Procoagulant microparticles promote coagulation in a factor XI‐dependent manner in human endotoxemia

BACKGROUND: Human endotoxemia is characterized by acute inflammation and activation of coagulation, as well as increased numbers of circulating microparticles (MPs). Whether these MPs directly promote coagulation and through which pathway their actions are mediated, however, has not been fully explored. OBJECTIVES: In this study, we aimed to further characterize endotoxin-induced MPs and their procoagulant properties using several approaches. METHODS: Enumeration and characterization of MPs were performed using a new generation flow cytometer. Relative contributions of the extrinsic and intrinsic pathways in MP-mediated procoagulant activity were assessed using plasmas deficient in FVII or FXI or with blocking antibodies to tissue factor (TF) or FXIa. RESULTS: Total MPs and platelet MPs were significantly elevated in plasma at 6 hours after infusion of endotoxin in healthy human subjects. MPs isolated from plasma following endotoxin infusion also demonstrated increased TF activity in a re-constituted buffer system. When added to re-calcified platelet poor plasma, these MPs also promoted coagulation, as judged by a decreased clotting time with shortening of the lag time and time to peak thrombin using calibrated automated thrombography (CAT). However, the use of FVII deficient plasma or blocking antibody to TF did not inhibit these procoagulant effects. In contrast, plasma clotting time was prolonged in FXI deficient plasma, and a blocking antibody to FXIa inhibited all MP-mediated parameters in the CAT assay. CONCLUSIONS: The initiation of coagulation by cellular TF in endotoxemia is in contrast to (and presumably complemented by) the intrinsic pathway-mediated procoagulant effects of circulating MPs