HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Roles of protease-activated receptors in a mouse model of endotoxemia

Endotoxemia is often associated with ex-treme inflammatory responses and dis-seminated intravascular coagulation. Pro-tease-activated receptors (PARs) mediate cellular responses to coagulation pro-teases, including platelet activation and endothelial cell reactions predicted to pro-mote inflammation. These observations suggested that PAR activation by coagu-lation proteases generated in the setting of endotoxemia might promote platelet activation, leukocyte-mediated endothe-lial injury, tissue damage, and death. To-ward testing these hypotheses, we exam-ined the effect of PAR deficiencies that ablate platelet and endothelial activation by coagulation proteases in a mouse en-dotoxemia model. Although coagulation was activated as measured by thrombin-antithrombin (TAT) production and anti-thrombin III (ATIII) depletion, Par1/, Par2/, Par4/, Par2/:Par4/, and Par1/:Par2/ mice all failed to show improved survival or decreased cytokine responses after endotoxin challenge com-pared with wild type. Thus, our results fail to support a necessary role for PARs in linking coagulation to inflammation or death in this model. Interestingly, endotox-in-induced thrombocytopenia was not di-minished in Par4/ mice. Thus, a mecha-nism independent of platelet activation by thrombin was sufficient to cause thrombocytopenia in our model. These results raise the possibility that decreases in platelet count in the setting of sepsis may not be caused by disseminated intra-vascular coagulation but instead report on a sometimes parallel but independent process. (Blood. 2006;107:3912-3921) © 2006 by The American Society of Hematolog