Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia

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...

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Bibliographic Details
Published in:	Blood 2005-01, Vol.105 (1), p.131-138
Main Authors:	Rauova, Lubica, Poncz, Mortimer, McKenzie, Steven E., Reilly, Michael P., Arepally, Gowthami, Weisel, John W., Nagaswami, Chandrasekaran, Cines, Douglas B., Sachais, Bruce S.
Format:	Article
Language:	eng
Subjects:	Animals Antibodies, Monoclonal Biological and medical sciences Chromatography, High Pressure Liquid Drug toxicity and drugs side effects treatment Hematologic and hematopoietic diseases Heparin - chemistry Heparin - pharmacology Heparin - ultrastructure Humans Medical sciences Microscopy, Electron, Transmission Models, Molecular Mutagenesis, Site-Directed Pharmacology. Drug treatments Platelet Activation - drug effects Platelet Activation - immunology Platelet diseases and coagulopathies Platelet Factor 4 - chemistry Platelet Factor 4 - genetics Platelet Factor 4 - metabolism Platelet Factor 4 - ultrastructure Protein Binding Protein Structure, Tertiary Swine Thrombocytopenia - chemically induced Thrombocytopenia - metabolism Toxicity: blood
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Summary:	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 FcγRIIA-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.
ISSN:	0006-4971 1528-0020