THROMBOSIS AND HEMOSTASIS Intracellular cyclophilin A is an important Ca2 regulator in platelets and critically involved in arterial thrombus formation

Platelet adhesion and aggregation play a critical role in primary hemostasis. Uncontrolled platelet activation leads to pathologic thrombus formation and organ failure. The decisive central step for different processes of platelet activation is the increase in cytosolic Ca2 activity ([Ca2 ]i). Activation-dependent depletion of intracellular Ca2 stores triggers Ca2 entry from the extracellular space. Stromal interaction molecule 1 (STIM1) has been identified as a Ca2 sensor that regulates store-operated Ca2 entry through activation of the pore-forming subunit Orai1, the major store-operated Ca2 entry channel in platelets. In the present study, we show for the first time that the chaperone protein cyclophilin A (CyPA) acts as a Ca2 modulator in platelets. CyPA deficiency strongly blunted activation-induced Ca2 mobilization from intracellular stores and Ca2 influx from the extracellular compartment and thus impaired platelet activation substantially. Furthermore, the phosphorylation of the Ca2 sensor STIM1 was abrogated upon CyPA deficiency, as shown by immunoprecipitation studies. In a mouse model of arterial thrombosis, CyPAdeficient mice were protected against arterial thrombosis, whereas bleeding time was not affected. The results of the present study identified CyPA as an important Ca2 regulator in platelets, a critical mechanism for arterial thrombosis. (Blood. 2012;120(6):1317-1326)