Platelet 12-LOX is essential for FcγRIIa-mediated platelet activation.

[heparin-induced thrombocytopenia]

Platelets are essential in maintaining hemostasis following inflammation or injury to the vasculature . Dysregulated platelet activity often results in thrombotic complications leading to myocardial infarction and stroke . Activation of the FcγRIIa receptor leads to immune-mediated thrombosis , which is often life threatening in patients undergoing heparin-induced thrombocytopenia or sepsis . Inhibiting FcγRIIa-mediated activation in platelets has been shown to limit thrombosis and is the principal target for prevention of immune-mediated platelet activation . In this study , we show for the first time that platelet 12 (S )-lipoxygenase (12 -LOX ), a highly expressed oxylipin-producing enzyme in the human platelet , is an essential component of FcγRIIa-mediated thrombosis . Pharmacologic inhibition of 12 -LOX in human platelets resulted in significant attenuation of FcγRIIa-mediated aggregation . Platelet 12 -LOX was shown to be essential for FcγRIIa-induced phospholipase Cγ 2 activity leading to activation of calcium mobilization , Rap 1 and protein kinase C activation , and subsequent activation of the integrin αIIbβ 3 . Additionally , platelets from transgenic mice expressing human FcγRIIa but deficient in platelet 12 -LOX , failed to form normal platelet aggregates and exhibited deficiencies in Rap 1 and αIIbβ 3 activation . These results support an essential role for 12 -LOX in regulating FcγRIIa-mediated platelet function and identifies 12 -LOX as a potential therapeutic target to limit immune-mediated thrombosis .