Hematology: Challenging Cases with Your Participation COPYRIGHT

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1 Hematology: Challenging Cases with Your Participation Reed E. Drews, MD Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA

2 Question 1

3 Question 1 64-year-old man is evaluated during routine exam He takes aspirin and acetaminophen for osteoarthritis On exam, pallor is absent. BP = 116/72 with no orthostatic changes; P = 68.

4 Labs Hgb = 9.7 g/dl WBC = 5.8 K/μL MCV = 83 fl Plts = 265 K/μL Retic count = 0.5% LDH = 80 U/L Iron = 40 μg/dl TIBC = 200 μg/dl Ferritin = 210 ng/ml Peripheral smear is normal

5 Which of the following is the most likely diagnosis? A. Inflammatory anemia B. Hemoglobin C disease C. Iron deficiency D. Thalassemia

6 Answer = A

7 Anemia of Inflammation (AI) Characterized by low serum iron concentration and low TIBC with elevated serum ferritin concentration Initially normochromic, normocytic, can become hypochromic, microcytic Inflammatory cytokines block iron utilization, erythropoietin (EPO) production, and EPO responsiveness Hepcidin, made by the liver, decreases iron absorption from gut and decreases release of iron from macrophages Causes internalization of ferroportin ion channel

8 Hemoglobin C Disease Mild hemolytic anemia in persons of African ancestry Serum iron chemistries are typically normal Prominent targeting in addition to microcytosis on peripheral blood smear

9 Hgb CC

10 Iron Deficiency Anemia (IDA) Characterized by low serum iron concentration, elevated TIBC, and decreased serum ferritin

11 IDA

12 Thalassemia Hypochromic, microcytic anemia Evidence of hemolysis Targets, tear drops, and prominent basophilic stippling

13 Factors Distinguishing the 3 Most Common Causes of Microcytosis Iron deficiency anemia (IDA) Low serum ferritin Increased total iron binding capacity Low serum iron concentration Anemia of inflammation (AI) Low serum iron Low total iron binding capacity Normal to increased serum ferritin Alpha or beta thalassemia minor Patients may not be anemic Target cells, tear-drop forms, and basophilic stippling IDA b-thalassemia minor

14 Laboratory Characteristics of AI, IDA, and IDA + Inflammation From MKSAP 15 Parameter AI IDA IDA+AI MCV fl <85 fl <100 fl MCHC <36 g/dl <32 g/dl <32 g/dl Serum iron <60 μg/dl <60 μg/dl <60 μg/dl TIBC <250 μg/dl >400 μg/dl <400 μg/dl TIBC saturation 2%-20% <15% (usually <10%) <15% Ferritin >35 ng/ml < 15 ng/ml <100 ng/ml Bone marrow iron Present Absent Absent

15 Iron Deficiency Happens in Stages Iron deficiency without anemia Ferritin < 20 ng/ml; Fe/TIBC > 15% Iron deficiency with mild anemia Ferritin < 15 ng/ml; Fe/TIBC < 15% Severe iron deficiency with severe anemia Ferritin < 10 ng/ml; Fe/TIBC < 10% Bone marrow iron absent in all stages

16 Ferritin Levels in IDA Virtually all patients with serum ferritin levels <10 to 15 ng/ml are iron deficient Sensitivity 59%, specificity 99% 25% of women with absent stainable bone marrow iron have ferritin levels >15 ng/ml Assuming no inflammation, higher ferritin cutoff limits provide improved diagnostic efficiency 30 ng/ml: sensitivity 92%, specificity 98% 41 ng/ml: sensitivity 98%, specificity 98%

17 Anemia of Inflammation Inflammation decreases serum iron and plasma transferrin concentrations Transferrin saturations are in iron deficiency range in 20% of patients with anemia of inflammation 20 to 30% of patients with inflammatory anemia do not have underlying inflammatory condition Guyatt GH et al. Am J Med 1990;88:205.

18 Ferritin Levels in Iron Deficiency AND Inflammatory States Inflammation increases ferritin levels by about 3-fold Iron deficiency should be suspected in patients with inflammatory states and ferritin levels <100 ng/ml In anemic patients with rheumatoid arthritis, ferritin levels < 60 ng/ml predicted response to oral iron therapy with 83% accuracy (Hansen TM, Hansen NE. Ann Rheum Dis 1986;45:596)

19 Question 2

20 Question 2 27-year-old woman undergoes follow-up evaluation 5 months after diagnosis of unprovoked PE for which she was prescribed a 6-month course of anticoagulant therapy Family history Maternal grandmother took warfarin for many years for unknown reason Older brother with DVT at age 32 years Meds: no contraceptives or other medications Labs: CBC normal; INR = 3.0

21 Which of the following is the most appropriate next step in the evaluation of this patient? A. Immediate thrombophilic screening B. JAK2 mutation analysis C. No further evaluation needed D. Thrombophilic screening at least 2 weeks after therapy cessation

22 Answer = D

23 Thrombophilia Unprovoked PE + family history of VTE = high likelihood of underlying thrombophilic condition Screening decisions Strongly thrombophilic 1 st unprovoked VTE before 50 yrs of age; or History of recurrent thromboses; or 1 st -degree relative(s) with documented VTE before age 50 yrs Weakly thrombophilic All others Do NOT screen during acute episode or during anticoagulant therapy when heparin or warfarin influence certain tests Risk of recurrent VTE cannot be estimated without screening for inherited thrombophilia

24 Thrombophilic Disorders with High Risk for Recurrence Antithrombin, protein C or protein S deficiency Homozygous factor V Leiden (FVL) or prothrombin gene mutation (PTM) Compound heterozygous FVL + PTM Patients with these disorders are candidates for long-term, if not lifelong, anticoagulation therapy

25 Thrombophilia due to Myeloproliferative Neoplasm PV and ET predispose to venous and arterial thromboses, particularly when RBC mass and platelet count are not controlled JAK2 mutation is found in nearly all pts with PV and ~50% of pts with ET Routine screening for this mutation is not recommended unless pts have Budd-Chiari syndrome of portal vein thrombosis

26 Target INR Target INR of 1.5 to 2 has efficacy in preventing recurrent VTE However, target INR of 2 to 3 is more efficacious Risk for major bleeding is similar for the two target INR ranges (1) Ridker PM et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348: (2) Kearon C et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 349:631-9.

27 Major Risk Factors for Thrombosis: Acquired From MKSAP 15 Prior thrombosis Advancing age Obesity Immobilization Major surgery Estrogens (OCPs, HRT, SERMs) Malignancy Prolonged air travel Antiphospholipid antibody syndrome MPNs (PV, ET) PNH Hemoglobinuria HIT Inflammatory bowel disease Nephrotic syndrome

28 Major Risk Factors for Thrombosis: Inherited From MKSAP 15 Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden (FVL) Prothrombin G20210A Dysfibrinogenemias (rare)

29 Uncertain Risk Factors for Venous Thrombosis From MKSAP 15 Hyperhomocysteinemia High levels of factor VIII APC-resistance in the absence of FVL High levels of factor IX High levels of factor XI High levels of TAFI Low levels of free TFPI Decreased fibrinolytic potential TAFI = thrombin-activatable fibrinolysis inhibitor; TFPI = tissue factor pathway inhibitor.

30 Risks and Incidence of a First Episode of Venous Thrombosis (From The Leiden Thrombophilia Study) Relative Risk Incidence/y (%) Normal Prothrombin G20210A mutation Oral contraceptives Factor V Leiden heterozygote Oral contraceptives + factor V Leiden Factor V Leiden homozygous to 1.0

31 Site of Thrombosis According to Coagulation Defect Abnormality Arterial Venous Factor V Leiden - + Antithrombin III deficiency - + Protein C deficiency - + Protein S deficiency - + Prothrombin gene mutation - + Hyperhomocysteinemia + - Lupus anticoagulant/apl + + APL = antiphospholipid antibody syndrome.

32 Testing for Risk Factors In all patients Cancer screening 20% of all patients with symptomatic VTE have cancer Unprovoked venous thrombosis and/or unexplained arterial thrombosis Antiphospholipid antibody syndrome (venous and/or arterial) Hyperhomocysteinemia (arterial) In patients younger than 50 years AT, protein C, protein S Less than 5% over 50 In patients older than 50 years FVL, prothrombin G20210A 26% of men over 60 in the Physicians Health Study

33 Indefinite Anticoagulation in Patients at High Risk 2 or more spontaneous events 1 spontaneous life-threatening event Near fatal pulmonary embolus Cerebral, mesenteric, or portal vein thrombosis 1 spontaneous event in association with Antiphospholipid antibody syndrome Antithrombin deficiency More than 1 genetic or allelic abnormality

34 T H G I R Question Y P O C 3

35 Question 3 A 68-year old woman has hypertension for which she takes HCTZ and low-dose aspirin daily. On routine blood testing, she is found to have a high total protein. On exam, she appears well without lymphadenopathy, hepatosplenomegaly or bony pain to palpation or percussion. Hgb = 12.9 g/dl; WBC = 6.2K/μL; platelets = 245K/μL. SPEP shows 1.2 g/dl monoclonal IgG-kappa. UPEP is negative for protein, including Bence Jones protein.

36 Question 3 (continued) Bone marrow biopsy shows 7% plasma cells, and skeletal survey is normal, without lytic lesions. Which is the most appropriate management for this patient? 1. Obtain a bone scan 2. Begin bisphosphonate therapy 3. Begin thalidomide + dexamethasone 4. Monitor expectantly and repeat the SPEP and UPEP in 3 to 6 months

37 Answer = 4

38 Monoclonal gammopathy of undetermined significance No symptoms No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder No lymphadenopathy, organomegaly, hypercalcemia, renal failure, anemia, bone abnormalities (skeletal survey)* Relatively low paraprotein level (<3 g/dl) < 10% plasmacytosis in bone marrow Phenomenon of aging *No role for bone scans or PET scans

39 Prevalence of MGUS According to Age Group and Sex among Residents of Olmsted County, Minnesota Age Men Women Total percent yr yr yr yr Total Kyle RA et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006; 354:

40 Management of MGUS No role for anti-plasma cell therapy Monitor expectantly Monitor for signs and symptoms of progression to multiple myeloma Follow CBCs, BUN/cre, albumin/calcium, SPEP, UPEP, and free serum kappa & lambda light chains Assess risk for progression Lowest with paraprotein levels 0.9 g/dl Highest with paraprotein levels 3 g/dl Serum free light chain assay (FLC) Ratio of serum free kappa to serum free lambda

41 Risk of progression to myeloma or related disorder in 1148 pts with MGUS Rajkumar SV et al. Blood 2005; 106:812-7

42 Risk of progression of MGUS in patients with abnormal FLC ratio Rajkumar SV et al. Blood 2005; 106:812-7

43 Diagnostic criteria for myeloma Myeloma Serum or urinary monoclonal protein Clonal plasma cell in bone marrow or plasmacytoma End organ damage related to plasma cell dyscrasia Aymptomatic (smoldering) myeloma Serum monoclonal protein 3 g/dl and/or bone marrow plasma cells 10 percent No end organ damage related to plasma cell dyscrasia

44 Treatment of Myeloma Alkylating agent and corticosteroid Melphalan mainstay of myeloma therapy for more than 40 years Now use cyclophosphamide + bortezomib +/- lenalidomide +/- dexamethasone Thalidomide Fetal malformations; VTE; somnolence; neuropathy Bortezomib Neuropathy Carfilzomib Less neuropathy; more heart failure Lenalidomide Myelosuppression; VTE; less somnolence & neuropathy than thalidomide Autologous stem cell transplantation with high-dose melphalan Improves survival to a median of 4.5 to 5 years Bisphosphonate therapy once monthly (1-2 years) Osteonecrosis of jaw; renal dysfunction

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46 Other Findings of Undetermined Significance Steensma DP et al. Blood 2015; 126:9.

47 Question 4

48 Question 4 A 65-year old presents with cervical adenopathy and splenomegaly. HCT = 37%; WBC = 34,000/µL with 2% polys and 98% lymphs; platelets = 177,000/µL. Peripheral blood smear review reveals mature appearing lymphocytes and smudge cells (see next slide).

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50 Question 4 (continued) Which of the following is true of this patient? 1. Patients in late childhood or young adulthood are as likely to have this disease as older patients 2. One should be alert for the blast phase of disease 3. The patient might present with autoimmune hemolytic anemia and/or immune thrombocytopenia 4. The evidence favors early treatment

51 Answer = 3

52 HCL CLL PLL

53 Approximate Median Time to Treatment and Median Survival of Patients with Early-Stage Disease according to Prognostic Variables Prognostic Variable Median Time to Treatment, y Median Survival, y Result of FISH 13q- (sole abnormality) 7.5 >11 to 15 Normal karyotype 4 >10 to q- 1 6 to 9 17p- <1 2 to 4 IgV H gene mutation status ZAP-70 CD38 Mutated 8 20 Not mutated <4 7 to 10 Negative 9 to Positive 3 to 4 8 to 10 Negative 5 20 Positive <4 8 to 10

54 Question 5

55 Question 5 A 63-year old patient develops exertional dyspnea. On exam, sclerae are slightly icteric. HCT = 28% with MCV = 105; reticulocyte count = 9%; WBC and platelet counts are normal. The laboratory reports bite cells on peripheral blood smear (see next slide).

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57 Question 5 (continued) What is the most likely underlying mechanism of anemia in this patient? 1. Autoimmune hemolysis 2. Microangiopathic hemolytic anemia 3. Oxidant hemolysis 4. Paroxysmal nocturnal hemoglobinuria

58 Answer = 3

59 Bite cells Heinz body prep By Carola von Kapff, SH (ASCP) from UpToDateÒ

60 Drugs and chemicals in glucose-6- phosphate dehydrogenase deficiency Acetanilid Dapsone Furazolidone Methylene blue Nalidixic acid Unsafe for class I, II, and III variants Naphthalene (mothballs, henna) Niridazole Nitrofurantoin Phenazopyridine Phenylhydrazine Primaquine Sulfacetamide Sulfamethoxazole Source: UpToDate Sulfanilamide Sulfapyridine Thiazosulfone Toluidine blue Trinitrotoluene

61 Drugs and chemicals in glucose-6- phosphate dehydrogenase deficiency Acetaminophen Safe for class II and III variants* Ascorbic acid (except in very high doses) Phenacetin Phenytoin Aspirin Probenecid Chloramphenicol Chloroquine Colchicine Diphenhydramine Isoniazid L-DOPA Pyrimethamine Quinine Streptomycin Sulfisoxazole Trimethoprim Vitamin K * Safety for class I variants is usually not known. Source: UpToDate

62 Question 6

63 Question 6 A 24-year old patient develops dyspnea and is found to be anemic with HCT = 28%, MCV = 104 fl, and reticulocyte count = 6%. The laboratory reports 2+ spherocytes on peripheral blood smear (see next slide).

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65 Question 6 (continued) Coombs testing is positive for IgG and negative for C3. What is the most appropriate management in this patient? 1. Transfuse packed red blood cells 2. Begin prednisone 1 mg/kg and folic acid 5 mg daily 3. Begin danazol 4. Administer rituximab

66 Answer = 2

67 Macrophage Ingesting an IgG-Coated RBC Bessis M. Corpuscles. Atlas of Red Cell Shape. Berlin, Springer- Verlag, 1974

68 Etiologies of WAIHA Idiopathic Viral infections (usually in children) Autoimmune and connective tissue diseases (particularly SLE) Malignancies of the immune system NHL; CLL Treatment with purine nucleoside analogs Immune deregulation Prior allogeneic blood transfusion or HSCT Certain drugs Hydralazine, isoniazid, methyldopa, penicillin, procainamide, quinidine, quinine

69 Lab Findings in WAIHA Combination of increased LDH and reduced haptoglobin 90% specific for diagnosing hemolysis Combination of normal LDH and haptoglobin > 25 mg/dl 92% sensitive for ruling out hemolysis Reticulocytosis > 4-5% (median, 9%) Lower than expected degree of reticulocytosis in 20-37% Lag in marrow responsiveness to hemolytic stress Hemolysis of reticulocytes Parvovirus B19 infection Spherocytosis with elevated MCHC May not be obvious in milder cases (1) Liesveld JL et al. Blood 1987; 69:820. (2) Marchand A et al. JAMA 1980; 243:1909. (3) Galen RS. Clin Lab Med 1982; 2:685. (4) Conley CL et al. JAMA 1980; 244:1688.

70 Treatment of WAIHA Can present as a medical emergency requiring immediate PRBC transfusion Contact Blood Bank personnel Stop any possible offending drug (e.g., penicillin) Treat underlying disease (e.g., SLE, CLL) Reduce autoantibody production

71 Reduction in Antibody Production Corticosteroids (Wendell Rosse & Stanley Schrier) Prednisone 1 mg/kg per day Maintain high dose for 1 week beyond goal Hgb level (e.g., >10 g/dl) Rapidly taper by 20 mg increments every 1 to 2 weeks to 20 mg/day Maintain 20 mg/day for 1 month If remission persists Gradually reduce dose on alternate days to 10 mg/day and maintain for 1 month Omit the dose on alternate days Reduce dose to 10 mg/day on alternate days Maintain this dose as long as remission persists and the DAT remains positive Danazol (may be steroid sparing)

72 Reduction in Antibody Production Immunosuppressive and cytotoxic agents Azathioprine 100 to 150 mg/day Cyclophosphamide 100 mg/day by mouth 500 to 700 mg IV every 3 to 4 weeks High-dose (as in aplastic anemia) 50 mg/kg per day IV for 4 days with Mesna and G-CSF Cyclosporine and mycophenolate mofetil Vincristine Rituximab Alemtuzumab

73 Reduction in Antibody Effectiveness Splenectomy IVIg Less effective than in management of ITP

74 The End