M J Mooberry1, R Bradford2, E L Hobl3, F C Lin4, B Jilma3, N S Key1,2. 1. Department of Medicine, University of North Carolina, Chapel Hill, NC, USA. 2. McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA. 3. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. 4. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
Abstract
UNLABELLED: 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 (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 factor (F) VII 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 h after infusion of endotoxin in healthy human subjects. MPs isolated from plasma following endotoxin infusion also demonstrated increased TF activity in a reconstituted buffer system. When added to recalcified 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.
UNLABELLED: 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 Humanendotoxemia 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 factor (F) VII 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 h after infusion of endotoxin in healthy human subjects. MPs isolated from plasma following endotoxin infusion also demonstrated increased TF activity in a reconstituted buffer system. When added to recalcified 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.
Authors: P E J Van Der Meijden; M Van Schilfgaarde; R Van Oerle; T Renné; H ten Cate; H M H Spronk Journal: J Thromb Haemost Date: 2012-07 Impact factor: 5.824
Authors: F B Mayr; A O Spiel; J M Leitner; C Firbas; P Jilma-Stohlawetz; J-Y Chang; N S Key; B Jilma Journal: J Thromb Haemost Date: 2009-01-24 Impact factor: 5.824
Authors: M C Minnema; D Pajkrt; W A Wuillemin; D Roem; W K Bleeker; M Levi; S J van Deventer; C E Hack; H ten Cate Journal: Blood Date: 1998-11-01 Impact factor: 22.113
Authors: Reed W Kamyszek; Matthew W Foster; Brooke A Evans; Keaton Stoner; Jessica Poisson; Amudan J Srinivasan; J Will Thompson; M Arthur Moseley; Micah J Mooberry; Ian J Welsby Journal: Blood Transfus Date: 2020-08-06 Impact factor: 3.443
Authors: Bethany L Walton; Marcus Lehmann; Tyler Skorczewski; Lori A Holle; Joan D Beckman; Jeremy A Cribb; Micah J Mooberry; Adam R Wufsus; Brian C Cooley; Jonathan W Homeister; Rafal Pawlinski; Michael R Falvo; Nigel S Key; Aaron L Fogelson; Keith B Neeves; Alisa S Wolberg Journal: Blood Date: 2017-03-01 Impact factor: 22.113
Authors: Wolfgang Bergmeier; Silvio Antoniak; Edward M Conway; Cécile V Denis; Lindsey A George; Berend Isermann; Nigel S Key; Sriram Krishnaswamy; Wilbur A Lam; David Lillicrap; Jian Liu; Mark R Looney; José A López; Coen Maas; Flora Peyvandi; Wolfram Ruf; Anil K Sood; Henri H Versteeg; Alisa S Wolberg; Pancras C Wong; Jeremy P Wood; Hartmut Weiler Journal: Res Pract Thromb Haemost Date: 2018-04-12