Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through Fc gamma RIIA

Heparin-induced thrombocytopenia/thrombosis (HIT/HITT) is a severe, life-th reatening complication that occurs in 1% to 3% of patients exposed to hepar in. Interactions between heparin, human platelet factor 4 (hPF4), antibodie s to the hPF4/heparin complex, and the platelet Fc receptor (FcR) for immun oglobulin G, Fc gamma RIIA, are the proposed primary determinants of the di sease on the basis of in vitro studies. The goal of this study was to creat e a mouse model that recapitulates the disease process in humans in order t o understand the factors that predispose some patients to develop thrombocy topenia and thrombosis and to investigate new therapeutic approaches. Mice that express both human platelet Fc gamma RIIA and hPF4 were generated. The Fc gamma RIIA/hPF4 mice and controls, transgenic for either Fc gamma RIIA or hPF4, were injected with KKO, a mouse monoclonal antibody specific for h PF4/heparin complexes, and then received heparin (20 U/d). Nadir platelet c ounts for KKO/heparin-treated Fc gamma RIIA/hPF4 mice were 80% below baseli ne values, significantly different (P <.001) from similarly treated control s. Fc<gamma>RIIA/hPF4 mice Injected with KKO and 50 U/d heparin developed s hock and showed fibrin-rich thrombi in multiple organs, including thrombosi s in the pulmonary vasculature. This is the first mouse model of HIT to rec apitulate the salient features of the human disease and demonstrates that F c gamma RIIA and hPF4 are both necessary and sufficient to replicate HIT/ H ITT in an animal model. This model should facilitate the identification of factors that modulate disease expression and the testing of novel therapeut ic interventions. (C) 2001 by The American Society of Hematology.