Insights from mouse models of heparin-induced thrombocytopenia and thrombosis.
Heparin-induced thrombocytopenia/thrombosis (HIT/T) is the most frequent cause of drug-induced antibody-mediated thrombocytopenia, a common cause of life-and limb-threatening platelet activation and thrombosis. Although antibodies to heparin-platelet factor 4 (PF4) complexes are found in essentially all patients with HIT/T, it is unclear how antibody formation is initiated, why only a small subset of these antibodies cause disease, or the mechanism by which they initiate thrombosis. The recent development of a transgenic mouse model of HIT/T showed, for the first time in vivo, that heparin, PF4, antibodies to the heparin-PF4 complex, and Fc gamma RIIA are necessary and sufficient to recapitulate the severe thrombocytopenia and thrombosis seen in patients. This model can be expanded to systematically study individual factors important to HIT/T development in vivo, to determine their contribution to the spectrum of human disease. Several recent papers have examined the role of other contributors, such as monocyte tissue factor, endothelial cell activation, and leukocyte-platelet aggregates in the pathogenesis of the disease. Mouse models will provide a means to test new diagnostic and therapeutic approaches.
Reilly
Michael P
MP
Cardeza Foundation for Hematologic Research and Division of Hematology, Department of Medicine, Thomas Jefferson University, 1015 Walnut Street - Room 705, Philadelphia, Pennsylvania 19107, USA. michael.reilly@mail.tju.edu
McKenzie
Steven E
SE
D000818:Animals; D000917:Antibody Formation; D006493:Heparin / Q000009:adverse effects* / Q000276:immunology; D051379:Mice; D023421:Models, Animal; D010978:Platelet Factor 4 / Q000276:immunology; D011961:Receptors, Fc / Q000502:physiology; D013921:Thrombocytopenia / Q000139:chemically induced*; D013927:Thrombosis / Q000139:chemically induced*
D011961:Receptors, Fc; D010978:Platelet Factor 4; D006493:Heparin