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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 23, 2004 Accepted July 25, 2004 Ultralarge complexes of heparin and PF4 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* Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA Cardeza Foundation for Hematologic Research, Jefferson Medical College, Philadelphia, PA, USA Division of Hematology, Duke University Medical Center, Durham, NC, USA Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA * Corresponding author; email: sachais{at}mail.med.upenn.edu. Heparin-induced thrombocytopenia/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 (ULC) only over a narrow molar range with an optimal ratio of PF4 to heparin ~1:1. These ULC were stable and visible by electron microscopy, but could be dissociated into smaller complexes upon addition of heparin. ULC formed inefficiently when PF4 was incubated with low molecular weight heparin, and none formed with the pentasaccharide fondaparinux. In addition, mutation studies showed that formation of ULC depended on the presence of PF4 tetramers. The ULC 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 ULC 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. Greinacher Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia Blood, November 1, 2006; 108(9): 2937 - 2941. [Abstract] [Full Text] [PDF] A. Greinacher, M. Gopinadhan, J.-U. Gunther, M. A. Omer-Adam, U. Strobel, T. E. Warkentin, G. Papastavrou, W. Weitschies, and C. A. Helm Close Approximation of Two Platelet Factor 4 Tetramers by Charge Neutralization Forms the Antigens Recognized by HIT Antibodies Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2386 - 2393. [Abstract] [Full Text] [PDF] L. Rauova, L. Zhai, M. A. Kowalska, G. M. Arepally, D. B. Cines, and M. Poncz Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications Blood, March 15, 2006; 107(6): 2346 - 2353. [Abstract] [Full Text] [PDF] G. M. Arepally The immune paradox of fondaparinux Blood, December 1, 2005; 106(12): 3686 - 3687. [Full Text] [PDF] T. E. Warkentin, R. J. Cook, V. J. Marder, J.-A. I. 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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