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¹ Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, ² Department of Neurology, ³ Department of Neuroradiology, and ⁴ Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97078 Würzburg, Germany
⁵ Department of Neuroradiology, University of Heidelberg, 69120 Heidelberg, Germany

CORRESPONDENCE Bernhard Nieswandt: bernhard.nieswandt{at}virchow.uni-wuerzburg.de

Platelet activation and aggregation are essential to limit posttraumatic blood loss at sites of vascular injury but also contributes to arterial thrombosis, leading to myocardial infarction and stroke. Agonist-induced elevation of [Ca²⁺]_i is a central step in platelet activation, but the underlying mechanisms are not fully understood. A major pathway for Ca²⁺ entry in nonexcitable cells involves receptor-mediated release of intracellular Ca²⁺ stores, followed by activation of store-operated calcium (SOC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) has been identified as the Ca²⁺ sensor in the endoplasmic reticulum (ER) that activates Ca²⁺ release–activated channels in T cells, but its role in mammalian physiology is unknown. Platelets express high levels of STIM1, but its exact function has been elusive, because these cells lack a normal ER and Ca²⁺ is stored in a tubular system referred to as the sarcoplasmatic reticulum. We report that mice lacking STIM1 display early postnatal lethality and growth retardation. STIM1-deficient platelets have a marked defect in agonist-induced Ca²⁺ responses, and impaired activation and thrombus formation under flow in vitro. Importantly, mice with STIM1-deficient platelets are significantly protected from arterial thrombosis and ischemic brain infarction but have only a mild bleeding time prolongation. These results establish STIM1 as an important mediator in the pathogenesis of ischemic cardio- and cerebrovascular events.

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