Heparin-induced thrombocytopenia: an autoimmune disorder regulated through dynamic autoantigen assembly/disassembly.

Published

Journal Article (Review)

Heparin-induced thrombocytopenia (HIT) is the most common drug-induced, antibody-mediated cause of thrombocytopenia and thrombosis. HIT is caused by IgG antibodies that bind to epitopes on platelet factor 4 (PF4) released from activated platelets that develop when it forms complexes with heparin. Anti-PF4/antibodies develop in over 50% of patients undergoing surgery involving cardiopulmonary bypass (CPB), an incidence 20-fold higher than HIT. Why might this occur? Binding of HIT IgG occurs only over a narrow molar ratio of reactants, being optimal at 1 mol PF4 tetramer to 1 mol unfractionated heparin (UFH). At these ratios, PF4 and UFH form ultralarge (>670 kD) complexes that bind multiple IgG molecules/complex, are highly antigenic, and promote platelet activation. Low molecular weight heparin (LMWH), which is less antigenic, forms ultralarge complexes less efficiently and largely at supratherapeutic concentrations. In transgenic mice that vary in expression of human PF4 on their platelets, antigenic complexes form between PF4 and endogenous chondroitin sulfate. Binding of HIT IgG to platelets and induction of thrombocytopenia in vivo is proportional to PF4 expression. Heparin prolongs the duration and exacerbates the severity of the thrombocytopenia. High doses of heparin, as used in CPB, or protamine, which competes with PF4 for heparin, disrupts antigen formation and prevents thrombocytopenia induced by HIT antibody. These studies may help explain the disparity between the incidence of antibody formation and clinical disease and may help identify patients at risk for HIT (high platelet PF4). They also demonstrate that this autoimmune disease can be modulated at the level of autoantigen formation and point to rational means to intervene proximal to thrombin generation.

Full Text

Duke Authors

Cited Authors

  • Cines, DB; Rauova, L; Arepally, G; Reilly, MP; McKenzie, SE; Sachais, BS; Poncz, M

Published Date

  • February 2007

Published In

Volume / Issue

  • 22 / 1

Start / End Page

  • 31 - 36

PubMed ID

  • 17285619

Pubmed Central ID

  • 17285619

International Standard Serial Number (ISSN)

  • 0733-2459

Digital Object Identifier (DOI)

  • 10.1002/jca.20109

Language

  • eng

Conference Location

  • United States