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Procoagulant microparticles promote coagulation in a factor XI ‐dependent manner in human endotoxemia
Author(s) -
Mooberry M. J.,
Bradford R.,
Hobl E. L.,
Lin F. C.,
Jilma B.,
Key N. S.
Publication year - 2016
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13285
Subject(s) - coagulation , tissue factor , blood coagulation factors , medicine , chemistry , immunology
Essentials The procoagulant effects of microparticles (MPs) on coagulation in endotoxemia are not known. MPs from endotoxemia volunteers were evaluated for procoagulant activity in a plasma milieu. MPs from endotoxemia volunteers shortened clotting times and enhanced thrombin generation. MP procoagulant effects were mediated in a factor XI‐dependent manner.Summary Background Human endotoxemia is characterized by acute inflammation and activation of coagulation, as well as increased numbers of circulating microparticles ( MP s). Whether these MP s 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 MP s and their procoagulant properties using several approaches. Methods Enumeration and characterization of MP s 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 factor (F) VII or FXI or with blocking antibodies to tissue factor ( TF ) or FXI a. Results Total MP s and platelet MP s were significantly elevated in plasma at 6 h after infusion of endotoxin in healthy human subjects. MP s isolated from plasma following endotoxin infusion also demonstrated increased TF activity in a reconstituted buffer system. When added to recalcified platelet‐poor plasma, these MP s 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 FXI a 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 MP s.