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Blood, 1 January 2005, Vol. 105, No. 1, pp. 131-138. Prepublished online as a Blood First Edition Paper on August 10, 2004; DOI 10.1182/blood-2004-04-1544. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-04-1544v1 105/1/131    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rauova, L. Articles by Sachais, B. S. Search for Related Content PubMed PubMed Citation Articles by Rauova, L. Articles by Sachais, B. S. Related Collections Hemostasis, Thrombosis, and Vascular Biology Free Research Articles Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia Lubica Rauova, Mortimer Poncz, Steven E. McKenzie, Michael P. Reilly, Gowthami Arepally, John W. Weisel, Chandrasekaran Nagaswami, Douglas B. Cines, and Bruce S. Sachais From the Division of Hematology, Children's Hospital of Philadelphia, PA; the Cardeza Foundation for Hematologic Research, Jefferson Medical College, Philadelphia, PA; the Division of Hematology, Duke University Medical Center, Durham, NC; the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia; and the Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia. Heparin-induced thrombocytopenia and thrombosis (HITT) is a severe complication of heparin therapy caused by antibodies to complexes between unfractionated heparin (UFH) and platelet factor 4 (PF4) that form over a narrow molar range of reactants and initiate antibody-induced platelet activation. We observed that UFH and tetrameric PF4 formed ultralarge (> 670 kDa) complexes (ULCs) only over a narrow molar range with an optimal ratio of PF4 to heparin of approximately 1:1. These ULCs were stable and visible by electron microscopy, but they could be dissociated into smaller complexes upon addition of heparin. ULCs formed inefficiently when PF4 was incubated with low-molecular-weight heparin, and none formed with the pentasaccharide fondaparinux sodium. In addition, mutation studies showed that formation of ULCs depended on the presence of PF4 tetramers. The ULCs were more reactive as determined by their capacity to bind to a HITT-like monoclonal antibody and showed greater capacity to promote platelet activation in an antibody- and FcRIIA-dependent manner than were the smaller complexes. The capacity of PF4 to form ULCs composed of multiple PF4 tetramers arrayed in a lattice with several molecules of UFH may play a fundamental role in autoantibody formation, antibody-dependent platelet activation, and the propensity for thrombosis in patients with HITT. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: New insights in heparin-induced thrombocytopenia Michael H. Rosove Blood 2005 105: 4-5. [Full Text] [PDF] This article has been cited by other articles: J. G. Kelton and T. E. Warkentin Heparin-induced thrombocytopenia: a historical perspective Blood, October 1, 2008; 112(7): 2607 - 2616. [Full Text] [PDF] K. Kuczka, S. Harder, B. Picard-Willems, A. Warnke, F. Donath, P. Bianchini, B. Parma, and H. Blume Biomarkers and Coagulation Tests for Assessing the Biosimilarity of a Generic Low-Molecular-Weight Heparin: Results of a Study in Healthy Subjects With Enoxaparin J. Clin. Pharmacol., October 1, 2008; 48(10): 1189 - 1196. [Abstract] [Full Text] [PDF] S. Suvarna, B. Espinasse, R. Qi, R. Lubica, M. Poncz, D. B. Cines, M. R. Wiesner, and G. M. Arepally Determinants of PF4/heparin immunogenicity Blood, December 15, 2007; 110(13): 4253 - 4260. [Abstract] [Full Text] [PDF] T. E. Warkentin, J.-A. I. Sheppard, C. S. Sigouin, T. Kohlmann, P. Eichler, and A. 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Sheppard, J. C. Moore, B. I. Eriksson, A. Greinacher, and J. G. Kelton Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin Blood, December 1, 2005; 106(12): 3791 - 3796. [Abstract] [Full Text] [PDF] S. Suvarna, L. Rauova, E. K. E. McCracken, C. M. Goss, B. S. Sachais, S. E. McKenzie, M. P. Reilly, M. D. Gunn, D. B. Cines, M. Poncz, et al. PF4/heparin complexes are T cell-dependent antigens Blood, August 1, 2005; 106(3): 929 - 931. [Abstract] [Full Text] [PDF]

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