Disabled-2 Is Required for Efficient Hemostasis and Platelet Activation by Thrombin in Mice

Objective—The essential role of platelet activation in hemostasis and thrombotic diseases focuses attention on unveiling the underlying intracellular signals of platelet activation. Disabled-2 (Dab2) has been implicated in platelet aggregation and in the control of clotting responses. However, there is not yet any in vivo study to provide direct evidence for the role of Dab2 in hemostasis and platelet activation. Approach and Results—Megakaryocyte lineage-restricted Dab2 knockout (Dab2−/−) mice were generated to delineate in vivo functions of Dab2 in platelets. Dab2−/− mice appeared normal in size with prolonged bleeding time and impaired thrombus formation. Although normal in platelet production and granule biogenesis, Dab2−/− platelets elicited a selective defect in platelet aggregation and spreading on fibrinogen in response to low concentrations of thrombin, but not other soluble agonists. Investigation of the role of Dab2 in thrombin signaling revealed that Dab2 has no effect on the expression of thr...