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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1257-1265. Prepublished online as a Blood First Edition Paper on November 7, 2007; DOI 10.1182/blood-2007-05-092684.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosisDepartments of1 Pediatrics and 2 Internal Medicine, University of Iowa Carver College of Medicine, Iowa City; 3 Department of Pediatrics, University of Cincinnati, OH; and 4 Veteran Affairs Medical Center, Iowa City, IA
Many of the cellular responses that occur in activated platelets resemble events that take place following activation of cell-death pathways in nucleated cells. We tested the hypothesis that formation of the mitochondrial permeability transition pore (MPTP), a key signaling event during cell death, also plays a critical role in platelet activation. Stimulation of murine platelets with thrombin plus the glycoprotein VI agonist convulxin resulted in a rapid loss of mitochondrial transmembrane potential (
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
m) in a subpopulation of activated platelets. In the absence of cyclophilin D (CypD), an essential regulator of MPTP formation, murine platelet activation responses were altered. CypD-deficient platelets exhibited defects in phosphatidylserine externalization, high-level surface fibrinogen retention, membrane vesiculation, and procoagulant activity. Also, in CypD-deficient platelet-rich plasma, clot retraction was altered. Stimulation with thrombin plus H2O2, a known activator of MPTP formation, also increased high-level surface fibrinogen retention, phosphatidylserine externalization, and platelet procoagulant activity in a CypD-dependent manner. In a model of carotid artery photochemical injury, thrombosis was markedly accelerated in CypD-deficient mice. These results implicate CypD and the MPTP as critical regulators of platelet activation and suggest a novel CypD-dependent negative-feedback mechanism regulating arterial thrombosis. 
