests. Immune thrombocy- topenic purpura is a disease of exclusion; the diagnosis is most probable in patients with isolated thrombocytopenia. The leukocyte count should be normal, and the hemo- globin concentration is normal or reduced as a result of blood loss secondary to throm- bocytopenia (Table 2). Measurement of platelet-associated antibody is not helpful be- cause the test lacks both sensitivity and specificity. The physical examination is nor- mal, with the exception of signs of bleeding, most often petechiae (punctuate red macular lesions that do not blanch with pressure) on the skin or mucous membranes. Patients may have ecchymoses on the skin or more overt bleeding, especially in the gastrointestinal tract. The presence of fever or hepatosplenomegaly suggests another diagnosis. The blood smear will show decreased platelets and occasional large plate- lets (megathrombocytes). Bone marrow aspirate, if necessary to exclude other diagno- ses, will show increased numbers of megakaryocytes and normal erythroid and mye- loid precursors. Hematology consultation is advised for patients with severe thrombo- cytopenia or an uncertain diagnosis
When ITP need emergent treatment
Patients with ITP require emergent treatment when thrombocytopenia is severe (<10,000/μL [10 × 109/L]) or when active bleeding is present. Treatment is often rec- ommended in newly diagnosed patients with more modest thrombocytopenia (<50,000/μL [50 × 109/L]), whether or not they are actively bleeding. Both glucocorti- coids and intravenous immune globulin (IVIG) are effective therapies, but thrombocy- topenia often relapses when treatment is discontinued. In patients with chronic ITP, the risks of prolonged therapy with glucocorticoids or IVIG must be balanced against the benefits. Some patients who remain asymptomatic or who have mild, easily con- trolled bleeding are best managed without immunosuppressive therapy. Alternative immunosuppressive agents may be used for patients who do not respond to or who have intolerable toxicity from glucocorticoids or IVIG. Rho(D)-positive patients with ITP may be treated with anti-Rho(D) immunoglobulin. Another second-line immuno-
48
suppressive agent, rituximab, a chimeric monoclonal antibody directed against the CD20 surface marker on B lymphocytes, will lead to doubling of the platelet count in 40% of patients. Thrombopoiesis-stimulating agents, such as romiplostim or eltrombo- pag, are also effective in augmenting platelet counts in patients with ITP, but the ex- pense of therapy and need for continued treatment to maintain response need to be considered; these agents are not commonly used in clinical practice
CBC
Low platelet count with normal hemoglobin, hematocrit, and leukocyte count is evidence for the diagnosis of ITP
Peripheral blood smear
Exclude platelet clumping. Myeloid and erythroid morphology should be borla . Platelets should appear normal or large in size. Abnormal or immature leukocytes should be absent. The presence of schistocytes is associated with TTP, DIC< and HELLP syndrome and is evidence against ITP. The presence of polychromatophilia, poikilocytosis, and spherocytes suggests hemolytic anemia. Nucleated erythrocytes should be absent
Bone marrow
Consider bone marrow aspiration and biopsy to establish the diagnosis only in patients with atypical or nondiagnostic findings, espicially with additional cytopenias or immature leukocytes or with additional abnormalities on peripheral blood smear. ITP will show normal or increased numbers of megakaryocytic, normal myeloid and erythroid morphology and no malignant cells
HIV antibodies
Indicated in all patients
PT/aPTT
Coagulation studies should be normal; an abnormal PT or aPTT is evidence against ITP
ANA and other serologic tests
ANA is not recommended for routine diagnosis; however consider ANA and other serologic tests in patients with rash , synovitis, or other signs of rheumatologic disease
Bleeding SC
Rarely, patients with significant bleeding unresponsive to immunosuppressive medica- tion require splenectomy. Although platelet counts will improve, perioperative compli- cations and long-term asplenia sequelae (ie, infection with encapsulated bacteria) must be anticipated. Pneumococcal, meningococcal, and Haemophilus influenzae vac- cines are administered before splenectomy
HIT
Heparin-induced thrombocytopenia is a unique, drug-triggered platelet disorder that develops in 1% to 2% of patients receiving unfractionated heparin. The incidence of HIT is 2 to 3 times lower in patients receiving low-molecular-weight heparin. Other patient-specific variables also influence the incidence of disease. For example, patients
49
undergoing open-heart surgery have a higher incidence of HIT than do patients receiv- ing heparin products for thromboembolism prophylaxis. Most patients develop clini- cal signs of HIT, including a decrease of approximately 50% in platelet count from baseline levels, 5 to 10 days after initiating heparin therapy. Perhaps 5% of patients will have delayed thrombocytopenia a mean of 14 days after heparin exposure, and those patients may have the first clinical signs of HIT noted after the heparin has been discontinued. Conversely, HIT may be detected as early as 10 hours after heparin ad- ministration in patients with prior heparin exposure in the last 1 to 3 months. Throm- bocytopenia nadir in HIT is modest; mean platelet counts are approximately 60,000/ μL (60 × 109/L), and patients typically do not bleed excessively. To the contrary, pa- tients with HIT have a dramatic risk of thromboembolic complications, including deep venous thrombosis and pulmonary embolism, as well as unusual clotting problems such as portal vein thrombosis or acute arterial occlusion.
Early stage HIT
The early stages of HIT are asymptomatic; all patients receiving heparin should have periodic screening of platelet counts. In patients on heparin who develop thrombocy- topenia, laboratory tests will reveal antibodies that cause heparin-induced serotonin release or platelet aggregation, although the clinical circumstances may suggest the di- agnosis before confirmatory laboratory data are available
Treat HIT
Heparin must be discontinued and an alternative rapidly acting anticoagulant must be used instead. Warfarin is not a suitable alternative agent. Direct thrombin inhibitors (eg, lepirudin or argatroban) should be administered, often under a hematologist’s guidance. Hospitalized patients may have a broad differential to explain thrombocy- topenia. A clinical decision tool (4T scoring system) incorporates features of the magni- tude of fall and timing of thrombocytopenia, along with the presence or absence of new thromboses or skin necrosis to prioritize the likelihood of HIT. This scoring sys- tem may be useful in considering whether heparin should be stopped and a costly and potentially risky anticoagulant alternative, such as argatroban, begun while awaiting more definitive laboratory assays for HIT (Table
TTP-HUS
Patients with TTP-HUS develop consumptive thrombocytopenia and microangio- pathic hemolysis from platelet thrombi that form throughout the microvasculature. The multisystem nature of this syndrome is unpredictable. Fever, acute kidney injury, and fluctuating neurologic abnormalities are components of the syndrome, but all are seldom present during earlier phases of the illness. seldom present during earlier phases of the illness. Patients with little to no kidney in- volvement and prominent neurologic symptoms fall more into the TTP category, whereas those with acute kidney injury and fewer neurologic manifestations (often seen in children with significant diarrhea) fit better with HUS. Cli
Clinical features TTP and HUS
nical features often overlap, and a precise distinction between TTP and HUS may be difficult to make. Thrombotic thrombocytopenic purpura–hemolytic uremic syndrome is a syndrome with diverse triggers and pathophysiology, including abnormal von Willebrand factor metabolism and very high-molecular-weight polymers that predispose to platelet mi- crothrombi. Most patients with TTP have an autoantibody that inhibits a metalloprote- inase (ADAMTS13) that normally cleaves unusually large von Willebrand factor mul- timers into smaller fragments. Pregnant women, HIV-infected patients, and patients receiving cancer chemotherapy or immunosuppressive agents following organ trans-
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plantation are at increased risk. Patients develop HUS with prominent gastrointesti- nal symptoms from Shiga toxin-producing enteric bacteria (eg, Escherichia coli O157:H7).
Lab finding TTP HUS
Laboratory findings sug- gestive of TTP-HUS in- clude microangiopathic hemolysis with promi- nent schistocytes on pe- ripheral blood smear, de- creased haptoglobin, ele- vated serum lactate dehy- drogenase, and thrombo- cytopenia. Assays for AD- AMTS13 activity may help to confirm the diag- nosis, but the test is nei- ther uniformly standard- ized nor easily available, and therapy should not be withheld while await- bocytopenic purpura. ing test results. Malig- nant hypertension, dis- seminated intravascular coagulation, and prosthetic heart valves can be associated with microangiopathic hemolysis, although the additional presence of thrombocy- topenia and fever, kidney, and neurologic findings strongly supports the diagnosis of TTP-HUS
Treat TTP HUS
Most patients with TTP-HUS should receive plasma exchange transfusion, although young patients with features suggesting enteric bacterial toxins as the etiology have a much better prognosis and may be managed supportively. Automated equipment and large-bore, secure intravenous access are needed for plasma exchange; plasma infu- sion therapy may be initiated in the interim. Glucocorticoids are also recommended. Patients with more severe disease, especially with prominent neurologic manifesta- tions, or those with delayed response to plasma exchange and glucocorticoids, may be treated with alternative immunosuppressive agents (eg, rituximab). Platelet transfu-
Schistocytes on peripheral smear of a patient with thrombotic throm-
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sions in patients with untreated TTP-HUS are associated with acute kidney injury, stroke, and sudden death
Diagnose ET
Essential thrombocythemia (ET) is another myeloproliferative neoplasm, the hall- mark of which is thrombocytosis that cannot be explained by clinical conditions known to cause a reactive elevation in platelet count, such as iron deficiency, chronic bleeding, infection, cancer, or autoimmune inflammatory disease. Most patients are asymptomatic, with the diagnosis made by finding unexpected thrombocytosis on a blood count; however, some patients may present with headache and erythromelalgia, similarly to those with PRV. At times, the patient may present with a thromboembolic event or acute bleeding, which are known complications of the disease. The diagnosis is made by finding persistent platelet counts >600,000/μL (600 x 109/L), with no other condition present leading to reactive thrombocytosis. Occasionally, the platelet count is so high (>1,000,000/μL [1000 × 109/L]) as to exclude secondary thrombocy- tosis. Since thrombocytosis may also be seen in CML and PRV, and since approxi- mately one-half of patients with ET have the JAK2 mutation, the diagnosis further re- quires that the Philadelphia chromosome be negative and that the patient not have concomitant erythrocytosis
Treat ET
Patients with ET are at significant risk for both bleeding and thromboembolic compli- cations. However, individuals who are aged <60 years, have no prior thromboembolic event, and whose platelet count is <1,000,000/μL (1000 × 109/L) have an excellent prognosis and should be followed without therapy. Those who are not in the low-risk category should be treated with the myelosuppressive agent hydroxyurea, as well as low-dose aspirin. If platelet reduction is deemed necessary on the basis of symptoms refractory to salicylates alone, pegylated IFN-α or anagrelide can be used to reduce the platelet count
Reactive thrombocytosis
Reactive thrombocytosis is the leading differential in patients with suspected ET, and should be excluded as a potential explanation for an elevated platelet count. It is al- most always due to (1) iron deficiency; (2) inflammation; (3) cancer; or (4) infection.
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Patients presenting with an elevated platelet count should be evaluated for underlying inflammation or malignancy, and iron deficiency should be ruled out. Thrombocytosis in response to acute or chronic inflammation has not been clearly associated with an increased thrombotic risk
Clincal thrombocytosis
Primary theombocythemia
Other myeloproliferative disorders
Familial thrombocytosis
Familial
Reactive theombocytosis causes
Blood loss
Iron defiency
Postsplenectomy, asplenia states
Recovery from thrombocytopenia
Malignancies
Chronic inflammatory and infectious diseases
Acute inflammatory and infectious diseases
Response to exercise
Response to drugs (vincristine, epi, retinóico, cytokines, growth factors)
Hemolytic anemia
Hodgkin lymphoma
Hodgkin lymphoma has a bimodal age distribution with the initial peak at age 15 to 34 years and a second peak at age 55 to 70 years. Although the etiology is unclear, there is
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a suggested association between HL and the Epstein-Barr virus (EBV). People with a history of infectious mononucleosis are more likely to develop HL, and EBV genomic material is often found within HL nodes. Later onset of HL may be a consequence of latent virus reactivation with age-related decline in immunity. Hodgkin lymphoma is also seen with increased frequency in patients with HIV or AIDS; however, HL is not an AIDS-defining illness
Two categories hodgkin lymphoma
Hodgkin lymphoma is divided by the World Health Organization (WHO) into two ma- jor categories: classical HL and nodular lymphocyte predominant HL (NLPHL). Classi- cal HL is the most common form of HL and is characterized by the Reed-Sternberg cell, the malignant cell of origin. There are four histologic subtypes of classical HL, each named for the appearance of the background infiltrate of inflammatory cells: nodular sclerosis (the most common), mixed cellularity, lymphocyte rich, and lympho- cyte depleted. The prognosis of classical HL varies by stage of disease and individual patient risk factors. However, cure rates for early-stage disease are in excess of 90%. For patients with advanced-stage HL, the cure rates are between 60% to 70%. NLPHL typically affects men between ages 30 and 50, behaves in an indolent fashion, and is distinguished from classical HL by distinct immunohistochemical markers
Diagnose HL
Painless peripheral lymphadenopathy is the primary clinical presentation in patients with HL. The most common site of enlarged nodes is in the cervical and/or supraclavi- cular region. Axillary lymphadenopathy is found in 10% to 20% of patients, and ingui- nal lymphadenopathy is rare. The second most common presentation is a mediastinal mass identified on chest x-ray. Up to half of patients, especially those with advanced- stage disease, may experience “B symptoms”: body temperatures >100.4°F (38.0°C), weight loss of >10% of body weight, or drenching night sweats. An unusual but rela- tively common symptom is generalized pruritus.
The diagnosis of HL can only be made with a tissue biopsy
Histo HL
Within an HL tumor mass or involved lymph node, the characteristic malignant Reed-Sternberg cells comprise only a small minority of the cellular makeup. The majority of the tumor mass is com- posed of a background of inflammatory cells and/or fibrosis of the nodal tissue; there- fore, a fine needle aspirate (FNA) is inadequate for diagnosis due to potential sam- pling error.
Biopsy HL
The preferred method of biopsy is an excisional biopsy. The biopsy mate- rial should be examined for histologic morphology and with immunohistochemical staining for the characteristic immunophenotype of HL.
Ann Arbor staging HL
HL is staged using the Ann Arbor staging system (Table 3). Staging for HL is clinical rather than pathologic. Computed tomography (CT) and positron emission tomogra- phy (PET) imaging are important in the initial staging of HL. Bone marrow biopsy and aspirate for the evaluation of bone marrow involvement is also commonly used
Stage I
Involvement of a single lymph node region or a single extranodal organ or site
Stage II
Involvement of two or more lymph node regions or lymphatic structures not he same side of the diaphragm or with involvement of limited, contiguous extranodal tissue
Stage III
Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm may involve spleen or limites, contiguous extranodal tissue
Stage IV
Diffuse or disseminated involvement of one or more extranodal organs or tissues, with or without lymphatic involvement
Why PFT with HL
Because the treatment of HL involves the use of chemotherapy with an anthracycline and bleomycin, a baseline cardiac function study (such as echocardiography) and pul- monary function testing are recommended. Patients of childbearing potential should receive fertility preservation counseling
Before chemo what do with patients of child bearing age
Fertility preservation counseling
Treatment HL
The goal in the treatment of HL is to choose a treatment that is aggressive enough to achieve a cure while minimizing unnecessary toxicity from treatment, including both immediate toxicity and late treatment effects (such as secondary cancers and cardiac toxicity). The treatment of HL has evolved to include a decrease in radiation fields and total dose, the use of combination chemotherapy administered in conjunction with ra- diation (to allow for less total chemotherapy), and the use of multiagent chemother- apy alone (to avoid radiation exposure in patients with a high risk of late effects due to radiation). Prognostic risk factors are used to guide treatment choice and length of therapy. Adverse risk factors vary for disease stage; however, some common risk fac- tors include elevated erythrocyte sedimentation rate (ESR), male gender, age 40 years or greater, stage IV disease, and bulky mediastinal lymphadenopathy
Most common chemo HL
The most commonly used chemotherapy regimen is the four-drug ABVD regimen, which contains doxorubicin, bleomycin, vinblastine, and dacarbazine. Patients with early-stage disease usually receive an abbreviated course (2 to 3 months) of chemother- apy followed by a course of radiation therapy to the involved region, especially if bulky mediastinal disease is present. Those with advanced-stage disease or with additional risk factors often receive a longer course (6 months) of chemotherapy alone. Radiation may be offered to select patients with advanced-stage disease as consolidation
Follow up during treatment HL
During treatment, patients are monitored for side effects and toxicity of the treatment regimen. After completion of treatment, follow-up is performed regularly to assess for relapse. For the first 3 years, patients are seen every 3 to 6 months for clinical evalua- tion, every 6 months in the fourth and fifth year, and annually thereafter. Imaging studies (chest x-ray, CT scans) are often performed regularly during the first 2 to 3 years, although the optimum use and frequency of CT imaging is unclear
Long term follow up HL
Because HL survivors are at risk for developing secondary complications (late effects) from treatment, long-term follow-up is important. Examples of late effects include sec- ondary cancers (acute leukemia, non-Hodgkin lymphoma, lung cancer, breast cancer) and organ dysfunction (cardiac disease, radiation-induced thyroid dysfunction). Women who received mediastinal radiation for HL between the ages of 10 and 35 are at the greatest risk for breast cancer. Long-term follow-up for HL survivors should include annual visits with a complete blood count (CBC) to screen for bone marrow dysfunction, thyroid function testing in patients who received radiation to the neck, and annual influenza vaccination in pa- tients who received bleomycin or chest irradiation. Women who received mediastinal radiation prior to age 35 should undergo breast cancer screening with annual mam- mography and breast magnetic resonance imaging beginning 8 to 10 years post- treatment or at age 40, whichever comes first
NHL
Non-Hodgkin lymphoma represents a diverse set of malignancies. The various lympho- mas that comprise NHL are classified by ontogeny (B cell, T cell, NK cell) and stage of differentiation. Approximately 80% to 85% of NHLs in adults are of B-cell origin, with the remainder derived from T cells or, more rarely, natural killer (NK) cells.
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Generally, the incidence of NHL increases with age. Autoimmune disease and immu- nodeficiency states (patients with HIV/AIDS or chronic immune suppression after or- gan transplantation) have a known association with NHL. Infectious agents (EBV, Helicobacter pylori, Chlamydia psitacci, hepatitis C) have also been associated with some types of NHL. However, in most patients the etiology is not known
Diagnosis NHL
The patient presentation in NHL varies depending on the aggressiveness of the lym- phoma type. The various histologic subtypes of NHL are classified by their level of ag- gressiveness into three categories: indolent (low-grade), aggressive (intermediate- grade), or highly aggressive (high-grade). Indolent lymphomas often present with slowly growing lymphadenopathy, enlarged spleen or liver, or with abnormalities in the CBC such as anemia, thrombocytopenia, or leukopenia. Aggressive lymphomas pre- sent more acutely, with rapidly enlarging lymph nodes or a rapidly growing mass. Pa- tients with aggressive lymphomas are more likely to have B symptoms (fevers, weight loss, and night sweats), elevated lactate dehydrogenase (LDH), and elevated uric acid
Tissue biopsy NHL
A tissue biopsy is crucial in the diagnosis of NHL and should be performed urgently if an aggressive lymphoma is suspected. Enlarged peripheral lymph nodes are preferred for biopsy due to the ease of obtaining a specimen; however, enlarged intrathoracic, in- traabdominal, or retroperitoneal lymph nodes or masses may be biopsied through image-guided techniques or laparoscopy. Bone marrow biopsy and aspirate may also be helpful in diagnosis, especially in patients with advanced disease or cytopenias. While FNA may yield a diagnosis of NHL, it is usually inadequate to determine the type of lymphoma. As with HL, the lymph node architecture and morphology are im- portant in subclassifying NHL; thus, an excisional biopsy is preferred
How diagnose NHL
The diagnosis of NHL is based on evaluation of morphology, immunophenotype, and genetic studies. Histologic examination may reveal a nodular or follicular pattern (as seen in follicular NHL), a diffuse pattern (as seen in diffuse large B-cell lymphoma), and the grade of the lymphoma (higher grade correlates to more aggressiveness). Im- munophenotype is determined by flow cytometry on a fresh (not fixed) lymph node sample or through immunohistochemical staining. For example, all B-cell–derived NHLs are CD19 and CD20 positive, and T-cell lymphomas express CD3. Characteristic cytogenetic markers may be found in patients with some forms of NHL, such as a translocation in the c-MYC oncogene (most commonly the t(8;14) translocation) in highly aggressive Burkitt lymphoma
What do after diagnosis NHL
Once the diagnosis of a specific type of NHL has been made, staging is performed us- ing the Ann Arbor staging system (Table 3). All patients should have laboratory stud- ies performed to include a CBC, comprehensive metabolic panel (including blood urea nitrogen, creatinine, albumin, electrolytes, and liver function tests), serum calcium, se- rum uric acid, and LDH. Because of the association of NHL with HIV and with viral hepatitis, patients with NHL should be tested for HIV and hepatitis B and C. Imaging studies with CT scans of the chest, abdomen, and pelvis should be performed, and in some cases, integrated PET/CT scans are useful. Bone marrow biopsy and aspirate is used to identify NHL within the bone marrow, and lumbar puncture with cytologic evaluation of the cerebrospinal fluid is important in highly aggressive NHL (eg, Burkitt lymphoma) and in some types of aggressive NHL (eg, testicular diffuse large B-cell lymphoma).
Before treatment NHL
Prior to receiving treatment that may affect the cardiovascular or pulmonary systems, patients should undergo baseline functional testing such as with echocardiography or pulmonary function studies. All patients of childbearing potential should receive fertil- ity preservation counseling prior to the initiation of chemotherapy or radiation ther- apy
Treatment NHL
Treatment and prognosis generally depend on whether a patient has indolent, aggres- sive, or highly aggressive NHL. The median survival of patients with indolent lympho- mas is 10–15 years. Indolent subtypes of NHL may often be observed without treat- ment, and they nearly always respond to chemoimmunotherapy when treatment is in- dicated. For B-cell lymphoid malignancies, chemoimmunotherapy most often consists of cytotoxic chemotherapy used concurrently with the anti-CD20 monoclonal anti- body, rituximab. Despite their responsiveness to treatment, indolent lymphomas are generally considered incurable, but patient survival may be long. Aggressive and highly aggressive NHLs are curable with chemoimmunotherapy, with cure rates vary- ing depending on the underlying biology of the disease as well as prognostic factors, such as the patient’s age and overall health status, tumor stage, and serum LDH level. T-cell lymphomas typically have a worse prognosis than B-cell-derived lymphomas, and T-cell lymphomas are more likely to relapse. In addition, because only B-cell lym- phomas express CD20, rituximab is not used in the treatment of T-cell lymphomas
Follow up during therapy NHL
Patients should be seen frequently during initial therapy to assess for side effects. Af- ter treatment, the frequency of follow-up often depends on the indolence or aggressive- ness of the lymphoma. Patients are usually seen every 3 to 6 months for clinical evalua- tion for the first 3 to 5 years after treatment and annually thereafter. Imaging of the chest, abdomen, and pelvis with CT scans is often performed regularly during the first 2 years; however, the optimum use and frequency of CT imaging is unclear.
Follow up after late treatment NHL
Similar to patients with HL, survivors of NHL are at risk for late treatment effects. Sec- ond malignancies occur with higher frequency in NHL survivors than the average population, including acute leukemia, various solid tumors, and second lymphoid ma- lignancies. Survivors who received anthracycline-based chemotherapy and/or radia- tion are at higher risk for late cardiovascular complications. The risk for infertility and gonadal dysfunction depends on both the type and amount of chemotherapy received and whether radiation therapy to the pelvis was received. Patients who received radia- tion therapy to the neck often develop hypothyroidism
Leukemia
Leukemia can be a scary disorder…not just to be the patient or a family member, but to be the student trying to understand a variety of complicated malignant disorders with often-dramatic presentations and profound ramifications.
We will focus on the basics of acute leukemia…its presentation, diagnosis, and some of the foundational understanding of its treatment. Genetics and flow cytometry are very important and, since they are a target-rich source of board examination questions,
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we’ll want to link the genetics to the disease so that you understand how it can affect treatment. The chronic leukemias have a much different flavor to them, and under- standing the role of staging in determining prognosis and treatment options will be helpful
Acute leukemia
Acute leukemias are clonal proliferations of myeloid or lymphoid cells that fail to dif- ferentiate beyond the blast or promyelocyte stage. These immature cells lack the func- tional capability of mature granulocytes or lymphocytes and replicate aggressively, dis- placing normal white cell, red cell, and platelet precursors, and cause bone marrow failure as well as infiltration of other organs. Although the clinical presentation of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) may be simi- lar, they are treated differently
AML
While AML most commonly occurs in patients with no antecedent risk factors, its inci- dence is increased in patients who are exposed to radiation or benzene or following therapy with chemotherapy, especially alkylating agents. AML also occurs as a result of transformation of a pre-existing myeloproliferative neoplasm (eg, CML, polycythe- mia vera) or in patients with a known myelodysplastic syndrome
Presentation AML
Patients with AML present with nonspecific symptoms of fatigue, pallor from anemia and bleeding manifestations, including bruising and petechiae, from underlying thrombocytopenia. Inadequate numbers of mature functioning leukocytes lead to in- fection. Patients have a variable degree of lymphadenopathy and hepatosplenomegaly. Leukemic cells may infiltrate extramedullary sites, such as the gingivae, skin, and men- inges. When the leukocyte count is very high, patients may present with leukostasis syndrome, which is presumed to be secondary to leukemic blasts occluding the micro- circulation and leading to respiratory failure and cerebral dysfunction
Diagnose AML
The diagnosis of AML is suggested by an elevated leukocyte count, anemia, thrombocy- topenia, and blasts on the peripheral blood smear (Image 5.1). At times, patients may have an “aleukemic” form of AML with severe leukopenia (often pancytopenia), and a scarcity of circulating immature blast forms. The diagnosis of AML is confirmed by bone marrow aspiration and biopsy showing >20% blasts. Typical myeloblasts demon-
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strate antigens found on IMAGE 6.1 Acute Leukemia immature cells, such as
CD34 (a stem cell marker)
and HLA-DR, as well as an-
tigens more specific for granulocytic maturation,
such as CD33 and CD13. Cytogenetic studies are cru-
cial, because specific ge-
netic abnormalities are as-
sociated with either a fa-
vorable or a poor progno-
sis. The morphology of the
bone marrow cells com-
bined with immunopheno-
type and results of cytoge-
netic studies are used to
classify AML according to leukemia. the World Health Organi-
zation and French-
American-British (FAB) classification systems
AML APL
Acute promyelocytic leukemia is a special subset of AML characterized by a t(15;17) translocation (which disturbs a retinoic acid receptor) and by proliferation of promye- locytes, with their characteristic primary granules. Patients with acute promyelocytic leukemia have significant bleeding at the time of their presentation due to fibrinolysis and disseminated intravascular coagulation
AML de novo
Clonal chromosomal abnormalities are detected in 80 to 90 percent of patients with AML. The most frequent abnormalities are +8 and −7, which are seen in most sub- types of AML. Specific rearrangements are closely associated with particular subtypes of AML as recognized by the WHO and French-American-British (FAB) classification schemes
8; 21
The 8;21 translocation [t(8;21)(q22;q22.3)], described in 1973, was the first transloca- tion identified in AML. The t(8;21) is common and is observed in 5 to 10 percent of all patients with AML with an abnormal karyotype and in 10 percent of patients with AML with maturation. This translocation is the most frequent abnormality in children with AML and occurs in 15 to 20 percent of karyotypically abnormal cases. Loss of a sex chromosome (−Y in males, −X in females), or a del(9q) with loss of 9q22, accompa- nies the t(8;21) in 75 percent of cases. The presence of the t(8;21) identifies a morpho- logically and clinically distinct subset of AML, and most cases with the t(8;21) are clas- sified as AML with maturation. AML with the t(8;21) has a favorable prognosis in adults (overall 5-year survival of 70 percent), but the outcome in children is poor. At the molecular level, the t(8;21) involves the RUNX1/AML1 gene, which encodes a tran- scription factor, also known as core-binding factor, that is essential for hematopoiesis. The RUNX1 gene on chromosome 21 is fused to the RUNX1T1/ETO gene on chromo- some 8 and results in a RUNX1-RUNX1T1 chimeric protein. Transformation by RUNX1-RUNX1T1 likely results from transcriptional repression of normal RUNX1 tar- get genes via aberrant recruitment of nuclear transcriptional corepressor complexes
Inversion 16 and translocation 1616
Another clinical–cytogenetic association involves acute myelomonocytic leukemia (AMML) with abnormal eosinophils, including large and irregular basophilic granules, and positive reactions with periodic acid–Schiff and chloroacetate esterase. Most pa- tients have an inversion of chromosome 16, inv(16)(p13.1q22), but some have a t(16;16)(p13.1;q22), and the WHO classification system now recognizes these as a dis- tinct form of AML. These aberrations are relatively common, occurring in 5 percent of AML and 25 percent of AMML patients. These patients have a good response to inten- sive chemotherapy with a complete remission rate of approximately 90 percent and an overall 5-year survival of 60 percent. The breakpoint at 16q22 occurs within the CBFB gene, which encodes one subunit of the RUNX1/CBFB transcription factor. Thus, like the t(8;21), the inv(16) disrupts the RUNX1/AML1 pathway regulating hematopoiesis. Secondary cooperating mutations of KIT, KRAS, and NRAS are common in core- binding factor-associated leukemias, although only KIT mutations confer a poor prog- nosis.
Translocation 15:17
The t(15;17)(q24.1;q21.1) is specific for acute promyelocytic leukemia (APL) and has not been found in any other disease. Establishing the diagnosis of APL with the typical 70 t(15;17) is important, because this disease is sensitive to therapy with all-trans retinoic acid, whereas other cases of AML do not respond to this treatment. The t(15;17) re- sults in a fusion retinoic acid receptor-α protein (PML-RARA). The oncogenic poten- tial of the APL fusion proteins appears to result from the aberrant repression of RARA-mediated gene transcription through histone deacetylase (HDAC)-dependent chromatin remodeling. Genetic mutations that cooperate with PML-RARA include FLT3 internal tandem duplications (ITDs), observed in 35 percent of patients
Translocations 11q
Recurring translocations involving 11q23.3 are seen in approximately 35 percent of acute monocytic leukemia patients. With the exception of the t(9;11) which may have an intermediate outcome, translocations of 11q23.3 are associated with a poor out- come. Translocations of 11q23.3 involve KMT2A/MLL, a very large gene (>100 kb) with multiple transcripts of 12 to 15 kb. KMT2A protein is a histone methyltransferase that assembles in protein complexes that regulate gene transcription via chromatin re- modeling. All of the KMT2A translocations identified to date result in fusion proteins
Mutations AML
The prognosis of patients with AML is also determined by mutations, most commonly of the FLT3, NPM1, CEBPA, or KIT genes. Mutations of the FLT3 gene, including both point mutations within the tyrosine kinase domain and ITDs, are among the most com- mon genetic changes seen in AML, occurring in 15 to 35 percent of cases. FLT3-ITD mutations may occur in any subtype of AML, but are most common in APL and AML with a normal karyotype, and are associated with a poor prognosis, particularly in those cases with loss of the remaining wild type FLT3 allele. Mutations of the FLT3 ty- rosine kinase domain (codons 835 or 836 of the second tyrosine kinase domain) are noted in 5 to 8 percent of AML. Mutations of NPM1 also occur frequently in AML (35 percent of adult cases, and 80 to 90 percent of acute monocytic leukemia), but are less frequent in patients with recurring cytogenetic abnormalities. In the absence of FLT3 mutations, NPM1 mutations are associated with a favorable prognosis. NPM1 muta- tions, most commonly involve exon 12, resulting in alterations at the C-terminus, that is, replacement of tryptophan(s) at position 288 and 290, and aberrant localization of the protein to the cytoplasm. CEBPA mutations (6 to 15 percent of all AMLs), are often biallelic, and are usually associated with intermediate risk cytogenetics, but are gener- ally associated with a favorable prognosis
Therapy AML
Patients require immediate hospitalization for placement of durable venous access (Hickman catheter, subcutaneous port), initiation of chemotherapy, irradiated blood and platelet transfusion support, and, if febrile and leukopenic, antibiotics for pre- sumed infection
Standard chemo MAL
The standard chemotherapy induction regimen is 3 days of an anthracycline, such as daunorubicin or idarubicin, and 7 days of a continuous infusion of cytarabine. With the initiation of chemotherapy, some patients are at risk for abrupt necrosis of a large mass of leukemia cells and release of their intracellular contents into the circulation causing the tumor lysis syndrome. After induction therapy, patients remain pancy- topenic for many days, and infectious and bleeding complications are common. Pa- tients with neutropenic fever should receive broad-spectrum antibiotics until the bone marrow recovers, regardless of whether cultures remain negative. Persistent neutro- penic fever despite antibiotics warrants empiric antifungal therapy
Younger patients AML treat
Younger patients and patients with favorable cytogenetic abnormalities achieve remis- sion rates of 60% to 70%; remission is defined as normalization of the blood count, <5% bone marrow blasts, and normalization of the karyotype. Most of these patients will remain in remission and achieve 10-year disease-free survival. Older patients with significant comorbidities and high-risk cytogenetic abnormalities have much lower re- mission rates as well as a higher risk of treatment mortality; these patients may be bet- ter treated palliatively rather than with induction chemotherapy. In addition to ad- vanced age, poor performance status, and certain cytogenetic abnormalities, AML that is related to prior cancer chemotherapy or a preexisting myeloproliferative neoplasm or dysmyelopoietic syndrome has a poor prognosis. Once remission is achieved, con- solidation chemotherapy is given and patients with high-risk disease may be referred for allogeneic BMT
Treat APL
Treatment for acute promyelocytic leukemia is initiated with all-trans-retinoic acid, which induces maturation of the promyelocyte and ameliorates disseminated intravas- cular coagulation
Follow up AMP
Patients with AML who relapse tend to do so within 18 to 24 months of achieving com- plete remission. Patients are seen frequently during the first 2 years after remission to perform an interim history, physical examination, and blood count; bone marrow aspi-
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ration is performed only if there are abnormalities in the CBC. Patients who have un- dergone allogeneic BMT should be monitored for posttransplantation complications, including opportunistic infections and graft-versus-host disease, usually at specialized treatment centers
Induction AML
3+7 (anthracycline and Ara-C)
Consolidation AML
High dose Ara-C (HDAC)
Maintenance AML
PML only ATRÁS
ALL induction
Vincristine/prednisone plus others
Consolidation ALL
Multiple agents plus CNS prophylaxis (MTX or Ara-C)
Maintenance ALL
6-MP and MTX
ALL
ALL is a malignancy of B or T lymphoblasts and is more common in children although it may occur in adults, predominately in the seventh decade of life. Patients frequently present with circulating lymphoblasts and progressive marrow failure with fatigue, dyspnea, bleeding, and infection–related fever. Lymphadenopathy and hepatosple- nomegaly are common, and central nervous system involvement may occur. Severe cy- topenias and metabolic derangements related to tumor lysis syndrome are common
Diagnosis ALL
Diagnosis requires the presence of 20% or more lymphoblasts on bone marrow exami- nation. Cytochemical stains and flow cytometry can help distinguish ALL from AML and B-cell from T-cell ALL. Cerebrospinal fluid examination for evidence of central nervous system involvement is an essential part of the initial diagnostic evaluation
Translocation 9;22
The incidence of the t(9;22) in ALL is 30 percent in adults (the incidence may ap- proach 50 percent in adults older than 60 years of age) and 5 percent in children. Thus, the Ph chromosome is the most frequent rearrangement in adult ALL. Approxi- mately 70 percent of the patients show additional abnormalities. Most cases have a B- lineage phenotype (CD10+, CD19+, and TdT+), but there is frequent expression of myeloid-associated antigens (CD13 and CD33). The disease in both adults and chil- dren is characterized by high white blood cell counts, a high percentage of circulating blasts, and a poor prognosis. As in CML, the t(9;22) in ALL results in a BCR-ABL1 fu- sion gene. However, in more than half of the patients, the break in BCR is more proxi- mal, resulting in a smaller fusion protein with even greater tyrosine kinase activity (BCR-ABL1p190). Genetic alterations of the IKZF1 gene are detectable in up to 80 per- cent of patients with Ph chromosome–positive ALL, and are associated with an unfa- vorable outcome even with the use of TKIs
Hyper diploids
The leukemia cells of some patients with ALL are characterized by a gain of many chro- mosomes. Two distinct subgroups are recognized: a group with 1 to 4 extra chromo- somes (47 to 50), and the more common group with more than 50 chromosomes. Chromosome numbers usually range from 51 to 60, and a few patients may have up to 65 chromosomes. Hyperdiploidy (>50 and usually <66 chromosomes) is common in children (approximately 30 percent), but is rarely observed in adults (<5 percent). Cer- tain additional chromosomes are common (X chromosome, and chromosomes 4, 6, 10, 14, 17, 18, and 21). Chromosome 21 is gained most frequently (100 percent of cases). Patients who have hyperdiploidy with more than 50 chromosomes have all of the previously recognized clinical factors that indicate a good prognosis. The favorable prognosis associated with high hyperdiploidy is associated with gains of chromosomes 4, 10, and 17, whereas a gain of chromosomes 5 and i(17q) is associated with a poor outcome.
Translocation 1;19 and 8;14
The t(1;19)(q23;p13.3) has been identified in approximately 6 percent of children with a B-lineage leukemia. The leukemia cells have cytoplasmic immunoglobulin and are CD10+, CD19+, CD34−, and CD9+. A reciprocal translocation involving the long arms 74 of chromosomes 8 and 14 [t(8;14)(q24.2;q32.3)] is observed in mature B-cell ALL. These patients have a high incidence of central nervous system involvement and/or ab- dominal nodal involvement at diagnosis. Although the outcome for both children and adults with a t(8;14) has been poor, the use of high intensity chemotherapy has mark- edly improved the outcome (EFS of 80 percent in children
Philadelphia chromosome
Ph-like ALL is a novel subgroup of high-risk ALL, characterized by increased expres- sion of HSC genes, and a similar gene expression profile to Ph-positive ALL. Like Ph- positive ALL, Ph-like cases are also characterized by a high frequency of IKZF1 dele- tions and mutations, which confer a poor prognosis. Ph-like ALL comprises up to 15 percent of pediatric ALL and up to 30 percent of adult ALL and is associated with a higher risk of relapse compared to other Ph-negative cases. Genetic alterations respon- sible for the activated kinase and cytokine receptor signaling signature in Ph-like ALL are starting to be elucidated, and include point mutations and gene fusions affecting CRLF2, JAK2, ABL1, PDGFRB, EPOR, EBF1, FLT3, IL7R, SH2B3, and other genes
Therapy ALL
In adults, cure rates for ALL approach 30% to 40% with standard chemotherapy. In- duction therapy commonly consists of an anthracycline, vincristine, L-asparaginase, and a glucocorticoid. Given the risk for central nervous system involvement in ALL, in- trathecal chemoprophylaxis is routinely administered with or without cranial irradia- tion. Tumor lysis syndrome is common at diagnosis or shortly after institution of che- motherapy; consequently, all patients should receive intravenous fluid hydration and allopurinol
Follow up ALL
Patients who achieve complete remission receive further intensive chemotherapy with multiple chemotherapeutic agents for several months followed by 2 to 3 years of main- tenance chemotherapy. Patients with high-risk disease who are otherwise healthy and have a suitable donor are considered for allogeneic hematopoietic stem cell transplan- tation in first remission
CML
Chronic myeloid leukemia is a clonal proliferation of mature granulocytes associated with a translocation between chromosomes 9 and 22, t(9;22)(q34;q11), which results in a truncated chromosome 22 (the Philadelphia chromosome). This reciprocal translo- cation results in the BCR-ABL fusion gene and the production of a unique tyrosine ki- nase protein. Although patients usually present in the chronic phase of disease and may do well for years, CML, if untreated, will invariably transform into acute leukemia (myeloid in two-thirds of patients, lymphoid in one-third). The transformation may be preceded by an “accelerated phase” of disease characterized by progressive leukocyto- sis and splenomegaly, extreme thrombocytosis or thrombocytopenia, and systemic symptoms, all of which are resistant to treatment. Patients with CML present with fa- tigue, lethargy, low-grade fever, and weight loss. Splenomegaly may be striking and may be associated with early satiety, abdominal distention, or left upper-quadrant pain. Physical examination may reveal pallor and splenomegaly, but lymphadenopa- thy is not common in the chronic phase
Recognize CML
Chronic myeloid leukemia is recognized by an elevated blood leukocyte count and in- creased number of granulocytic cells in all phases of development on the peripheral blood smear. The magnitude of the leukocytosis varies from 15,000/μL (15 × 109/L) to 50,000/μL (50 × 109/L), but is still within the range that could be triggered by an in- fectious process (termed a leukemoid reaction). In some patients, the leukocyte count will be >100,000/μL (100 × 109/L), which is more pathognomonic of a myeloprolifera- tive neoplasm. Very immature cells, such as myeloblasts and promyelocytes, may be seen in small numbers in the peripheral blood smear, but myelocytes and metamyelo- cytes are more predictably found. Basophils and eosinophils are increased, as they are in other myeloproliferative neoplasms. The platelet count is often elevated, and strik- ing thrombocytosis (>1,000,000/μL [1000 × 109/L]) may be seen. Patients often have anemia. The bone marrow aspirate tends to mirror findings in the peripheral blood, with marked expansion of myeloid cells and a shift toward less mature forms. When
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blasts represent >10% of leukocytes, the accelerated or blast phase should be consid- ered. Increased megakaryocytes are seen, and increased collagen and reticulin fibrosis will be noted on bone marrow biopsy
Diagnosis confirmation CML
The diagnosis is confirmed by cytogenetic studies of the bone marrow aspirate show- ing a t(9:22) chromosomal abnormality or the presence of the novel BCR-ABL gene produced by the translocation. The BCR-ABL gene is detected and quantitated by po- lymerase chain reaction (PCR). Patients with abdominal pain or discomfort should un- dergo abdominal ultrasonography or computed tomography to identify splenomegaly or splenic infarction
Therapy therapy CML
The treatment of CML was revolutionized by the development of therapy targeting the novel tyrosine kinase produced by the BCR-ABL gene. Inhibition of this kinase by imatinib reduces the leukocyte count, shrinks the spleen, and clears the bone marrow of Philadelphia chromosome–positive cells. Imatinib treatment often achieves molecu- lar remissions in which no BCR-ABL transcripts can be identified in the blood or bone marrow. Imatinib must be given indefinitely; BCR-ABL-positive cells will appear 3 to 4 months after discontinuation of therapy. Dasatinib and nilotinib are newer options that may work more rapidly and cause more noticeable inhibition of tyrosine kinase. These newer agents may be used to initiate therapy or to treat patients who become re- sistant to imatinib
Allogenic BMT CML w
Allogeneic BMT was the preferred treatment option for patients with CML before the discovery of tyrosine kinase inhibitors. Allogeneic BMT remains the most definitive op- tion to cure the disease, albeit at the cost of significantly greater treatment toxicity (in- cluding mortality) and subsequent complications from graft-versus-host disease. There are no randomized trials to compare BMT to tyrosine kinase inhibitors, and most experts recommend beginning therapy with a tyrosine kinase inhibitor. Alloge- neic BMT might be used as initial therapy in very young patients with CML but is more typically used in patients showing signs of resistance to tyrosine kinase inhibi- tors. Once the disease has transformed into an accelerated phase or blastic phase (which clinically may resemble de novo acute leukemia), the prognosis is poor, regard- less of the treatment option
Transfusion CML
Patients may require transfusion occasionally to treat anemia and rarely for thrombo- cytopenia. Massive splenomegaly with splenic infarction may require splenectomy for patient comfort
Follow up CML
Patients are typically seen every 1 to 2 weeks during the initiation of treatment with imatinib. Once stable blood counts are achieved, patients are followed every month to monitor blood counts. Peripheral blood or bone marrow samples are obtained periodi- cally to assess the efficacy of treatment; the best results are associated with a 4-fold re- duction of BCR-ABL transcripts determined by quantitative PCR. Increasing leukocyte counts, basophilia, fever, and an enlarging spleen are signs of accelerated phase and blast crisis
CLL
Chronic lymphocytic leukemia (CLL) is the most common leukemia encountered in adults. CLL is classified as a chronic lymphoproliferative disorder (a lymphoid malig- nancy). It is considered to be the same disease process as small lymphocytic lym- phoma (SLL), one of the indolent B-cell NHL subtypes; the two lymphoid malignan- cies are often referred to singularly as CLL/SLL
Epidemiology CLL
The median age of diagnosis is approximately 70 years, and the disease affects males more than females. CLL is characterized by clonal proliferation of mature B- lymphocytes within the blood, bone marrow, lymph nodes, and spleen. Though the dis- ease is incurable, survival may be long
Diagnosis CLL symptoms
Patients may be asymptomatic in 25% of cases, usually diagnosed after the incidental finding of lymphocytosis on a CBC, with or without lymphadenopathy. Some patients have symptoms related to bulky lymph node enlargement or may have symptoms re- lated to splenomegaly (early satiety, abdominal fullness). Patients also may have sys- temic symptoms, including fever, malaise, night sweats, and weight loss
Immune effects CLL
Patients with CLL may develop various immune defects that predispose to infectious complications, the most common being infection with encapsulated organisms (eg, Streptococcus pneumoniae), due to inadequate B-cell function or hypogammaglobu- linemia. Patients may also have cell-mediated immune defects that predispose to re- current herpes simplex virus infections. Patients with CLL also are at increased risk for autoimmune disease, most commonly autoimmune thrombocytopenia; autoim- mune hemolytic anemia is less common. Management of the underlying autoimmune disorder often requires concomitant treatment of CLL
PE CLL
Physical exam may reveal signs of anemia (pallor, tachycardia), lymphadenopathy, and hepatomegaly or splenomegaly. Key laboratory findings include a peripheral leu- kocytosis due to increased numbers of mature lymphocytes and “smudge” cells (lym-
phocytes that appear flat- IMAGE 6.2 Chronic Lymphocytic Leukemia tened or distorted) dur-
ing the process of prepar- ing the peripheral smear (Image 5.2).
The diagnosis of CLL is made when there is (1) an absolute increase in ma- ture lymphocytes (>5000/μL [5 × 109/L]) in the absence of an acute viral illness or other trig- ger of reactive lymphocy- tosis, and (2) the demon- stration on flow cytome-
try of clonality of the cir- Peripheral smear of a patient with chronic lymphocytic leukemia, culating B-lymphocytes. demonstrating an increased number of circulating mature lympho-
Diagnose CLL
diagnosis of CLL is made when there is (1) an absolute increase in ma- ture lymphocytes (>5000/μL [5 × 109/L]) in the absence of an acute viral illness or other trig- ger of reactive lymphocy- tosis, and (2) the demon- stration on flow cytome-
try of clonality of the cir- Peripheral smear of a patient with chronic lymphocytic leukemia, culating B-lymphocytes. demonstrating an increased number of circulating mature lympho-
cytes and “smudge cells” as a result of lysis during preparation of the smear. ASH Image Bank #00061350.
Immunophenotyping by
flow cytometry will show
a monoclonal prolifera-
tion of mature B-lymphocyte phenotype with expression of CD19 and CD20, along with expression of a T-lymphocyte antigen (CD5). Immunophenotyping distinguishes CLL from reactive lymphocytosis and identifies less common variants of CLL, includ- ing those arising from clonal T-lymphocytes. Bone marrow biopsy is not required for the diagnosis of CLL; flow cytometry on a peripheral blood sample is adequate.
Statins CLL
Staging of CLL is based on the physical examination and CT imaging to assess lympha- denopathy and hepatosplenomegaly. Two staging schemes are used:
• The Rai staging system ranges from asymptomatic patients with lymphocytosis (stage 0); these patients account for about 25% of the population and have a mean survival of >10 years. Patients with stage I CLL (lymphocytosis plus lymphadenopathy) or stage II CLL (lymphocytosis, lymphadenopathy, and
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hepatosplenomegaly) account for 50% of the population and survive 6 to 9 years. Patients with stage III (anemia) or stage IV (thrombocytopenia) CLL account for the remaining 25% and have a more lethal course, with a mean survival of <2 years.
• The Binet system is based on the number of lymph node sites involved. For example, bilateral cervical lymph node enlargement is counted as one site, bilateral cervical and axillary lymphadenopathy is counted as two sites, and an enlarged liver and enlarged spleen each count as one lymph node site. Stage A has fewer than three sites involved, and survival is comparable to that in age-matched controls without CLL. Stage B has three or more sites involved, with survival of 7 years. Stage C, defined as the additional presence of either anemia or thrombocytopenia, is associated with survival of approximately 2 years.
Stage 1
Lymphocytosis only (ALC>10000)
150 month survival
Stage I
Plus lymphadenopathy
101 moths survival
Stage II
Plus hepatosplenomegaly
71 months
Stage III
Plus anemia Hb<11 gm
22 months
Stage IV
Plus theombocytopenia <100000
11 months
Treatment CLL
Patients with asymptomatic, early-stage disease require only observation. Later-stage disease, often associated with symptoms, requires active treatment. Specialized test- ing, such as cytogenetic studies to assess for genetic mutations and determination of
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the mutational status of the immunoglobulin variable (V) gene, is becoming increas- ingly important in establishing risk for disease progression
Complications CLL
Complications associated with CLL may require treatment. About 10% of patients will develop autoimmune thrombocytopenia or hemolytic anemia, and they may respond to chemotherapy for CLL, prednisone, or anti-CD20 treatment. Recurrent bacterial in- fections and hypogammaglobulinemia are frequently treated with intravenous immu- noglobulin (IVIG) infusion therapy; however, the use of IVIG to restore immune globu- lin levels to normal remains controversial. Pneumococcal and yearly influenza vaccina- tions are recommended for all those with CLL due to the risk for infectious complica- tions. About 10% of patients experience a transformation of their chronic leukemia to a very aggressive and difficult-to-treat diffuse large B-cell lymphoma; this is known as Richter transformation
Goal for CLL therapy
The goal of therapy for CLL is not cure, but rather to slow the rate of progression, in- duce a period of remission, and control symptoms or complications. There is no con- sensus on initial therapy for CLL. Choices include the purine analogs (eg, fludarabine and pentostatin), alkylating agents (such as chlorambucil, bendamustine, and cyclo- phosphamide), and monoclonal antibodies against CD20 (including rituximab and ofa- tumumab). Treatment choice is made only after carefully considering patient factors such as functional status, comorbid conditions, age, and patient preferences. Young pa- tients with high-risk genetic features (eg, 17p deletion or 11q deletion) may be consid- ered for hematopoietic stem cell transplantation
Follow up CLL before treatment
For those patients who have not yet required treatment for their CLL or those achiev- ing remission through chemoimmunotherapy, routine monitoring of the CBC every 3 to 6 months is recommended to assess the lymphocyte count or the development of anemia or thrombocytopenia. Physical examination should include a full lymph node examination and careful assessment of liver and spleen size. History should focus on new disease-related symptoms, such as fatigue, fevers, night sweats, or weight loss. Routine imaging is generally not recommended but is instead symptom-directed or used to evaluate response to treatment
Hairy cell leukemia
Hairy cell leukemia is a tumor of small lymphocytes with oval nuclei, abundant cyto- plasm, and distinctive membrane projections (hairy cells) (Image 6.4). Patients have splenomegaly and diffuse bone marrow involvement. While some circulating cells are noted, the clinical picture is dominated by symptoms from the enlarged spleen and pancytopenia. The mechanism of the pancytopenia is not completely clear and may be mediated by both inhibitory cytokines and marrow replacement. The marrow has an increased level of reticulin fibers; indeed, hairy cell leukemia is a common cause of in- ability to aspirate bone marrow or so-called “dry tap.” Monocytopenia is profound and may explain a predisposition to atypical mycobacterial infection that is observed clini- cally. The tumor cells have strong expression of CD22, CD25, and CD103; soluble CD25 level in serum is an excellent tumor marker for disease activity. The cells also ex- press tartrate-resistant acid phosphatase. The immunoglobulin genes are rearranged and mutated, indicating the influence of a germinal center. No specific cytogenetic ab-
IMAGE 6.4 Hairy Cell Leukemia
normality has been found, but most cases contain the activating BRAF mutation V600E
Median age of affected hairy cell
The median age of af- fected patients is mid- fifties, and the male-to- female ratio is 5:1. Treat- ment options are numer- ous. Splenectomy is often associated with prolonged remission. Nucleosides in- cluding cladribine and de- oxycoformycin are highly active but are also associ- ated with further immuno- suppression and can in- crease the risk of certain opportunistic infections.
Treat hairy cell
The median age of af- fected patients is mid- fifties, and the male-to- female ratio is 5:1. Treat- ment options are numer- ous. Splenectomy is often associated with prolonged remission. Nucleosides in- cluding cladribine and de- oxycoformycin are highly active but are also associ- ated with further immuno- suppression and can in- crease the risk of certain opportunistic infections.
After treatment hairy cell leukemia
However, after brief courses of these agents, patients usually obtain very durable re- missions during which immune function spontaneously recovers. Interferon α is also an effective therapy but is not as effective as nucleosides. Chemotherapy-refractory pa- tients have responded to vemurafenib, a BRAF inhibitor. It is not yet clear if vemuraf- enib can induce long-term remissions without continuous treatment
Myelodysplastic and myeloproliferative neoplasma
In this section, we’ll focus on two specific disease entities: myelodysplasia and myeloproliferative neoplasms. Since essential thrombocythemia has been discussed under platelet disorders, our only myeloproliferative neoplasms left are myelofibrosis and polycythemia vera.
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Please don’t let the small size of this section fool you…there’s a lot of information packed into this topic, and there are a lot of considerations in patients with these disor- ders
Epidemiology Myelodysplasia
Myelodysplastic syndrome (MDS) is a disease of the elderly; the mean age at onset is older than 70 years. There is a slight male preponderance. MDS is a relatively com- mon form of bone marrow failure, with reported incidence rates of 35 to >100 per mil- lion persons in the general population and 120 to >500 per million in older adults. Es- timates of incidence in the United States range from 30,000 to 40,000 new cases an- nually and a prevalence of 60,000–120,000 in the population. MDS is rare in chil- dren, in whom it often has an identifiable genetic basis. Secondary or therapy-related MDS is not age related. Rates of MDS have increased over time, due to better recogni- tion of the syndrome by physicians, and an aging population
MDS and treatments
MDS is associated with environmental exposures such as radiation and benzene; other risk factors have been reported inconsistently. Secondary, therapy-related MDS occurs as a late toxicity of radiation therapy and chemotherapy, especially the alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5–7 years), or the DNA topoisomerase inhibitors (2-year latency). Occasionally, MDS in adults is recognized as due to germline GATA2, RUNX1, or telomere repair gene muta- tions. The typical MDS patient does not have a suggestive environmental exposure his- tory or a preceding hematologic disease. MDS is a disease of aging, suggesting random cumulative intrinsic and environmental damage to marrow cells
Characterization MDS
MDS is a clonal hematopoietic stem cell disorder characterized by disordered cell pro- liferation and impaired differentiation, resulting in cytopenias and risk of progression to leukemia. Both chromosomal and genetic instability have been implicated: both are aging-related. Cytogenetic abnormalities are found in approximately one-half of pa- tients, and some of the same specific lesions are also seen in leukemia; aneuploidy (chromosome loss or gain) is more frequent than translocations. Accelerated telomere
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attrition may destabilize the genome in marrow failure and predispose to acquisition of chromosomal lesions. Cytogenetic abnormalities are not random (loss of all or part of 5, 7, and 20, trisomy of 8) and may be related to etiology (11q23 following topoi- somerase II inhibitors). The type and number of cytogenetic abnormalities strongly correlate with the probability of leukemic transformation and survival
Genes MDS
Recurrent somatic mutations, acquired in the abnormal marrow cells and absent in the germline, have been identified in about 100 genes. Many of the same genes are also mutated in AML without MDS, whereas others are distinctive in subtypes of MDS. A prominent example of the latter is the discovery of mutations in genes of the RNA splicing machinery, especially SF3B1, which strongly associates with sideroblas- tic anemia. Some mutations correlate with prognosis: spliceosome defects with favor- able outcome, and mutations in EZH2, TP53, RUNX1, and ASXL1 with poor outcome. Pathophysiology has been linked to mutations and chromosome abnormalities in some specific MDS syndromes. The 5q– deletion leads to heterozygous loss of a ribo- somal protein gene (ribosomal protein gene mutations cause Diamond-Blackfan ane- mia, like much MDS characterized by deficient erythropoiesis). An immune patho- physiology may underlie trisomy 8 MDS; selected younger MDS patients can respond to immunosuppressive therapy as administered for aplastic anemia
Diagnose MDS
The myelodysplastic syndromes are invariably manifest by anemia (often macrocytic) that cannot be explained by vitamin B12 or folate deficiency, but instead arise from a stem cell defect that leads to ineffective erythropoiesis. The anemia may range from mild to severe and may be accompanied by leukopenia and thrombocytopenia. Pa- tients are diagnosed while asymptomatic when otherwise unexplained macrocytic ane- mia is found on a routine CBC, or they may have symptoms of more severe anemia as well as bleeding and/or infection from pancytopenia. Examination of the bone mar- row will establish the diagnosis and reveals dysplastic cell maturation, increased num- bers of immature white blood cell precursors, and characteristic cytogenetic abnor- malities. Since myelodysplastic syndromes occur most often in the elderly, many pa- tients may have other comorbidities that decrease their tolerance for pancytopenia. The myelodysplastic syndromes all have some propensity for evolving into an acute leukemia, although the likelihood and the rapidity of such transformation vary and can be predicted by whether the patient presents with anemia versus more severe pan- cytopenia, as well as the percentage of immature blasts in the bone marrow
Therapy MDS
No treatment is needed for patients with mild and asymptomatic anemia. Patients with more severe anemia associated with fatigue and exercise intolerance may require chronic transfusion support, and a small percentage will respond to erythrocyte- stimulating agents. Similarly, symptomatic bleeding from thrombocytopenia requires platelet transfusion support, and patients who develop infections related to underlying granulocytopenia will need antibiotics. Chemotherapy with agents such as the pyrimid-
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ine nucleoside analogue azacitidine will prolong survival and delay the time of trans- formation to leukemia and should be used in patients with poor prognosis, sympto- matic myelodysplastic syndrome. Allogeneic hematopoietic stem cell transplantation is potentially curative but is associated with considerable treatment toxicity and not of- ten advised in elderly patients, who are the typical patient population with myelodys- plastic syndromes
Cure MDS
Only hematopoietic stem cell transplantation offers cure of MDS. The survival rate in selected patient cohorts is ~50% at 3 years but improving. Results using unrelated matched donors are now similar to those with siblings, and patients in their fifties and sixties have been successfully transplanted. Nevertheless, treatment-related mortality and morbidity increase with recipient age. The transplant conundrum is that the high- risk patient (by IPSS score and presence of monosomal karyotype), for whom the pro- cedure is most obviously indicated, has a high probability of a poor outcome from transplant-related mortality or disease relapse, whereas the low-risk patient, who is more likely to tolerate transplant, also may do well for years with less aggressive thera- pies. In practice, only a small proportion of MDS patients undergo transplantation
MDS drugs
MDS has been regarded as particularly refractory to cytotoxic chemotherapy regi- mens, and as in AML in the older adult, drug toxicity is frequent and often fatal, and remissions if achieved are brief. Low doses of cytotoxic drugs have been administered for their “differentiation” potential, and therapies have emerged based on pyrimidine analogues. These drugs are classified as epigenetic modulators, believed to act through a demethylating mechanism to alter gene regulation and allow differentiation to ma- ture blood cells from the abnormal MDS stem cell. The hypomethylating agents azaciti- dine and decitabine are frequently used. Azacitidine improves blood counts and sur- vival in MDS, compared to best supportive care. Response is dependent on continued drug administration, and most patients eventually become refractory to drug interven- tion and experience recurrent cytopenias or progression to AML. Decitabine is closely related to azacitidine and more potent; 30–50% of patients show responses in blood counts, with a duration of response of almost a year. The major toxicity of azacitidine and decitabine is myelosuppression, leading to worsening blood counts. Hypomethy- lating agents are frequently used in the high-risk patient who is not a candidate for stem cell transplant. In the lower risk patient, they are also effective, but alternative therapies should be considered
Lena lido ide , a thalidomide
Lenalidomide, a thalidomide derivative with a more favorable toxicity profile, is par- ticularly effective in reversing anemia in MDS patients with 5q– syndrome; not only do a high proportion of these patients become transfusion independent with normal or near-normal hemoglobin levels, but their cytogenetics also become normal. The drug has many biologic activities, and it is unclear which is critical for clinical efficacy. Lenalidomide is administered orally. Most patients will improve within 3 months of initiating therapy. Toxicities include myelosuppression (worsening thrombocytopenia and neutropenia, necessitating blood count monitoring) and an increased risk of deep vein thrombosis and pulmonary embolism
Immunosuppression MDS
Immunosuppression may produce sustained independence from transfusion and im- prove survival. ATG, cyclosporine, and the anti-CD52 monoclonal antibody alemtuzu- mab are especially effective in younger MDS patients (<60 years old) with more favor- able IPSS scores and who bear the histocompatibility antigen HLA-DR15
Hematopoietic growth factors MDS
Hematopoietic growth factors can improve blood counts but, as in most other marrow failure states, have been most beneficial to patients with the least severe pancytopenia. EPO alone or in combination with G-CSF can improve hemoglobin levels, particularly in those with low serum EPO levels who have no or a modest need for transfusions. Survival may be enhanced by EPO and amelioration of anemia. The same principles of supportive care described for aplastic anemia apply to MDS. Many patients will be ane- mic for years. RBC transfusion support should be accompanied by iron chelation to prevent secondary hemochromatosis
Diagnose primary myelofibrosis
Primary myelofibrosis, the least common of the myeloproliferative neoplasms, results from excessive proliferation of dysplastic megakaryocytes that may or may not pro- duce thrombocytosis but invariably secrete factors that stimulate collagen production that leads to bone marrow fibrosis. Consequently, extramedullary hematopoiesis oc- curs in the liver and spleen and, more rarely, in other unusual sites. Patients typically present with symptoms from anemia and may have prominent systemic features, such as fever, night sweats, anorexia, and weight loss. Splenomegaly may be massive and cause abdominal pain and compressive symptoms, such as early satiety. Physical ex- amination reveals pallor, hepatomegaly, and dramatic splenomegaly that may extend to the pelvic brim. Patients are anemic, but while pancytopenia is not uncommon, the white blood cell and platelet counts may also be elevated. The peripheral smear re- veals a typical, so-called myelophthisic or leukoerythroblastic picture with immature leukocytes, nucleated erythrocytes, and teardrop-shaped erythrocytes. The bone mar- row is difficult to aspirate in these patients, leading to a “dry tap,” but the diagnosis is established from bone marrow biopsy that shows increased collagen and reticulin fi- brosis, increased numbers of dysplastic-appearing megakaryocytes, and osteosclero- sis. Other conditions that cause secondary bone marrow fibrosis, such as metastatic cancer or miliary tuberculosis, need to be excluded. The JAK2 mutation is found in 50% of patients
Primary myelofibrosis
Chronic primary myelofibrosis (other designations include idiopathic myelofibrosis, agnogenic myeloid metaplasia, or myelofibrosis with myeloid metaplasia) is a clonal hematopoietic stem cell disorder associated with mutations in JAK2, MPL or CALR and characterized by marrow fibrosis, extramedullary hematopoiesis, and sple- nomegaly. Primary myelofibrosis is the least common myeloproliferative neoplasm, and establishing its diagnosis in the absence of a specific clonal marker is difficult be-
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cause myelofibrosis and splenomegaly are also features of both polycythemia vera and chronic myelocytic leukemia. Furthermore, myelofibrosis and splenomegaly also oc- cur in a variety of benign and malignant disorders, many of which are amenable to spe- cific therapies not effective in primary myelofibrosis. In contrast to the other myeloproliferative neoplasm and so-called acute or malignant myelofibrosis, which can occur at any age, primary myelofibrosis primarily afflicts men in their sixth dec- ade or later
Etiology myelofibrosis
Nonrandom chromosome abnormalities such as 9p, 20q−, 13q−, trisomy 8 or 9, or par- tial trisomy 1q are common in primary myelofibrosis, but no cytogenetic abnormality specific to the disease has been identified. JAK2 V617F is present in ∼50% of primary myelofibrosis patients, and mutations in the thrombopoietin receptor, MPL, occur in about 8%. Most of the rest have mutations in the calreticulin gene (CALR) that alter the carboxy-terminal portion of the protein, permitting it to bind and activate MPL. The degree of myelofibrosis and the extent of extramedullary hematopoiesis are not re- lated. Fibrosis in this disorder is associated with overproduction of transforming growth factor β and tissue inhibitors of metalloproteinases, while osteosclerosis is as- sociated with overproduction of osteoprotegerin, an osteoclast inhibitor. Marrow angi- ogenesis occurs due to increased production of vascular endothelial growth factor. Im- portantly, fibroblasts in PMF are polyclonal and not part of the neoplastic clone but can be induced by it to produce inflammatory cytokines
Clincila features myelofibrosis
No signs or symptoms are specific for primary myelofibrosis. Many patients are asymp- tomatic at presentation, and the disease is usually detected by the discovery of splenic enlargement and/or abnormal blood counts during a routine examination. In contrast to its companion myeloproliferative neoplasms, night sweats, fatigue, and weight loss are common presenting complaints. A blood smear will show the characteristic fea- tures of extramedullary hematopoiesis: teardrop-shaped red cells, nucleated red cells, myelocytes, and promyelocytes; myeloblasts may also be present. Anemia, usually mild initially, is common, whereas the leukocyte and platelet counts are either normal or increased, but either can be depressed. Mild hepatomegaly may accompany the sple- nomegaly but is unusual in its absence; isolated lymphadenopathy should suggest an- other diagnosis. Both serum lactate dehydrogenase and alkaline phosphatase levels can be elevated. Marrow is usually inaspirable due to the myelofibrosis, and bone rays may reveal osteosclerosis. Exuberant extramedullary hematopoiesis can cause as- cites; portal, pulmonary, or intracranial hypertension; intestinal or ureteral obstruc- tion; pericardial tamponade; spinal cord compression; or skin nodules. Splenic en- largement can be sufficiently rapid to cause splenic infarction with fever and pleuritic chest pain. Hyperuricemia and secondary gout may ensue
Treat primary myelofibrosis
Treatment
As there is no definitive therapy for primary myelofibrosis, symptom palliation is the goal of treatment. The attenuated anabolic steroid danazol has been used to treat ane- mia, although transfusions are often required. Myelosuppressive drugs, such as hy- droxyurea, are used to control splenomegaly. Splenic irradiation is, at best, temporar- ily palliative and associated with a significant risk of neutropenia, infection, and subse- quent operative hemorrhage if splenectomy is attempted. Allopurinol can control sig- nificant hyperuricemia, and bone pain can be alleviated by local irradiation. Pegylated IFN-α can ameliorate fibrosis in early primary myelofibrosis, but in advanced disease, it may exacerbate the bone marrow failure
Jak2 inhibitors myelofibrosis
The JAK2 inhibitor, ruxolitinib, has proved effective in reducing splenomegaly and al- leviating constitutional symptoms in a majority of advanced primary myelofibrosis pa- tients while also prolonging survival, although it does not significantly influence the JAK2 V617F neutrophil allele burden. Although anemia and thrombocytopenia are its major side effects, these are dose-dependent, and with time, anemia stabilizes and thrombocytopenia may improve. Allogeneic bone marrow transplantation is the only curative treatment for primary myelofibrosis and should be considered in younger pa- tients and older patients with high risk disease; nonmyeloablative conditioning regi- mens may permit hematopoietic cell transplantation to be extended to older individu- als, and is currently under investigation
Diagnosis pcv
Patients with polycythemia (rubra) vera (PRV) often present with vague, nonspecific symptoms such as headache or malaise. Pruritus is a less common symptom that, un- like the pruritus associated with skin or liver disease, tends to worsen following a warm bath—a phenomenon attributed to release of histamine from an expanded pool of basophils. Patients may also note a burning pain in the hands or feet, termed eryth- romelalgia. Thromboembolic events or stroke are also known complications of the dis- ease. Not uncommonly, asymptomatic patients are diagnosed from an abnormal CBC. Physical examination may reveal plethora and hepato-splenomegaly. Erythrocytosis is the hallmark of PRV and is often accompanied by leukocytosis and thrombocytosis. The leukocyte differential includes increased numbers of bands and myelocytes, as well as increased eosinophils and basophils. These patients lack other conditions, such as severe hypoxic lung disease or cyanotic heart disease, that lead to a compensatory secondary erythrocytosis. The erythropoietin level will be low, although that test is not typically necessary to make the diagnosis. Measurement of the red blood cell mass was traditionally advised, but many laboratories no longer perform this test routinely and it is not necessary in patients with erythrocytosis and a hemoglobin level of >16.5 g/dL (165 g/L). Virtually all patients with PRV have a mutation in the Janus kinase 2 (JAK2) gene, a tyrosine kinase involved in regulating proliferation. Examination of the bone marrow will reveal hypercellularity and a modest shift toward less mature blood cell precursors, but is rarely needed to establish the diagnosis
Therapy PRV
Patients with PRV are at significant risk for stroke, myocardial infarction, and other thromboembolic disease. Therapeutic phlebotomy is the mainstay of treatment, per- formed weekly when the diagnosis is first established, and less often, subsequently, to reduce the hemoglobin to <15 g/dL (150 g/L). Patients who are aged >60 years or who have had prior thromboembolic events remain at high risk for morbidity despite phle- botomy and should receive a myelosuppressive agent, such as hydroxyurea. Low-dose aspirin treatment has been controversial because these patients also have an increased risk of bleeding from qualitative platelet defects. Other interventions for stroke preven-
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tion independent of the polycythemia should be employed, such as blood pressure con- trol, tobacco cessation, and management of hyperlipidemia
Follow up PRV
Patients with PRV receiving appropriate therapy have a median survival of >10 years. The frequency of follow-up visits is determined by how often they need phlebotomy to maintain a normal hemoglobin level and whether or not they require additional myelo- suppressive drug therapy. While patients have a small risk of PRV evolving into an acute leukemia, there is no specific screening recommended
Plasma cell disorders
Essential monoclonal gammopathy is defined by two key features: (1) the presence of a monoclonal immunoglobulin or a monoclonal immunoglobulin light chain in the serum and (2) the absence of evidence for an overt malignancy of B lymphocytes or plasma cells (e.g., lymphoma, myeloma, or amyloidosis). The prevalence of essential monoclonal gammopathy depends on the demographic features in the population under study. In Americans of European descent, the prevalence increases from
approximately 2 percent in individuals 50 years of age to approximately 7 percent in octogenarians
Epidemiology plasma cell disorders
It is two to three times as prevalent in persons of African descent. The condition has been reported in association with a large variety of disorders, especially nonlymphocytic cancers. These coincidences are thought, in most cases, to be the chance concurrence of conditions that have a high prevalence in older persons
Symptoms monoclonal gammopathy
Some cases of essential monoclonal gammopathy are symptomatic because in those cases the immunoglobulin can interact with plasma proteins, blood cells, kidney, ocular structures, or neural tissue and cause serious dysfunction, for example, an acquired bleeding disorder, renal insufficiency, or an incapacitating neuropathy. In such cases, disability may be so great that attempts to remove the immunoglobulin by plasmapheresis and to suppress its production using immune or cytotoxic therapy can be warranted. Because
Diagnose monoclonal immunoglobulin
Because myeloma or lymphoma may emerge at the time the monoclonal immunoglobulin is first detected, periodic evaluation of the patient is required to
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ascertain if essential monoclonal gammopathy is the appropriate diagnosis
Long term follow up monoclonal gammopathy
Long- term followup at appropriate intervals is prudent to detect conversion from a stable, asymptomatic condition to a progressive lymphoma or myeloma, which occurs in approximately 0.5 to 1.0 percent of cases per year. In the absence of a symptomatic gammopathy or evolution to a progressive clonal gammopathy, periodic followup is all that is required
Multiple myeloma
Multiple myeloma (MM) is a malignant clonal proliferation of plasma cells. Several chromosomal abnormalities have been implicated in the pathogenesis of MM, includ- ing translocation at a chromosome region involved in immunoglobulin synthesis, onco- gene activation, and inactivation of kinase inhibitors. The net result of these abnor- malities is a malignant expansion of a plasma cell clone that secretes a specific immu- noglobulin (most often an intact IgG, less often IgA or IgM). In approximately 20% of cases, the malignant plasma cells secrete a monoclonal light chain (kappa or lambda). These monoclonal proteins, whether in the form of intact immunoglobulins or light chains, are termed M proteins. Multiple myeloma accounts for approximately 1% of cancer cases and typically occurs in the seventh decade of life. New chemotherapy op- tions and the use of autologous stem cell transplantation have improved the outlook for what was a uniformly fatal disease. Today, approximately one-third of patients aged <60 years achieve a 10-year survival, although a lasting cure of the disease re- mains unusual
MM signs
In MM, the uncontrolled clonal proliferation of plasma cells leads to bone marrow fail- ure, initially manifesting as a normocytic anemia and progressing to other cytopenias. The clonal expansion also results in inadequate numbers of normal plasma cells, with subsequent hypogammaglobulinemia predisposing to infection with encapsulated bac- teria (eg, Streptococcus pneumoniae). Neoplastic proliferation within the marrow is also associated with osteoclast activation, resulting in hypercalcemia and bone dam- age that produces pain and increases the risk of compression fracture of the spine and pathologic fracture of weight-bearing bones. Some patients develop plasma cell tu- mors (plasmacytomas), which may arise adjacent to or directly from bony structures or in extramedullary sites. Clinical features vary with location, but plasmacytomas aris- ing from the vertebrae increase the risk of spinal cord compression. The M protein, when filtered through the glomerulus, can cause renal tubular injury; large M proteins (eg, IgM or multimers of IgA) may also cause symptoms related to hyperviscosity. Symptoms of hyperviscosity include bleeding (hyperviscosity interferes with normal coagulation factor activation and platelet function), decreased vision and other neuro- logic symptoms, dyspnea, and heart failure
Diagnose MM
Multiple myeloma should be suspected in patients with anemia, bone pain, osteopenia or osteoporosis, pathologic fracture, lytic bone lesions, hypercalcemia, recurrent infec- tions (particularly pneumococcal infections), or kidney failure. Asymptomatic disease may be found in patients who have elevated total serum protein levels on routine labo- ratory screening, with subsequent electrophoresis revealing an M protein. Rarely, the uniform cationic electrical charge of M proteins may create a seemingly narrow anion gap on the basic metabolic panel. The large numbers of M proteins also alter blood rheology and lead to erythrocytes sticking to one another (rouleaux formation on pe- ripheral blood smear
Evaluation MM
Evaluation of MM (Table 2) begins with serum protein electrophoresis and urine pro- tein electrophoresis on a 24-hour urine sample
Lab finding MM chain
Up to 20% of patients with MM se- crete lambda or kappa light chains rather than an intact immunoglobulin. The smaller molecular weight of the light chains allows them to be filtered by the glomerulus and excreted in the urineelectrophoresis chains
Electrophoresis MM
Thus, electrophoresis of the serum will not reveal an M protein, although it may reveal hypogammaglobulinemia. An M protein in either urine or se- rum would be further characterized by immunoelectrophoresis. Light chains in the urine (Bence-Jones proteins) are not detected in a routine urinalysis, emphasizing the need for urine protein electrophoresis and subsequent immunoelectrophoresis in pa- tients in whom MM is suspected.
CBC MM
Additional studies include a complete blood count (CBC), a radiographic bone survey, and serum creatinine, blood urea nitrogen, and se- rum calcium levels. Normochromic anemia is the most common CBC abnormality, whereas patients with more advanced disease may also have leukopenia and thrombo- cytopenia.
Kidney MM
Multiple myeloma may be associated with kidney disease (“myeloma kid- ney”) caused by several mechanisms, most commonly the direct renal tubular toxicity of light chains. Associated hypercalcemia may cause acute kidney injury, and amyloi- dosis is often associated with nephrotic syndrome and azotemia. Although diffuse lytic bone lesions are more specific for MM, osteopenia is a more common finding.
Bone MM
Bone scans are not obtained, because the myeloma lesions are usually lytic and lack the asso- ciated increase in osteoblast activity that leads to positive bone scans typical of other forms of metastatic cancer. A bone marrow aspirate and biopsy are performed to docu- ment the presence of increased plasma cells. Although excessive in number, plasma cells are normal in individual appearance in most patients; however, in some patients, binucleate or other frankly dysplastic plasma cell morphologies may assist in the diag- nosis. Quantitative immunoglobulin measurement will show depressed amounts o
Diagnose MM
Quantitative immunoglobulin measurement will show depressed amounts of nonmonoclonal immunoglobulins, aiding in the diagnosis and providing clinically rele- vant information (ie, depressed levels of normal immunoglobulins predisposes the pa- tient to recurrent infection). Significant elevations in serum lactate dehydrogenase
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and β2-microglobulin suggest a high myeloma tumor burden and are used to deter- mine prognosis and guide therapy
CBC MM
Anemia is present in 60% . Thrombocytopenia and leukopenia
Peripheral blood smear MM
Rouleaux formation, due to increased serum proteins
Serum calcium
Hypercalcemia is initially seen due to cytokine mediated destruction of bone
Serum Cr MM
At diagnosis, have >2. Causes include hyperca “myeloma kidney” dehydration nad hyperuricemia
Serum protein electrophoresis
M protein is seen . Presence or absence does not guarantee or exclude the diagnosis. Note whether there is a spike or a diffuse increase in M protein levels. A spike in y globulin is more consistent with an M protein; a diffuse increase correlates with a polyclonal gammopathy. A polyclonal gammopathy almost never related to MM
Immunofixation of serum
At diagnosis have M protein in serum by immunofoxation
Quanta tive immunoglobulin measurement
Confirms monoclonal gammopathy
B2 microglobulin
Need for prognosis. Measures tumor burden
24 hour urine protein electrophoresis wit immunofixation
75% of patients have M protein int heir urine by immunofixation. Bc approximately of patients have light chain only, the free monoclonal light chain may be missed int he serum in theses patients; this test is essential, espicially in this subgroup of patients
Radiographically bone survey
Have punched out lyric lesions, osteoporosis or fractures on conventional radiography. Bc myelmatous bone lesions are lyric, conventional rediography is superior to t-99 scan
Bone marrow aspirate and biopsy MM
Essential but not sufficient for MM diagnosis. Plasma cells account for >10% of bone marrow cells
Bone marrow plasma cell labeling index
Specifically measures plasma cell proliferation . Prognostic for survival.
Cytogenetic and FISH MM
Obtained at diagnosis. Certain chromosomal abnormalities are associated with shorter disease free and overall survival
MGUS
MGUS (a premalig- nant condition that may remain stable for decades), MM, and an in-between condition termed smoldering myeloma. Patients with MGUS are asymptomatic. They have smaller amounts of M protein and normal amounts of the other immunoglobulins. Ex- amination of the bone marrow reveals <10% plasma cells. These patients do not have signs of bone marrow failure, skeletal abnormalities, hypercalcemia, or kidney injury
MM
MM have larger quantities of M protein associated with hy- pogammaglobulinemia. Most have anemia and/or bone pain or other radiographic signs of bone involvement. Hypercalcemia and kidney disease may be noted, and the bone marrow will show a higher percentage of plasma cells. Patients with smoldering myeloma have increased numbers of plasma cells in the bone marrow and a corre- spondingly larger amount of M protein, but they are otherwise asymptomatic
Treat MM
Multiple myeloma is a heterogeneous illness, ranging from smoldering or asympto- matic myeloma, which requires no therapy, to rapidly progressive disease. The first goal is to determine whether therapy is needed. Patients with MGUS should not be treated, and patients with myeloma who lack any end-organ damage and who are as- ymptomatic should not be treated. Patients with myeloma that is causing symptoms and end-organ dysfunction require treatment, ideally involving autologous human stem cell transplantation. Markers of poor prognosis include various cytogenetic ab- normalities, such as deletion of chromosome 13 and certain chromosome transloca- tions. Other high-risk markers include acute kidney injury, hypercalcemia, severe ane- mia, elevated β2-microglobulin, hypoalbuminemia, and >50% plasma cells on bone marrow aspirate. A simple staging system considers patients with low serum β2- microglobulin and normal serum albumin to be a good prognosis (Stage 1), those with β2-microglobulin >5.5 mg/L poor prognosis (Stage III), and all others not Stage I or III to be intermediate in their prognosis
Patients over 75 MM
Patients aged <75 years with good performance status are candidates for autologous stem cell transplantation, which is now considered the best therapy for symptomatic MM
Contraindications to autologous stem cell transplant MMM
Contraindications to autologous stem cell transplantation beyond advanced age and poor performance status include unstable and progressive kidney disease, decom- pensated cirrhosis, and New York Heart Association class III or IV heart failure
Patients for stem cell transplant
Pa-
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tients who are eligible for transplantation are treated with an induction chemotherapy regimen for 2 to 4 months to reduce the tumor burden and to demonstrate responsive- ness to chemotherapy
Why avoid melphalan during transplantation
In general, agents such as melphalan, which will be used dur- ing the transplantation, should be avoided during induction treatment
Initial treatment MM
Initial treat- ment typically includes high-dose dexamethasone and thalidomide. Lenalidomide (which is related to thalidomide in its antineoplastic action) and bortezomib (a protea- some inhibitor) are newer agents used at some centers for induction therapy.
Thalidomide and lenalidomide
Thalido- mide and lenalidomide are potent teratogens and must be used cautiously in women of childbearing age, although most female patients are postmenopausal. Patients re- ceiving either thalidomide or lenalidomide with dexamethasone as combination ther- apy have a very high risk for venous thromboembolism and require thromboprophy- laxis with aspirin, low-molecular-weight heparin, or warfarin.
Response to treatment MM
he response to treat- ment is determined by monitoring serum protein electrophoresis and/or urine protein electrophoresis; the amount of immunoglobulin should decrease significantly after 3 to 4 months of treatment. If a response is achieved, the patient is referred for autolo- gous stem cell transplantation. Patients who are not candidates for transplantation are treated with chemotherapy regimens similar to those used for induction the
Follow up MM during tratment
Patients with MM are followed on a monthly basis to determine their response to ther- apy and to assess kidney function, blood cell counts, and calcium levels.
Treatment MM
Beyond specific chemotherapy and stem cell transplantation, a number of interven- tions can prevent complications of MM. Although the immune response may be blunted, pneumococcal vaccine and annual influenza vaccine should be given to all pa- tients. Trimethoprim-sulfamethoxazole should be administered to prevent Pneumocys- tis pneumonia in all patients receiving prolonged glucocorticoids, and acyclovir pro- phylaxis is recommended for patients receiving bortezomib to prevent varicella zoster virus reactivation. Bisphosphonates (pamidronate or zoledronate) should be given pro- phylactically to all patients, as such treatment has been proven to decrease subsequent bone fractures and bone pain. Bisphosphonates should also be used to treat hypercal- cemia. Bisphosphonate therapy is limited to 2 years
Radiation MM
Radiation therapy can provide effective palliation of localized bone pain. Patients with MM and back pain need prompt radiographic evaluation, often with magnetic reso- nance imaging, to rule out spinal cord compression. The evaluation should be done
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even if there is no motor or sensory deficit or other neurologic manifestation of cord compression. Paralysis, sensory loss, or incontinence would be more worrisome, and once patients develop neurologic deficits, emergent management with glucocorticoids (typically dexamethasone), radiation therapy, or neurosurgery leads to neurologic re- covery in only 50% of patients. Radiation therapy or surgery should be considered to treat impending long bone fracture unresponsive to chemotherapy
Hydration with treatment MM
Hydration should be maintained and nephrotoxic drugs and contrast dyes should be avoided in patients with MM to prevent acute kidney injury. Mild hypercalcemia may resolve with hydration alone, and early acute kidney injury may improve with hydra- tion and treatment of hypercalcemia. Patients with severe kidney injury may require dialysis. Erythropoietic-stimulating agents will improve symptomatic anemia. Plasma- pheresis should be initiated for symptomatic hyperviscosity
Waldenstrom macroglobulinemia
In contrast to myeloma, Waldenström macroglobulinemia is associated with lymphadenopathy, hepatosplenomegaly, and hyperviscosity syndrome. The disease resembles the related diseases CLL, myeloma, and lymphocytic lymphoma. It originates from a postgerminal center B cell that has undergone somatic mutations and antigenic selection in the lymphoid follicle and has the characteristics of an IgM-
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bearing memory B cell. Waldenström’s macroglobulinemia (WM) and IgM myeloma follow a similar clinical course, but therapeutic options are different. The diagnosis of IgM myeloma is usually reserved for patients with lytic bone lesions and predominant infiltration with CD138+ plasma cells in the bone marrow. Such patients are at greater risk of pathologic fractures than patients with WM
Cytogemica WM
A familial occurrence is common in WM, but its molecular bases are yet unclear. A distinct MYD88 L265P somatic mutation is present in >90% of patients with WM and the majority of IgM essential monoclonal gammopathy. Other commonly occurring mutations include CXCR4, ARID1A, and CD79B. Presence of MYD88 mutation status is now used as a diagnostic test to discriminate WM from marginal zone lymphomas, IgM-secreting myeloma, and CLL with plasmacytic differentiation. This mutation also explains the molecular pathogenesis of the disease. MYD88 mutation also triggers Bruton tyrosine kinase, hemopoietic cell kinase growth, and survival signaling, which are now important therapeutic targets in WM
Clincial MW
The disease is similar to myeloma in being slightly more common in men and occurring with increased incidence with increasing age (median 64 years). The IgM in some patients with macroglobulinemia may have specificity for myelin-associated glycoprotein (MAG), a protein that has been associated with demyelinating disease of the peripheral nervous system and may be lost earlier and to a greater extent than the better known myelin basic protein in patients with multiple sclerosis. Sometimes patients with macroglobulinemia develop a peripheral neuropathy, and half of these patients are positive for anti-MAG antibody. The neuropathy may precede the appearance of the neoplasm. The whole process may begin with a viral infection that may elicit an antibody response that cross-reacts with a normal tissue component
Bone marrow MW
Like myeloma, the disease involves the bone marrow, but unlike myeloma, it does not cause bone lesions or hypercalcemia. Bone marrow shows >10% infiltration with lymphoplasmacytic cells (surface IgM+, CD19+, CD20+, and CD22+, rarely CD5+, but CD10− and CD23−) with an increase in number of mast cells
M component MW
Like myeloma, an M component is present in the serum in excess of 30 g/L (3 g/dL), but unlike myeloma, the size of the IgM paraprotein results in little renal excretion, and only ~20% of patients excrete light chains.
Light chain MW
he light chain isotype is kappa in 80% of the cases. Patients present with weakness, fatigue, and
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recurrent infections similar to myeloma patients, but epistaxis, visual disturbances, and neurologic symptoms such as peripheral neuropathy, dizziness, headache, and transient paresis are much more common in macroglobulinemia.
Mutations MW
Presence of MYD88 and CXCR4 mutations also affects disease presentation. Presence of CXCR4 mutations is associated with higher bone marrow disease burden and higher incidence of hyperviscosity. Patients with wild-type MYD88 show lower bone marrow disease burden.
PE MW
Physical examination reveals adenopathy and hepatosplenomegaly, and ophthalmoscopic examination may reveal vascular segmentation and dilation of the retinal veins characteristic of hyperviscosity states. Patients may have a normocytic, normochromic anemia, but rouleaux formation and a positive Coombs’ test are much more common than in myeloma. Malignant lymphocytes are usually present in the peripheral blood. About 10% of macroglobulins are cryoglobulins. These are pure M components and are not the mixed cryoglobulins seen in rheumatoid arthritis and other autoimmune diseases. Mixed cryoglobulins are composed of IgM or IgA complexed with IgG, for which they are specific. In both cases, Raynaud’s phenomenon and serious vascular symptoms precipitated by the cold may occur, but mixed cryoglobulins are not commonly associated with malignancy. Patients suspected of having a cryoglobulin based on history and physical examination should have their blood drawn into a warm syringe and delivered to the laboratory in a container of warm water to avoid errors in quantitating the cryoglobulin.
Treat MW
Control of serious hyperviscosity symptoms such as an altered state of consciousness or paresis can be achieved acutely by plasmapheresis because 80% of the IgM paraprotein is intravascular. The median survival of affected individuals is ~50 months. However, many patients with WM have indolent disease that does not require therapy. Pretreatment parameters including older age, male sex, general symptoms, and cytopenias define a high-risk population. Treatment is usually not initiated unless the disease is symptomatic or increasing anemia, hyperviscosity, lymphadenopathy, or hepatosplenomegaly is present
Ibrutinib
Ibrutinib is approved for use in patients with symptomatic WM. It targets the constitutively activated Bruton tyrosine kinase. Other first line treatments include rituximab (anti-CD20) alone or combined with alkylators (bendamustine and cyclophosphamide), or proteasome inhibitors (bortezomib
Fludarabine
Fludarabine and
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cladribine are also highly effective single agents. Although high-dose therapy plus autologous transplantation is an option, its use has declined due to the availability of other effective agents
POEMS
Patients usually have a severe, progressive sensorimotor polyneuropathy associated with sclerotic bone lesions from myeloma. Polyneuropathy occurs in ~1.4% of myelomas, but the POEMS syndrome is only a rare subset of that group. Unlike typical myeloma, hepatomegaly and lymphadenopathy occur in about two-thirds of patients, and splenomegaly is seen in one-third
LAD POEMS
The lymphadenopathy frequently resembles Castleman’s disease histologically, a condition that has been linked to IL-6 overproduction.
Endocrine POEMS
The endocrine manifestations include amenorrhea in women and impotence and gynecomastia in men. Hyperprolactinemia due to loss of normal inhibitory control by the hypothalamus may be associated with other central nervous system manifestations such as papilledema and elevated cerebrospinal fluid pressure and protein. Type 2 diabetes mellitus occurs in about one-third of patients. Hypothyroidism and adrenal insufficiency are occasionally noted. Skin changes are diverse: hyperpigmentation, hypertrichosis, skin thickening, and digital clubbing.
Manifestations POEMS
The endocrine manifestations include amenorrhea in women and impotence and gynecomastia in men. Hyperprolactinemia due to loss of normal inhibitory control by the hypothalamus may be associated with other central nervous system manifestations such as papilledema and elevated cerebrospinal fluid pressure and protein. Type 2 diabetes mellitus occurs in about one-third of patients. Hypothyroidism and adrenal insufficiency are occasionally noted. Skin changes are diverse: hyperpigmentation, hypertrichosis, skin thickening, and digital clubbing.
Pathogenesis POEMS
The pathogenesis of the disease is unclear, but high circulating levels of the proinflammatory cytokines IL-1, IL-6, VEGF, and TNF have been documented, and levels of the inhibitory cytokine transforming growth factor β are lower than expected. Treatment of the myeloma may result in an improvement in the other disease manifestations.
Treat POEMS
Patients are often treated similarly to those with myeloma. Plasmapheresis does not appear to be of benefit in POEMS syndrome. Patients presenting with isolated sclerotic lesions may have resolution of neuropathic symptoms after local therapy for plasmacytoma with radiotherapy. Similar to MM, novel agents and high-dose therapy with autologous stem cell transplantation have been pursued in selected patients and have been associated with prolonged progression-free survival
Heavy chain diseases
The heavy chain diseases are rare lymphoplasmacytic malignancies. Their clinical manifestations vary with the heavy chain isotype. Patients have absence of light chain and secrete a defective heavy chain that usually has an intact Fc fragment and a deletion in the Fd region. Gamma, alpha, and mu heavy chain diseases have been described, but no reports of delta or epsilon heavy chain diseases have appeared. Molecular biologic analysis of these tumors has revealed structural genetic defects that may account for the aberrant chain secreted
Gamma heavy chain disease
This disease affects individuals of widely different age groups and countries of origin. It is characterized by lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly, and weakness. It is frequently associated with autoimmune diseases, especially rheumatoid arthritis
Symptom gamma heavy chain
Its most distinctive symptom is palatal edema, resulting from involvement of nodes in Waldeyer’s ring, and this may progress to produce respiratory compromise.
Diagnosis gamma heavy chain
he diagnosis depends on the demonstration of an anomalous serum M component (often <20 g/L [<2 g/dL]) that reacts with anti-IgG but not antilight chain reagents. The M component is typically present in both serum and urine. Most of the paraproteins have been of the γ1 subclass, but other subclasses have been seen. The patients may have thrombocytopenia, eosinophilia, and a nondiagnostic bone marrow that may show increased numbers of lymphocytes or plasma cells that do not stain for light chain
Prognosis gamma heavy chain disease
Patients usually have a rapid downhill course and die of infection; however, some patients have survived 5 years with chemotherapy.
Treat gamma heavy change
herapy is
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indicated when symptomatic and involves chemotherapeutic combinations used in low-grade lymphoma. Rituximab has also been reported to show efficacy.
Alpha heavy change
This is the most common of the heavy chain diseases. It is closely related to a malignancy known as Mediterranean lymphoma, a disease that affects young persons in parts of the world where intestinal parasites are common, such as the Mediterranean, Asia, and South America
Characterization alpha heavy chain
The disease is characterized by an infiltration of the lamina propria of the small intestine with lymphoplasmacytoid cells that secrete truncated alpha chains.
Demonstrate alpha heavy chain
Demonstrating alpha heavy chains is difficult because the alpha chains tend to polymerize and appear as a smear instead of a sharp peak on electrophoretic profiles. Despite the polymerization, hyperviscosity is not a common problem in alpha heavy chain disease. Without J chain–facilitated dimerization, viscosity does not increase dramatically. Light chains are absent from serum and urine.
Patients present alpha heavy chain
The patients present with chronic diarrhea, weight loss, and malabsorption and have extensive mesenteric and paraaortic adenopathy. Respiratory tract involvement occurs rarely. Patients may vary widely in their clinical course. Some may develop diffuse aggressive histologies of malignant lymphom
Treat alpha heavy chain
Chemotherapy may produce long-term remissions. Rare patients appear to have responded to antibiotic therapy, raising the question of the etiologic role of antigenic stimulation, perhaps by some chronic intestinal infection. Chemotherapy plus antibiotics may be more effective than chemotherapy alone.
IPSID
IPSID is recognized as an infectious pathogen–associated human lymphoma that has association with Campylobacter jejuni. It involves mainly the proximal small intestine resulting in malabsorption, diarrhea, and abdominal pain. IPSID is associated with excessive plasma cell differentiation and produces truncated alpha heavy chain proteins lacking the light chains as well as the first constant domain. Early-stage IPSID responds to antibiotics (30–70% complete remission). Most untreated IPSID patients progress to lymphoplasmacytic and immunoblastic lymphoma.
Patients not responding to chemo alpha heavy chain
Patients not responding to antibiotic therapy are considered for treatment with combination chemotherapy used to treat low-grade lymphoma.
Mu heavy chain disease
The secretion of isolated mu heavy chains into the serum appears to occur in a very rare subset of patients with chronic lymphocytic leukemia (CLL
Features distinguish Mu heavy chain from
he only features that may distinguish patients with mu heavy chain disease are the presence of vacuoles in the malignant lymphocytes and the excretion of kappa light chains in the
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urine
Diagnosis Mu heavy chain
he diagnosis requires ultracentrifugation or gel filtration to confirm the nonreactivity of the paraprotein with the light chain reagents because some intact macroglobulins fail to interact with these serums. The tumor cells seem to have a defect in the assembly of light and heavy chains because they appear to contain both in their cytoplasm. Such patients are not treated differently from other patients with CLL
Amyloidosis
Amyloidosis is the term for a group of protein misfolding disorders characterized by the extracellular deposition of insoluble polymeric protein fibrils in tissues and or- gans. Many diseases, ranging from cystic fibrosis to Alzheimer’s disease, are now known to involve protein misfolding. In the amyloidoses, the aggregates are typically extracellular, and the misfolded protein subunits assume a common antiparallel, β- pleated sheet–rich structural conformation that leads to the formation of higher-order oligomers and then fibrils with unique staining properties.
Define amyloid disease
Amyloid diseases, defined by the biochemical nature of the protein composing the fi- bril deposits, are classified according to whether they are systemic or localized, whether they are acquired or inherited, and their clinical patterns
AL refers to amyloid composed of immunoglobulin light chains
this disorder, termed primary amyloidosis, arises from a clonal B cell or plasma cell disorder and can be associated with myeloma or lymphoma
AA amyloid
AA amyloid is composed of the acute-phase reactant pro-
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tein serum amyloid A (SAA) and occurs in the setting of chronic inflammatory or infec- tious diseases; for this reason, this type is known as secondary amyloidosi
Diagnosis and treatment amyloidosis
Diagnosis and treatment of the amyloidoses rest upon the histopathologic identifica- tion of amyloid deposits and immunohistochemical, biochemical, or genetic determi- nation of amyloid type
Systemic amyloidosis
the systemic amyloidoses, the clinically involved organs can be biopsied, but amyloid deposits may be found in any tissue of the body
but the most easily accessible tissue—positive in more than 80% of patients with systemic amyloidosis
Abdominal fat
The regular β-sheet structure of amyloid deposits exhibits a unique “ap- ple green” birefringence by polarized light microscopy when stained with Congo red dye; other regular protein structures (e.g., collagen) appear white under these condi- tions. The patient’s history, physical findings, and clinical presentation, including age and ethnic origin, organ system involvement, underlying diseases, and family history, may provide helpful clues as to the type of amyloidosis.
There can be considerable overlap in clinical presentations, and accurate typing is essential to guide appropriate therapy.
Etiology and incidence amyloid
AL amyloidosis is most frequently caused by a clonal expansion of bone-marrow plasma cells that secrete a monoclonal immunoglobulin LC depositing as amyloid fi- brils in tissues. AL amyloidosis can occur with multiple myeloma or other B lymphop- roliferative diseases, including non-Hodgkin’s lymphoma and Waldenström’s macro- globulinemia. AL amyloidosis is the most common type of systemic amyloidosis diag- nosed in North America. Its incidence has been estimated at 4.5 cases/100,000 popu- lation; however, the true incidence may be much higher. AL amyloidosis, like other plasma cell diseases, usually occurs after age 40 and is often rapidly progressive and fatal if untreated
AL amyloidosis
Pathology AL amyloidosis is often a rapidly progressive disease that presents as a pleiotropic set of clinical syndromes, recognition of which is key for initiation of the appropriate workup. Nonspecific symptoms of fatigue and weight loss are common; however, the diagnosis is rarely considered until symptoms referable to a specific organ develop. The kidneys are the most frequently involved organ and are affected in 70–80% of pa- tients. Renal amyloidosis usually manifests as proteinuria, often in the nephrotic range and associated with hypoalbuminemia, secondary hypercholesterolemia and hy-
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pertriglyceridemia, and edema or anasarca. In some patients, interstitial rather than glomerular amyloid deposition can produce azotemia without proteinuria. The heart is the second most commonly affected organ (50–60% of patients), and cardiac involve- ment is the leading cause of death from AL amyloidosis
Early on emyloidosis : cardiology
Early on, the electrocardio- gram may show low voltage in the limb leads with a pseudo-infarct pattern. Echocar- diographic features of disease include concentrically thickened ventricles and diastolic dysfunction with an abnormal global longitudinal strain pattern; a “sparkly” appear- ance has been described but is often not seen with modern high-resolution echocardio- graphic techniques. Poor atrial contractility occurs even in sinus rhythm, and patients with cardiac amyloidosis are at risk for development of atrial thrombi and stroke. Car- diac MRI can show increased wall thickness, and characteristic delayed enhancement of the subendocardium has been described following injection of gadolinium contrast
Nervous system AL
Nervous system symptoms include peripheral sensorimotor neuropathy and/or auto- nomic dysfunction manifesting as gastrointestinal motility disturbances (early satiety, diarrhea, constipation), dry eyes and mouth, impotence, orthostatic hypotension, and/or neurogenic bladder.
Macroglossia AL
Macroglossia, a pathognomonic sign of AL amyloidosis, is seen in only ~10% of patients
Liver LA
Liver involvement causes cholestasis and hepa- tomegaly.
Spleen AL
spleen is frequently involved, and there may be functional hyposplen- ism in the absence of significant splenomegaly.
Bruising AL
Many patients experience “easy bruis- ing” due to amyloid deposits in capillaries or deficiency of clotting factor X due to bind- ing to amyloid fibrils; cutaneous ecchymoses appear, particularly around the eyes, pro- ducing another uncommon but pathognomonic finding, the “raccoon-eye” sign
One finding AL
Other findings include nail dystrophy, alopecia, and amyloid arthropathy with thickening of synovial membranes in the wrists and shoulders. The presence of a multisystemic ill- ness or general fatigue along with any of these clinical syndromes should promp
Diagnosis AL
Identification of an underlying clonal plasma cell or B lymphoproliferative process and a clonal LC are key to the diagnosis of AL amyloidosis. Serum protein electropho- resis and urine protein electrophoresis, although of value in multiple myeloma, are not useful screening tests if AL amyloidosis is suspected because the clonal LC or whole immunoglobulin often is not present in sufficient amounts to produce a mono- clonal “M-spike” in the serum or LC (Bence Jones) protein in the urine. However, more than 90% of patients with AL amyloidosis have serum or urine monoclonal LC or whole immunoglobulin detectable by immunofixation electrophoresis of serum or
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urine or by measurement of serum “free” LCs . Examining the ratio as well as the abso- lute amount of serum-free LCs is essential, as renal insufficiency reduces LC clear- ance, nonspecifically elevating both isotypes. In addition, an increased percentage of plasma cells in the bone marrow—typically 5–30% of nucleated cells—is found in ~90% of patients. Kappa or lambda clonality should be demonstrated by flow cytome- try, immunohistochemistry, or in situ hybridization for LC mRNA
What is diagnostic for amyloidosis
A monoclonal serum protein by itself is not diagnostic of amyloidosis, since mono- clonal gammopathy of uncertain significance is common in older patients. However, when monoclonal gammopathy of uncertain significance is found in patients with biopsy-proven amyloidosis, the AL type should be ruled out. Similarly, patients thought to have “smoldering myeloma” because of a modest elevation of bone-marrow plasma cells should be screened for AL amyloidosis if they have signs or symptoms of renal, cardiac, or neurologic disease. Accurate tissue amyloid typing is essential for ap- propriate treatment. In ambiguous cases, other forms of amyloidosis should be thor- oughly excluded with appropriate genetic and other testing
Treat AL
Extensive multisystemic involvement typifies AL amyloidosis, and the median survival period without treatment is usually one to two years from the time of diagnosis. Cur- rent therapies target the clonal bone-marrow plasma cells, using approaches em- ployed for multiple myeloma
Oral mephalan and prednisone amyloidosis
eatment with oral melphalan and prednisone can de- crease the plasma cell burden but rarely leads to complete hematologic remission, meaningful organ responses, or improved survival and is no longer widely used
Substitute dexamethasone for prednisone
The substitution of dexamethasone for prednisone produces a higher response rate and more durable remissions, although dexamethasone is not always well tolerated by pa- tients with significant edema or cardiac disease.
High dose IV melphalan followed by autologous stem cell transplantation
High-dose IV melphalan followed by autologous stem cell transplantation (HDM/SCT) produces complete hematologic re- sponses in ~40% of treated patients, as determined by loss of clonal plasma cells in the bone marrow and disappearance of the amyloidogenic monoclonal LC, as deter- mined by SIFE/UIFE and free LC quantitation.
6-12 months after achieving a hematológicas response amyloid
to 12 months after achieving a he- matologic responses, improvements in organ function and quality of life may occur. Hematologic responses appear to be more durable after HDM/SCT than in multiple myeloma, with remissions continuing in some patients beyond 15 years without addi- tional treatment.
Aggressive treatment AL
Unfortunately, only about 30–40% of all AL amyloidosis patients are suitable for aggressive treatment, and, even at specialized treatment centers,
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transplantation-related mortality rates are higher than those for other hematologic dis- eases because of impaired organ function at initial presentation. Amyloid cardiomyo- pathy, poor nutritional and performance status, and multiorgan disease contribute to excess morbidity and mortality.
AL with impaired cardiac function
or patients with AL amyloidosis and impaired cardiac function or arrhythmias due to involvement of the myocardium, the median survival period is only ~6 months with- out treatment. In these patients, cardiac transplantation can be performed and fol- lowed by HDM/SCT to eliminate the noxious LC clone and prevent amyloid deposi- tion in the transplanted heart or other organs
Novel anti plasma cell agents amyloid
Novel anti–plasma cell agents have been investigated for treatment of plasma cell dis- eases. The immunomodulators thalidomide, lenalidomide, and pomalidomide display activity; dosing may need to be adjusted compared to their usage for myeloma
Supportive amyloidosis
Supportive care is important for patients with any type of amyloidosis. For nephrotic syndrome, diuretics and supportive stockings can ameliorate edema; angiotensin- converting enzyme inhibitors should be used with caution and have not been shown to slow renal disease progression. Effective diuresis can be facilitated with albumin infu- sions to raise intravascular oncotic pressure. Congestive heart failure due to amyloid cardiomyopathy is best treated with diuretics; it is important to note that digitalis, cal- cium channel blockers, and beta blockers are relatively contraindicated as they can in- teract with amyloid fibrils and produce heart block and worsening heart failure. Amio- darone has been used for atrial and ventricular arrhythmias. Automatic implantable defibrillators appear to have reduced effectiveness due to the thickened myocardium, but they may benefit some patients. Atrial ablation is an effective approach for atrial fibrillation. For conduction abnormalities, ventricular pacing may be indicated. Atrial contractile dysfunction is common in amyloid cardiomyopathy and associated with in- creased thromboembolic complications, prompting considerations of anticoagulation even in the absence of atrial fibrillation. Autonomic neuropathy can be treated with α agonists such as midodrine to support postural blood pressure; gastrointestinal dys- function may respond to motility or bulk agents. Nutritional supplementation, either oral or parenteral, is also important
Bleeding disorders
Bleeding disorders are characterized by defects in primary and secondary hemostasis. Primary hemostasis involves the formation of a platelet plug at the site of vascular dis- ruption, a process that begins with adhesion of platelets to the exposed subendothelial matrix. Adhesion is mediated through interactions of specific platelet receptors, such as the collagen receptor and the glycoprotein Ib-IX-V complex, which binds von Wille- brand factor (vWF) with the subepithelial matrix. Adhesion induces platelet activa- tion, with attendant change in platelet shape, secretion of alpha granules and dense bodies, and exposure of fibrinogen receptors that mediate platelet aggregation through binding of the dimeric fibrinogen molecule to adjacent platelets. Platelet acti- vation also leads to rearrangement of membrane phospholipid, with increased expres- sion of anionic phospholipid on the platelet surface; anionic phospholipid provides a surface that supports secondary hemostasis. Secondary hemostasis is initiated by the exposure of tissue factor at the site of vascular damage; tissue factor binds activated factor VII and activates factor X and factor IX. Activated factor IX, in turn, activates additional factor X, leading to the generation of thrombin and cleavage of fibrinogen to form fibrin. It is important to note that some bleeding disorders feature patho- physiologic evidence of both processes
H and p bleeding patient
A detailed bleeding history should be obtained, including duration (> or <5 minutes), timing, (immediately after a procedure), and sites of bleeding (local or systemic); fam- ily history; medications (eg, aspirin, antiplatelet agents, nonsteroidal anti- inflammatory drugs [NSAIDs], or anticoagulants); and medical history (eg, liver dis- ease, uremia, or poor nutrition). This information may provide clues to possible causes and help estimate bleeding risk
bleeding pattern
A mucocutaneous bleeding pattern, often seen at multiple sites, is the hallmark of dis- orders of primary hemostasis. etechiae, easy bruising, gingival bleeding, epistaxis, and menorrhagia are characteristic. Persistent oozing after an injury is common, be- cause the initial platelet plug is not formed. Disorders of secondary hemostasis are characterized by more localized bleeding into the soft tissues (such as muscles) and joints (hemarthrosis). Delayed bleeding is common, because the platelet plug gradu-
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ally succumbs to the pressures of blood flow without reinforcement from a strong fi- brin mesh. Excessive bleeding after childbirth, surgery, or trauma can occur with disor- ders of primary or secondary hemostasis
Lab analysis bleeding disorder
The laboratory analysis must begin with a complete blood count and a thorough re- view of the peripheral smear that might suggest other causes. Studies to assess for pri- mary hemostasis disorders include a quantitative platelet count and platelet function analysis (PFA). Platelet function screening is most commonly performed with auto- mated testing (ie, PFA-100), which measures the ability of activated platelets treated with collagen and epinephrine to occlude an aperture in vitro (the closure time) and is a sensitive method for assessing the effects of drugs or other disorders on platelet ac- tivity. This testing has replaced measurement of the in vivo bleeding time, which was difficult to interpret and is no longer used. Patients with evidence of abnormal platelet function may require additional testing for specific primary hemostatic disorders (such as von Willebrand disease [vWD]) and more detailed PFA. Screening for secon- dary hemostatic disorders is typically done with measurement of the prothrombin time (PT) and the activated partial thromboplastin time (aPTT), which detect clotting factor deficiencies as well as inhibitors that interfere with effective fibrin clot forma- tion (Table 1). Clotting factor levels <30% of the reference range are needed to prolong the PT and aPTT, and reliance on these tests alone underestimates bleeding risk. A mixing study differentiates factor deficiency from presence of a factor inhibitor by mix- ing patient plasma with normal plasma; factor deficiencies correct with mixing. Thrombin time tests the rate of conversion of fibrinogen to fibrin. Levels of fibrinogen, fibrinogen degradation products, and D-dimer are used to identify excessive fibrinoly-
PT bleeding
Warfarin, factor VII defiency or inhibitor, VK defiency, liver disease
PTT
Heparin, lupus anticoagulant vin williebrand disease; factor VII, IX, XI, or XII defiency or inhibitor
Combined PT and PTT
Supratherapeutic dose of heparin or warfarin; DIC liver disease; factor V or X , prothrombin, or fibrinogen defiency direct thrombin inhibitor
Thrombin time
Heparin, direct thrombin inhibitor, factor Ca inhibitor, factor Xa inhibitos, fibrin degradation product, hypo or dysfibrinogenemia
PAF
ASA, platelet dysfunction such as von williebrand disease
Disorders of primary hemostasis
Disorders of primary hemostasis include abnormalities of platelets or the vascular en- dothelium. Quantitative platelet disorders may cause bleeding; spontaneous bleeding does not usually occur until the platelet count is <10,000 μL (10 × 109/L). Conditions causing abnormally low platelets are discussed in Thrombocytopenia. Dysfunction of platelet adhesion occurs in vWD, Glanzmann thrombasthenia, Bernard-Soulier syn- drome, and other hereditary disorders. Platelet activation can be limited due to drugs such as aspirin, antiplatelet agents, and NSAIDs, or in uremia. Medications such as as- pirin and other non-steroidal anti-inflammatory drugs are the most common cause of abnormal platelet function
Vwf
The most common inherited bleeding disorder is vWD, an autosomal dominant disor- der that occurs in 1% of the population with random screening, but is not usually clini- cally evident. Patients have mild to moderate bleeding evidenced by nosebleeds, heavy menstrual flow, gingival bleeding, easy bruising, and bleeding associated with surgery or trauma
How does vwf work
Von Willebrand factor plays a critical role in platelet adhesion to injured vessels. It also functions as a carrier for factor VIII. Disorders of secondary hemostasis can occur due to low factor VIII levels in vWD; this distinction is important for treatment pur- poses. Diagnostic testing includes a PFA (although this may be normal in mild cases), vWF antigen level, vWF activity assay, factor VIII level (which may also be normal in mild cases), and a multimer study used to diagnose subtypes of vWD (Table 2). Desmo- pressin releases stored vWF and factor VIII from endothelial cells and is used as first- line therapy for most subtypes of vWD; in vitro documentation of a response to desmo- pressin with platelet function testing or vWF assay is performed prior to administra- tion. It can readily be administered intravenously or intranasally. Intermediate-purity factor VIII concentrates, which contain vWF, can also be given. Cryoprecipitate is rich in vWF but carries the risk of transfusion-transmitted infection
Disorders of secondary hemostasis
Disorders of secondary hemostasis are characterized by defects or deficiencies of co- agulation factors and include inherited hemophilias, liver disease, vitamin K defi-
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ciency, acquired inhibitors of coagulation (antibodies), and consumptive processes (eg, disseminated intravascular coagulation) (Table 2). Medications such as warfarin, heparin, low-molecular-weight heparin, factor Xa inhibitors (eg, fondaparinux, rivar- oxaban, and apixaban), and direct thrombin inhibitors (eg, argatroban, lepirudin, and dabigatran) also interfere with secondary hemostasis
Look at chart
Ok
Hemophilia IX
VIII
X linked
Hemophilia B
IX X linked
Epidemiology hemophilia
s. Hemo- philia A affects about 1 in 10,000 people, while hemophilia B occurs less frequently. All daughters of patients with hemophilia are obligate carriers, whereas all sons are normal. Sons of carrier mothers have a 50% chance of having hemophilia, and daugh- ters have a 50% chance of being carriers. The spontaneous mutation rate is 3%. Fi- brinogen deficiency and factor II, V, VII, X, and XI deficiencies are usually autosomal recessive disorders and are rare in comparison
Both hemophilia symptoms
Both types of hemophilia are classified as mild, moderate, or severe according to base- line levels of clotting factors. Patients present in childhood with muscle hematomas, hemarthrosis, and persistent delayed bleeding after trauma or surgery. Mild hemo- philia can be missed until adulthood. Assessing factor VIII and IX levels is indicated in any male who presents with a prolonged aPTT that corrects with a mixing study (see Table 1)
Treat hemophilia
Factor VIII and IX deficiencies are treated with factor replacement (recombinant or purified). Fresh frozen plasma (FFP) is a diluted source of clotting factors with limited efficacy for high-level replacement.
Acquired inhibitors
Although uncommon, acquired inhibitors are more likely to manifest as a life- threatening bleed than the deficiency of factor VIII. Patients may present with severe soft tissue bleeding, but not hemarthrosis. In addition, this disorder is seen in associa- tion with certain medications (phenytoin, sulfa drugs, and penicillin), malignancies, or autoimmune disorders (systemic lupus erythematosus and rheumatoid arthritis). The diagnosis is suggested in the proper clinical setting by the inability to correct the aPTT with the addition of normal plasma in a mixing study. Further testing can then quantify the inhibitor and guide therapy. Weak inhibitors may respond to factor VIII concentrates; stronger inhibitors may demand agents that bypass the inhibited factor, such as factor VIII inhibitor bypass activity or activated recombinant factor VII. Long- term management includes immunosuppressive therapy
Liver disease
The liver synthesizes almost all proteins involved in hemostasis, with exceptions being vWF and tissue plasminogen activator. The PT is a sensitive indicator of hepatic syn-
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thetic function due to the short half-life of factor VII (6 hours), which the failing liver cannot maintain. The PT and aPTT are both prolonged with more severe hepatic syn- thetic dysfunction. Fresh frozen plasma transiently replaces all coagulation factors but is short lived. Cryoprecipitate is useful if the fibrinogen level is <100 mg/dL (2.9 μmol/L
Vitamin K defiency and inhibiton
Clotting factors II, VII, IX, and X, as well as protein C and protein S, require vitamin K-dependent gamma-carboxylation for full activity. Dietary vitamin K is obtained pri- marily from the intake of dark green vegetables and is modified by gut flora to the ac- tive form. Interruption of bile flow prevents absorption of vitamin K, and antibiotic- related elimination of enteric bacteria limits intestinal sources of vitamin K. Vitamin K antagonists (such as warfarin) used for therapeutic anticoagulation directly antago- nize vitamin K activity
VK PT and PTT
The PT is first to prolong, but the aPTT will also lengthen with further factor deficien- cies or inhibition. In adults with normal hepatic function, oral or subcutaneous vita- min K usually corrects the clotting times within 24 hours; however, the risk of anaphy- laxis is increased with intravenous vitamin K. Fresh frozen plasma is used when ur- gent correction is required
Treat VK defiency
The management of a supratherapeutic international normalized ratio (INR) in pa- tients taking vitamin K antagonists is challenging. Current guidelines suggest with- holding the drug if the INR is <5, the addition of oral vitamin K in the presence of addi- tional risk factors for bleeding with an INR ≥5 and <9, and the use of FFP or recombi- nant factor VII if the INR is ≥9 and there is a serious bleed or the patient is being pre- pared for surgery
Other anticoagulants
Newer-generation anticoagulants act at different points in the coagulation cascade. In cases of bleeding from direct thrombin inhibitors, it is important to recognize first that the aPTT or thrombin time are only reliable as an indicator that an effect of the an- ticoagulant is present, as they are not useful enough to guide therapy. Mild bleeding should warrant discontinuation of the drug, while moderate bleeding may require sup- port with fluid and blood products. Hemodialysis may also be beneficial. Severe bleed- ing may respond to prothrombin complex concentrates (PCC) or activated recombi- nant factor VII. A similar approach holds for the new generation of factor Xa inhibi-
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tors. However, in this case, anti-Xa assays may be useful to detect the presence of the drug effect. A prolonged PT only indicates the drug was used in the last 7 hours. Minor bleeding demands discontinuation of the agent. Hemodialysis is not effective with these agents. Moderate bleeding will require blood product support. As with the direct thrombin inhibitors, there is not a role for FFP; severe bleeding may be managed by PCC or recombinant factor VII
DIC
Disseminated intravascular coagulation (DIC) is frequently considered to be both a dis- order of primary and secondary hemostasis. It involves widespread activation of coagu- lation that leads to formation of fibrin clots. Some patients have a thrombotic disorder characterized by deep venous thrombosis or pulmonary embolism. Arterial thrombi and infarction may also occur rarely. In most patients, secondary fibrinolysis dissolves the fibrin clot, and consumption of platelets and coagulation factors causes thrombocy- topenia, clotting factor deficiencies, bleeding, and vascular injuries. Disseminated in- travascular coagulation most commonly occurs in patients with infection, cancer (typi- cally mucin-producing adenocarcinoma), and obstetric complications. Gram-negative sepsis is the most common infection associated with DIC, although infection due to gram-positive organisms and viruses, including human immunodeficiency virus, may also be causative
Diagnose DIC
The diagnosis of DIC is based on the presence of a prolonged PT, aPTT, and thrombin time, a high D-dimer titer, and a reduced serum fibrinogen level and platelet count; in some cases, schistocytes may be seen on the peripheral smear. Serial fibrinogen levels are often helpful, but there remains no diagnostic test specific for DIC. The degree of these abnormalities depends on the extent of consumption of platelets and coagula- tion factors and the ability of the patient to compensate for these defects
Treat DIC
Treatment of DIC is focused on correcting the underlying cause. Patients may require FFP/cryoprecipitate to replace coagulation factors or transfusion of platelets or eryth- rocytes. Antithrombin III is occasionally useful. Unfractionated heparin and low- molecular-weight heparin are rarely used today because these formulations may in- crease the bleeding risk and do not improve outcomes.
Thrombophlebitis
hrombophilia refers to the increased likelihood to form clots (thrombosis). In 1856, Virchow hypothesized that thrombosis developed as a consequence of abnormalities in 3 distinct factors: blood flow, the blood vessel wall, or the blood itself. Today, we know these factors as stasis, injury to the endothelium, and a hypercoagulable state. A patient can be hypercoagulable from a genetically inherited condition or an acquired state that may be reversible (eg, immobilization) or persistent (eg, age) (Table 1). Pa- tients often manifest their first clinical venous thromboembolic event (VTE) due to the interaction of multiple risk factors. For example, an older patient without a known in- herited hypercoagulable condition might develop VTE if immobilized after surgery. Or, an asymptomatic woman heterozygous for factor V Leiden mutation may have a moderately increased risk for VTE compared with the general population, but her risk would increase substantially if she were to start an oral contraceptive (Table 2)
Clot formation
Clot formation is a homeostatic process that carefully balances procoagulation and an- ticoagulation pathways. In the normally functioning coagulation cascade, an initial dis- ruption in the tissue activates platelets, which starts the process of clot formation. Clot- ting factors are activated, which results in fibrin being deposited along with the plate- lets. Protein C and S and antithrombin regulate clot formation by preventing excess thrombin production. If any of these naturally occurring anticoagulant pathways are disrupted, thrombin is increased, which leads to an abnormal state thrombophilia (Fig- ure 1)
Finding source thrombophlebitis
The process of finding the source of thrombophilia begins with a thorough evaluation of the patient’s risk factors. A strong family history may point to an inherited condi- tion. Many acquired thrombophilic states occur during hospitalization including sur- gery, immobilization, malignancy, and trauma. The pathogenesis of the acquired thrombophilic states varies depending on the condition. Surgery and immobilization activate the coagulation cascade by mechanisms that are not clearly understood be- yond the associated increased stasis and possible vascular damage. Malignancy in- creases clot formation in multiple ways depending on the type of tumor. Multiple mechanisms have been studied involving tumor factors and production of substances h procoagulant activity by surrounding tissues. Comorbid factors such as pro- longed bed rest, malnutrition, drugs, and infection also contribute
Inherited thrombophlebitis
The inherited thrombophilic disorders include deficiencies in coagulation factors and cofactors that allow thrombin to be produced in an unregulated manner. The most common of these disorders is factor V Leiden mutation, which causes activated pro tein C resistance. The mutation results in protein C being unable to inactivate factor V and VIII, which then leads to unregulated prothrombin activation. Heterozygosity of this gene increases the lifetime risk of thrombosis 7 fold, whereas homozygosity in- creases the risk 20 to 80 fold. This mutation is found in approximately 20% of indi- viduals presenting with a VTE
Protein C and S
Protein C and protein S are vitamin K-dependent proteins. Protein C deficiency is in- herited as an autosomal recessive trait, has a half-life of approximately 6 hours, and decreases to low levels soon after initiation of warfarin therapy; it is the cause of warfarin-induced skin necrosis in some patients. Protein S deficiency is inherited as an autosomal dominant trait; it is a cofactor of protein C, so decreased levels of this protein also lead to less protein C activity, resulting in increased fibrin formation. Pro- tein S deficiency is very rare.
G20210A
A mutation in the prothrombin gene at position G20210A causes increased levels of prothrombin that leads to excess thrombin formation. This condition occurs in ap- proximately 3% of Caucasians in the United States and confers a 3- to 4-fold risk for VTE
Antithrombin defiency
Antithrombin deficiency is an autosomal dominant genetic mutation associated with thrombophilia. It should be suspected in a patient whose clot does not respond to heparin therapy, since heparin requires the presence of antithrombin that is deficient in this condition
Hyperhomocysteinemia
yperhomocysteinemia can rarely be inherited through mutations of the MTHFR gene. Levels of homocysteine increase, leading to increased clot formation. Elevated plasma factor VIII coagulant activity (VIII:C) also increases thrombotic risk independ- ently but not as strongly as the top 5 inherited thrombophilias (factor V Leiden, prothrombin gene mutation, and deficiencies of antithrombin, protein C, and protein S). The exact genetic mutation that causes this elevated factor is not yet known
Antiphospholipid syndrome
Antiphospholipid syndrome (APS) is the most common form of acquired thrombo- philia resulting from the development of antibodies directed toward plasma proteins that are bound to phospholipids. Antiphospholipid antibodies may be detected in a number of different ways.
Anticardiolupin antibodies
nticardiolipin antibodies are antiphospholipid antibodies that react with proteins associated with cardiolipin, and these antibodies are also re- sponsible for false-positive tests for syphilis (such as the rapid plasma reagin test) that use cardiolipin in their ass
Lupus anticoagulants
Lupus anticoagulants are antiphospholipid antibodies that, when bound to their target proteins, prolong clotting times (such as the prothrombin time and activated partial thromboplastin time); despite this clotting time prolongation, patients with lupus anticoagulants are actually thrombophilic. Be- cause lupus anticoagulants act as inhibitors, these measures do not correct when a mixing study is performed in which the patient’s plasma is combined with plasma that
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contains all of the normal clotting factor
B2 microglobulin
Antiphospholipid autoantibodies may also be directed toward β2-microglobulin, which is an inhibitor of coagulation and platelet aggregation. Some patients may have one or more of these antiphospholipid antibod- ies present. Although the mechanism is not completely understood, these antibodies may lead to disruption of normal coagulation and an increased risk of thrombosis. An- tiphospholipid syndrome can present with one or more arterial or venous thrombosis in any tissue or organ, recurrent fetal loss, or premature births. The diagnosis of APS requires both clinical and laboratory criteria
Acquired hyperhomocysteinemia
Acquired hyperhomocysteinemia has been associated with both arterial and venous thrombosis. The increased homocysteine can stem from vitamin B6, vitamin B12, and folate deficiencies. The thrombotic risk is most closely associated with the increased fasting plasma homocysteine level, regardless of etiology, and roughly doubles the risk of venous thrombosis
Screening
Controversy exists as to whom and when to screen for inherited thrombophilias since the quality of evidence to support such recommendations is poor or conflicting. Uni- versal screening of unselected populations for inherited thrombophilias should be avoided. However, a targeted selective screening strategy based on specific high-risk patient groups may be of some value. A careful discussion with a patient about the po- tential benefits and risks of screening may be necessary. For example, most experts do not recommend general screening for inherited thrombophilias in all women consider- ing taking oral contraceptives. However, if a patient with a strong family history of thrombosis is considering the use of oral contraception or hormone replacement ther- apy, then screening may be helpful in this decision. Many consultants would advise against taking these hormones in patients who have factor V Leiden, prothrombin mu- tation, or protein C, protein S, or antithrombin deficiency because of a significant in- creased risk for thrombophilia (see Table 2 :). However, the avoidance of oral contra- ception may place the woman at increased risk of thrombophilia if she becomes preg- nant. Most experts do not routinely recommend screening for inherited thrombo- philias at the onset of pregnancy in all women without a history of VTE or recurrent pregnancy loss
Routine screening thrombophlebitis
Routinely screening for inherited thrombophilias in patients undergoing high-risk sur- gical procedures (such as certain orthopedic surgeries) is not recommended. Instead,
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routine thromboprophylaxis should be prescribed for all patients according to evidence-based guidelines without testing
Cost of testing
The cost of testing is a significant downside to undergoing universal population screen- ing for inherited thrombophilias given the frequency found in the general population but the low absolute risk for VTE. For example, most experts recommend against test- ing for inherited thrombophilias in asymptomatic children younger than age 15, even if they have a parent with a known congenital thrombophilia, because of the low abso- lute risk (see Table 2). Other issues to consider when counseling about screening are the potential psychological impacts of being diagnosed an asymptomatic carrier
Diagnosis
The decision to test for an inherited thrombophilia in all patients presenting with a VTE remains controversial. Epidemiologic studies have found an increased risk of in- herited thrombophilia in patients presenting with a first-time VTE, although the per- centage varies considerably on the selected population chose (Table 3). However, the evidence that identification of these disorders leads to improved clinical outcomes is limited or conflicting. Most experts do not recommend general screening to determine treatment duration of anticoagulant therapy, except perhaps for those with APS. Therefore, the decision should include a determination of the risk of recurrent throm-
Most common thrombophlebitis
Factor V Leiden
Risk factors for inherited thrombocytopenia
Thrombosis <50
History recurrent thrombosis, espicially if idiopathic
First degree relative with thrombosis, esp if VTE
Unusual site of thrombosis
Thrombotic event during pregnancy or postpartum
Thrombotic event while talking oral contraceptives
History of recurrent pregnancy loss
Testing for inherited thrombophilia
Testing for inherited causes of thrombophilia in the setting of an acute VTE may not be reliable since the acute phase reactants of the VTE may interfere with factor meas- urements. When testing patients treated for a VTE while on heparin, antithrombin lev- els will be artificially decreased or look like a lupus anticoagulant. When testing pa- tients on warfarin, levels of protein C and S may be artificially decreased. There is no ideal time to test for all of the inherited conditions, and the current recommendations suggest testing in multiple phases based on the risk factors present. Finally, all test re- sults should be confirmed before changing management decisions, as transient labora- tory abnormalities are possible
Treat thrombocytopenia
Patients who have had a venous thromboembolism and are found to have a concomi- tant thrombophilia are at increased risk for recurrent VTE. Most experts do not recom- mend testing for the congenital thrombophilias to determine the method, intensity or duration of treatment for patients presenting with their first venous thromboembo- lism unless there is a suggestive or known history of familial thrombophilia. General guidelines are based on the estimate of VTE recurrence, the nature of the first VTE, and the risk of bleeding with continued therapy. Some experts believe that lifelong an- ticoagulation is necessary for any patient who has had a VTE and has any of the follow- ing thrombophilias: lupus anticoagulant, anticardiolipin antibody, homozygosity for factor V Leiden mutation, homozygosity for prothrombin G20210A, combined hetero-
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zygosity for factor V Leiden mutation and prothrombin G20210A, and antithrombin deficiency
Huh
Others recommend a determination of the risk of recurrence and prescribe temporary anticoagulation when the patient is at higher risk, such as in surgery, immo- bilization, or pregnancy. Full-dose anticoagulation with warfarin must be weighed with the known risks including death from bleeding (0.1% per year) and major compli- cations requiring hospitalization or blood transfusions (1%-3% per year
When stop anticoagulation
The American College of Chest Physicians clinical practice guidelines recommend dis- continuation of anticoagulation after 3 to 6 months in a patient with heterozygous fac- tor V Leiden or prothrombin G20210A mutation. They advise extending therapy (1 year to lifetime) only in those with active cancer, persistently elevated anticardiolipin antibodies, or antithrombin deficiency. In patients with hyperhomocysteinemia, reduc- ing levels with B vitamins or folic acid has not reduced the incidence of subsequent VTEs
Follow up
Except to monitor the effectiveness of anticoagulant therapy, routinely checking labo- ratory studies once the diagnosis of thrombophilia has been established is not recom- mended. Platelet levels should be monitored in patients with anticardiolipin antibod- ies or lupus anticoagulant since these conditions may cause thrombocytopenia
Venous stasis
Venous stasis occurs most commonly in the lower extremities and is usually the result of venous insufficiency caused by chronic insufficiency of the dependent venous sys- tem (varicose veins), or damage to veins due to prior inflammation (post-phlebitic syn- drome
Diagnosis thrombosis
Patients with venous stasis typically present with progressive lower extremity edema with achy pain in the legs that may be worse with prolonged standing. Examination re- veals edema with shiny, atrophic skin as well as cutaneous telangiectasia. Varicose veins may also be present. In severe cases, there is breakdown of skin or ulceration, es- pecially around the medial malleolus.
Lower extremity edema secondary to venous stasis must be differentiated from other causes including congestive heart failure, mechanical venous obstruction, liver failure, and chronic kidney disease. Venous stasis may also be confused with cellulitis, al- though cellulitis is rarely bilateral, and the erythema associated with cellulitis is blanching
Treat dvt
xternal compression, most often through the use of specialized stockings, is the first line of treatment in addition to behavior modification (eg, eliminating prolonged peri- ods of standing, leg elevation). When varicosities are present, consideration can be given to radiofrequency or laser ablation, although the efficacy of these procedures in reducing stasis is unclear. Avoiding systemic volume overload is desirable, although diuresis in otherwise euvolemic patients is not usually an effective treatment
Treat ulcers secondary to chronic venous stasis
Ulcers secondary to chronic venous stasis are difficult to treat and often recur. Unna boots are specialized compressive dressings treated with agents to decrease edema and promote healing, although they must be applied periodically by medical profes- sionals. Aspirin may also be effective
DVT
Deep venous thrombosis (DVT) and pulmonary embolism (PE) are manifestations of the same disease, collectively referred to as venous thromboembolism (VTE). Venous stasis, hypercoagulability, and endothelial damage are the underlying predisposing conditions for VTE (Figure 1). The syndrome of DVT includes thrombosis of the proxi- mal leg veins and large veins of the upper extremities. DVT of the upper extremities is rising in incidence, in large part secondary to increasing use of indwelling venous catheters
Diagnosis DVT
Patients with lower extremity DVT often present with erythema, swelling, and tender- ness of the affected limb, although the clinical manifestations may be variable and need to be differentiated from other potential causes (Table 1). Homan sign (conven- tionally known as pain in the calf on forced dorsiflexion of the foot) is neither sensitive nor specific for DVT. The initial and most important step in evaluating a possible DVT is estimating the clinical likelihood of disease, as this will determine the proper test- ing. Clinical prediction rules, such as the Wells score (Section 3), are useful for initial assessment. Patients with a low clinical likelihood of DVT should undergo testing with D-dimer as the combination of a low clinical probability, and negative D-dimer rules out DVT. If the D-dimer is positive, or if the clinical likelihood is high, then duplex ul- trasonography should be performed. This test has an excellent sensitivity and specific- ity for DVT such that the gold standard test (venography) is rarely performed
Venous insuffiency
Usually due to venous HTN from such causes as venous reflux or obesity. Obtain US
Muscle strain, tear or trauma
Pain occurring with range of motion more characteristic of orthopedic problem due to trauma
Ruptured baker cyst
Pain localized to popliteal region of leg. Diagnosedwith US
Cellulitis
Skin tenderness, erythema and warmth. Normal US
Lymphedema
Toe edema is more characteristic of lymphedema than of venous edema. Lymphedema can occur in one leg or both legs
Prevent
Patients with known thrombophilic conditions with an indication for treatment should receive prophylaxis for VTE. All hospitalized patients with VTE risk factors and no significant contraindications should receive risk-appropriate venous thromboembo- lism prophylaxis to decrease their risk of VTE (Table 3 :). Pharmacologic prophylaxis is the most effective treatment and is preferred in these patients; mechanical prophy- laxis measures (eg, pneumatic compression stockings) are not well studied in medical patients, and the use of graduated compression stockings is discouraged because of un- proven efficacy and the risk of lower extremity skin damage. There is no indication for routine screening for DVT in asymptomatic patients at risk for VTE
Therapy DVT
All patients with established DVT and no contraindications should undergo immedi- ate anticoagulation. Intravenous unfractionated heparin may be used, but many pa-
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tients are treated with low-molecular-weight heparin, which facilitates outpatient treatment
Long term anticoagulation
Longer-term anticoagulation is usually with warfarin, which may be initiated simulta- neously with heparin, and both therapies are overlapped for a minimum of 5 days and until the international normalized ration (INR) has reached the therapeutic range (2.0 to 3.0) for two measurements taken 24 hours apart. Multiple newer oral anticoagulant agents are available (eg, dabigatran, rivaroxaban, apixaban, edoxaban). In general, they have a rapid onset of action, do not require routine monitoring of their anticoagu- lant effect, do not require overlap with heparin, and have minimal interactions with food or other medications. Most cannot be used in patients with significant kidney fail- ure, however, and there is a lack of reliable reversal agents if bleeding occurs. Newer oral anticoagulation medications tend to be very expensive and their long-term safety remains to be established
Treat extensive thrombosis
Patients with extensive thrombosis may be considered for thrombolytic therapy, in- cluding catheter-directed therapy. The proper role of thrombolysis, however, is poorly defined
Once a patient is on stable anticoagulation
Once a patient is on stable anticoagulation, therapy should be continued for a dura- tion based on his or her risk factor profile (see podcast on duration of anticoagulation therapy); all patients should be treated for a minimum of 3 months of anticoagulation
Strong indications to anticoagulation,
If there are strong contraindications to anticoagulation, an inferior vena cava filter should be placed. These filters decrease the likelihood PE in the short term, but they may actually increase the long-term risk of recurrent DVT. If the contraindication to anticoagulation is temporary, consider initiating a standard course of anticoagulation as well as filter removal
Pulmonary embolism
Pulmonary embolism (PE) and deep venous thrombosis (DVT) are different manifesta- tions of the same disease, often collectively referred to as venous thromboembolism (VTE). An estimated 2 million cases of DVT, 600,000 cases of symptomatic PE, and 300,000 VTE-related deaths occur annually in the United States. PE is the result of DVT formation and subsequent embolization into the pulmonary arteries. The throm- botic material obstructing blood flow through the pulmonary arteries has several physiologic consequences, including ventilation-perfusion aberrations and relative ischemia of the peripheral lung tissues. Pulmonary infarction is relatively uncommon due to the lungs’ dual circulation. In some cases, the amount of thrombotic material may be large enough to cause an acute increase in pulmonary vascular resistance, in- creasing demand on the right ventricle and possibly lowering cardiac output. In its ex- treme form, this combination of effects can cause right ventricular dysfunction, infarc- tion, and even cardiac arrest. The differential diagnosis of PE is reviewed in Table
Acute coronary syndrome
Chest pain associated with specific dynamic ECG and echocardiographic changes. Elevated cardiac enzymes can be seen in both acute coronary syndrome and large pulmonary emboli
Pericarditis
Substernal pain that is sharp, dull, or pressure like, often relieved with sitting forward; usually pleuritic. Ecg usually shows st-segment elevation, Pr segment depression and sinus tachycardia
Aortic dissection
Substernal chest pains ith radiaiton to the back or mid scapular region. Chest radiograph may show a widened mediastinal silouhette, a pleural effusion or both
Acute pulmonary edema
Elevated venous pressure, s3, bl crackles, and characteristic chest radiograph
Pleurisy
Sharp localized chest pain and fever. Pleural effusion may be present. Diagnosis of exclusion
Pneumothorax
Sudden onset of chest pain and dyspnea. Chest radiograph establishes the diagnosis
Asthma or chronic obstructive pulmonary disease exacerbation
Dyspnea and wheezing; positive response to bronchodilator. History of these disorders with a compatible course of illness is helpful
Panic attack
Diagnosis of exclusion. Patient may have a history of somatization
Prevent PE
Patients with known thrombophilic conditions but without contraindications should receive prophylaxis for VTE, and all hospitalized patients with VTE risk factors and no significant contraindications should receive risk-appropriate prophylaxis to decrease their risk of venous thromboembolism. Inferior vena cava filters should not be used routinely for perioperative prophylaxis for pulmonary embolism
Screening PE
Screening for either DVT or PE in asymptomatic patients at risk for VTE is not indi- cated as noninvasive diagnostic tests are insensitive and not associated with improved clinical outcomes
Diagnosis PE
The most common symptoms of PE are dyspnea, pleuritic chest pain, cough, and he- moptysis; tachypnea, crackles, tachycardia, and accentuated pulmonic component of S2 are the most common findings. Although these symptoms and signs are sensitive, they lack specificity. Laboratory studies may be suggestive but lack adequate sensitiv- ity and specificity to confirm a diagnosis of PE. Chest radiography may show atelecta- sis, a small pleural effusion, focal oligemia (lack of vascularity distal to the pulmonary embolus, termed Westermark sign), a peripheral wedge-shaped density above the dia- phragm (Hampton hump), or an enlarged right descending pulmonary artery. An elec- trocardiogram often shows sinus tachycardia but this is a nonspecific finding. Electro- cardiographic signs of right-sided heart strain (P-pulmonale, right axis deviation, right bundle branch block, and the combined presence of an S wave in lead I, Q wave in lead III, and T wave inversion in lead III [the S1Q3T3 pattern]) are uncommon but can suggest the presence of a hemodynamically significant embolus. Arterial blood gases are frequently abnormal, but the distributions of arterial PO2 and the alveolar- arterial oxygen gradient are similar in patients with and without PE; approximately one of every four patients with PE has an arterial PO2 ≥80 mm
Prediction PE
Because of this, clinical prediction rules have been developed to estimate the pretest probability of PE. Similar to a prediction rule for DVT, there is also a set of Wells crite- ria specifically for PE (Section 3). In clinically stable patients (eg, outpatients without hemodynamic compromise) with a low probability of PE, a normal D-dimer value ef- fectively rules out PE and is correlated with an excellent outcome without further workup or treatment. However, in patients with a higher probability of PE or clinical
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instability, D-dimer testing should not be used to confirm or exclude the diagnosis, and further testing is indicated (Table 3
Contrast enhanced CT or V/Q
As an initial imaging test for PE, contrast-enhanced CT (also called CT angiography) or ventilation-perfusion (V/Q) scanning is appropriate. Either test can reliably diag- nose a large PE; however, only a totally normal V/Q scan excludes PE. CT scans that do not disclose intraluminal filling defects or V/Q scans with matched or small defects are nondiagnostic, and the decision about whether to pursue further workup should be based on a consideration of the pretest probability. If the patient’s pretest probabil- ity is moderate or high, additional diagnostic tests are required, such as lower extrem- ity ultrasonography or pulmonary angiography
Because a V/Q scan detects alterations in pulmonary blood flow rather than providing a direct image of a clot (as does contrast-enhanced CT), there are many more indeter- minate studies because many cardiopulmonary diseases affect pulmonary blood flow
However, V/Q scans have several favorable characteristics. There is no radiocontrast agent load; therefore, renal failure and low perfusion states are not a contraindication. V/Q scans are also less affected by obesity than contrast-enhanced CT. Contrast-
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enhanced CT has excellent specificity and ability to provide alternative diagnoses but may not visualize small subsegmental pulmonary emboli.
Therapy DVT and PE
The pharmacologic treatment options for DVT and PE are similar. Some carefully se- lected patients with PE but without hemodynamic and gas exchange compromise may be candidates for outpatient therapy. Otherwise, most patients with PE are managed in the hospital until stable with supportive care, including treatment of hypoxia and management of hemodynamic instability, if present. Hemodynamic changes resulting from acutely elevated pulmonary arterial resistance suggest a large clot burden and are associated with a high mortality rate. Therefore, a more intensive approach may be justified. Thrombolytic therapy may be effective in patients with circulatory shock due to PE and in patients with acute embolism and pulmonary hypertension or right ven- tricular dysfunction but without arterial hypotension or shock. Rapid clot lysis may lead to hemodynamic improvement and resolution of right ventricular dysfunction
Surgical embolectomy for massive PE
Surgical embolectomy for massive PE is indicated if the patient is unstable and throm- bolytic therapy is contraindicated or if drug therapy has been unsuccessful. Surgical embolectomy requires the immediate availability of cardiopulmonary bypass; the op- erative mortality ranges from 10% to 75%.
Inferior vena cava filters prevent PE
Inferior vena cava filters prevent PE in patients with DVT within the first 2 weeks of filter placement. Indications include failure of medical therapy (evidence of PE despite adequate anticoagulation) and contraindications to anticoagulant therapy due to unac- ceptably high bleeding risk. After 1 year, patients may have a higher incidence of post- phlebitic syndrome and increased risk of recurrent lower extremity thromboses
Follow up DVT PE
Follow-Up
Once a patient is on stable anticoagulation, therapy should be continued for a dura- tion based on the individual risk factor profile (see podcast on duration of anticoagu- lant therapy
Wells for DVT
A score of 0 or lower is associated with DVT unlikely (5%). • These patients should proceed to d-dimer testing:
- A negative high or moderate sensitivity d-dimer results in a probability <1 % and no further imaging is required. 2. A positive d-dimer should precede to ultrasound (US) testing
a. A negative US is sufficient to rule out DVT.
b. A positive US is concerning for DVT; strongly consider treatment with anticoagulation. A score of 1-2 is considered moderate risk with a (pretest probability = 17%). - These patients should proceed to high-sensitivity d-dimer testing (moderate sensitivity d-dimer is not sufficient). a. A negative high-sensitivity d-dimer is sufficient for rule out of DVT (probability <1%).
b. A positive high sensitivity d-dimer should precede to US testing.
a. A negative US is sufficient for ruling out DVT.
b. A positive US is concerning for DVT, strongly consider treatment with anticoagulation. A score of 3 or higher suggests DVT is likely. Pretest probability 17-53%
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