Role of Syk tyrosine kinase in the mechanism of platelet activation and thrombosis in heparin-induced thrombocytopenia (HIT). Platelet factor 4 (PF4) released from platelet α-granules binds with high affinity to heparin through a charge-charge interaction. The heparin-PF4 complex acts as an immunogen, and exposure to heparin after an initial sensitization will lead to the formation of immune complexes, in which the heparin-PF4 aggregates are coated with IgG. These circulating immune complexes activate blood cells expressing Fcγ receptors, including human platelets that express FcγRIIA. After binding to the immune complex, this receptor signals through Syk and activation of phospholipase Cγ2, leading to platelet shape change, aggregation and secretion of granule contents, including ADP. Platelet aggregates form thrombi, which lead to ischemic disease complications characteristic of HIT. (Professional illustration by Marie Dauenheimer.)