Semin Thromb Hemost 2004; 30(5): 559-568
DOI: 10.1055/s-2004-835676
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Heparin-Induced Thrombocytopenia and Other Immune Thrombocytopenias: Lessons from Mouse Models

Steven E. McKenzie1 , 2 , Michael P. Reilly2
  • 1Professor of Medicine and Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania
  • 2Cardeza Foundation for Hematologic Research and Division of Hematology, Departments of Medicine and Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania
Further Information

Publication History

Publication Date:
21 October 2004 (online)

The prototype immune thrombocytopenia is (auto)immune thrombocytopenic purpura, ITP. The major issues in the pathophysiology, diagnosis, and therapy of ITP are presented. Mouse models of the pathophysiology of ITP have allowed greater understanding of the role of antiplatelet antibodies and of antibody effector mechanisms. In addition, there has been a substantial increase in interest in the use of mouse models to understand the mechanisms of action of therapeutics for ITP, with notable progress for intravenous immunoglobulin (IVIG) and anti-red blood cell therapies. The immune-mediated thrombocytopenia and thrombosis syndromes are a common cause of morbidity and mortality; the prototype is heparin-induced thrombocytopenia and thrombosis (HITT). There has been substantial progress in understanding the pathophysiology, diagnosis, and therapy of HITT in the last decade, but there remain major questions. The four necessary and sufficient elements for HITT in vivo were established in our mouse model (namely platelet factor 4 [PF4], heparin, antibody to the heparin/PF4 complex, and platelet Fc receptor for immunoglobulin G [FcγRIIa]). Currently, our HITT mouse models are being used to address a number of questions. For example, what are the roles of antibody titer, isotype, and epitope targets? Are there genetic determinants of platelet activation, such as the platelet FcγRIIa receptor density, operable in HITT? What are the roles of tissue factor/factor VIIa (TF/VIIa), monocytes, and blood cell-derived microparticles? What is the contribution of pre-existing endothelial cell (EC) dysfunction, and/or induced EC dysfunction? As in many human disorders, preclinical mouse models will continue to be important in the immune thrombocytopenia syndromes to achieve translation into improved patient care.

REFERENCES

  • 1 McMillan R. Antiplatelet antibodies in chronic adult immune thrombocytopenic purpura: assays and epitopes.  J Pediatr Hematol Oncol. 2003;  25(suppl 1) S57-S61
  • 2 Beardsley D S. Pathophysiology of immune thrombocytopenic purpura.  Blood Rev. 2002;  16 13-14
  • 3 Beardsley D S. Platelet autoantibodies in immune thrombocytopenic purpura.  Transfus Sci. 1998;  19 237-244
  • 4 McMillan R. Autoantibodies and autoantigens in chronic immune thrombocytopenic purpura.  Semin Hematol. 2000;  37 239-248
  • 5 George J N, Woolf S H, Raskob G E et al.. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology.  Blood. 1996;  88 3-40
  • 6 Vesley S K, Buchanan G R, Adix L et al.. Self-reported initial management of childhood idiopathic thrombocytopenic purpura: results of a survey of members of the American Society of Pediatric Hematology/Oncology.  J Pediatr Hematol Oncol. 2003;  25 130-133
  • 7 Drachman J G. Inherited thrombocytopenia: when a low platelet count does not mean ITP.  Blood. 2004;  103 390-398
  • 8 Aggarwal A, Catlett J P. Rituximab: an anti-CD20 antibody for the treatment of chronic refractory immune thrombocytopenic purpura.  South Med J. 2002;  95 1209-1212
  • 9 Giagounidis A A, Anhuf J, Schneider P et al.. Treatment of relapsed idiopathic thrombocytopenic purpura with the anti-CD20 monoclonal antibody rituximab: a pilot study.  Eur J Haematol. 2002;  69 95-100
  • 10 Kuwana M, Nomura S, Fujimura K et al.. Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet-specific autoimmune response in patients with immune thrombocytopenic purpura.  Blood. 2004;  103 1229-1236
  • 11 Kuwana M, Kawakami Y, Ikeda Y. Suppression of autoreactive T-cell response to glycoprotein IIb/IIIa by blockade of CD40/CD154 interaction: implications for treatment of immune thrombocytopenic purpura.  Blood. 2003;  101 621-623
  • 12 Riksen N P, Keuning J J, Vreugdenhil G. Rituximab in the treatment of relapsing idiopathic thrombocytopenic purpura.  Neth J Med. 2003;  61 262-265
  • 13 Shanafelt T D, Madueme H L, Wolf R C, Tefferi A. Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome.  Mayo Clin Proc. 2003;  78 1340-1346
  • 14 Schwartz J, Bussel J B. Anti-CD40L: biology and therapy in ITP.  Blood. 2004;  103 1178-1179
  • 15 Nomura S, Dan K, Hotta T, Fujimura K, Ikeda Y. Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura.  Blood. 2002;  100 728-730
  • 16 Chang M, Nakagawa P A, Williams S A et al.. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro .  Blood. 2003;  102 887-895
  • 17 Amiral J, Bridey F, Dreyfus M et al.. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia.  Thromb Haemost. 1992;  68 95-96
  • 18 Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen.  Thromb Haemost. 1994;  71 247-251
  • 19 Kelton J G, Smith J W, Warkentin T E, Hayward C P, Denomme G A, Horsewood P. Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4.  Blood. 1994;  83 3232-3239
  • 20 Mizutani H, Engelman R W, Kurata Y, Ikehara S, Good R A. Development and characterization of monoclonal antiplatelet autoantibodies from autoimmune thrombocytopenic purpura-prone (NZW x BXSB)F1 mice.  Blood. 1993;  82 837-844
  • 21 McKenzie S E, Schreiber A D. Biological advances and clinical applications of Fc receptors for IgG.  Curr Opin Hematol. 1994;  1 45-52
  • 22 Qiu W Q, de Bruin D, Brownstein B H, Pearse R, Ravetch J V. Organization of the human and mouse low-affinity FcγR genes.  Science. 1990;  248 732-735
  • 23 McKenzie S E, Taylor S M, Malladi P et al.. The role of the human Fc receptor/FcγRIIA in the immune clearance of platelets: a transgenic mouse model.  J Immunol. 1999;  162 4311-4318
  • 24 Clynes R, Ravetch J V. Cytotoxic antibodies trigger inflammation through Fc receptors.  Immunity. 1995;  3 21-26
  • 25 Samuelsson A, Towers T, Ravetch J. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor.  Science. 2001;  291 484-486
  • 26 Crow A R, Song S, Semple J, Freedman J, Lazarus A. IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity.  Br J Haematol. 2001;  115 679-686
  • 27 Hansen R J, Balthasar J P. Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia.  Blood. 2002;  100 2087-2093
  • 28 Arepally G M, Kamei S, Park K S et al.. Characterization of a murine monoclonal antibody that mimics heparin-induced thrombocytopenia antibodies.  Blood. 2000;  95 1533-1540
  • 29 Reilly M P, Taylor S M, Hartman N K, Arepally G, Cines D B, Poncz M. Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcγRIIA.  Blood. 2001;  98 2442-2447
  • 30 Rauova L, Poncz M, McKenzie S E et al.. High molecular weight complexes of heparin and PF4 are central to the pathogenesis of heparin-induced thrombocytopenia.  Blood. 2003;  102 126A
  • 31 Arepally G M, Mayer I M. Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8.  Blood. 2001;  98 1252-1254
  • 32 Pouplard C, Iochmann S, Renard B et al.. Induction of monocyte tissue factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia.  Blood. 2001;  97 3300-3302
  • 33 George J, Mulkins M, Casey S, Schatzman R, Sigal E, Harats D. The effects of N-6 polyunsaturated fatty acid supplementation on the lipid composition and atherogenesis in mouse models of atherosclerosis.  Atherosclerosis. 2000;  150 285-293

Steven E McKenzieM.D. Ph.D. 

Cardeza Foundation for Hematologic Research and Division of Hematology, Departments of Medicine and Pediatrics, Thomas Jefferson University

1015 Walnut St., Room 705

Philadelphia, PA 19107

Email: steven.mckenzie@mail.tju.edu