Heme Part 1 Flashcards
Reticulocytes
Slightly immature RBCs
Nl reticulocyte count
0.5-1.5%
Plasma cell
A type of B lymphocyte that is differentiated
Makes all the antibodies
What are the two main categories of blood disorders of hematopoietic stem cells?
Hematopoietic stem cells level More differentiated level -Myeloid -Lymphoid -Erythroid
Characteristics of aplastic anemia
Pancytopenia
Severely hypocellular bone marrow
Usually acquired- secondary
Causes of aplastic anemia
Toxic
Viral
Autoimmune mechanisms- dominant causes
Medication causes of aplastic anemia
NSAIDs
B-lactam antibiotics
Antiepileptic drugs
Psychotropic meds
Aplastic anemia tx
Immunosuppression (70%) -Cyclosporine -Antithymocyte globulin HSC transplantation -Allogenic HSCT is a potentially curative therapy and should be considered for those younger than 50 yrs who have compatible donors
Pure red cell aplasia
Isolated, severe anemia without an adequate reticulocyte response
Bone marrow shows an absence or erythrocyte precursors
Causes of pure red cell aplasia
Similar to aplastic anemia including parvovirus B19
Dx of pure red cell aplasia
Requires bone marrow examination to exclude secondary causes, such as lymphoproliferative disorders
Tx of pure red cell aplasia
Immunosuppression
Prednisone
Cyclosporine
Cyclophsophamide
Types of neutropenia
Isolated
Immune-mediated
Nutritional deficiencies
Isolated neutropenia
Hereditary, toxic or immune causes
Immune-mediated neutropenia
Connective tissue diseases
-SLE or RA
Treat with antirheumatic drugs
Nutritional disease neutropenia
Vit B12
Folate deficiency
Myelodisplastic syndromes-MDS
Bone marrow is most commonly hypercellular
Full bone marrow yields low blood counts because the cells are ineffectively formed and have limited survival
Peripheral counts are low because they’re staying in the bone marrow and not going in the periphery
Causes of myelodisplastic syndromes
Primary process- more common
Secondary process- radiation or chemo
Severity of myelodisplastic syndromes
Ranges from asymptomaatic with mild normocytic or macrocytic anemia to transfusion-dependent anemia heralding conversion to AML
When to suspect myelodysplastic syndromes
Suspect in pts with macrocytic anemia or pancytopenia in whom vit B12 or folate deficiency have been excluded
Tx of myelodisplastic syndromes
Transfusions or erythropoiesis-stimulating agents
Prevent transformation to AML
-If pt has complex cytogenetics and a marrow blast count of greater than 10% __________
-Allogenic HSCT or hypomethylating chemo
Myeloproliferative neoplasms
Acquired genetic defects in myeloid stem cells that have deregulated production of leukocytes, erythrocytes, or platelets
Types of myeloproliferative neoplasms
Chronic myeloid leukemia (CML) -Too many white cells Polycythemia vera (PV) -Too many red cells Essential thrombocytopenia (ET) -Too many platelets Primary myelofibrosis Eosinophilia and hypereosinophilic syndrome
Polycythemia vera
D/o of the myeloid/erthyroid stem cell -Mutation of JAK2 (JAK2 V617F)-97% present Hgb >18.5 g/dL in men Hgb >16.5 g/dL in women Must r/o secondary causes
Sx of secondary polycythemia vera- hypoxemia
Thrombosis, TIA
Erythromelalgia unlikely, pruritis unlikely
Conditions in which secondary polycythemia vera can happen
Sleep apnea
COPD
Congenital heart disease
Severe renal artery stenosis
PE of secondary polycythemia vera
Plethora
No splenomegaly
Lab studies of secondary polycythemia vera
No basophilia, no leukocytosis
JAK 2 negative
HIGH epo
Sx of polycythemia vera
Pruritis after a warm shower
Erythromelalgia
TIA
DVT/PE
PE of primary polycythemia vera
Splenomegaly
Plethora
Lab studies of primary polycythemia vera
Basophilia, leukocytosis, thrombocytosis
JAK 2 pos
LOW epo
Tx of polycythemia vera
Low-dose ASA
Phlebotomy
-Goal of Hct <45%
Hydroxyuria- antimetabolite chemotherapeutic agent
Prognosis of polycythemia vera
5-10% evolve into AML
Essential thrombocytopenia
Suspect when platelets >600,000 on 2 occasions at least 1 mo apart in the absence of secondary causes (IDA, infections, etc)
JAK 2 mutation is present in 50% of pts
Philadelphia chromosome must also be excluded
Sx of essential thrombocytopenia
Asymptomatic Digital ischemia Erythromelalgia TIA Visual disturbances Venous thromboembolism Bleeding
International prognostic score for essential thrombocytopenia
Low- age <60, no thrombosis, WBC <11,000
High- score of 3-4
Tx of essential thrombocytopenia
Low risk: low-dose ASA
High risk: platelet-lowering therapy
-Hydroxyurea
-Anagrelide: may exacerbate heart failure
-Interferon alpha: only agent safe in pregnancy
Plateletpheresis- temporary decrease
-Can be done in the hospital
Primary myelofibrosis
Abnl, proliferating megakaryoctyes that produce excess fibroblast growth factor
No dominant blood count
JAK2 present in 50%
Extramedullary hematopoiesis
-Blood production in sites that don’t usually make blood
–LNs, bone marrow, spleen, liver: places that usually make blood
Sx of primary myelofibrosis
Asymptomatic
Cytokine-mediated sx
-Fever, chills, night sweats, malaise
Early satiety, weight loss, abd discomfort
Tx of primary myelofibrosis
Hydroxyurea
Ruxolitinib- first JAK2 inhibitor
Allogenic hematopoietic stem cell transplantation
Eosinophilia and hypereosinophilic syndromes
Eosinophilia >1500/microL and tissue infiltrates
Causes of eosinophilia and hypereosinophilic syndromes
Collagen vascular dz Helminthic infections Idiopathic Neoplasia (lymphomas MC) Allergy, atopy, asthma (carbamazepine, sulfonamides)
Tx of eosinophilia and hypereosinophilic syndromes
Glucocorticoids (lytic effect)
Imatinib
G-CSF
Stands for granulocytic colony stimulating factor
Used to stimulate production of neutrophils in autoimmune neutropenia, to hasten neutrophil recovery after cytotoxic chemo, and for HSC mobilization
Recombinant erythropoietin
Indicated for chemo-associated anemia and CKD anemia
Target hemoglobin level of no more than 11 g/dL
Allogenic HSCT
HLA-matched sibling or matched unrelated donor
Chemo-less intense
Immunosuppression
Peripheral blood infusion of HSc
Donor immune cells recognize the pt’s cancer cells as foreign and mount T-cell/NK-cell mediated attack
What is an HSCT most helpful in treating?
Aplastic anemia
High-risk MDS
Acute leukemias
What are the risks of an HSCT?
Opportunistic infection -Aspergillus -Different viral and fungal infections Graft-versus-host dz (GVHD) -Severe treated with glucocorticoids
Plasma cell dyscrasias
Clonal plasma or lymphoplasmacytic cell disorders characterized by the production of monoclonal antibody (M protein) detectable in serum or urine
Plasma cell disorders
Monoclonal gammopathy of undetermined significance (MGUS)
-Not full-blown multiple myeloma
Multiple myeloma
B-cell disorders
Waldenstrom macroglobulinemia
Chronic lymphocytic leukemia/small lymphocytic lymphoma
Lab diagnostics of multiple myeloma and related disorders
CMP (calcium, creatinine, albumin) CBC SPEP/UPEP Serum or urine immunofixation Serum FLC (free light chain testing)
Definition of monoclonal gammopathy of undetermined significance (MGUS)
M protein level < 3 g/dL
Clonal plasma cells comprising less than 10% of the bone marrow cellularity
Absence of PCD-related signs and sx
F/u of monoclonal gammopathy of undetermined significance
Reevaluate yearly with: CBC Serum calcium Creatinine Repeat M protein testing 1% risk of transformation into multiple myeloma yearly (or other conditions)
Multiple myeloma
Plasma cell malignancy involving the bone marrow
Asymptomatic multiple myeloma
Smoldering disease
M protein >3 g/dL or >10% bone marrow plasma cells
Symptomatic multiple myeloma
End-organ damage Fatigue Anemia Rouleaux formation Leukopenia Osteopenia Kidney dysfunction
CRAB criteria for myeloma-related s/sx
HyperCalcemia: >11 mg/dL
Renal failure: serum Crt >2 mg/dL
Anemia: Hgb <10 g/dL
Bone disease: lytic bone lesion
Additional diagnostic for multiple myeloma
Skeletal survey -X-ray -CT -MRI Bx -Bone marrow - +/- kidney biopsy
Tx for multiple myeloma
Induction chemo
Autologous hematopoietic stem cell transplantation
Surgical stabilization for pathologic fxs
Surgical stabilization for pathologic fxs
Pamidronate or zoledronic acid once very 3-4 wks for a minimum of 2 yrs in new pts with symptomatic myeloma
Hypercalcemia tx
Vaccinations- influenza, pneumococcal
Anemia
Decreased circulating RBC mass or hemoglobin
Results from blood loss or underproduction or destruction of erythrocytes
Anemia is not a dx but a sign of an underlying condition
General anemia s/sx
Fatigue
Dizziness
SOB
Palpitations
Microcytic anemia
MCV <80
Iron deficiency
Thalassemia
Normocytic anemia
Anemia of kidney dz
Inflammatory anemia
Hereditary spherocytosis
Sickle cell dz
Marcrocytic anemia
MCV >100 Vit B12 or folate deficiency Liver dz Hypothyroidism Myelodysplastic syndrome Autoimmune hemolytic anemia
Iron deficiency anemia
Iron is absorbed in the duodenum
The most common nutritional deficiency worldwide
Causes of iron deficiency anemia
Loss of iron- bleeding
Decrease uptake- decrease absorption
Increase requirements- pregnancy
Ferritin in iron deficiency anemia
Low with iron deficiency anemia
May be in the nl range when associated with inflammatory conditions (RA, malignancy)
Reticulocytes in iron deficiency anemia
Reflects bone marrow response to anemia
Tx of iron deficiency anemia
Treat underlying cause
Replace iron
-Oral supplementation takes mos to correct, GI SEs
-IV infusion: good if malabsorption issues
-Erythrocyte transfusion: only if profoundly anemic and symptomatic
Oral replacement for iron deficiency anemia
Ferrous sulfate: 65 mg per 325 mg tablet
Ferrous gluconate: 36 mg per 300 mg tablet
Ferrous fumarate: 33 mg per 100 mg tablet
IV replacement for iron deficiency anemia
Ferric gluconate: 12.5 mg/mL
Iron dextran: 50 mg/mL
Iron sucrose: 20 mg/mL
Ferumoxytol: 30 mg/mL
Inflammatory anemia
AKA: anemia of chronic dz Common in hospitalized pts Infection, cancer, autoimmune diseases -Chronic heart failure, DM Usually mild Often normocytic with a low TIBC
Anemia of kidney disease
Very common with CKD
-Affects 90% of pts with GFR <30
Components of anemia of kidney dz
Decreased epo
Decreased lifespan of RBC
Blood marrow suppression (from uremic toxins) and blood destruction during hemodialysis
Usually normochromic and normocytic with low retic count
Vitamin B12 deficiency
Cofactor needed by 2 enzymes in human cells
Deficiency causes increased methylmalonic acid and homocysteine levels and affects myelopoiesis
What does vit B12 deficiency result in?
Macrocytic anemia
Demyelinating nervous system disease
Risk factors for vit B12 deficiency
Vegetarians Absorption issues -IBD -Gastric -Bariatric or ileal surgery Pernicious anemia -MCC of severe deficiency -Destruction of gastric parietal cells- makes intrinsic factor Increased with autoimmune conditions -Thyroid dz -DM -Vitiligo
S/sx of vitamin B12 deficiency
Anemia Neurologic dysfunction Glossitis Hyperpigmentation Infertility
Neurologic dysfunction in vit B12 deficiency
Symmetric paresthesias Numbness Decreased vibratory sense Gait problems Neuropsychiatric sx
Peripheral blood smear for vit B12 deficiency
Large oval erythrocytes
Hypersegmented neutrophils
Possible pancytopenia
Other tests for vit B12 deficiency
Cobalamin level
Methylmalonic acid
Homocysteine level
Tx of vit B12 deficiency
Oral replacement
-1000 to 2000 micrograms/d
Cobalamin injections
-IM or SC
-1,000 micrograms several times per week for 1-2 wks, then weekly until symptom relief or improved findings
-Monthly injections thereafter if pernicious anemia
-Usually corrects in 6-8 wks
Folate deficiency
Megaloblastic anemia with impaired DNA synthesis
Causes of folate deficiency
Poor intake Alcoholics Malabsorption Meds that accelerate folate metabolism -Phenytoin -Trimethoprim -Methotrexate
Lab findings of folate deficiency
Similar to cobalamin deficiency, except methylmalonic acid levels will NOT be elevated
Tx of folate deficiency
Oral folate 1-5 mg/d
Categories of hemolytic anemias
Inherited or acquired
Intravascular or extravascular
Findings in hemolytic anemias
Compensatory reticulocytosis (usually)
Elevated indirect bilirubin and LDH
Free hemoglobin secretion (hemoglobinuria)
Sx of hemolytic anemias
Anemia Jaundice Dark urine Cholelithiasis- chronic hemolysis Extramedullary hematopoiesis \_\_\_\_\_\_\_\_\_\_\_ LAD
Hereditary spherocytosis
Mostly autosomal dominant (75%)
Osmotically fragile spherocytes
Splenomegaly
Lab testing for hereditary spherocytosis
Osmotic fragility testing
Cryohemolysis, eosin-5-malemide binding
Tx for hereditary spherocytosis
Folic acid supplementation
Splenectomy with vaccinations prior strep pneumo, hib, and meningococcal
G6PD deficiency
X-linked disorder
Most common enzyme deficiency in humans
Hemolysis triggers for G6PD deficiency
Sulfonamides, nitrofurantoin
Antimalarials
Infection
Lab findings in G6PD deficiency
Bite cells Heinz bodies -Denatured oxidized hemoglobin Fluorescent spot screening test Quantitative testing
Tx of G6PD deficiency
Avoid offending agents
Supportive +/- blood transfusions
Thalassemia
Mutation in either the alpha or beta globin
At least 1-5% of the world has a mutation
Most commonly in Mediterranean, Middle East, southeast Asia
Lab findings in thassemia
Microcytic
Nl iron studies
Target cells
Electrophoresis
Tx of thalassemia
Trait- education
Oral folic acid 1 mg/d
Hemoglobin H dz (deletion of 3 alpha genes)
-Occasional blood transfusions
–Higher risk of iron overload
Allogenic hematopoietic stem cell transplantation can be curative and should be considered with severe forms before the onset of end-organ damage
Sickle cell syndromes
Hemoglobinopathy with mutation in the B-globin chain
Pathophysiology of sickle cell syndromes
Oxidative stress Adhesion of cells to the endothelium Inflammation Decreased nitric oxide Vasoconstriction
Complications of thalassemia
Chronic hemolytic anemia
Infections- parvovirus B19, vaccines
Vit deficiencies- folate
ACS, PE, ischemic stroke, pulm HTN, CKD, hepatic crisis
Tx of thalassemia
HSCT
Prophylactic transfusions
Hydroxyurea therapy- reduces vaso-occlusive episodes
Chronic pain
Primary hemochromatosis
Autosomal recessive defect
Affects 1 in 400 persons of N. European ancestry
S/sx of primary hemochromatosis
Chronic fatigue Weakness Nonspecific abd pain Athralgia Mildly elevated liver enzymes \+/- hypothyroidism DM Gonadal failure Eventual hepatic fibrosis and chirrhosis (HCC)
Lab findings in primary hemochromatosis
Fasting serum transferrin saturation
- > 60% in men, >50% in women
- Elevated ferritin
Tx of primary hemochromatosis
Phlebotomy- 1 unit weekly until ferritin levels decrease to 10-50 ng/mL
Iron chelation if phlebotomy is contraindicated
Platelet physiology
Made in the bone marrow from megakaryocytes
Lifespan is around 10 days
Nl range: 150K-450K/microL
Hormonal stimulus is thrombopoietin
Form the initial plug at the site of vascular injury
-Adhesion, aggregation, secretion
Activated glycoprotein IIb-IIIa allows the fibrinogen binding
Thrombocytopenia sx
Mucocutaneous bleeding- epistaxis, gum bleeding, heavy menses, easy bruising, petechiae
Seldom seen if platelet count >30K
Hx in thrombocytopenia
Medications TTP, HUS ITP, HIT Use hematology: purple top Sodium citrate anticoagulant
Meds associated with drug-induced thrombocytopenia
Anticonvulsants Anti-inflammatory agents Antimicrobials CV drugs Chemotherapeutic agents Glycoprotein IIb/IIIa inhibitors Haloperidol Ranitidine Simvastatin
What are the three causes of thrombocytopenia?
Disorders of underproduction
Peripheral destruction
Splenic sequestration
Disorders of underproduction in thrombocytopenia
Marrow failure- aplastic anemia, B12/folate deficiency
Marrow invasion- leukemias
Marrow injury- drugs (EtOH, chemo), radiation
Peripheral destruction in thrombocytopenia
Immune or non-immune mechanisms
Non-immuned mediated thrombocytopenia
Thrombotic Thrombocytopenia Purpura (TTP)
Hemolytic Uremic Syndrome (HUS)
Immune-mediated (platelet antibodies) thrombocytopenia
Immune Thrombocytopenia Purpura (ITP)
Heparin-Induced Thrombocytopenia (HIT)
TTP
Congenical or acquired deficiency of protease ADAMTS-13
Abnl activation of platelets and endothelial cells, deposition of fibrin in microvasculature, and peripheral destruction of RBC and platelets
Clinical pentad of TTP
Thrombocytopenia Anemia- Microangiopathic Hemolytic Anemia (MAHA) Fever Kidney disease Neurologic findings Abd pain
Additional laboratory findings of TTP
Elevated bilirubin and LDH
Schistocytes
Tx of TTP
Emergent plasma exchange
Platelet transfusions are contraindicated
HUS
Frequently overlaps with TTP
Occurs more frequently in children
-Has MORE kidney and fewer neurologic manifestations
Can be precipitated by infectious diarrheal illnesses
-E. coli 0157:H7
Tx for HUS
Plasma exchange
ITP
Suspect with isolated new-onset thrombocytopenia
Causes of ITP
Autoimmune conditions
Leukemia/lymphoma
Viral illnesses (Hep C, HIV)
Pregnancy
What to r/o in ITP
Splenomegaly and thyroid dz
ANY new meds, supplements
Tx of ITP
Reserve for platelet counts <30K or if the pt is bleeding
Glucocorticoids
-Prednisone 1 mg/kg then taper over weeks
-Dexamethasone 40 mg/d x 4 days
IVIG
Splenectomy
Off-label rituximab
HIT
Drug-induced with antibody against the heparin/PF4 complex that can activate platelets causing thrombocytopenia +/- thrombosis
Platelet counts decrease by at least 50% 5-10 days after tx with heparin
Lab testing for HIT
Serology for anti-heparin/PF4 antibodies
Tx of HIT
STOP heparin
Begin Argatroban therapy
Baseline doppler u/s of all 4 extremities
Do not start warfarin therapy until platelet 100-150K
Pt education regarding heparin
Acquired platelet dysfunction
Suspect in pts with clinical bleeding whose platelet count, PT, and aPTT are nl
Abnl bleeding time or platelet function analyzer- 100 result
Some disorders respond to desmopressin, whereas others require transfusions
Causes of acquired platelet dysfunction
Uremia Liver dz Myeloproliferative neoplasms Post-cardiac bypass Antiplatelet drugs -IIb-IIIa inhibitors -ASA -Clopidogrel -NSAIDs: temporary
