Investigation of whether the acute hemolysis associated with Rho(D) immune globulin intravenous (human) administration for treatment of immune thrombocytopenic purpura is consistent with the acute hemolytic transfusion reaction model
Ann Reed Gaines
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorHallie Lee-Stroka
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorKaren Byrne
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorDorothy E. Scott
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorLynne Uhl
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorEllen Lazarus
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorDavid F. Stroncek
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorAnn Reed Gaines
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorHallie Lee-Stroka
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorKaren Byrne
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorDorothy E. Scott
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorLynne Uhl
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorEllen Lazarus
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorDavid F. Stroncek
From the Office of Biostatistics and Epidemiology, the Office of Blood Research and Review, and the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland; the Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland; and the Division of Laboratory and Transfusion Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Search for more papers by this authorThe article was produced by employees of the United States Government and Beth Israel Deaconess Medical Center/Harvard Medical School as part of their official duties.
The content of this publication does not necessarily reflect the views or polices of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.
None of the authors has financial interest in Cangene Corporation, the company whose product was studied in the present work, or in any other company(ies) whose products were mentioned in this article. This study was not supported by research funding from Cangene or any other entity.
Abstract
BACKGROUND: Immune thrombocytopenic purpura and secondary thrombocytopenia patients treated with Rho(D) immune globulin intravenous (human; anti-D IGIV) have experienced acute hemolysis, which is inconsistent with the typical presentation of extravascular hemolysis—the presumed mechanism of action of anti-D IGIV. Although the mechanism of anti-D-IGIV–associated acute hemolysis has not been established, the onset, signs/symptoms, and complications appear consistent with the intravascular hemolysis of acute hemolytic transfusion reactions (AHTRs). In transfusion medicine, the red blood cell (RBC) antigen-antibody incompatibility(-ies) that precipitate AHTRs can be detected in vitro with compatibility testing. Under the premise that anti-D-IGIV–associated acute hemolysis results from RBC antigen-antibody–mediated complement activation, this study evaluated whether the incompatibility(-ies) could be detected in vitro with a hemolysin assay, which would support the AHTR model as the hemolytic mechanism.
STUDY DESIGN AND METHODS: Seven anti-D IGIV lots were tested to determine the RBC antibody identities in those lots, including four lots that had been implicated in acute hemolytic episodes. Hemolysin assays were performed that tested each of 73 RBC specimens against each lot, including the RBCs of one patient who had experienced acute hemolysis after anti-D IGIV administration.
RESULTS: Only two anti-D IGIV lots contained RBC antibodies beyond those expected. No hemolysis endpoint was observed in any of the hemolysin assays.
CONCLUSION: Although the findings did not support the AHTR model, the results are reported to contribute knowledge about the mechanism of anti-D-IGIV–associated acute hemolysis and to prompt continued investigation into cause(s), prediction, and prevention of this potentially serious adverse event.
REFERENCES
- 1 Cangene Corporation. Rho(D) immune globulin intravenous (Human): WinRho® SDF [professional package insert]. Winnipeg (MB): Cangene Corporation; 2006.
- 2 Hong F, Ruiz R, Price H, Griffiths A, Malinoski F, Woloski M. Safety profile of WinRho anti-D. Semin Hematol 1998; 35 Suppl 1: 9-13.
- 3 Tarantino MD, Young G, Bertolone SJ, Kalinyak KA, Shafer FE, Kulkarni R, Weber LC, Davis ML, Lynn H, Nugent DJ; Acute ITP Study Group. Single dose of anti-D immune globulin at 75 µg/kg is as effective as intravenous immune globulin at rapidly raising the platelet count in newly diagnosed immune thrombocytopenic purpura in children. J Pediatr 2006; 148: 489-94.
- 4 Bussel J. Treatment of immune thrombocytopenic purpura in adults. Semin Hematol 2006; 43 3 Suppl 5: S3-S10.
- 5 Scaradavou A, Cunningham-Rundles S, Ho JL, Folman C, Doo H, Bussel JB. Superior effect of intravenous anti-D compared with IV gammaglobulin in the treatment of HIV-thrombocytopenia: results of a small, randomized prospective comparison. Am J Hematol 2007; 82: 335-41.
- 6 Scaradavou A, Woo B, Woloski BM, Cunningham-Rundles S, Ettinger LJ, Aledort LM, Bussel JB. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood 1997; 89: 2689-700.
- 7 George JN, Raskob GE, Vesely SK, Moore D Jr, Lyons RM, Cobos E, Towell BL, Klug P, Guthrie TH. Initial management of immune thrombocytopenic purpura in adults: a randomized controlled trial comparing intermittent anti-D with routine care. Am J Hematol 2003; 74: 161-9.
- 8 Bussel JB, Graziano JN, Kimberly RP, Pahwa S, Aledort LM. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood 1991; 77: 1884-93.
- 9 Kjaersgaard M, Hasle H. A review of anti-D treatment of childhood idiopathic thrombocytopenic purpura. Pediatr Blood Cancer 2006; 47 5 Suppl: 717-20.
- 10 Blanchette V, Adams M, Wang E, McMillan J, Imbach P, Andrew M, Milner R, Ali K, Barnard D, Bernstein M, Esseltine D, Chan KW, DeVeber B, Israels S, Kobrinsky N, Luke N. Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet 1994; 344: 703-7.
- 11 Freiberg A, Mauger D. Efficacy, safety, and dose response of intravenous anti-D immune globulin (WinRho SDF) for the treatment of idiopathic thrombocytopenic purpura in children. Semin Hematol 1998; 35 1 Suppl 1: 23-7.
- 12 Tarantino MD, Bolton-Maggs PH. Update on the management of immune thrombocytopenic purpura in children. Curr Opin Hematol 2007; 14: 526-34.
- 13 Tarantino MD, Bussel JB, Cines DB, McCrae KR, Gernsheimer T, Liebman HA, Wong WY, Kulkarni R, Grabowski E, McMillan R. A closer look at intravascular hemolysis (IVH) following intravenous anti-D for immune thrombocytopenic purpura (ITP) [letter. Blood 2007; 109: 5527.
- 14 Gaines AR. Acute onset hemoglobinemia and/or hemoglobinuria and sequelae following Rho(D) immune globulin intravenous administration in immune thrombocytopenic purpura patients. Blood 2000; 95: 2523-9.
- 15 Barbolla L, Nieto S, Llamas P, Moreno C, Contreras M, Lubenko A, Garner S. Severe immune haemolytic anaemia caused by intravenous immunoglobulin anti-D in the treatment of autoimmune thrombocytopenia [letter. Vox Sang 1993; 64: 184-5.
- 16 El Alfy MS, Mokhtar GM, El-Laboudy MA, Khalifa AS. Randomized trial of anti-D immunoglobulin versus low-dose intravenous immunoglobulin in the treatment of childhood chronic idiopathic thrombocytopenic purpura. Acta Haematol 2006; 115: 46-52.
- 17 Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia and/or hemoglobinuria following Rho(D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood 2005; 106: 1532-7.
- 18 Ortho Pharmaceuticals. Rho(D) immune globulin (Human): RhoGAM™[professional package insert]. In: Physician's desk reference. Oradell (NJ): Medical Economics; 1981.
- 19 Friesen AD, Bowman JM, Price HW. Column ion exchange preparation and characterization of an Rh immune globulin (WinRho) for intravenous use. J Appl Biochem 1981; 3: 164-75.
- 20 Bowman JM, Friesen AD, Pollock JM, Taylor WE. WinRho: Rh immune globulin prepared by ion exchange for intravenous use. Can Med Assoc J 1980; 123: 1121-7.
- 21 Yu X, Wagner FF, Witter B, Flegel WA. Outliers in RhD membrane integration are explained by variant RH haplotypes. Transfusion 2006; 46: 1343-51.
- 22 Sandler SG, Mallory D, Trimble J, Nance ST. Intravenous anti-D treatment for immune thrombocytopenic purpura [letter. Blood 1998; 91: 2624-5.
- 23
Klein HG,
Anstee DJ.
Mollison's blood transfusion in clinical medicine. Malden (MA): Blackwell Publishing Ltd; 2005.
10.1002/9780470986868 Google Scholar
- 24
Daniels G.
Human blood groups. Malden (MA): Blackwell Publishing Ltd; 2002.
10.1002/9780470987018 Google Scholar
- 25 Sandler SG. Intravenous Rh immune globulin for treating immune thrombocytopenic purpura. Curr Opin Hematol 2001; 8: 417-20.
- 26 Petz LD, Garratty G. Immune hemolytic anemias. Philadelphia (PA): Churchill Livingstone; 2004.
- 27 Harmening DM. Modern blood banking and transfusion practices. Philadelphia (PA): F.A. Davis; 2005.
- 28 Davenport RD. Pathophysiology of hemolytic transfusion reactions. Semin Hematol 2005; 42: 165-8.
- 29 Brecher M. Technical manual. Bethesda (MD): American Association of Blood Banks; 2005.
- 30 Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P. Hematology: basic principles and practice. New York: Churchill Livingstone; 2005.
- 31 Rushin J, Rumsey DH, Ewing CA, Sandler SG. Detection of multiple passively acquired alloantibodies following infusions of IV Rh immune globulin. Transfusion 2000; 40: 551-4.
- 32 Garratty G. Immune hemolytic anemia—a primer. Semin Hematol 2005; 42: 119-21.
- 33 Josephson CD, Mullis NC, Van Demark C, Hillyer CD. Significant numbers of apheresis-derived group O platelet units have “high-titer” anti-A/A,B: implications for transfusion policy. Transfusion 2004; 44: 805-8.
- 34 Harris SB, Josephson CD, Kost CB, Hillyer CD. Nonfatal intravascular hemolysis in a pediatric patient after transfusion of a platelet unit with high-titer anti-A. Transfusion 2007; 47: 1412-7.
- 35 Kim DD, Song WC. Membrane complement regulatory proteins. Clin Immunol 2006; 118: 127-36.
- 36 Yazdanbakhsh K. Review: complement receptor 1 therapeutics for prevention of immune hemolysis. Immunohematology 2005; 21: 109-18.
- 37 Garratty G. Do we really understand immune red cell destruction? [slide presentation. 25th Annual Scientific Meeting. Glasgow, Scotland: British Blood Transfusion Society; September 14, 2007. [cited 2008 Feb 9]. Available from: http://www.bbts.org.uk/diary/details.cfm?eventId=1268
- 38 Griffiths HL, Kumpel BM, Elson CJ, Hadley AG. The functional activity of human monocytes passively acquired with monoclonal anti-D suggests a novel role for Fc gamma RI in the immune destruction of blood cells. Immunology 1994; 83: 370-7.
- 39 Garratty G. Immune hemolytic anemia associated with negative routine serology. Semin Hematol 2005; 42: 156-64.
- 40 Chun NS, Savani B, Seder RH, Taplin ME. Acute renal failure after intravenous anti-D immune globulin in an adult with immune thrombocytopenic purpura. Am J Hematol 2003; 74: 276-9.
- 41 Kees-Folts D, Abt AB, Domen RE, Freiberg AS. Renal failure after anti-D globulin treatment of idiopathic thrombocytopenic purpura. Pediatr Nephrol 2002; 17: 91-6.
- 42 Levendoglu-Tugal O, Jayabose S. Intravenous anti-D immune globulin-induced intravascular hemolysis in Epstein-Barr virus-related thrombocytopenia. J Pediatr Hematol Oncol 2001; 23: 460-3.
- 43 Rewald MD, Francischetti MM. After eight-year-tolerance minimal i.v. anti-D infusions unleash hemolysis in a patient with immune thrombocytopenic purpura (ITP). Transfus Apher Sci 2004; 30: 105-10.
- 44 Olofinboba KA, Greenberg BR. Successful treatment of infectious mononucleosis-associated immune thrombocytopenia with WinRho anti-D immunoglobulin complicated by severe hemolysis [letter. Am J Hematol 2000; 65: 178.
- 45 Parker C. Intravenous Rho[D] immune globulin [human] (WinRho SDF): suspected hemolytic/renal adverse reactions. Can Med Assoc J 163: 881, 885.
- 46 Roberti I, Bagtas J, Reisman L, Murphy S. Severe acute renal failure due to hemoglobinuria after use of WinRho for the treatment of idiopathic thrombocytopenic purpura [letter. Clin Pediatr 2001; 40: 61-2.
- 47 Schwartz J, Spitalnik S, Grima KM. Severe hemolysis following administration of Rh(o)(D) immune globulin in an ITP patient associated with anti-C [letter. Blood 2006; 107: 2585.
- 48 Alioglu B, Avci Z, Ozyurek E, Ozbek N. Anti-D immunoglobulin-induced prolonged intravascular hemolysis and neutropenia. J Pediatr Hematol Oncol 2007; 29: 636-9.
- 49 Behring AG. Rho(D) immune globulin intravenous (human): Rhophylac [professional package insert]. Berne, Switzerland; CSL; 2007.
- 50 Meyer O, Kiesewetter H, Hermsen M, Salama A. Efficacy and safety of anti-D given by subcutaneous injection to patients with autoimmune thrombocytopenia [letter. Eur J Haematol 2004; 73: 71-2.
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