Hematology-Oncology Review Session

1. Hematology-Oncology Review Session Pete Voorhees

2. Iron Deficiency Anemia • Symptoms of anemia (fatigue / weakness, SOB / DOE). • Ice pica and koilonychia are specific for iron deficiency! • Microcytic (low MCV), hypochromic (low MCHC) RBCs. • Other causes of microcytosis include thalassemias, sideroblastic anemias. • Ferritin is low, Serum Fe low, TIBC or transferrin normal or high, Fe saturation (serum Fe / TIBC) low. • Causes: chronic blood loss, malabsorption, decreased intake, pregnancy. • Treatment: Give iron, fix source of blood loss.

3. Vitamin B12 Deficiency • Symptoms of anemia. • Peripheral neuropathy (decreased proprioception, vibratory sense). • Macrocytic (high MCV) RBCs. • Other causes of macrocytic anemias include liver disease, folate deficiency, anemias ass. with a high retic. ct., hypothyroidism, HIV therapy (AZT), chemotherapy. • Hypersegmanted neutrophils. • Dx: low B12 levels. • Causes: pernicious anemia (Ab to IF), malabsorption (ileal resection), pancreatic insufficiency. • Treatment: replace B12.

4. Folate Deficiency • Same symptoms as B12 deficiency but no neuropathy. • Macrocytic RBCs and hypersegmanted neutrophils. • Dx: low folate or RBC folate level. • Causes: Decreased intake (alcoholic), malabsorption, increased utilization (depletion) of body stores (chronic hemolytic anemia) • Treatment: Replace folate.

5. Hereditary Spherocytosis • Symptoms of waxing / waning anemia, jaundice. • Hemolysis accelerated by infection. • Splenomegaly (hyperplasia secondary to increased workload), pigmented gallstones (h/o cholecystectomy), ankle ulcers. • Family history • AD. 1 : 5000 people of european descent affected.

6. Hereditary Spherocytosis • Blood smear: spherocytes, polychromatophilia (increased reticulocytes). • Labs: Increased retic. ct., increased LDH, increased indirect bilirubin, increased osmotic fragility. • Treatment: folate replacement, splenectomy in some circumstances). • Genetic defect: Spectrin, ankyrin mutations. • Pearl: Parvovirus B19 infection in patients with hemolytic anemis in general = aplastic crisis.

7. G6PD Deficiency • Episodic hemolytic anemia. • Triggered by oxidant stress: drugs, infection. • Occurs in males • X-linked, 10 – 14% of males of African descent carry an unstable A- variant of G6PD. • More severe, chronic form seen in men of Mediterranean descent. • Think fava beans in a Mediterranean pt.

8. G6PD Deficiency • G6PD is required to generate NADPH and ultimately reduced glutathione. • Glutathione required to prevent oxidative damage to hemoglobin. • Deficient glutathione leads to oxidized, methemoglobin which precipitates out as Heinz bodies. • Macrophages of the RES phagocytose bits of RBC membrane with underlying precipitated hemoglobin.

9. G6PD Deficiency • Smear: Bite cells and blister cells. • Diagnosis: Smear, G6PD level, heinz body prep. • G6PD levels may be normal in the acute setting due to selective removal of older RBCs with lower baseline G6PD levels. • Treatment: Get rid of offending oxidant stress (drug, infection). • Important drugs to know that may precipitate hemolysis in these folks: SULFA, anti-malarial drugs, dapsone, vitamin K, fava beans.

10. Warm Autoimmune Hemolytic Anemia • Symptoms of anemia, jaundice, splenomegaly. • Smear: spherocytes, polychromatophilia. • Labs: Increased retic. ct., high LDH, high indirect bilirubin, + direct Coomb’s test (direct antiglobulin test or DAT). • Indirect Coomb’s usually positive as well. • Treatment: immune-suppression (steroids, spenectomy), treat / remove underlying trigger.

11. Warm Autoimmune Hemolytic Anemia • Causes: Idiopathic, SLE, lymphoproliferative disorder (lymphoma, CLL). • Drugs • Innocent bystander: quinine, quinidine, INH • Hapten: PCNs, cephs • Autoimmune: alpha-methyldopa, procainamide

12. Cold Agglutinin Disease • Symptoms of anemia, acrocyanosis. • Smear, RBC agglutination, polychromatophilia. • Labs: Increased retic. ct., LDH, bilirubin, + Coomb’s test (C3 +. IgG -), + cold agglutinin titer. • Treatment: avoidance of cold, treat underlying disease, immune-suppression (chemotherapy). • Associated diseases: lymphoproliferative diseases (lymphoma, CLL) or after infectious mononucleosis or mycoplasma infection (“walking” pneumonia).

13. Hemophilia A and B • X-linked. • Factor VIII (Hemo A) > Factor IX (Hemo B) deficiency. • Manifests as soft tissue and joint bleeds, provoked and spontaneous as well as other bleeding (intracranial, GU). • Long-term complications: Joint destruction from repeated bleeds, pseudotumors. • Labs: Prolonged aPTT, normal PT, normal TCT, normal platelet function screen and bleeding time. • Treatment: recombinant Factor VIII or IX replacement, ddAVP for mild hemophilia A (leads to release of endothelial stores of FVIII).

14. Von Willebrand’s Disease • Autosomal dominant. • The most common inherited bleeding disorder. • Mucocutaneous bleeding (epistaxis, gum bleeding, GU/GI bleeding, menorrhagia). • Types 1 (mild deficiency) , 2 (qualitative abnormality), and 3 (severe deficiency). • Labs: Prolonged bleeding time / platelet function screen, slightly prolonged aPTT (due to low FVIII levels), low von Willebrand activity level, +/- low vWF antigen levels. • Treatment: Type 1: ddAVP. Type 2 and 3: vWF and FVIII-containing plasma product (Humate-P).

15. Venous Thrombosis • Causes • Acquired • Cancer • Myeloproliferative disorders (P. Vera, Essential thrombocytosis) • Antiphospholipid antibody syndrome • Hyperhomocysteinemia • Pregnancy • OCPs, HRT • Prior venous thrombosis • Age • Immobilization • Surgery

16. Venous Thrombosis • Inherited causes • Factor V Leiden mutation!!!! • Prothrombin gene mutation • Protein C def. • Protein S. def. • Antithrombin def. • Dysfibrinogenemias, elevated FVIII, IX, XI levels

17. Venous Thrombosis • Symptoms: pain / swelling in leg, chest pain, SOB (pulmonary embolism). • Diagnosis: • Duplex ultrasonography (doppler ultrasound) • IPG • Contrast venography • Magnetic resonance venography • D-dimer

18. Venous Thrombosis • Treatment • Heparin or low-molecular weight heparin • Potentiates anticoagulant effect of endogenous anti-thrombin. • Warfarin • Depletes vitamin K-dependent coagulation factors (II, VII, IX, and X). • Fibrinolytics (tPA) if patient clinically unstable with extensive clot burden. • Activates the fibrinolytic enzyme, plasmin.

19. Pseudothrombocytopenia • Lab artifact! • The patient will have no bleeding history. • Clumps of platelets will be seen on the fringes of the smear. • Due to presence of EDTA in tube. • Diagnosis: smear, re-check plt count in citrated or heparin-anticoagulated tube.

20. Disseminated Intravascular Coagulation • Diffuse, abnormal activation of coagulation, leading to consumption of clotting factors, and thrombocytopenia. • Clinically manifests as bleeding but the clinical picture is typically dominated by the disease that led to the DIC. • Prolonged PT, aPTT, TCT, and low platelets, low fibrinogen, low antithrombin, elevated D-dimer. • MAHA may be seen on the smear. • Causes: Severe infection, AML (esp. APL or M3 AML), obstetrical complications (eclampsia), severe burns. • Treatment: replacement (platelets, clotting factors with FFP, fibrinogen with cryoprecipitate), treat underlying disease.

21. Thrombotic Thrombocytopenic Purpura (TTP) • Abnormal activation of platelets and endothelium leading to fibrin deposition in the microvasculature and destruction of RBCs and consumption of platelets. • Pentad • MAHA • Thrombocytopenia • Fever • Renal failure • Neurologic deficits • Smear shows MAHA • Labs: PT, aPTT, TCT, fibrinogen, d-dimer are normal. • Cause: Primary (idiopathic) TTP due to autoantibodies to ADAMTS-13; secondary causes: pregnancy, drugs (mitomycin-C, quinine, ticlopidine, cyclosporine), HIV • Treatment • Plasma exchange

22. Hemolytic Uremic Syndrome • Similar to TTP but renal failure dominates the clinical picture. • The blood smear will look the same and the lab work will be the same. • More common in children after diarrheal illness (esp. E. Coli O157/H7 and shigella). • Treatment: Supportive care +/- plasma exchange (less effective here than in TTP).

23. Idiopathic Thrombocytopenic Purpura • The platelet equivalent of warm AIHA. • Symptoms: mucocutaneuos bleeding. • PE: petechiae. • Smear: absent / few platelets. • Causes: idiopathic, drugs (PCNs, sulfa (TMP-sulfamethoxazole, quinine), SLE, HIV, lymphoproliferative disorders. • Heparin causes an immune-mediated thrombocytopenia paradoxically associated with excessive clotting. • Treatment: Corticosteroids +/- IVIG, splenectomy for relapse, anti-D immune globulin, immunosuppressants.

24. Polycythemia Vera • Symptoms of increased viscosity: decreased mental acuity, blurred vision, tinnitus, headache, dizziness, paresthesias. • PV specific findings: post-bathing pruritus, erythromelalgia, thrombosis, hemorrhage, hypermetabolic symptoms. • PE: plethora, retinal vein distention, hepatosplenomegaly. • Labs: Increased WBCs, HCT, and platelets. Basophilia, high LAP score, high uric acid and vitamin B12, low erythropoietin level. • Treatment: phlebotomy, hydroxyurea, interferon-alpha, busulfan, P32. • Aspirin reduces the incidence of thrombosis.

25. Essential Thrombocytosis • Similar to P. Vera. Asymptomatic or excessive bleeding and / or clotting, splenomegaly. • Smear: large platelets. Labs: thrombocytosis, leukocytosis. Must r/o CML. • Treatment: age < 60, no clotting risk factors (smoking, HTN, etc.), plts < 1 – 1.5 million, no h/o clotting / bleeding – observation. Otherwise, hydroxyurea, anagrelide, or interferon-alpha. • ASA alleviates symptoms of microvascular occlusion (e.g.. erythromelalgia).

26. Idiopathic Myelofibrosis • Symptoms of hypermetabolism (weight loss, fevers, sweats), splenomegaly (abd. pain, early satiety), anemia, +/- thrombocytopenia. • Leukoerythroblastic blood smear • Tear drop shaped RBCs, nucleated RBCs. • Left-shifted WBCs. • WBC count normal or high at diagnosis but eventually drops, HCT usually low at diagnosis, plts may be up, down or low. • Dry tap on bone marrow aspirate. • Increased fibrosis on bone marrow biopsy. • P. Vera and ET can evolve into a “spent,” myelofibrotic stage. • Treatment largely supportive, bone marrow transplant has been tried in younger patients.

27. CML • Symptoms of hypermetabolism, splenomegaly, anemia. • Smear with increased numbers of WBCs (granulocytes of all stages of maturation). • Labs: Increased WBCs, +/- anemia, low LAP score, low vitamin B12 level. • Cytogenetics: t(9;22), BCR-ABL. • Treatment: Bone marrow transplant, Gleevec. • Monitoring disease: cytogenetics, FISH for t(9;22), PCR for BCR-ABL.