Role of a JAK3-dependent biochemical signaling pathway in platelet activation and aggregation

Here we provide experimental evidence that identifies JAK3 as one of the re gulators of platelet function. Treatment of platelets with thrombin induced tyrosine phosphorylation of the JAK3 target substrates STAT1 and STAT3. Pl atelets from JAK3-deficient mice displayed a decrease in tyrosine phosphory lation of STAT1 and STAT3. In accordance with these data, pretreatment of h uman platelets with the JAK3 inhibitor WHI-P1E1 markedly decreased the base -line enzymatic activity of constitutively active JAK3 and abolished the th rombin-induced tyrosine phosphorylation of STAT1 and STAT3. Following throm bin stimulation, WHI-P131-treated platelets did not undergo shape changes i ndicative of activation such as pseudopod formation. WHI-P131 inhibited thr ombin-induced degranulation/serotonin release as well as platelet aggregati on. Highly effective platelet inhibitory plasma concentrations of WHI-P131 were achieved in mice without toxicity. WHI-P131 prolonged the bleeding tim e of mice in a dose-dependent manner and improved event-free survival in a mouse model of thromboplastin-induced generalized and invariably fatal thro mboembolism. To our knowledge, WHI-P131 is the first anti-thrombotic agent that prevents platelet aggregation by inhibiting JAK3.