First Pass Miss Flashcards
What is the lifespan of an average neutrophil, platelet, or RBC? How long does it take to make an RBC in the bone marrow?
Neutrophil - 6-8 hours
Platelet - 7-10 days
RBC - 120 days, produced in about 7 days
Where does hematopoesis first begin and where does it ultimately move to / when?
Starts in yolk sac, then liver / spleen, before finally moving to bone marrow
Moves to primarily bone marrow / some lymph nodes by birth
What causes basophilic stippling in RBCs?
Aggregation of residual ribosomes and RNA, seen in sideroblastic anemia, lead poisoning, etc
What are myeloid precursors called, where should they be found, and what CD markers are they positive for?
Myeloblasts, present in small amounts in bone marrow (should NOT be in blood)
Positive for CD34 and CD117
-> note, CD34 will be negative in APML because it is past the stem cell stage
What are some causes of neutrophil defects in chemotaxis?
Congenital - LAD1
Acquired - corticosteroid therapy (downregulates P-selectin), myelodysplastic syndromes
What is Hand-Schuller-Christian disease and what is it associated with?
Langerhan’s cell histocytosis seen in age >2 (greater than 2 names)
-> scalp rash, skull defects, exophthalmos, and diabetes insipidus (due to posterior pituitary involvement)
What is hemophagocytic syndrome? Symptoms?
Usually an acquired disease where histiocytes in bone marrow ingest RBCs, white cells, and/or platelets
Due to infection or cancer
Symptoms: pancytopenia, hepatosplenomegaly, fever, multi-organ dysfunction
What is Rosai-Dorfman disease?
Sinus Histiocytosis with Massive Lymphadenopathy
- > Marked expansion of lymph node sinuses causng a lymphadenopathy
- > chronic, cervical lymphadenopathy of unknown cause
What are the three forms of Gaucher’s disease? What disease is it associated with?
- Chronic, adult-type with no CNS involvement (most common)
- Acute, infantile type - CNS involvement but not bone involvement
- Subacute with CNS and bone, adolescent onset, better prognosis
Associated with multiple myeloma
In what states will you see target cells and why?
Target cells caused by too much cytoskeleton which is normally removed by spleen and liver to not be removed.
Can be seen in asplenia or liver disease
Also seen in iron deficiency -> overproduction of hypochromic, microcytic RBCs which do not have time to be properly filtered by spleen
When is G-CSF used?
To produce a rise in circulating neutrophils:
- Post-chemotherapy, radiotherapy, or stem-cell transplant to shorten neutropenia
- Severe neutropenia (congenital or acquired)
What problems can cause deficiencies in neutrophil chemotaxis?
- LAD-1 - integrin problem (CD18)
- Corticosteroid use - downregulates P-selection
- Myelodysplastic syndromes
What is the definition of anemia for men / women?
Decrease in hemoglobin in the blood
Men: Hgb < 13 g/dL or <40% hematocrit
Women: HgB <12 g/dL or <36% hematocrit
Hct is typically 3x the Hgb
What is the DDx of normocytic anemias?
Anemia of chronic disease - most common, can also be microcytic Chronic kidney disease - loss of EPO Blood loss Hemolysis Mixed etiologies, i.e. genetic Bone marrow disease
What is polychromasia and in what causes of anemia does it happen? What count is indicative of increased RBC turnover?
Increased reticulocytes (100,000 = absolute count showing increased turnover) on blood smear (stain blue due to residual DNA in cytoplasm, and are larger than normal RBC)
Happens in anemia due to acute blood loss or hemolysis -> more erythropoesis
What are some other important studies in the workup of anemia?
- Hemoglobin trend
- Creatinine - chronic kidney disease can cause anemia
- Iron studies - microcytic
- Hemolytic workup - reticulocyte count, LDH, bilirubin, haptoglobin
- Liver function tests - if macrocytic
- TSH - if macrocytic
What are the major storage and carrier proteins for iron?
Storage - ferritin, within reticuloendothelial cystem
Carrier - Transferrin - delivers iron to macrophages in RES and developing erythrocytes in bone marrow via transferrin receptor
What are the congenital and acquired causes of sideroblastic anemia?
Congenital - ALA synthase mutation
Acquired:
1. Alcohol - mitochondrial poison
2. Lead - inhibits ALA dehydratase and ferrochelatase
3. B6 deficiency - usually due to isoniazid therapy
4. myelodysplastic syndromes
What are more specific signs and symptoms for iron deficiency anemia (IDA)?
Pica - wanting to eat ice, baking power, clay, chalk
Restless legs - remember, iron is used to make dopamine and low levels (Ferritin <50) can cause RLS
Koilonychia - spooning of the nails - very severe cases, most specific
Why might a patient be refractory to ferrous sulfate / how long should they take to improve?
RBCs start increased in 4-7 days, resolution of anemia within 4-6 weeks depending on deficiency
Refractory reasons: Noncompliance Wrong diagnosis (more than one) Not enough iron - excessive bleeding Malabsorption
What is the cause of Classic hereditary hemochromatosis? What chromosome? Is it common?
Autosomal recessive HFE gene mutation on chromosome 6
-> increased intestinal absorption of iron, decreased hepcidin production, increased ferroportin transport
Most common inherited single-gene disease in US
Where does iron tend to accumulate in hereditary hemochromatosis?
Liver, pancreas, skin, heart, pituitary, and joints
What are the hepatic manifestions of HH?
Hepatomegaly, fibrosis and cirrhosis, with common progression to hepatocellular carcinoma (most common cause of death)
Causes restrictive -> dilated cardiomyopathy in heart
What is the classic triad of HH?
BCD
Bronzing of the skin - hyperpigmentation
Cirrhosis
Diabetes (due to pancreatic insufficiency)
What are the joint and pituitary manifestations of HH?
Joint - arthropathy of MCP and PIP joints
Pituitary - hypogonadism
How is HH treated if ferritin is >500 or there is end-organ damage? What is the goal? What if patient has sickle cell?
Serial phlebotomies - keep ferritin to <50-100
If intolerant to phlebotomy - i.e. patient has sickle cell disease
-> Desferoxamine IV or Deferasirox PO
What are the symptoms of acute intermittent porphyria?
NEUROVISCERAL SYMPTOMS
5 P’s of porphyria
Painful abdomen
Port-wine urine
Polyneuropathy - tingling nof limbs, respiratory failure
Psychological disturbances
Precipitated by drugs, alcohol and starvation
How is diagnosis of the porphyrias typically made?
Urine porphyrins, making sure to minimize light exposure which would break them down
- > best collected in acute exacerbation
- > test urine, blood, stool, then do genetic testing to confirm
How is PCT treated?
Avoid ETOH consumption (hepatic toxin), avoid sun exposure (werewolf), phlebotomy to reduce iron levels
What things precipitate AIP? Treatment?
Remember the last P of porphyrias:
Precipitated
Dehydration, starvation, CYP inducers induce ALA synthase (anticonvulsants), alcohol (also induces)
Treatment:
IV dextrose and heme to inhibit ALA synthase
Fluids and narcotics for pain
There are three alleles for the HFE gene, two of which cause some form of hereditary hemochromatosis. What combination is most likely to cause symptomatic overload.
Alleles include:
- Wild type
- C282Y
- H63D
Homozygous C282Y (C282Y/C282Y)
heterozygotes may have mild disease: C282Y / H63D
All others very unlikely to produce significant disease
What is a positive hemolytic workup?
increased reticulocyte count, increased LDH, increased bilirubin, decreased haptoglobin
What are the symptoms of Porphyria cutanea tarda (PCT)?
Cutaneous symptoms and iron overload (chronic)
- > blistering photosensitivity, hypertrichosis, iron overload, and chronic liver disease (associated with alcohol consumption)
- > makes you look like a werewolf
What is the DDx for macrocytic anemias?
Megaloblastic anemias (b9/b12) chronic liver disease / alcoholism hypothyroidism drugs bone marrow disorders red cell agglutination (warm or cold) very brisk reticulocytosis
Describe the pathway by which B12 is ingested and absorbed.
Ingested in animal products. Stomach enzymes detach B12 from protein and attach it to R-binder which was released by salivary glands.
In the duodenum, proteases detach R-binder from B12
B12 binds intrinsic factor released from parietal cells in the duodenum
IF-B12 complex attaches to receptor in terminal ileum for absorption
What can be seen on blood smear due to B9/B12 deficiencies?
Macro-ovalocytes (not round as in liver or hypothyroidism)
Hypersegmented neutrophils 5% with >5 lobes or any with >6
What are the usual causes of folate deficiency?
Alcoholism - inhibits absorption and poor diet
Intestinal malabsorptive disorders
High demand states: Hemolytic anemias, pregnancy
Drugs - phenytoin, pyrimethamine, trimethoprim, methotrexate
What are the neurological features of B12 deficiency and do the symptoms appear before or after anemia?
Subacute combined degeneration
Symmetrical polyneuropathy affecting legs more than arms
- > paresthesias happen more than motor
- > loss of proprioception and vibratory sense due to DC-ML loss
- > spastic paresis due to loss of lateral corticospinal tract
Can also affect memory / personality
What things do we typically screen our blood donations for nowadays?
Bacterial contamination, Hep B/C, HIV, HTLV, T. cruzi, syphilis, and Zika
What is fresh frozen plasma and cryoprecipitate?
Fresh frozen plasma is made from heavily spinning platelet-rich plasma, and removing platelets
Cryoprecipitate is composed of specific components of FFP
-> vWF, fibrinogen, Factor 8, Factor 13
What is the process of pre-transfusion compatibility testing?
- Forward ABO typing - test patient’s RBCs
- Reverse ABO typing - test patient’s blood type based on what antibodies they have in their serum
- Rh Typing - positive or negative
- Identification of allo-antibodies in patient’s plasma (if present)
- Selecting appropriate blood components
- Cross-match
What plasma can you transfuse to patients with the following blood types
- Group A
- Group B
- Group AB
- Group O
- Group A - A or AB
- Group B - B or AB
- Group AB - AB only (A, B, or O would have antibodies to A or B)
- Group O - universal receiver
Who are the universal RBC donors and universal plasma donors?
RBC - Type O
-> no antigens to react with anti A or anti B antibodies in plasma
O-neg given in emergencies
Plasma - Type AB
-> no antibodies to react with any blood type surface antigens
What are the symptoms of delayed hemolytic transfusion reaction? Treatment?
Worsening anemia after transfusion, bilirubin / jaundice, hemolysis evidence
renal failure / death are rare in this cause (extravascular, not as severe)
Treatment: supportive care
What is tranfusion associated acute lung injury (TRALI)? Treatment?
Siimilar to TACO, but noncardiogenic pulmonary edema and no cardiomegaly
- > due to donor antibodies against recipient neutrophils resulting in capillary leak
- > give supportive therapy and mechanical ventilation if needed
TACO (Transfusion associated circulatory overload) presents with CHF like symptoms and will have generalized edema
What process is done to prevent transfusion reactions in immunocompetent hosts? What type of tranfusion reaction is this normally?
Leukoreduction
-> filter out WBCs
Usually a febrile, non-hemolytic reaction due to Abs against donor leukocytes/platelets or cytokines present in donor plasma
Who is likely to have homozygous alpha+ trait vs alpha0 trait?
Homozygous alpha+ trait = two alpha genes knocked out, but on opposite chromosomes
-> trans, more common in Africans
alpha0 trait = two alpha genes knocked out on same chromosome, other chromosome is homozygous functional
-> cis, more common in Asians
What is thalassemia minor vs thalassemia major?
Bn / B+ or Bn / B0 = thalassemia minor
Any thalassemia without at least one Bn = thalassemia intermedia. Worst is B0/B0 = thalassemia major
What are the features of beta thalassemia anemia? What is seen on electrophoresis in minor / major?
Hypochromic, microcytic anemia with target cell formation
Minor: decreased HbA and mildly increased HbA2 (>4%) / HbF (>2%)
Major: little to no HbA (20%), almost all HbA2 (4+%) / HbF (70+%)
What happens when alpha chains accumulate in thalassemia major?
- Alpha chains are toxic to cell division and arrest hematopoiesis
- Alpha chains make RBC deformed for splenic removal
- RBC damage causes K+ flux
These factors all lead to intramedullary death and short RBC survival -> hemolytic anemia
What happens if beta thalassemia is left chronically untreated?
Splenomegaly due to work hypertrophy, bone changes (especially skull and facial bones) due to expanded hematopoesis (extramedullary), increased iron absorption from elevated EPO levels, growth failure, and cardiac dysfunction
What is the primary treatment of beta thalassemia major and what is the target?
Hypertransfusions of blood - target is 9 to 10 gm/dL
Improves growth, less organomegaly, fewer fractures, less facial deformity
What needs to be added to treatment regimens on patients with chronic blood transfusions as in beta thalassemia major? Name / describe them and their limitations
Iron chelators
Desferrioxamine - safest but cumbersome and painful - infused daily for 8-12 hours
Desferasirox and deferiprone - taken orally, have hepatic, renal and bone marrow side effects, but much easier
What is the difference between an intrinsic and an extrinsic hemolytic anemia?
Intrinsic - changes to RBC cause anemia, i.e. membrane changes, hemoglobin changes, enzyme changes
Extrinsic - Autoimmune, microangiopathic, and macroangiopathic (i.e. mechanical)
What are the clinical characteristics of Sickle cell trait? Is it common in the US?
Benign because HbA is made slightly more efficiently than HbS, and need >50% HbS for disease
- > hematuria, loss of urine concentration because hypertonicity of medulla causes sickling, causing microinfarctions & loss of ability to concentrate urine
- > problems with high altitude (hypoxia)
->10% carrier rate in US blacks
How does a vaso-occlusive crisis occur?
Whenever the sickled RBCs are stuck to the endothelial wall, they can rip off the endothelium as they are pulled away, exposing collagen and starting a clotting cascade
-> leads to thrombosis and further narrowing of vessel lumen
What symptom of sickle cell disease is often mistaken for osteomyelitis?
Dactylitis - swollen hands and feet due to vasoocclusive infarcts in bones
What is an inexpensive test to tell you if a patient may have sickle cell trait or disease?
Solubility test, uses a reagent to lyse RBCs and something to deoxygenate hemoglobin.
If a sample contains HbS, the solution will be turbid.
What is characteristic of the blood smear with hemoglobin C and what symptoms does it cause?
Hemoglobin C “c”rystals in RBCs, with target cells
Symptoms: mild extravascular hemolytic anemia with associated splenomegaly
Where is Hemoglobin E found and when is it a problem?
Found in patients in far east (Asia)
Trait - like beta thalassemia minor
Homozygous recessive - will cause mild hypochromia and microcytosis
E/B0 - transfusion dependent, like beta thalassemia major -> this heterozygous phenotype is bone bad.
What is the confirmatory test used to diagnose spherocytosis?
Eosin-maleimide (EMA) binding by flow. Spherocytosis will bind less EMA.
-> spherocytes have lower surface area to bind
What things precipitate hemolysis in G6PD deficiency? is this intravascular or extravascular?
Predominantly intravascular hemolysis, so will cause kidney damage (no splenomegaly)
Antimalarials (i.e. primaquine), slufa drugs, nitrofurantoin, Fava beans, naphthelene (mothballs, think mothball / basket cells), overwhelming infections
What causes Paroxysmal Nocturnal Hemoglobinuria?
Acquired defect in glycosylphosphatidylinositol (GPI) gene within myeloid stem cells
-> lack of GPI anchor prevents expression of decay-accelerating factor (CD55) and CD59, which are needed to inhibit C3 convertase and thus fixation of complement
What causes cold reactive AIHA? What type of antibodies are they?
IgM antibodies usually active at 2 to 4 degrees C in the lab, works more in cold temperatures of extremities
Antibodies (cold agglutinins) made in lymphoma, infectious mononucleosis, and Mycoplasma pneumoniae
What is Evan’s syndrome?
When autoimmune hemolytic anemia also associated with attacking platelets
-> causes mild thrombocytopenia not associated with bleeding
What is drug induced antibody hemolysis?
Very similar to warm agglutinin IgG-mediated disease, happens in one of two ways.
- Antibody is formed to drug-RBC membrane complex (i.e. penicillin)
- Antibody is formed to RBC membrane due to presence of drug, hemolytic anemia persists in absence of drug (i.e. a-methyldopa)
What are common causes of macroangiopathic anemia? What will be seen on blood smear?
Prosthetic heart valves, aortic stenosis, or arterial grafts
-> mechanical destruction of RBCs with Schistocytes on peripheral smear.
How is AIHA managed?
Keep hemoglobin at safe levels (>4 g/dL) with transfusions
High dose steroids - prevent Ab production
Alkalize urine to protect kidneys
Plasmapheresis - strain out Abs
Splenectomy
What mutations are associated with each of the four main Myeloproliferative neoplasms?
- Polycythemia Vera (PV) - JAK2 always
- Essential Thrombocytopenia (ET) - JAK2 50%
- Primary Myelofibrosis (MF) - JAK2 50%
- Chronic Myelogenous Leukemia (CML) - philadelphia chromosome
What are the rarer but classic symptoms of polycythemia vera?
- Intense pruritis (itching) following a shower due to increased mast cells (WBCs can also go up in this condition)
- Erythromelalgia - pain and red-blue discoloration in hands and feet
Including polycythemia vera, what, in general, can myeloproliferative disorders ultimately progress to?
Marrow fibrosis w/cytopenias, or acute leukemia
What are some causes of secondary polycythemia? One of these is a pseudopolycythemia.
- High EPO levels - i.e. malignancy
- Chronic hypoxemia in smokers
- Lung disease
- High altitudes
- Severe dehydration - reduced plasma volume makes a relatively increased hemoglobin
What are the treatments for ET? What can it progress to? What will peripheral smear show?
Aspirin (platelets) and hydroxyurea
Can progress to myelofibrosis and AML, much like all other myeloproliferative syndromes
Peripheral smear shows >10 platelets per hpf
What systemic symptoms are likely to develop in primary myelofibrosis and why?
- Massive hepatosplenomegaly due to extramedullary hematopoesis in liver and spleen since there’s no room in bone marrow to do this anymore
- Hypermetabolic state due to cytokines secreted by platelets, leading to fever, bone pain, and night sweats
- Anemia is also common
What does the peripheral blood smear show for PMF? Why?
Leukoerythroblastic smear - spleen is not built to hold all these hematopoesis so immature cells leak out
Includes “tear drop RBCs”, nucleated RBCs, and immature neutrophils
What are the phases of CML infection and when are most patients diagnosed?
Chronic phase - most patients diagnosed here by CBC when asymptomatic
Accelerated phase - increased output of mature myeloid cells, marked by enlargement of the spleen
Terminal blast crisis - right before it becomes an acute leukemia
What other malignancy displays the philadelphia chromosome and how can it be distinguished from CML?
De novo ALL (acute lymphoblastic leukemia not preceded by CML)
ALL has a 190kD fusion protein, whereas CML has a 210kD fusion protein
What are three ways that CML can be told from a normal leukemoid reaction (reactive neutrophilic leukocytosis)?
CML:
- Leukocyte alkaline phosphatase (LAP) negative. LAP+ = neutrophils made to fight infection, more well developed than CML
- Increased basophil count (absent in leukemoid)
- Philadelphia chromosome
What are myelodysplastic syndromes (MDS)? What can it progress to?
Heterogeneous disorders of myeloid stem cells with ineffective hematopoiesis (RBC production)
Can progress to AML
What is seen on peripheral blood smear of MDS in general?
Cytopenias - with variable reduction RBCs, platelets, and granulocytes, some with functional defects.
RBCs = normocytic or **macrocytic** WBCs = abnormal nuclear lobation and granules with impaired killing activity
How do patients with MDS diagnosis present?
Usually older adults with nonspecific symptoms due to cytopenias.
Anemia symptoms most common - macrocytic
Neutropenia causes infections
Thrombocytopenia causes bleeding
How do the RBCs appear in MDS?
Macrocytic and dysplastic
- multinucleated
- dyssynchrony between cytoplasm and nucleus
- ring sideroblasts could be present (failure to make RBCs properly)
How can you track how quickly MDS is progressing to AML? What are the two most common cytogenetic abnormalities of MDS?
WHO classifications of refractory anemia with excess blasts
RAEB-1 - 5-10% blasts - not very close
RAEB-2 - 10-20% blasts - getting very close
-> less blasts than this and you have some other type of MDS, i.e. Refractory anemia with ring sideroblasts, but must be less than 5%
5q deletion MDS which can be treated with lenalidomide, and 7q deletion
How are low, medium, and high risk patients with MDS treated?
Based on degree of cytopenias, %blasts in marrow, and cytogenetic abnormalities
Low - tranfusions and iron chelation
Medium - hypomethylating agents to stop methylation of tumor suppressors (slows progression)
High - bone marrow transplant
What is Fanconi anemia caused by? Symptoms?
Autosomal recessive mutation in DNA repair enzymes causing chromosomal breakages and bone marrow failure
Short stature, increased cancer incidence, cafe au lait spots, thumb /radial defects
What genetic abnormalities and benign hematologic disease can predispose to MDS?
Genetic - Down syndrome (also predisposes to AML), Fanconi anemia, Bloom syndrome, Ataxia-Telangectasia
Hematologic - Paroxysmal nocturnal hemoglobinuria, congenital neutropenia
Usually, however, this arises post-chemotherapy (alkylating agents, radiation), or benzene / tobacco carcinogens
What are the treatments for aplastic anemia, especially when autoimmune? How does it arise?
Immunosuppressive regimens: cyclosporine (blocks T cells), antithymocyte globulin
Bone marrow transplant
Transfusions and bone marrow stimulation via GM-CSF can also be tried
Usually arises idiopathically post-hepatitis, but can be post-viral, post-drug, or associated with Fanconi anemia / dyskeratosis congenita
-> overaction of lymphocytes following an adjuvating factor suppresses the bone marrow
How does inhibition of normal hematopoiesis explain the classic signs of acute leukemias?
Anemia -> fatigue, pallor
Thrombocytopenia -> bleeding (ecchymosis, epistaxis, menorrhagia, petechiae)
Neutropenia -> infections
Fever / bone pain from crowding out of bone marrow by blast cells
What leukemias are associated with Down syndrome and at what ages?
Before age 5: Acute megakaryoblastic anemia (type of AML)
After age 5: Acute lymphoblastic leukemia (ALL)
What are the monocyte markers for flow cytometry? What are the myeloid markers?
CD11 (integrin receptors for ICAM binding)
CD14 (TLR4)
-> note, these cells will also stain nonspecific esterase positive
Myeloid markers include: CD13 and CD33
What are the flow cytometry markers for B-cell ALL?
CD10
CD19
CD20
CD22
What genetic analysis is done on leukemic cells and why? Which AML has the worst prognosis? Best?
Whole genome molecular marker analysis
Worst: FLT-3+ (FMS-related tyrosine kinase)
Best: NPM1+, CEBPA+
NPM: Nucleophosphomin
What are the three AML’s which do NOT require >20% blasts in bone marrow to diagnose them as AML (this is unique)? What is wrong in the first two of them?
First two are related to dysfunction in core binding factors (CBF) which are essential for normal hematopoesis
- t(8;21) - RUNX1 - remember one less than 9;22
- inversion (16)
- t(15;17) - RAR dysfunction promyelocytic leukemia
(any number of blasts = AML)
How do you recognize APL and why is it important to recognize it early? What do RBCs look like in it?
Cells are distinctive because of many cytoplasmic granules and stacks of Auer rods (MPO+)
Recognize early because when cells are lysed, MPO activates coagulation cascade, causing a procoagulant state
DIC is a common presentation in these patients
RBCs - schistocytes due to microangiopathic cleavage
How do we treat fit patients with good risk in AML?
Good risk - any MDS exception, and FLT-3 negative
Induction - standard chemotherapy regimen of 7 days Ara-C + 3 days anthracycline
Consolidation with 3-4 cycles of high dose Ara-C
Fit patients with medium/high risk = might do some chemotherapy, but probably go right to bone marrow transplant
Non-fit (older) - supportive care, hypomethylating agents to slow progression of disease
What will PAS stain show for ALL? How does the nucleus of the lymphoblasts generally appear in ALL?
PAS - dot-like positive staining encircling nucleus
Nucleus has folds or grooves in them
What ALL is most commonly seen in children and has a good prognosis?
t(12;21) - B cell leukemia
How does treatment of ALL differ from AML?
Although the response to chemotherapy is excellent, ALL generally requires prophylaxis to the scrotum and CSF
-> cannot pass these blood barriers without direct injection of chemo (i.e. intrathecal)
In general, what patients have good prognosis vs high risk in AML?
Good risk:
t(8;21), inv16, t(15;17), (<20% leukemias) or normal cytogenetics with FLT-3 wild type
High risk: del(5) MDS progression, FTL-3 positive, multiple cytogenetic abnormalities
What disease are frequently treated by allogeneic transplantation?
- AML
- ALL
- MPD / MPN
- MDS
- Aplastic anemia
- Hemoglobinopathies
(only autologous would be multiple myeloma + HL / NHL)
What chromosome are the HLA antigens located on and what antigens do we need to match?
Chromosome 6
Need to match HLA-A,B,C, and HLA-DR
8/8 match is best
What is done in the conditioning phase of both allogeneic and autologous stem cell transplant?
Both - chemotherapy and radiation to reduce tumor burden
Allogeneic only - immunosuppress patient to allow engraftment
What is done in the recovery phase of stem cell transplant? What does recover coincide with?
Intense supportive care with platelets and transfusions
Reversible damage occurs to skin, liver, GI tract, and lung due to high dose chemotherapy. Infections are common due to disrupted mucosal barriers and immunosuppression
Recovery coincides with recovery of WBC count (~2 weeks after conditioning down to 0)
What are the common manifestations of GVHD in terms of which tissues are affected?
- Skin -> often maculopapular rash acutely, with dermal fibrosis chronically
- Liver -> often jaundice due to injured bile ducts
- GI Tract -> Mucosal surfaces like GI tract, eyes, and mouth can be damaged leading to N/V, eye dryness
Later - lymphoid organs -> destruction of thymus and LN
How is leukocytosis vs leukopenia defined?
Leukopenia - <5k / ul
Leukocytosis - >10k / ul
Lymphopenia - <1.5k / ul
Lymphocytosis - >4k / ul, 9k in children
A patient has lymphadenopathy AND lymphocytosis. What findings suggest the cause is more likely malignant than benign?
> 5 cm lymph node. (very large, anything over 1 cm is abnormal)
SEVERE anemia or thrombocytopenia (viral may be mild)
Older patient or constitutional symptoms
What are the general causes of generalized lymphadenopathy?
Infections
Non-infectious inflammatory processes (sarcoidosis, SLE, RA)
Malignant processes which have spread more
Miscellanous (drug reactions, hyperthyroidism, sinus histiocytosis with massive lymphadenopathy)
What are the benign chronic causes of lymphocytosis / lymphadenopathy (L/L)?
Brucellosis
Tuberculosis
Toxoplasmosis
Secondary and congenital syphilis
What are the four types of lymph node hyperplasia which can be detected by biopsy?
Follicular - stimulation of B cells
Paracortical - T cell hyperplasia
Sinus - expansion of sinus histiocytes (Rosai-Dorfman)
Angiofollicular hyperplasia - “onion skinning appearance”
-Castleman’s disease
What are the two types of Castleman’s disease? What is usually associated with second type, and their overall clinical course?
- Unicentric - localized angiofollicular hyperplasia - indolent, benign course
- > hyaline vascular type, onion peel mantle zone with lollipop appearance from penetrating sclerotis vessels - Multicentric - multicenter angiofollicular hyperplasia -HHV-8-associated, aggressive, lymphoma-like course
- > looks like sheets of plasma cells, treated like myeloma
- >IL-6 driven
What are the criteria for hypersplenism and its underlying pathophysiology?
- Splenomegaly
- Reduction of at least one cell line in the blood
- Normal bone marrow function
- > spleen is enlarging due to sequestering more WBCs/RBCs
- > may be an indication for splenectomy
What are the benign acute causes of lymphocytosis / lymphadenopathy (L/L)?
Bordetella Pertussis (think of the popcorn spilling in sketchy)
Infectious mononucleosis (reactive lymphocytosis in infectious process)
Infectious Hepatitis
Is MPN or MDS more likely to have splenomegaly and why?
Myeloproliferative neoplasms / disorders-> because you have an excess of elements in the blood due to too much proliferation, and they tend to accumulate in the spleen
Both conditions will have hypercellular marrow, but difference is in peripheral blood (Cytopenias in MDS, cytoses in MPNs)
What hemoglobin levels are P. vera diagnostic in men vs women?
Men: >18.5 g/dL
Women: >16.5 g/dL
What is refractory anemia with multilineage dysplasia?
A type of myelodysplastic syndrome causing more than just anemia (2+ cytopenias) but <5% blasts in bone marrow still
-> otherwise would be RAEB1 or RAEB2
What is the most common leukemia? Who gets it? What are the flow cytometry markers?
CLL - always older adults
Phenotype by flow cytometry:
CD19+,CD20+ (B-cell), CD5+ (T cell marker)
-> these are naive B cells which co-express B and T cell markers
Must be differentiated from mantle cell lymphoma
CLL: CD23+, FMC7-
MCL: CD23-, FMC7+
What are good and poor prognostic factors to have by FISH for CLL? By flow cytometry?
FISH:
Good: del13 - miRNA
Bad: del17 - p53
Flow cytometry, bad prognosticators:
High ZAP70
Positive CD38
What is the sister disease of CLL? How exactly are they related?
SLL = small lymphocytic lymphoma - involvement of lymph nodes leading to generalized lymphadenopathy. Absolute leukocyte count <5k
CLL = bone marrow and blood presentation, absolute lymphocyte count >5k
Both features present = phenotypically the same = treat the same
How is CLL staged?
Via the Rai Staging
0 - monoclonal lymphocytosis >5k
I - >5k + any lymphadenopathy
II - >5k +/- lymphadenopathy + hepatomegaly or splenomegaly
III - >5k + Anemia (<11 gm/dL) +/- lymphadenopathy or organomegaly
(progressed to AIHA)
IV - >5k + Thrombocytopenia (platelets <100K/ul) +/- lymphadenopathy or organomegaly
(progressed to Evan’s syndrome)
What are the distinctive clinical features of PLL?
Massive splenomegaly WITHOUT lymphadenopathy (except for T-cell PLL)
High lymphocyte count
More aggressive than CLL with poorer prognosis -> treat more aggressively
What will physical exam and CBC show with HCL? Why do these things happen?
Massive splenomegaly due to accumulation of hairy cells in red pulp
NO lymphadenopathy (similar to PLL)
Pancytopenia will be the rule
-> due to massive fibrosis of bone marrow
similar to myelofibrosis
What are the lab staining features of hairy cell leukemia? How do they look on peripheral smear? What is the mnemonic?
Mature B cells with hairy cytoplasmic processes (appear fuzzy on LM with indistinct borders)
Lab features - TRAP + (tartrate resistant acid phosphatase)
Remember these hairy cells are TRAPPED in the bone marrow (causing fibrosis) and TRAPPED in the red pulp causing splenomegaly
What will the CBC show for Large Granular Lymphocytic Leukemia (LGLL) and what does the peripheral smear show?
CBC shows cytopenias (neutropenia, anemia) with lymphocytosis
Peripheral smear shows GRANULES in lymphocytes (vs CLL) -> shows they are NK (CD56,CD57) or CD8 T cells
- > associated with rheumatoid arthritis
- > give no treatment, or G-CSF for neutropenia / steroids / MTX
How is PLL told apart from CLL?
PLL will be associated with massive splenomegaly while CLL is less so (still some). Also PLL usually has no lymphadenopathy while CLL usually does.
PLL is CD23- and FMC7+, CD5- (vs MCL)
CLL is CD23+ and FMC7-, and CD5+ (T cell marker)
How does the lymph node spread pattern differ between NHL and HL? Extranodal involvement?
Both are painless, non-tender lymphadenopathy
HL - usually contiguous lymph nodes and localized
NHL - usually skips lymph nodes (noncontiguous) with more extranodal involvement common
What are stages I-IV of the Ann Arbor staging system for lymphomas?
I - involvement of one group of LN
II - involvement of 2 or more groups of LN on same side of diaphragm (above or below)
III - 2 or more groups of LN on BOTH above and below diaphragm
IV - involvement of any organs or tissues outside of lymphatic system (extranodal sites), including bone marrow
What is the presentation of Adult T-cell leukemia/lymphoma?
Most common in Caribbean and Japan (endemic areas)
A diffuse erythematous rash due to skin infiltration, generalized lymphadenopathy with hepatosplenomegaly.
Lytic bone lesions, hypercalcemia
-> Easily confused with multiple myeloma, but note the presence of the rash
Bizarre clover-leaf nuclei of T-cells with CD4+ phenotype
What are the four types of classic HL? Which is most common?
- Nodular sclerosis - most common, especially females
- Lymphocyte-rich - best prognosis
- Mixed cellularity - high eosinophils due to RS cells producing IL-5
- Lymphocyte depleted - seen in immunocompromised, worst prognosis (elderly and HIV positive)
What is the treatment for HL?
Aggressive radiation in early stages, with ABVD regimen in all four stages
What are the CBC findings in HL?
Normocytic anemia
Leukocytosis
Lymphopenia (in advanced stage)
Platelets (increased early, decreased reactive)
Leukocytosis early because we have a reactive proliferation of plasma cells, lymphocytes, macrophages, and eosinophils
Elevated ESR due to cytokine production
What are the indolent (low grade) lymphomas?
Follicular lymphoma
Small lymphocytic lymphoma (sister of CLL)
Marginal zone lymphoma (MZL)
Waldenstrom’s macroglobulinemia
What are the three stages of follicular lymphoma?
Grade 1 - small cleaved cells
Grade 2 - mixture
Grade 3 - Large cells (getting closer to diffuse B cell lymphoma)
14;18 translocation
What is marginal zone lymphoma? What is the most common type?
Neoplastic proliferation of small B cells that expands the marginal zone (post-germinal center B cells)
Most common type is MALT (mucosal associated lymphoid tissue) lymphoma
-> primary splenic MZL exists, can cause massive splenomegaly without lymphadenopathy, despite being indolent
What are examples of intermediate aggressiveness lymphomas?
Diffuse large B cell lymphoma (DLBCL)
Mantle cell lymphoma - t(11;14)
What are the germinal center markers expressed by follicular lymphoma?
CD10 and Bcl-6
What is the most common NHL overall? What does it usually arise from?
Diffuse large B cell lymphoma - with poorly differentiated cells
Arises from follicular lymphoma progression, or Richter transformation of CLL
What causes mantle cell lymphoma? What chromosomal abnormality is associated?
Proliferation of small B cells that expands the mantle zone
Associated with t(11;14) - cyclin D1 from chromosome 11 is put at heavy chain locus
-> aggressive movement through growth cycle
What are the two forms of Burkitt lymphoma?
- Endemic form - Africa = jaw presentation in children
2. Sporadic - more loosely associated with EBV, lesion in pelvis (especially kidneys) or abdomen
What is the name of the disease causing Pautrier microabscesses, and what do the cells inside look like?
What is Sezary syndrome? Prognosis?
Mycosis fungoides
- > cells are called Sezary cells
- > CD4+ T cells with folded, cerebriform nucleoli
Sezary syndrome: Progression of mycosis fungoides to T cell leukemia -> sezary cells in blood.
Prognosis = indolent but incurable course
What T-cell lymphoma is not caused by HTLV-1 and causes a nodular rash rather than psoriasis-like? How do the cells look?
Anaplastic Large Cell Lymphoma (ALCL)
-> cells look anaplastic and bizarre, but prognosis is actually good
Cells have t(2;5), express CD30 but not CD15
What are the classic symptoms of symptomatic myeloma? Give why all these symptoms happen
CRAB
Calcemia - hypercalcemia due to plasma cells activating RANK on osteoclasts, increasing bone resorption
Renal impairment - Free light chain excreted in urine damages kidney tubules, renal failure
Anemia - normo-cytic or macrocytic - Rouleaux formation
Bone disease - lytic lesions due to increased bone resportion
What is smouldering myeloma vs symptomatic myeloma?
Symptomatic:
- Monoclonal protein in serum or urine
- > 10% plasma cells in bone marrow
- CRAB symptoms
Smouldering:
Asymptomatic - still >10% plasma cells and monoclonal protein, but no CRAB
<10% plasma cells = MGUS
How do plasma cells appear in MM? What markers do they express?
Deep blue cytoplasm with perinuclear halo where the Golgi is
Plasma cells nuclei are eccentric with clock-face chromatin
Express CD38 and CD138
What causes renal injury in MM?
- Bence Jones protein - kappa or lamda light chains deposit in renal tubules
- Amyloid deposition - in glomeruli and blood vessels
- Calcium deposition - nephrocalcinosis due to hypercalcemia
- Pyelonephritis - from inflammatory cells
- Uric acid crystal deposition (hyperuricemia from cell turnover)
What protein is produced by plasma cells and has prognostic value in MM? Give the staging scheme.
B2-microglobulin - a part of MHC1
<3.5 mg/L is favorable (Stage I), along with albumin >3.5 g/dL
Middle: Stage II
>5.5 mg/L is poor (Stage III)
What is the best new treatment for multiple myeloma, and what is the most common symptomatic treatment? What can you do if MM is located only at one site?
Only at one site - radiation may be effective
Common symptomatic treatment - bisphosphonates (for hypercalcemia and bone disease, stops osteoclasts)
Best new - Anti-CD38 (plasma cell marker) called Daratumumab
What condition sometimes follows multiple myeloma but is rarely a primary condition? What is the clinical definition?
Plasma Cell Leukemia (PCL)
>20% plasma cells in blood, with absolute plasma cell count >2k
Clinical features of pancytopenia with CRAB
What are the symptoms of Waldenstrom macroglobulinemia?
-> hepatosplenomegaly (absent in MM)
-> cytopenias
-> generalized lymphadenopathy
Hyperviscosity syndrome w/polyneuropathy
What are the clinical features of hyperviscosity syndrome?
All due to engorgement of small vessels with impaired platelet aggregation
Visual disturbances and retinal changes due to retinal hemorrhages / occlusion
Lethargy, confusion, weakness - stroke symptoms due to poor blood flow
Epistaxis - bleeding due to small vessels in nose and poor platelet function
CHF due to increased afterload
What are the two types of granules in platelets and what do they release?
Delta = Dense = Dark -> release 4 things: ATP, ADP, serotonin, Ca+2
Alpha granules - light colored, release all the rest
What type of bleeding occurs in disorders of primary hemostasis and why?
Primary hemostasis - blood vessel / platelet problem - bleeding from skin or mucous membranes (no initial plugs are formed), i.e. petechiae, ecchymoses and easy bruising
What is the platelet aggregation assay / how does it work?
Take platelet-rich plasma, measure the optical density with spectrophotometer
- > add an agonist
- > as platelets begin to clot, the optical density of the solution falls (reduced turbidity)
- > release of ADP by activated platelets also contributes
What agonists are used to detect defects in GPIIb/IIIa and fibrinogen via the platelet aggregation assay? What disease may see a defect in this?
ADP, epinephrine, collagen, and thromboxane A2
Glanzmann thrombasthenia may be detected (GPIIb/IIIa deficiency) -> glassman saying 2 be or not 2b
What machine has now supplanted the bleeding test, and what drugs extend the coagulation time with Epinephrine and with ADP as an agonist?
Platelet function analyzer-100
Collagen + epi: Prolonged by aspirin
Collagen + ADP: prolonged by clopidogrel
What are some common causes of prolonged aPTT?
- Heparin - inhibits Xa and IIa
- Fibrin or fibrinogen degradation products / increased consumption - DIC
- Antiphospholipid / anticardiolipin antibodies - Lupus anticoagulant
- Liver disease
causes of prolonged PT are the same except 1 = vitamin K deficiency (warfarin, fat malabsorption, newborn) and 3 is not present.
What is the TT and what does it measure? What are some causes of prolongation?
Thrombin Time
Thrombin-induced conversion of fibrinogen to fibrin, while bypassing all other factors
-> qualitative or quantitative defects in fibrin
-> thrombolytic therapy or heparin / thrombin inhibitor use
What vascular disease is also known as Osler-Weber-Rendu syndrome and what are its symptoms? Inheritance pattern?
Hereditary hemorrhagic telangiectasia - autosomal dominant
Dilated microvascular swellings (telangiectasias) which start in chidhood and increase in adulthood
- > recurrent bleeding of nose, skin, GI tract, and kidney
- > can lead to iron deficiency anemia and GI hemorrhage
What is Henoch-Schonlein syndrome and how is it acquired? Triad?
Most common childhood systemic vasculitis - follows acute URI
Triad: skin + GI + IgA nephropathy
Skin: palpable purpura on buttocks and lower legs
GI: abdominal pain
IgA nephropathy: hematuria and renal failure
Can also cause arthralgias
What is the TT and what does it measure? What are some causes of prolongation?
Thrombin Time
Thrombin-induced conversion of fibrinogen to fibrin, while bypassing all other factors
-> qualitative or quantitative defects in fibrin
-> thrombolytic therapy or heparin / thrombin inhibitor use
What vascular disease is also known as Osler-Weber-Rendu syndrome and what are its symptoms? Inheritance pattern?
Hereditary hemorrhagic telangiectasia - autosomal dominant
Dilated microvascular swellings (telangiectasias) which start in chidhood and increase in adulthood
- > recurrent bleeding of nose, skin, GI tract, and kidney
- > can lead to iron deficiency anemia and GI hemorrhage
What is Henoch-Schonlein syndrome and how is it acquired? Triad?
Most common childhood systemic vasculitis - follows acute URI
Triad: skin + GI + IgA nephropathy
Skin: palpable purpura on buttocks and lower legs
GI: abdominal pain
IgA nephropathy: hematuria and renal failure
Can also cause arthralgias
What are the pentad of symptoms seen in TTP?
- Fever
- Thrombocytopenia
- Microangiopathic hemolytic anemia (with schistocytes)
- Renal symptoms (worse in HUS)
- NEUROLOGIC symptoms - i.e. involving CNS vessels
treat with plasmapheresis + replacement of ADAMTS13 w/ donor plasma, but platelet replacement is contraindicated
What is the pathogenesis and treatment for ITP?
IgG antibodies are made to platelet receptors, and platelets are rapidly eaten by splenic macrophages
Treatment: Steroids, IVIG to distract macrophages, Rituximab to slow AB production, and splenectomy if refractory (removes site of removal)
How do you tell Bernard Soulier syndrome from von Willebrand disease?
Bernard-Soulier - bleeding tendency + thrombocytopenia + LARGE platelet size + no response to ristocetin
vWD - bleeding tendency + NO thrombocytopenia + NORMAL platelet size + no response to ristocetin
What are the pentad of symptoms seen in TTP?
- Fever
- Thrombocytopenia
- Microangiopathic hemolytic anemia (with schistocytes)
- Renal symptoms (worse in HUS)
- NEUROLOGIC symptoms - i.e. involving CNS vessels
treat with plasmapheresis + replacement of ADAMTS13 w/ donor plasma, but platelet replacement is contraindicated
What are the three broad types of von Willebrand disease?
Type 1 - All vWF multimer sizes present, but at low levels
Type 3 - All multimers absent
Type 2 - decrease in one particular multimer size
Autosomal dominant
How do you tell Bernard Soulier syndrome from von Willebrand disease?
BS: Mild thrombocytopenia + platelets appear large
What anomaly is associated with thrombocytopenia in Alport syndrome?
May-Hegglan anomaly
-> Autosomal dominant mutation in myosin heavy chain gene
Giant platelets, Dohle bodies in WBC, thrombocytopenia
Basically looks like BS + Dohle bodies
What are the three broad types of von Willebrand disease?
Type 1 - All vWF multimer sizes present, but at low levels
Type 3 - All multimers absent
Type 2 - decrease in one particular multimer size
Autosomal dominant
What is the definition of antiphospholipid syndrome and what is it commonly seen in? What two antibodies are normally seen?
Arterial or venous thrombosis or recurrent miscarriage in association with evidence of persistent antiphospholipid antibodies
- > commonly seen as lupus anticoagulant syndrome (anticardiolipin antibodies)
- > Two antibody types: anticardiolipin and anti-Beta2 glycoprotein
What is the classic presentation for an acute hypercoagulable state? How should you test them in the acute phase and why?
Classic presentation is recurrent DVTs or DVTs at a young age
Test them with DNA-based tests since the acute-phase response and anticoagulant therapy can affect test results
-> use schematic testing for inherited thrombophilia based on most common disorders
What is the second most common inherited hypercoagulability disorder in Caucasians and what causes it?
Prothrombin G->A Mutation
- > point mutation in 3’-UTR what causes overexpression of prothombin
- > increased prothrombin levels leads to hypercoagulability
Most common is Factor V Leiden, arginine to glutamate
What is the definition of antiphospholipid syndrome and what is it commonly seen in? What two antibodies are normally seen?
Arterial or venous thrombosis or recurrent miscarriage in association with evidence of persistent antiphospholipid antibodies
- > commonly seen as lupus anticoagulant syndrome (anticardiolipin antibodies)
- > Two antibody types: anticardiolipin and anti-Beta2 glycoprotein
How long should clopidogrel be held before surgery, and what are the adverse effects of concern?
At least 5 days as well (like aspirin)
GI distress and bleeding may occur (especially if history of NSAID-induced ulcers)
Thrombotic thrombocytopenic purpura may be associated
What are the advantages of Dabigatran over warfarin? Include standard time window for stopping dabigatran before surgery.
- No INR monitoring is required (aPTT values often not elevated)
- Significantly shorter onset / offset action (can stop 1-2 days before surgery)
- Reduced risk for intracranial bleeding (tissue factor - 7 complex needed to control intracranial bleeds)
What are the disadvantages of dabigatran vs warfarin?
- Renally cleared -> may need more time to clear from system in chronic renal failure (up to 5 days)
- No antidote except a monoclonal antibody
- More GI bleeding and dyspepsia (acidic)
- No reliable way to measure anticoagulation state in the ACUTE setting (i.e. MI, stroke, PE)
What are the contraindications of prasugrel?
Prior TIA or stroke
>75 years of age (elderly)
Underweight patients <60kg
What are two hypomethylating agents and what is their mechanism? Why does it take a while for them to work?
Azacitidine, Decitabine
Inhibit DNA methyltransferase by incorporating into the DNA and inhibiting enzymatic function. Takes a couple cycles of semiconservative replication before an entire strand becomes demethylated and the effect is seen.
Improves survival in myelodysplastic syndromes
-> when no other treatment is available, it slows progression of cancer
What side effects does bolus dose 5-FU cause vs continuous infusion dose?
Bolus dose - RNA effects more -> myelosuppression
Slow drip - DNA incorporation more -> hand-and-foot syndrome
-> pain, redness, numbness, and desquamation of palms bilaterally
“Schedule dependent toxicity”
What are the contraindications of prasugrel?
Prior TIA or stroke
>75 years of age (elderly)
Underweight patients <60kg
What is the most common side effect of anti-fibrinolytic agents and why?
Dyspepsia -> acidic nature of the drugs (aminocaproic acid and tranexamic acid) makes for local irritation of the GI tract
-> much like dabigatran
Patients with which deficiencies will present with prolonged aPTT but no history of bleeding?
Factor 12
Prekallikrein
HMWK
What are the prognostic factors for diffuse large B cell lymphoma?
Age, stage, performance status, LDH, number of extranodal sites
