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Hemolytic Anemias

Hemolytic Anemias. Dr. Neil Lachant Hematology Oncology. cjtmeustaquio, md Pgy3. Internal Medicine. Introduction Case 1 General approach to anemia General approach to hemolytic anemia Specific diagnosis/course/complications/treatment Iron overload Case 2

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Hemolytic Anemias

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  1. Hemolytic Anemias Dr. Neil Lachant Hematology Oncology cjtmeustaquio, md Pgy3. Internal Medicine

  2. Introduction • Case 1 • General approach to anemia • General approach to hemolytic anemia • Specific diagnosis/course/complications/treatment • Iron overload • Case 2 • Specific diagnosis/course/complications/treatment • Case 3 • Specifics diagnosis/course/complications/treatment • Conclusion

  3. Introduction • Anemia – dec in RBCs in blood • Hgb < 12 g/dL (F) • Hgb < 13 g/dL (M) • Symptom of underlying disease

  4. Introduction • Mechanisms of anemia: • Dec production of RBCs • Inc destruction of RBCs (Hemolysis) • Acute blood loss

  5. Case 1: JH, 51F.Cc: anemia & hyperbilirubinemia History: • Middle aged Filipino F • No known anemia/jaundice in childhood • Intermittent jaundice, anemia x years – multiple hospitalizations • Otherwise asymptomatic between episodes • Prior workup • For further evaluation & mgt

  6. PMH: - lifelong, intermittent jaundice • 1994: jaundice, inc LFTs, inc indirect bilirubin • H/O: hemolysis w/u WNL - Iron overload: inc transferrin, ferritin - liver biopsy done, no iron dry weight - Desferoxamine + Phlebotomy x1 • GI: hepatitis w/u negative • 1995: gallstones, cholecystectomy done • 1995: “coma” etiol unknown • 2004: inc LFTs, bilirubins, iron overload

  7. - Mental delay - 2005: cataract extraction, OU - DM type II – on Metformin Allergies: NKDA Transfusions: none (no iron pills either) SH: married, no children, works at Goodwill, no smoking/EtOH/illicit drugs. Living in the US x 15 years. Did not drink well water.

  8. Filipino-Chinese FH Filipino-Spanish + + + + + + 92 82 GB DM DM GB GB DM 51  GB GB LFTs GB DM

  9. ROS • No fevers, chills, systemic sx • Small vs other family members • (+) mental delay • Quiet, no abnormal behavior • (+) jaundice, intermittent • (+) rash, ear • No abdominal pain, nausea, vomiting, early satiety • No headaches, paresthesias, neurologic sx

  10. PE 98.5 F 90/62 68 4’11” 94 lbs HEENT: anicteric sclerae, no scleral hge, clear oropharynx, no thrush/lesions Neck: supple; no epitrochlear, axillary, cervical, supraclavicular LNP C/L: CTA CVS: no gallop Abd: soft, NT, no HSM, no masses Ext: calves/thighs NT; no edema Neuro: nonfocal, quiet but responds

  11. Problem list • Normocytic anemia, chronic HEMOLYTIC • Inc retic count ANEMIA • Inc indirect bilirubins • Spherocytes in PBS • Hgb eletrophoresis WNL • Inc ferritin IRON OVERLOAD • Mental delay • FH: GB/liver ds FAMILIAL • DM COMPONENT

  12. Evaluation of anemia Low Hgb/Hct Corr. Retic Ct <2% Corr. Retic Ct >2% Acute Blood Loss MCV<80 MCV 80-100 MCV>100 YES NO Evaluate for microcyticanemias Evaluate for normocyticanemias Evaluate for macrocyticanemias Evaluate & treat appro- priately Evaluate for Hemolytic Anemias

  13. Step by step approach 1. Calculate for Corrected Reticulocyte Count Retic count: 10% Pt’s Hct 29 Control Hct 40 Corrected Retic Count = % Retic x Pt’s Hct Control Hct = 10% x 29/ 40 = 7.73 % > 2% if no blood loss (+) hemolysis

  14. Hemolytic Anemia • Premature destruction of RBCs • Confirm (+) hemolysis: • Corrected retic count > 2% (7.3%) • Inc indirect bilirubins (3.5) • Inc LDH (206) • Low/absent haptoglobin (<6) • Look for cause of hemolysis - occult blood in urine, urine hemosiderin - peripheral blood smear - direct antiglobulin test, Hgb electrophoresis, RBC enzyme analysis

  15. Causes of Hemolytic Anemias Corrretic ct > 2% No blood loss + Enzyme deficiencies Hemoglobinopathies Membrane defects Hemolytic anemias Intravascular Hemolysis ExtravascularHemolysis Intrinsic RBC defects Extrinsic RBC defects Liver Ds, Hypersplenism, Infection (malaria/babesia), Oxidant agents, Others (lead), Microangiopathic (DIC, TTP-HUS), Autoimmune Hemolytic Anemia (warm or cold-reacting, drugs), IV immune globulin, Large granular lymphocyte leukemia

  16. Corrretic ct > 2% No blood loss + Hemolytic anemias Intravascular Hemolysis ExtravascularHemolysis Intrinsic RBC defects Extrinsic RBC defects Microangiopathy (Aortic stenosis, prosthetic valve), Transfusion recations, infection, Paroxysmal cold hemoglobinuria, Paroxysmal Nocturnal Hemoglobinuria, IV infusion of Rho D Ig, Snake bites

  17. Hemolytic Anemia (CRC>2% + no blood loss) Sickled cells Bite cells Target cells Schisto- cytes parasite inclusions Acantho- cytes Sphero- cytes PT/PTT Crea platelets DAT (+) DAT (-) Hgb electro- phoresis G6PD level Auto- Immune Hemo- lytic Anemia Heredi- tary Sphero- cytosis Sickle Cell Ds G6PD Deficient Vs Unstable Hgbs Thalas- semias Hemo- globino- pathy Liver Ds TTP-HUS DIC Prosthe- tic Valve Malignant HTN Malaria Babe- siosis Barto- nella Liver Ds

  18. 1. Hemolytic Anemia – Prob Hereditary Spherocytosis - Do Hemoglobin electrophoresis - Do enzyme studies - Direct Coombs test (DAT), osmotic fragility 2. Iron Overload - MRI liver

  19. Hemoglobinopathy/Thalassemia Panel: (JH: NORMAL) Hgb S – if inc => Sickle Cell Ds Hgb A – normal if ~ 97% Hgb A2 & F – if inc => Beta Thalassemia or other Hgb C – if inc => Hgb C trait or comb. Hgb A2 – if dec & all else normal => maybe alpha Thalassemia Osmotic fragility – increased Direct Coombs test – negative => not autoimmune hemolytic anemia LDH – 206 (inc) => (+) hemolysis

  20. Final Dx: Hereditary Spherocytosis - Inherited nonimmune hemolytic anemia • anemia, splenomegaly, jaundice • Gallstones common • Aplastic crisis – from viral infections • Dx: (+) spherocytes in PBS AND Direct Coombs Test negative • Tx: Conservative mgt: folic acid, immunize (pneumovax, meningovax, H flu vaccine) Splenectomy – severely symptomatic pts

  21. 2. Iron overload – inc ferritin, inc transferrin saturation, mildly elevated LFTs Iron overload HFE gene C282Y, H63D If (+) If (-), as in JH Primary Hemochromatosis Other gene defect vs Secondary Iron Overload Liver biopsy Fe2+ dry weight >71 umol/g Fe2+ dry weight < 71 umol/g Secondary Iron Overload Primary Hemochromatosis

  22. Case 2: CB, 73FCc: anemia History: AAF 1996 – at 60 y/o, admitted at OSH? bec of anemia sx (unclear hx – SOB? Weakness? Jaundice?) - possibility of OTC med - no report of overt bleeding - w/u done: Hgb 8-9, inc retic ct – 20-30% est inc LDH, inc Bil, ?? LFTs, DAT neg (1) Coombs negative hemolytic anemia (2) Hepatosplenomegaly on CT a/p - mgt: transfused, consult Heme-Onc on OPD basis

  23. PMH: Chronic anemia No chronic meds on initial consult at H/O office FH: DM – mother, brother lung CA – father Parkinson’s Ds – sister SH: cook in daycare center, not married no smoking, EtOH drinks 4 cups of coffee daily

  24. PE & Initial Labs VS: 98.3 F 96 142/76 5’3” 139 lbs Gen: NAD, no jaundice C/L: CTA b/l Abd: soft, NT, (+) HSM – splenic tip palpable 2-3 cm below left costophrenic angle Ext: no edema, pain. 102.2 5.6 11.5 145 36.9 MCHC 31.2 MCH 31.9 RDW 16.4

  25. Problem list • Coombs negative hemolytic anemia • Macrocytic anemia • Hepatosplenomegaly

  26. Evaluation of anemia Low Hgb/Hct Corr. Retic Ct <2% Corr. Retic Ct >2% Acute Blood Loss MCV<80 MCV 80-100 MCV>100 YES NO Evaluate for microcyticanemias Evaluate for normocyticanemias Evaluate for macrocyticanemias Evaluate & treat appro- priately Evaluate for Hemolytic Anemias

  27. Step by step approach (1) Corrected retic ct, no blood loss CRC % = Pt’s retic ct x Pt’s Hct Control Hct = 18% x 36.9= 16.6 % > 2%, no blood loss 40 (+) Hemolysis (2) Confirm hemolytic process LDH 240 (110-230) haptoglobin < 6 (low) (+) indirect hyperbilirubinemia (3) Peripheral blood smear: moderate macrocytes no spherocytes, no anisocytosis, no polychromasia, no microcytosis (4) Test for hemoglobinopathies, enzyme levels to r/o deficiencies, DAT to r/o autoimmune HA

  28. Hemolytic Anemia (CRC>2% + no blood loss Sickled cells Bite cells Target cells Schisto- cytes parasite inclusions Acantho- cytes Sphero- cytes PT/PTT Crea platelets DAT (+) DAT (-) Hgb e-phoresis G6PD level Auto- Immune Hemo- lytic Anemia Heredi- tary Sphero- cytosis Sickle Cell Ds G6PD Deficient Vs Unstable Hgbs Thalas- semias Hemo- globino- pathy Liver Ds TTP-HUS DIC Prosthe- tic Valve Malignant HTN Malaria Babe- siosis Barto- nella Liver Ds

  29. (4) Test for hemoglobinopathies, enzyme levels to r/o deficiencies, DAT to r/o autoimmune HA Hgb variants Hgb A 97.2% (96.5 – 100) Thalassemias, Hgb A2 2.8 (0 - 3.5) sickle cell ds Hgb S undetected ruled out Hgb C undetected other none DAT: neg Autoimmune Hemolytic Anemia ruled out RBC Enzymes (qualitative) (quantitative) G6PD: deficient  1.1 (10.8-16.2) Pyruvate kinase: detected  32.5 (9-22)

  30. Final Dx: Hemolytic Anemia 2° to G6PD Deficiency - X-linked recessive hereditary ds - G6PD: enzyme in pentose P04 pathway - maintains NADPH  inc glutathione protects Hgb in RBC from oxidative damage dt drugs, toxin, illness (severe infxn), DKA - primaquine, sulfas, dapsone, nitrofurantoin - Favism

  31. - Dx of G6PD deficiency: (1) (+) Nonimmune Hemolytic Anemia - Dec Hgb, inc retic ct - Normal LFTs except for inc indirect bilirubins - Dec haptoglobin - Direct Coombs test/DAT negative (2) PBS: (+) Heinz bodies in RBC assume G6PD bite cells deficiency

  32. - Dx of G6PD deficiency: (3) Do initial qualitative tests for RBC enzymes - rapid, inexpensive - Beutler Fluorescent Spot Test, under UV light - NADPH + BFST = (+) fluorescence => G6PD adequate = no fluorescence => G6PD insuff levels - may be falsely (+) during acute hemolysis (4) Get quantitative levels to confirm

  33. Tx: Avoid drugs, foods that cause hemolysis Folic acid Supportive/ expectant mgt - transfuse PRN - treat other complications - gallstones – cholecystectomy - iron overload Genetic testing if needed . . .

  34. Bite cells Heinz bodies

  35. Some dilemmas … CB’s course, followed as out-patient - intermittent bouts of anemia & hemolysis - more frequent, more severe in recent years - increasing retic cts (40+%) 2005: absolute retic ct = 334,400 retic ct 45% B 3.4/0.7 Indirect B = 2.7 - needed more frequent transfusions for symptoms (OSH) 2005: 5.3 8.6 119 26 - gallstones, biliary colic  cholecystectomy - levels of G6PD enzyme much lower - iron overload 2003: Serum iron 60/ Transferrin sat 128/ Ferritin 939

  36. 4 forms of G6PD deficiency • Hereditary nonspherocytic hemolytic anemia • Severe deficiency – (our pt years after initial presentation) • Mild deficiency – (our pt initially, for years) • Nondeficient variant

  37. Genetics: - MALES – affected bec of x-linked inheritance - Females: (1) may be carriers – (+) clinical s/sx if lyonization occurs (inactivation of normal x-chromosome) - usually mild ds (2) Homozygous female – G6PD coexists with Chronic Granulomatous Disease (3) Double heterozygosity for G6PD genes???

  38. Her other issues . . . (2) Macrocytic anemia – presumed folate deficiency B12 – 329 (211-911) Folate - 12.6 normal, on supplements (3) Hepatosplenomegaly – presumed 2° to inc hemolysis LFTs normal except for indirect bilirubins Hepatitis panel negative Seen & evaluated by GI (4) 2003, 7 years after initial clinic consult, after transfusions  still with frequent, recurrent bouts of hemolysis, now with Ferritin 939

  39. (4) 2003: iron overload 2007: MRI liver – major iron overload - started on iron chelation therapy: Deferasirox (Exjade)

  40. Case 3: JE, 52Mcc: jaundice, dark urine, abdominal pain Present Illness: - Dark urine, scleral yellowing x several days - (+) abdominal pain, fatigue x 1 day - (+) nausea, vomiting - No fever, diarrhea - (+) similar episodes in the past few years, but much milder, just occasional dark urine, without the abdominal pain/fatigue, no hospitalization needed

  41. PMH: cerebral palsy (since birth) • Chronic anemia, on iron pills, multiple workups done in the past • HTN • BPH • GERD • s/p Appendectomy • s/p EGD 1989 • Multiple blood transfusions – 11/2004 (2 units), 7/04 – 6 units • Allergies: PCN - rash MEDICATIONS: Iron pills Amlodipine, Enalapril, vasoretic 10/25mg Tamsulosin Lansoprazole, promethazine Chromagen Forte

  42. SH: goes to day care center • No smoking, recent EtOH, IVDU. • Quit EtOH years ago. • FH: DM – mother • Breast CA – mother • Lung CA – mother (smoker) • Hodgkin’s disease – brother • Stomach CA – father • DM nephropathy - grandfather • ROS: intermittent dark urine, (+) black stools since PO iron pills were started, no frank blood per rectum, no chest pain, no shortness of breath. (+) generalized fatigue.

  43. PE VS: temp: 100.2F HR=88 BP=184/116, (176/100 off amlodipine & enalapril) BP on ED admission 80/40, responded to IVF Gen: anxious, mild jaundice Neck: supple. No JVD HEENT: EOMs intact; icteric sclerae, pale conj C/L: CTA b/L CVS: RRR, (+) S1/S2, no m/r/g. Abd: soft, NT, ND, (+) BS, (+) hepatomegaly Ext: +1 to +2 bipedal edema; contracted LE’s 2° to CP.

  44. Initial Lab Tests 5.0104 11.7 1319359 99 5.3 14.5 232 1.0 3.2 23 3.5 Crea = 0.9 (2008) Retic ct= 14.1 Serum Iron 43 (45-170) Lipase 107 TIBC 78 (250-425) ALT 53Transferrin sat 55 (20-50) AST 443Ferritin459 (15-400) Aφ 34 P/A 6.8/3.7 Hepatitis Panel negative B 2.5/0.3 B1 = 2.2 RPR nonreactive

  45. Radiologic studies RUQ USG: Mild echogenic liver sugg of fatty liver Inc echogenicity of both kidneys, suggesting medical renal disease. No hydronephrosis of kidneys. No renal calculi. MRI A/P, no contrast done.

  46. Problem list 1. Hypotension 2. Severe anemia, hemolytic, macrocytic, acute exacerbation of chronic problem 3. Hematuria 4. Acute renal failure 5. Hyponatremia, hypokalemia 7. Abdominal pain with inc AST, lipase

  47. Evaluation of anemia Low Hgb/Hct Corr. Retic Ct <2% Corr. Retic Ct >2% Acute Blood Loss MCV<80 MCV 80-100 MCV>100 YES NO Evaluate for microcyticanemias Evaluate for normocyticanemias Evaluate for macrocyticanemias Evaluate & treat appro- priately Evaluate for Hemolytic Anemias

  48. Step by step approach (1) Compute for corrected reticulocyte count CRC = % retic ct x Pt’s Hct Control Hct = 14% x 14.5= 5.075% > 2%, no blood loss 40 Hemolytic anemia (2) Confirm (+) hemolysis LDH 1,024 B 2.5/0.3 B1 2.3 Haptoglobin < 10 (3) Etiology of Hemolytic Anemia: Periph Blood Smear hypochromic RBCs, (+) macrocytes, (+) microcytes

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