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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1515-1522.
Prepublished online as a Blood First Edition Paper on October 14, 2004; DOI 10.1182/blood-2004-05-1896.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Activated protein C induces the release of microparticle-associated endothelial protein C receptor
Margarita Pérez-Casal,
Colin Downey,
Kenji Fukudome,
Gernot Marx, and
Cheng Hock Toh
From the Roald Dahl Haemostasis and Thrombosis Centre and Department of Anaesthesia and Intensive Care Medicine, Royal Liverpool University Hospital, United Kingdom; and the Department of Immunology, Saga Medical School, Nabeshima, Saga, Japan.
Activated protein C (APC) treatment is now used for patients with severe sepsis. We investigated its effect in vitro on primary, physiologically relevant cells and demonstrate a novel mechanism of endothelial protein C receptor (EPCR) release that is not inhibited by metalloproteinase inhibitors. Exposure of human umbilical vein endothelial cells or monocytes to APC (6.25-100 nM) results in the release of EPCR-containing microparticles, as demonstrated by confocal microscopy and characterized through flow cytometry, enzyme-linked immunosorbent assay quantitation of isolated microparticles, and Western blotting. The phenomenon is time- and concentration-dependent and requires the APC active site, EPCR, and protease activated receptor 1 (PAR1) on endothelial cells. Neither protein C nor boiled or D-Phe-Pro-Arg-chloromethylketone–blocked APC can induce microparticle formation and antibody blockade of EPCR or PAR1 cleavage and activation abrogates this APC action. Coincubation with hirudin does not alter the APC effect. The released microparticle bound is full-length EPCR (49 kDa) and APC retains factor V–inactivating activity. Although tumor necrosis factor- (10 ng/mL) can also induce microparticle-associated EPCR release to a similar extent as APC (100 nM), it is only APC-induced microparticles that contain bound APC. This novel observation could provide new insights into the consequences of APC therapy in the septic patient.
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