Disclosures. Hemolytic Anemia: Hemolysis. Typical Clinical Manifestations. Laboratory Findings 10/1/2014

Transcription

1 Disclosures I have no conflicts of interest or financial disclosures for this presentation Off label rituximab usage described in this presentation Hemolytic Anemia: Evolving Pathogenesis and new Treatment Paradigms Matt Graham UT Erlanger Oncology and Hematology October 2, 2014 Hemolysis Shortened RBC Survival RBC survival is less than 120 days RBCs die daily and there is age independent random hemolysis on the order of 0.05 to 0.5 % per day Compensatory increase in EPO production Increased RBC production Increased reticulocyte % and absolute reticulocyte count Typical Clinical Manifestations Dyspnea Fatigue Hyperdynamic state Palpitations Lethargy Confusion Pallor Jaundice Splenomegaly Laboratory Findings Spectrum of Anemia Reticulocytosis Increased MCV Low haptoglobin Elevated LDH Unconjugated hyperbilirubinemia + DAT AE Lichtin. The Merck Manual

2 DAT Pearls Weakly + test in 1 in 10K healthy donors + in 5 10% of hospitalized patients without any evidence of hemolysis; complement mediated Low titers of autoantibody may appear negative Cannot detect fewer than Ab molecules Cannot detect fewer than C Commonly used reagents, Erlanger s included, cannot identify IgA or IgM autoantibodies AE Lichtin. The Merck Manual. 2013/Up To Date AE Lichtin. The Merck Manual Classification of Hemolytic Anemias Hereditary Hemolytic Disorders RBC enzyme defects RBC membrane defects Hemoglobinopathies Thalassemias Immune mediated Hemolytic Anemias Paroxysmal Cold Hemoglobinuria Warm Autoantibody Hemolytic Anemia Cold Agglutinin Disease Acquired Hemolytic Disorders Immune mediated hemolytic anemias Microangiopathic hemolytic anemias (MAHAs) Paroxysmal nocturnal hemoglobinuria (PNH) Spur cell anemia Direct toxins Paroxysmal Cold Hemoglobinuria (PCH) One of the 1 st hematologic syndromes recognized clinically Red to brown urine after cold exposure described in 1872 Donath and Landsteiner s work identified the causative antibody in 1904 PCH A polyclonal, cold reacting IgG Fixes complement directly Thermal amplitude varies greatly Blood in the periphery cools and Ab and 1 st 2 components of complement are fixed to the RBC surface Lysis occurs when the RBC are subsequently warmed (complement cascade completes) MA Lichtman. In: Hematology

3 PCH PCH Associations In the past, primarily secondary or tertiary syphilis association Post viral or post bacterial Varicella, measles, mumps, EBV, CMV, Adenovirus, Influenza A Mycoplasma, Klebsiella, E. coli, Haemophilus Autoimmune CLL, lymphomas Post measles vaccine K. Weigel Kelly, Blood, Dec PCH Clinical Manifestations Ab appears 7 10 days after febrile illness and persists for up to 12 weeks Dark urine (hemoglobinuria) Back or leg pain Cramps Fever Raynaud s phenomenon Warm Autoantibody Hemolytic Anemia IgG Abs react with RBCs at 37 degrees Celsius No direct lysis or agglutination Fc receptor expressing macrophages within the spleen remove the Ab coated RBCs from the circulation Partial phagocytosis alters RBC membrane resulting in spherocytes C3 can deposit on membrane and enhance hemolysis SPHEROCYTES Warm Antibody Kalyan Mantripragada and Peter J. Quesenberry, ASH Image Bank 2014; % of cases of antibody mediated hemolytic presentations Most are idiopathic Can be secondary Viral infections (CMV, Influenza A, HSV) Malignancies (NHL, CLL, Rarely carcinomas) Connective tissue disorders Prior peripheral blood stem cell transplant Drug induced Copyright 2014 American Society of Hematology. Copyright restrictions may apply. 3

4 Drug Induced Warm Reactive Treatment Alpha methyldopa Fludarabine Procainamide Diclofenac Quinidine, Quinine Sulfa drugs Isoniazid Amphotericin Penicillins Cephalosporins Tetracycline Ribavirin Treat any known underlying condition Stop any implicated drug Folic Acid 5 mg daily Prednisone 1 mg/kg/day Splenectomy Cytotoxic Drugs Cyclophosphamide Immunosuppresants Cyclosporine, mycophenolate mofetil, azathioprine IVIG AE Lichtin. The Merck Manual. 2013/Up To Date Rituximab Chimeric, monoclonal anti CD20 antibody Multiple case studies and retrospective reports Off label usage by Genentech Transfusion Concerns 64 patients with newly dx WAIHA Prednisolone + rituximab vs prednisolone alone After 12 months, 75% on P R vs 36% P alone with satisfactory response After 36 months, 70% vs 45% remission No significant difference in adverse events Pan agglutination with usual cross matching with all normal donor cells Allo reactive Abs may be present in up to 1/3 of patients with AIHA Undetected ALLO Abs could cause massive hemolysis after transfusion 4

5 Transfusion Concerns If patient never pregnant or no history of transfusion, low probability of an alloantibody Adequate testing for alloantibodies may take up to 6 hours Testing diluted serum against RBC panel taking advantage of differences in reaction strength Autoadsorption technique Remove the autoantibody and use these clean cells to keep removing autoantibody, leaving allo Ab behind for ID L. Dean, Blood Groups and Red Cell Antigens, Petz LD. British Journal of Haematology, 124, Transfusion Concerns Severe anemia may preclude obtaining a large enough volume of RBCs for autoadsorption procedure and not useful in those transfused within 3 months Allogeneic adsorption may be needed Use several samples of allogeneic red cells of varying phenotypes responsible for clinically important hemolytic reactions to remove the autoab Transfusion Concerns The clinician must balance risk and benefit of transfusion No patient should die from lack of transfusion, give most compatible blood Transfuse the minimal amount of blood required to alleviate symptoms and maintain a tolerable hgb/hct Transfuse slowly and with close monitoring Petz LD. British Journal of Haematology, 124, Cold Reactive/Cold Agglutinin Dz COLD AGGLUTININ DISEASE IgM complement fixing antibodies Anti I and anti imost common Ab binds to RBCs and causes agglutination at low temperatures (4 degrees Celsius) Intravascular hemolysis DAT positive for complement only since IgM is released at 37 degrees Celsius John Lazarchick, ASH Image Bank 2011; Copyright 2011 American Society of Hematology. Copyright restrictions may apply. 5

6 Testable Associations Mycloplasma pneumonia Infectious mononucleosis Influenza B HIV Hepatitis C Lymphoproliferative disorders Treatment of Cold Agglutinins Avoid cold Warm the patient Use in line warmer Folic acid 5 mg daily Rituximab or combination of rituximab and fludarabine Steroids and splenectomy not effective Plasma exchange of only temporary value Thrombotic Microangiopathy Syndromes Thrombotic=intravascular coagulation Microangiopathy= a disease of very fine blood vessels All share clinical features of microangiopathic hemolytic anemia, thrombocytopenia and organ injury Pathological features are vascular damage with arteriolar and capillary thrombosis MKSAP 16 Pathological Features of the Nine Primary Thrombotic Microangiopathy (TMA) Syndromes. 6

7 Thrombotic Thrombocytopenic Purpura (TTP) Definition: Coombs negative microangiopathic hemolytic anemia and thrombocytopenia in the absence of an alternative explanation Minimum criteria: Thrombocytopenia Rock. Br J Haematol 2000 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR

8 Complement Mediated TMA (CM TMA) 1 st recognized as a familial disorder in 1975 Two brothers with TMA were found to have a deficiency of complement factor H Associated mutations in the gene encoding complement factor H (CFH) characterized 1998 Loss of function mutations in regulatory genes or gain of function effector gene mutations Functional deficiencies in complement factors Diagnostic Criteria Serum creatinine above the normal range MAHA Thrombocytopenia ADAMTS13 activity of 5% or more Negative stool tests for Shiga toxin producing infection CM TMA Diagnosis Plasma levels of C3, C4, CF H, B and I are not helpful Need access to cost effective, rapid and commercially available genetic studies Noris et al. published an in vitro assay to measure serum induced endothelial C5b 9 deposition to monitor complement activation and treatment effectiveness Noris et al. Blood. 2014;124(11): Eculizumab is now considered the standard in CM TMA. This is a monoclonal antibody that is a complement protein C5 inhibitor that can terminate complementmediated hemolysis and thrombotic microangiopathy. Theodore Warkentin GWBR 2011 Neal Young GWBR

9 Highlights 37 patients (17 trial one, 20 trial two) received eculizumab for a median of 64 and 62 weeks, respectively Mean increase in platelet count was 73 x 10 9 from baseline to week 26 in trial one 80% had thrombotic microangiopathy eventfree status in trial two Continuous time dependent increases in GFR End Points. Eculizumab The only currently available anti complement agent Induction phase of 900 mg for 4 weeks followed by maintenance 1200 mg week 5 and then every 2 weeks Extremely expensive (Wholesale cost for 1 year $600K+)?Indefinite treatment? Must vaccinate and prophylax against meningococcus Legendre C et al. N Engl J Med 2013;368: Shiga Toxin Mediated HUS (ST HUS) ST producing E. coli are common intestinal bacteria in cattle Contaminated water, beef products, vegetables and other foods Popularized by large outbreaks but most cases are sporadic ST HUS Toxin binds to CD77 on endothelial cells, renal mesangial cells and renal epithelial cells Leads to cell apoptosis Toxin is pro inflammatory and pro thrombotic Induces endothelial secretion of von Willebrand factor 9

10 ST HUS Presentation, Diagnosis & Treatment Severe abdominal pain and bloody diarrhea begin within several days of consumption Renal failure and thrombocytopenia begin as GI symptoms resolve Stool analyses diagnostic during acute colitis phase Supportive treatment Aggressive hydration Plasma exchange and anti complement therapy inconclusive Drug induced MAHA Ticlopidine, clopidogrel Quinine Mitomycin C, cisplatin and bleomycin Cyclosporine, tacrolimus and sirolimus Penicillamine, penicillins Metabolism Mediated TMA Common Disorders Associated with Microangiopathic Hemolytic Anemia and Thrombocytopenia. Occurs in infants, only reported in one adult Mutations in gene encoding the methylmalonic aciduria and homocystinuria type C protein (MMACHC) Hyperhomocysteinemia, low methionine and methlymalonic aciduria with normal folate and B12 levels Parenteral hydroxycobalamin treatment of choice Neal Young GWBR 2010 Neal Young GWBR

11 TREATMENT OF PNH Anticoagulation in the face of thrombosis Prophylaxis may be considered if more than 50% of cells are CD55 or CD59 deficient. If marked bone marrow failure, treatment consists of immunosuppressive therapy or allogeneic bone marrow transplantation Transplant preferred with young patient with a donor with bone marrow failure Eculizumab Decreases transfusions and thromboses and improves quality of life but does not reverse bone marrow failure Spur Cell Hemolytic Anemia Secondary to severe impaired liver function or cirrhosis Unable to esterify cholesterol causing free cholesterol to bind to the red cell membrane, increasing its surface area Allen DW Blood 1994 Direct Toxins Arsenic hydride Lead Copper Chlorates Insect, Spider and Snake Venoms Heat Radiation January 1, 2003; Blood: 101 (1) Williams Hematology Chapter 53. Thank you for your time and attention! References The Merck Manual 2013 Up To Date Lichtman MA, Spivak JL, eds. Ueber paroxysmale Haemoglo binurie [Concerning paroxysmal hemoglobinuria]. In: Hematology: Landmark Papers of the Twentieth Century. San Diego, Calif: Academic Press; 2000:21. Weigel Kelley KA et al. α5β1 integrin as a cellular coreceptor for human parvovirus B19: requirement of functional activation of β1 integrin for viral entry. Blood. December 2003, Vol. 102:12. The American Society of Hematology Image Bank Birgens H et al. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol Nov;163(3): Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); Available from: Petz LD. Br J Haematol Mar;124(6): Review. Medical Knowledge Self Assessment Program 16 George JN et al. Syndromes of thrombotic microangiopathy. N Engl J Med Aug 14;371(7): Rock GA. Management of thrombotic thrombocytopenic purpura. Br J Haematol Jun;109(3): The George Washington Board Review Series 2010 and Noris M et al. Dynamics of complement activation in ahus and how to monitor eculizumab therapy. Blood. September 2014, Vol. 124:11. Legendre CM et al. Terminal complement inhibitor eculizumab in atypical hemolytic uremic syndrome. N Engl J Med. 2013; 368: Allen DW et al. Abnormal phospholipid metabolism in spur cell anemia: decreased fatty acid incorporation into phosphatidylethanolamine and increased incorporation into acylcarnitine in spur cell anemia erythrocytes. Blood 1994;84: Beutler E. In: Williams Hematology, Chapter

12 Disclosures I have no conflicts of interest or financial disclosures for this presentation Off label rituximab usage described in this presentation Hemolytic Anemia: Evolving Pathogenesis and new Treatment Paradigms Matt Graham UT Erlanger Oncology and Hematology October 2, 2014 Hemolysis Shortened RBC Survival RBC survival is less than 120 days RBCs die daily and there is age independent random hemolysis on the order of 0.05 to 0.5 % per day Compensatory increase in EPO production Increased RBC production Increased reticulocyte % and absolute reticulocyte count Typical Clinical Manifestations Dyspnea Fatigue Hyperdynamic state Palpitations Lethargy Confusion Pallor Jaundice Splenomegaly Laboratory Findings Spectrum of Anemia Reticulocytosis Increased MCV Low haptoglobin Elevated LDH Unconjugated hyperbilirubinemia + DAT AE Lichtin. The Merck Manual

13 DAT Pearls Weakly + test in 1 in 10K healthy donors + in 5 10% of hospitalized patients without any evidence of hemolysis; complement mediated Low titers of autoantibody may appear negative Cannot detect fewer than Ab molecules Cannot detect fewer than C Commonly used reagents, Erlanger s included, cannot identify IgA or IgM autoantibodies AE Lichtin. The Merck Manual. 2013/Up To Date AE Lichtin. The Merck Manual Classification of Hemolytic Anemias Hereditary Hemolytic Disorders RBC enzyme defects RBC membrane defects Hemoglobinopathies Thalassemias Immune mediated Hemolytic Anemias Paroxysmal Cold Hemoglobinuria Warm Autoantibody Hemolytic Anemia Cold Agglutinin Disease Acquired Hemolytic Disorders Immune mediated hemolytic anemias Microangiopathic hemolytic anemias (MAHAs) Paroxysmal nocturnal hemoglobinuria (PNH) Spur cell anemia Direct toxins Paroxysmal Cold Hemoglobinuria (PCH) One of the 1 st hematologic syndromes recognized clinically Red to brown urine after cold exposure described in 1872 Donath and Landsteiner s work identified the causative antibody in 1904 PCH A polyclonal, cold reacting IgG Fixes complement directly Thermal amplitude varies greatly Blood in the periphery cools and Ab and 1 st 2 components of complement are fixed to the RBC surface Lysis occurs when the RBC are subsequently warmed (complement cascade completes) MA Lichtman. In: Hematology

14 PCH PCH Associations In the past, primarily secondary or tertiary syphilis association Post viral or post bacterial Varicella, measles, mumps, EBV, CMV, Adenovirus, Influenza A Mycoplasma, Klebsiella, E. coli, Haemophilus Autoimmune CLL, lymphomas Post measles vaccine K. Weigel Kelly, Blood, Dec PCH Clinical Manifestations Ab appears 7 10 days after febrile illness and persists for up to 12 weeks Dark urine (hemoglobinuria) Back or leg pain Cramps Fever Raynaud s phenomenon Warm Autoantibody Hemolytic Anemia IgG Abs react with RBCs at 37 degrees Celsius No direct lysis or agglutination Fc receptor expressing macrophages within the spleen remove the Ab coated RBCs from the circulation Partial phagocytosis alters RBC membrane resulting in spherocytes C3 can deposit on membrane and enhance hemolysis SPHEROCYTES Warm Antibody Kalyan Mantripragada and Peter J. Quesenberry, ASH Image Bank 2014; % of cases of antibody mediated hemolytic presentations Most are idiopathic Can be secondary Viral infections (CMV, Influenza A, HSV) Malignancies (NHL, CLL, Rarely carcinomas) Connective tissue disorders Prior peripheral blood stem cell transplant Drug induced Copyright 2014 American Society of Hematology. Copyright restrictions may apply. 3

15 Drug Induced Warm Reactive Treatment Alpha methyldopa Fludarabine Procainamide Diclofenac Quinidine, Quinine Sulfa drugs Isoniazid Amphotericin Penicillins Cephalosporins Tetracycline Ribavirin Treat any known underlying condition Stop any implicated drug Folic Acid 5 mg daily Prednisone 1 mg/kg/day Splenectomy Cytotoxic Drugs Cyclophosphamide Immunosuppresants Cyclosporine, mycophenolate mofetil, azathioprine IVIG AE Lichtin. The Merck Manual. 2013/Up To Date Rituximab Chimeric, monoclonal anti CD20 antibody Multiple case studies and retrospective reports Off label usage by Genentech Transfusion Concerns 64 patients with newly dx WAIHA Prednisolone + rituximab vs prednisolone alone After 12 months, 75% on P R vs 36% P alone with satisfactory response After 36 months, 70% vs 45% remission No significant difference in adverse events Pan agglutination with usual cross matching with all normal donor cells Allo reactive Abs may be present in up to 1/3 of patients with AIHA Undetected ALLO Abs could cause massive hemolysis after transfusion 4

16 Transfusion Concerns If patient never pregnant or no history of transfusion, low probability of an alloantibody Adequate testing for alloantibodies may take up to 6 hours Testing diluted serum against RBC panel taking advantage of differences in reaction strength Autoadsorption technique Remove the autoantibody and use these clean cells to keep removing autoantibody, leaving allo Ab behind for ID L. Dean, Blood Groups and Red Cell Antigens, Petz LD. British Journal of Haematology, 124, Transfusion Concerns Severe anemia may preclude obtaining a large enough volume of RBCs for autoadsorption procedure and not useful in those transfused within 3 months Allogeneic adsorption may be needed Use several samples of allogeneic red cells of varying phenotypes responsible for clinically important hemolytic reactions to remove the autoab Transfusion Concerns The clinician must balance risk and benefit of transfusion No patient should die from lack of transfusion, give most compatible blood Transfuse the minimal amount of blood required to alleviate symptoms and maintain a tolerable hgb/hct Transfuse slowly and with close monitoring Petz LD. British Journal of Haematology, 124, Cold Reactive/Cold Agglutinin Dz COLD AGGLUTININ DISEASE IgM complement fixing antibodies Anti I and anti imost common Ab binds to RBCs and causes agglutination at low temperatures (4 degrees Celsius) Intravascular hemolysis DAT positive for complement only since IgM is released at 37 degrees Celsius John Lazarchick, ASH Image Bank 2011; Copyright 2011 American Society of Hematology. Copyright restrictions may apply. 5

17 Testable Associations Mycloplasma pneumonia Infectious mononucleosis Influenza B HIV Hepatitis C Lymphoproliferative disorders Treatment of Cold Agglutinins Avoid cold Warm the patient Use in line warmer Folic acid 5 mg daily Rituximab or combination of rituximab and fludarabine Steroids and splenectomy not effective Plasma exchange of only temporary value Thrombotic Microangiopathy Syndromes Thrombotic=intravascular coagulation Microangiopathy= a disease of very fine blood vessels All share clinical features of microangiopathic hemolytic anemia, thrombocytopenia and organ injury Pathological features are vascular damage with arteriolar and capillary thrombosis MKSAP 16 Pathological Features of the Nine Primary Thrombotic Microangiopathy (TMA) Syndromes. 6

18 Thrombotic Thrombocytopenic Purpura (TTP) Definition: Coombs negative microangiopathic hemolytic anemia and thrombocytopenia in the absence of an alternative explanation Minimum criteria: Thrombocytopenia Rock. Br J Haematol 2000 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR

19 Complement Mediated TMA (CM TMA) 1 st recognized as a familial disorder in 1975 Two brothers with TMA were found to have a deficiency of complement factor H Associated mutations in the gene encoding complement factor H (CFH) characterized 1998 Loss of function mutations in regulatory genes or gain of function effector gene mutations Functional deficiencies in complement factors Diagnostic Criteria Serum creatinine above the normal range MAHA Thrombocytopenia ADAMTS13 activity of 5% or more Negative stool tests for Shiga toxin producing infection CM TMA Diagnosis Plasma levels of C3, C4, CF H, B and I are not helpful Need access to cost effective, rapid and commercially available genetic studies Noris et al. published an in vitro assay to measure serum induced endothelial C5b 9 deposition to monitor complement activation and treatment effectiveness Noris et al. Blood. 2014;124(11): Eculizumab is now considered the standard in CM TMA. This is a monoclonal antibody that is a complement protein C5 inhibitor that can terminate complementmediated hemolysis and thrombotic microangiopathy. Theodore Warkentin GWBR 2011 Neal Young GWBR

20 Highlights 37 patients (17 trial one, 20 trial two) received eculizumab for a median of 64 and 62 weeks, respectively Mean increase in platelet count was 73 x 10 9 from baseline to week 26 in trial one 80% had thrombotic microangiopathy eventfree status in trial two Continuous time dependent increases in GFR End Points. Eculizumab The only currently available anti complement agent Induction phase of 900 mg for 4 weeks followed by maintenance 1200 mg week 5 and then every 2 weeks Extremely expensive (Wholesale cost for 1 year $600K+)?Indefinite treatment? Must vaccinate and prophylax against meningococcus Legendre C et al. N Engl J Med 2013;368: Shiga Toxin Mediated HUS (ST HUS) ST producing E. coli are common intestinal bacteria in cattle Contaminated water, beef products, vegetables and other foods Popularized by large outbreaks but most cases are sporadic ST HUS Toxin binds to CD77 on endothelial cells, renal mesangial cells and renal epithelial cells Leads to cell apoptosis Toxin is pro inflammatory and pro thrombotic Induces endothelial secretion of von Willebrand factor 9

21 ST HUS Presentation, Diagnosis & Treatment Severe abdominal pain and bloody diarrhea begin within several days of consumption Renal failure and thrombocytopenia begin as GI symptoms resolve Stool analyses diagnostic during acute colitis phase Supportive treatment Aggressive hydration Plasma exchange and anti complement therapy inconclusive Drug induced MAHA Ticlopidine, clopidogrel Quinine Mitomycin C, cisplatin and bleomycin Cyclosporine, tacrolimus and sirolimus Penicillamine, penicillins Metabolism Mediated TMA Common Disorders Associated with Microangiopathic Hemolytic Anemia and Thrombocytopenia. Occurs in infants, only reported in one adult Mutations in gene encoding the methylmalonic aciduria and homocystinuria type C protein (MMACHC) Hyperhomocysteinemia, low methionine and methlymalonic aciduria with normal folate and B12 levels Parenteral hydroxycobalamin treatment of choice Neal Young GWBR 2010 Neal Young GWBR

22 TREATMENT OF PNH Anticoagulation in the face of thrombosis Prophylaxis may be considered if more than 50% of cells are CD55 or CD59 deficient. If marked bone marrow failure, treatment consists of immunosuppressive therapy or allogeneic bone marrow transplantation Transplant preferred with young patient with a donor with bone marrow failure Eculizumab Decreases transfusions and thromboses and improves quality of life but does not reverse bone marrow failure Spur Cell Hemolytic Anemia Secondary to severe impaired liver function or cirrhosis Unable to esterify cholesterol causing free cholesterol to bind to the red cell membrane, increasing its surface area Allen DW Blood 1994 Direct Toxins Arsenic hydride Lead Copper Chlorates Insect, Spider and Snake Venoms Heat Radiation January 1, 2003; Blood: 101 (1) Williams Hematology Chapter 53. Thank you for your time and attention! References The Merck Manual 2013 Up To Date Lichtman MA, Spivak JL, eds. Ueber paroxysmale Haemoglo binurie [Concerning paroxysmal hemoglobinuria]. In: Hematology: Landmark Papers of the Twentieth Century. San Diego, Calif: Academic Press; 2000:21. Weigel Kelley KA et al. α5β1 integrin as a cellular coreceptor for human parvovirus B19: requirement of functional activation of β1 integrin for viral entry. Blood. December 2003, Vol. 102:12. The American Society of Hematology Image Bank Birgens H et al. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol Nov;163(3): Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); Available from: Petz LD. Br J Haematol Mar;124(6): Review. Medical Knowledge Self Assessment Program 16 George JN et al. Syndromes of thrombotic microangiopathy. N Engl J Med Aug 14;371(7): Rock GA. Management of thrombotic thrombocytopenic purpura. Br J Haematol Jun;109(3): The George Washington Board Review Series 2010 and Noris M et al. Dynamics of complement activation in ahus and how to monitor eculizumab therapy. Blood. September 2014, Vol. 124:11. Legendre CM et al. Terminal complement inhibitor eculizumab in atypical hemolytic uremic syndrome. N Engl J Med. 2013; 368: Allen DW et al. Abnormal phospholipid metabolism in spur cell anemia: decreased fatty acid incorporation into phosphatidylethanolamine and increased incorporation into acylcarnitine in spur cell anemia erythrocytes. Blood 1994;84: Beutler E. In: Williams Hematology, Chapter

23 Disclosures I have no conflicts of interest or financial disclosures for this presentation Off label rituximab usage described in this presentation Hemolytic Anemia: Evolving Pathogenesis and new Treatment Paradigms Matt Graham UT Erlanger Oncology and Hematology October 2, 2014 Hemolysis Shortened RBC Survival RBC survival is less than 120 days RBCs die daily and there is age independent random hemolysis on the order of 0.05 to 0.5 % per day Compensatory increase in EPO production Increased RBC production Increased reticulocyte % and absolute reticulocyte count Typical Clinical Manifestations Dyspnea Fatigue Hyperdynamic state Palpitations Lethargy Confusion Pallor Jaundice Splenomegaly Laboratory Findings Spectrum of Anemia Reticulocytosis Increased MCV Low haptoglobin Elevated LDH Unconjugated hyperbilirubinemia + DAT AE Lichtin. The Merck Manual

24 DAT Pearls Weakly + test in 1 in 10K healthy donors + in 5 10% of hospitalized patients without any evidence of hemolysis; complement mediated Low titers of autoantibody may appear negative Cannot detect fewer than Ab molecules Cannot detect fewer than C Commonly used reagents, Erlanger s included, cannot identify IgA or IgM autoantibodies AE Lichtin. The Merck Manual. 2013/Up To Date AE Lichtin. The Merck Manual Classification of Hemolytic Anemias Hereditary Hemolytic Disorders RBC enzyme defects RBC membrane defects Hemoglobinopathies Thalassemias Immune mediated Hemolytic Anemias Paroxysmal Cold Hemoglobinuria Warm Autoantibody Hemolytic Anemia Cold Agglutinin Disease Acquired Hemolytic Disorders Immune mediated hemolytic anemias Microangiopathic hemolytic anemias (MAHAs) Paroxysmal nocturnal hemoglobinuria (PNH) Spur cell anemia Direct toxins Paroxysmal Cold Hemoglobinuria (PCH) One of the 1 st hematologic syndromes recognized clinically Red to brown urine after cold exposure described in 1872 Donath and Landsteiner s work identified the causative antibody in 1904 PCH A polyclonal, cold reacting IgG Fixes complement directly Thermal amplitude varies greatly Blood in the periphery cools and Ab and 1 st 2 components of complement are fixed to the RBC surface Lysis occurs when the RBC are subsequently warmed (complement cascade completes) MA Lichtman. In: Hematology

25 PCH PCH Associations In the past, primarily secondary or tertiary syphilis association Post viral or post bacterial Varicella, measles, mumps, EBV, CMV, Adenovirus, Influenza A Mycoplasma, Klebsiella, E. coli, Haemophilus Autoimmune CLL, lymphomas Post measles vaccine K. Weigel Kelly, Blood, Dec PCH Clinical Manifestations Ab appears 7 10 days after febrile illness and persists for up to 12 weeks Dark urine (hemoglobinuria) Back or leg pain Cramps Fever Raynaud s phenomenon Warm Autoantibody Hemolytic Anemia IgG Abs react with RBCs at 37 degrees Celsius No direct lysis or agglutination Fc receptor expressing macrophages within the spleen remove the Ab coated RBCs from the circulation Partial phagocytosis alters RBC membrane resulting in spherocytes C3 can deposit on membrane and enhance hemolysis SPHEROCYTES Warm Antibody Kalyan Mantripragada and Peter J. Quesenberry, ASH Image Bank 2014; % of cases of antibody mediated hemolytic presentations Most are idiopathic Can be secondary Viral infections (CMV, Influenza A, HSV) Malignancies (NHL, CLL, Rarely carcinomas) Connective tissue disorders Prior peripheral blood stem cell transplant Drug induced Copyright 2014 American Society of Hematology. Copyright restrictions may apply. 3

26 Drug Induced Warm Reactive Treatment Alpha methyldopa Fludarabine Procainamide Diclofenac Quinidine, Quinine Sulfa drugs Isoniazid Amphotericin Penicillins Cephalosporins Tetracycline Ribavirin Treat any known underlying condition Stop any implicated drug Folic Acid 5 mg daily Prednisone 1 mg/kg/day Splenectomy Cytotoxic Drugs Cyclophosphamide Immunosuppresants Cyclosporine, mycophenolate mofetil, azathioprine IVIG AE Lichtin. The Merck Manual. 2013/Up To Date Rituximab Chimeric, monoclonal anti CD20 antibody Multiple case studies and retrospective reports Off label usage by Genentech Transfusion Concerns 64 patients with newly dx WAIHA Prednisolone + rituximab vs prednisolone alone After 12 months, 75% on P R vs 36% P alone with satisfactory response After 36 months, 70% vs 45% remission No significant difference in adverse events Pan agglutination with usual cross matching with all normal donor cells Allo reactive Abs may be present in up to 1/3 of patients with AIHA Undetected ALLO Abs could cause massive hemolysis after transfusion 4

27 Transfusion Concerns If patient never pregnant or no history of transfusion, low probability of an alloantibody Adequate testing for alloantibodies may take up to 6 hours Testing diluted serum against RBC panel taking advantage of differences in reaction strength Autoadsorption technique Remove the autoantibody and use these clean cells to keep removing autoantibody, leaving allo Ab behind for ID L. Dean, Blood Groups and Red Cell Antigens, Petz LD. British Journal of Haematology, 124, Transfusion Concerns Severe anemia may preclude obtaining a large enough volume of RBCs for autoadsorption procedure and not useful in those transfused within 3 months Allogeneic adsorption may be needed Use several samples of allogeneic red cells of varying phenotypes responsible for clinically important hemolytic reactions to remove the autoab Transfusion Concerns The clinician must balance risk and benefit of transfusion No patient should die from lack of transfusion, give most compatible blood Transfuse the minimal amount of blood required to alleviate symptoms and maintain a tolerable hgb/hct Transfuse slowly and with close monitoring Petz LD. British Journal of Haematology, 124, Cold Reactive/Cold Agglutinin Dz COLD AGGLUTININ DISEASE IgM complement fixing antibodies Anti I and anti imost common Ab binds to RBCs and causes agglutination at low temperatures (4 degrees Celsius) Intravascular hemolysis DAT positive for complement only since IgM is released at 37 degrees Celsius John Lazarchick, ASH Image Bank 2011; Copyright 2011 American Society of Hematology. Copyright restrictions may apply. 5

28 Testable Associations Mycloplasma pneumonia Infectious mononucleosis Influenza B HIV Hepatitis C Lymphoproliferative disorders Treatment of Cold Agglutinins Avoid cold Warm the patient Use in line warmer Folic acid 5 mg daily Rituximab or combination of rituximab and fludarabine Steroids and splenectomy not effective Plasma exchange of only temporary value Thrombotic Microangiopathy Syndromes Thrombotic=intravascular coagulation Microangiopathy= a disease of very fine blood vessels All share clinical features of microangiopathic hemolytic anemia, thrombocytopenia and organ injury Pathological features are vascular damage with arteriolar and capillary thrombosis MKSAP 16 Pathological Features of the Nine Primary Thrombotic Microangiopathy (TMA) Syndromes. 6

29 Thrombotic Thrombocytopenic Purpura (TTP) Definition: Coombs negative microangiopathic hemolytic anemia and thrombocytopenia in the absence of an alternative explanation Minimum criteria: Thrombocytopenia Rock. Br J Haematol 2000 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR

30 Complement Mediated TMA (CM TMA) 1 st recognized as a familial disorder in 1975 Two brothers with TMA were found to have a deficiency of complement factor H Associated mutations in the gene encoding complement factor H (CFH) characterized 1998 Loss of function mutations in regulatory genes or gain of function effector gene mutations Functional deficiencies in complement factors Diagnostic Criteria Serum creatinine above the normal range MAHA Thrombocytopenia ADAMTS13 activity of 5% or more Negative stool tests for Shiga toxin producing infection CM TMA Diagnosis Plasma levels of C3, C4, CF H, B and I are not helpful Need access to cost effective, rapid and commercially available genetic studies Noris et al. published an in vitro assay to measure serum induced endothelial C5b 9 deposition to monitor complement activation and treatment effectiveness Noris et al. Blood. 2014;124(11): Eculizumab is now considered the standard in CM TMA. This is a monoclonal antibody that is a complement protein C5 inhibitor that can terminate complementmediated hemolysis and thrombotic microangiopathy. Theodore Warkentin GWBR 2011 Neal Young GWBR

31 Highlights 37 patients (17 trial one, 20 trial two) received eculizumab for a median of 64 and 62 weeks, respectively Mean increase in platelet count was 73 x 10 9 from baseline to week 26 in trial one 80% had thrombotic microangiopathy eventfree status in trial two Continuous time dependent increases in GFR End Points. Eculizumab The only currently available anti complement agent Induction phase of 900 mg for 4 weeks followed by maintenance 1200 mg week 5 and then every 2 weeks Extremely expensive (Wholesale cost for 1 year $600K+)?Indefinite treatment? Must vaccinate and prophylax against meningococcus Legendre C et al. N Engl J Med 2013;368: Shiga Toxin Mediated HUS (ST HUS) ST producing E. coli are common intestinal bacteria in cattle Contaminated water, beef products, vegetables and other foods Popularized by large outbreaks but most cases are sporadic ST HUS Toxin binds to CD77 on endothelial cells, renal mesangial cells and renal epithelial cells Leads to cell apoptosis Toxin is pro inflammatory and pro thrombotic Induces endothelial secretion of von Willebrand factor 9

32 ST HUS Presentation, Diagnosis & Treatment Severe abdominal pain and bloody diarrhea begin within several days of consumption Renal failure and thrombocytopenia begin as GI symptoms resolve Stool analyses diagnostic during acute colitis phase Supportive treatment Aggressive hydration Plasma exchange and anti complement therapy inconclusive Drug induced MAHA Ticlopidine, clopidogrel Quinine Mitomycin C, cisplatin and bleomycin Cyclosporine, tacrolimus and sirolimus Penicillamine, penicillins Metabolism Mediated TMA Common Disorders Associated with Microangiopathic Hemolytic Anemia and Thrombocytopenia. Occurs in infants, only reported in one adult Mutations in gene encoding the methylmalonic aciduria and homocystinuria type C protein (MMACHC) Hyperhomocysteinemia, low methionine and methlymalonic aciduria with normal folate and B12 levels Parenteral hydroxycobalamin treatment of choice Neal Young GWBR 2010 Neal Young GWBR

33 TREATMENT OF PNH Anticoagulation in the face of thrombosis Prophylaxis may be considered if more than 50% of cells are CD55 or CD59 deficient. If marked bone marrow failure, treatment consists of immunosuppressive therapy or allogeneic bone marrow transplantation Transplant preferred with young patient with a donor with bone marrow failure Eculizumab Decreases transfusions and thromboses and improves quality of life but does not reverse bone marrow failure Spur Cell Hemolytic Anemia Secondary to severe impaired liver function or cirrhosis Unable to esterify cholesterol causing free cholesterol to bind to the red cell membrane, increasing its surface area Allen DW Blood 1994 Direct Toxins Arsenic hydride Lead Copper Chlorates Insect, Spider and Snake Venoms Heat Radiation January 1, 2003; Blood: 101 (1) Williams Hematology Chapter 53. Thank you for your time and attention! References The Merck Manual 2013 Up To Date Lichtman MA, Spivak JL, eds. Ueber paroxysmale Haemoglo binurie [Concerning paroxysmal hemoglobinuria]. In: Hematology: Landmark Papers of the Twentieth Century. San Diego, Calif: Academic Press; 2000:21. Weigel Kelley KA et al. α5β1 integrin as a cellular coreceptor for human parvovirus B19: requirement of functional activation of β1 integrin for viral entry. Blood. December 2003, Vol. 102:12. The American Society of Hematology Image Bank Birgens H et al. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol Nov;163(3): Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); Available from: Petz LD. Br J Haematol Mar;124(6): Review. Medical Knowledge Self Assessment Program 16 George JN et al. Syndromes of thrombotic microangiopathy. N Engl J Med Aug 14;371(7): Rock GA. Management of thrombotic thrombocytopenic purpura. Br J Haematol Jun;109(3): The George Washington Board Review Series 2010 and Noris M et al. Dynamics of complement activation in ahus and how to monitor eculizumab therapy. Blood. September 2014, Vol. 124:11. Legendre CM et al. Terminal complement inhibitor eculizumab in atypical hemolytic uremic syndrome. N Engl J Med. 2013; 368: Allen DW et al. Abnormal phospholipid metabolism in spur cell anemia: decreased fatty acid incorporation into phosphatidylethanolamine and increased incorporation into acylcarnitine in spur cell anemia erythrocytes. Blood 1994;84: Beutler E. In: Williams Hematology, Chapter

34 Disclosures I have no conflicts of interest or financial disclosures for this presentation Off label rituximab usage described in this presentation Hemolytic Anemia: Evolving Pathogenesis and new Treatment Paradigms Matt Graham UT Erlanger Oncology and Hematology October 2, 2014 Hemolysis Shortened RBC Survival RBC survival is less than 120 days RBCs die daily and there is age independent random hemolysis on the order of 0.05 to 0.5 % per day Compensatory increase in EPO production Increased RBC production Increased reticulocyte % and absolute reticulocyte count Typical Clinical Manifestations Dyspnea Fatigue Hyperdynamic state Palpitations Lethargy Confusion Pallor Jaundice Splenomegaly Laboratory Findings Spectrum of Anemia Reticulocytosis Increased MCV Low haptoglobin Elevated LDH Unconjugated hyperbilirubinemia + DAT AE Lichtin. The Merck Manual

35 DAT Pearls Weakly + test in 1 in 10K healthy donors + in 5 10% of hospitalized patients without any evidence of hemolysis; complement mediated Low titers of autoantibody may appear negative Cannot detect fewer than Ab molecules Cannot detect fewer than C Commonly used reagents, Erlanger s included, cannot identify IgA or IgM autoantibodies AE Lichtin. The Merck Manual. 2013/Up To Date AE Lichtin. The Merck Manual Classification of Hemolytic Anemias Hereditary Hemolytic Disorders RBC enzyme defects RBC membrane defects Hemoglobinopathies Thalassemias Immune mediated Hemolytic Anemias Paroxysmal Cold Hemoglobinuria Warm Autoantibody Hemolytic Anemia Cold Agglutinin Disease Acquired Hemolytic Disorders Immune mediated hemolytic anemias Microangiopathic hemolytic anemias (MAHAs) Paroxysmal nocturnal hemoglobinuria (PNH) Spur cell anemia Direct toxins Paroxysmal Cold Hemoglobinuria (PCH) One of the 1 st hematologic syndromes recognized clinically Red to brown urine after cold exposure described in 1872 Donath and Landsteiner s work identified the causative antibody in 1904 PCH A polyclonal, cold reacting IgG Fixes complement directly Thermal amplitude varies greatly Blood in the periphery cools and Ab and 1 st 2 components of complement are fixed to the RBC surface Lysis occurs when the RBC are subsequently warmed (complement cascade completes) MA Lichtman. In: Hematology

36 PCH PCH Associations In the past, primarily secondary or tertiary syphilis association Post viral or post bacterial Varicella, measles, mumps, EBV, CMV, Adenovirus, Influenza A Mycoplasma, Klebsiella, E. coli, Haemophilus Autoimmune CLL, lymphomas Post measles vaccine K. Weigel Kelly, Blood, Dec PCH Clinical Manifestations Ab appears 7 10 days after febrile illness and persists for up to 12 weeks Dark urine (hemoglobinuria) Back or leg pain Cramps Fever Raynaud s phenomenon Warm Autoantibody Hemolytic Anemia IgG Abs react with RBCs at 37 degrees Celsius No direct lysis or agglutination Fc receptor expressing macrophages within the spleen remove the Ab coated RBCs from the circulation Partial phagocytosis alters RBC membrane resulting in spherocytes C3 can deposit on membrane and enhance hemolysis SPHEROCYTES Warm Antibody Kalyan Mantripragada and Peter J. Quesenberry, ASH Image Bank 2014; % of cases of antibody mediated hemolytic presentations Most are idiopathic Can be secondary Viral infections (CMV, Influenza A, HSV) Malignancies (NHL, CLL, Rarely carcinomas) Connective tissue disorders Prior peripheral blood stem cell transplant Drug induced Copyright 2014 American Society of Hematology. Copyright restrictions may apply. 3

37 Drug Induced Warm Reactive Treatment Alpha methyldopa Fludarabine Procainamide Diclofenac Quinidine, Quinine Sulfa drugs Isoniazid Amphotericin Penicillins Cephalosporins Tetracycline Ribavirin Treat any known underlying condition Stop any implicated drug Folic Acid 5 mg daily Prednisone 1 mg/kg/day Splenectomy Cytotoxic Drugs Cyclophosphamide Immunosuppresants Cyclosporine, mycophenolate mofetil, azathioprine IVIG AE Lichtin. The Merck Manual. 2013/Up To Date Rituximab Chimeric, monoclonal anti CD20 antibody Multiple case studies and retrospective reports Off label usage by Genentech Transfusion Concerns 64 patients with newly dx WAIHA Prednisolone + rituximab vs prednisolone alone After 12 months, 75% on P R vs 36% P alone with satisfactory response After 36 months, 70% vs 45% remission No significant difference in adverse events Pan agglutination with usual cross matching with all normal donor cells Allo reactive Abs may be present in up to 1/3 of patients with AIHA Undetected ALLO Abs could cause massive hemolysis after transfusion 4

38 Transfusion Concerns If patient never pregnant or no history of transfusion, low probability of an alloantibody Adequate testing for alloantibodies may take up to 6 hours Testing diluted serum against RBC panel taking advantage of differences in reaction strength Autoadsorption technique Remove the autoantibody and use these clean cells to keep removing autoantibody, leaving allo Ab behind for ID L. Dean, Blood Groups and Red Cell Antigens, Petz LD. British Journal of Haematology, 124, Transfusion Concerns Severe anemia may preclude obtaining a large enough volume of RBCs for autoadsorption procedure and not useful in those transfused within 3 months Allogeneic adsorption may be needed Use several samples of allogeneic red cells of varying phenotypes responsible for clinically important hemolytic reactions to remove the autoab Transfusion Concerns The clinician must balance risk and benefit of transfusion No patient should die from lack of transfusion, give most compatible blood Transfuse the minimal amount of blood required to alleviate symptoms and maintain a tolerable hgb/hct Transfuse slowly and with close monitoring Petz LD. British Journal of Haematology, 124, Cold Reactive/Cold Agglutinin Dz COLD AGGLUTININ DISEASE IgM complement fixing antibodies Anti I and anti imost common Ab binds to RBCs and causes agglutination at low temperatures (4 degrees Celsius) Intravascular hemolysis DAT positive for complement only since IgM is released at 37 degrees Celsius John Lazarchick, ASH Image Bank 2011; Copyright 2011 American Society of Hematology. Copyright restrictions may apply. 5

39 Testable Associations Mycloplasma pneumonia Infectious mononucleosis Influenza B HIV Hepatitis C Lymphoproliferative disorders Treatment of Cold Agglutinins Avoid cold Warm the patient Use in line warmer Folic acid 5 mg daily Rituximab or combination of rituximab and fludarabine Steroids and splenectomy not effective Plasma exchange of only temporary value Thrombotic Microangiopathy Syndromes Thrombotic=intravascular coagulation Microangiopathy= a disease of very fine blood vessels All share clinical features of microangiopathic hemolytic anemia, thrombocytopenia and organ injury Pathological features are vascular damage with arteriolar and capillary thrombosis MKSAP 16 Pathological Features of the Nine Primary Thrombotic Microangiopathy (TMA) Syndromes. 6

40 Thrombotic Thrombocytopenic Purpura (TTP) Definition: Coombs negative microangiopathic hemolytic anemia and thrombocytopenia in the absence of an alternative explanation Minimum criteria: Thrombocytopenia Rock. Br J Haematol 2000 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR 2011 Theodore Warkentin GWBR

41 Complement Mediated TMA (CM TMA) 1 st recognized as a familial disorder in 1975 Two brothers with TMA were found to have a deficiency of complement factor H Associated mutations in the gene encoding complement factor H (CFH) characterized 1998 Loss of function mutations in regulatory genes or gain of function effector gene mutations Functional deficiencies in complement factors Diagnostic Criteria Serum creatinine above the normal range MAHA Thrombocytopenia ADAMTS13 activity of 5% or more Negative stool tests for Shiga toxin producing infection CM TMA Diagnosis Plasma levels of C3, C4, CF H, B and I are not helpful Need access to cost effective, rapid and commercially available genetic studies Noris et al. published an in vitro assay to measure serum induced endothelial C5b 9 deposition to monitor complement activation and treatment effectiveness Noris et al. Blood. 2014;124(11): Eculizumab is now considered the standard in CM TMA. This is a monoclonal antibody that is a complement protein C5 inhibitor that can terminate complementmediated hemolysis and thrombotic microangiopathy. Theodore Warkentin GWBR 2011 Neal Young GWBR

42 Highlights 37 patients (17 trial one, 20 trial two) received eculizumab for a median of 64 and 62 weeks, respectively Mean increase in platelet count was 73 x 10 9 from baseline to week 26 in trial one 80% had thrombotic microangiopathy eventfree status in trial two Continuous time dependent increases in GFR End Points. Eculizumab The only currently available anti complement agent Induction phase of 900 mg for 4 weeks followed by maintenance 1200 mg week 5 and then every 2 weeks Extremely expensive (Wholesale cost for 1 year $600K+)?Indefinite treatment? Must vaccinate and prophylax against meningococcus Legendre C et al. N Engl J Med 2013;368: Shiga Toxin Mediated HUS (ST HUS) ST producing E. coli are common intestinal bacteria in cattle Contaminated water, beef products, vegetables and other foods Popularized by large outbreaks but most cases are sporadic ST HUS Toxin binds to CD77 on endothelial cells, renal mesangial cells and renal epithelial cells Leads to cell apoptosis Toxin is pro inflammatory and pro thrombotic Induces endothelial secretion of von Willebrand factor 9

43 ST HUS Presentation, Diagnosis & Treatment Severe abdominal pain and bloody diarrhea begin within several days of consumption Renal failure and thrombocytopenia begin as GI symptoms resolve Stool analyses diagnostic during acute colitis phase Supportive treatment Aggressive hydration Plasma exchange and anti complement therapy inconclusive Drug induced MAHA Ticlopidine, clopidogrel Quinine Mitomycin C, cisplatin and bleomycin Cyclosporine, tacrolimus and sirolimus Penicillamine, penicillins Metabolism Mediated TMA Common Disorders Associated with Microangiopathic Hemolytic Anemia and Thrombocytopenia. Occurs in infants, only reported in one adult Mutations in gene encoding the methylmalonic aciduria and homocystinuria type C protein (MMACHC) Hyperhomocysteinemia, low methionine and methlymalonic aciduria with normal folate and B12 levels Parenteral hydroxycobalamin treatment of choice Neal Young GWBR 2010 Neal Young GWBR

44 TREATMENT OF PNH Anticoagulation in the face of thrombosis Prophylaxis may be considered if more than 50% of cells are CD55 or CD59 deficient. If marked bone marrow failure, treatment consists of immunosuppressive therapy or allogeneic bone marrow transplantation Transplant preferred with young patient with a donor with bone marrow failure Eculizumab Decreases transfusions and thromboses and improves quality of life but does not reverse bone marrow failure Spur Cell Hemolytic Anemia Secondary to severe impaired liver function or cirrhosis Unable to esterify cholesterol causing free cholesterol to bind to the red cell membrane, increasing its surface area Allen DW Blood 1994 Direct Toxins Arsenic hydride Lead Copper Chlorates Insect, Spider and Snake Venoms Heat Radiation January 1, 2003; Blood: 101 (1) Williams Hematology Chapter 53. Thank you for your time and attention! References The Merck Manual 2013 Up To Date Lichtman MA, Spivak JL, eds. Ueber paroxysmale Haemoglo binurie [Concerning paroxysmal hemoglobinuria]. In: Hematology: Landmark Papers of the Twentieth Century. San Diego, Calif: Academic Press; 2000:21. Weigel Kelley KA et al. α5β1 integrin as a cellular coreceptor for human parvovirus B19: requirement of functional activation of β1 integrin for viral entry. Blood. December 2003, Vol. 102:12. The American Society of Hematology Image Bank Birgens H et al. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol Nov;163(3): Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); Available from: Petz LD. Br J Haematol Mar;124(6): Review. Medical Knowledge Self Assessment Program 16 George JN et al. Syndromes of thrombotic microangiopathy. N Engl J Med Aug 14;371(7): Rock GA. Management of thrombotic thrombocytopenic purpura. Br J Haematol Jun;109(3): The George Washington Board Review Series 2010 and Noris M et al. Dynamics of complement activation in ahus and how to monitor eculizumab therapy. Blood. September 2014, Vol. 124:11. Legendre CM et al. Terminal complement inhibitor eculizumab in atypical hemolytic uremic syndrome. N Engl J Med. 2013; 368: Allen DW et al. Abnormal phospholipid metabolism in spur cell anemia: decreased fatty acid incorporation into phosphatidylethanolamine and increased incorporation into acylcarnitine in spur cell anemia erythrocytes. Blood 1994;84: Beutler E. In: Williams Hematology, Chapter