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Pharmacodynamics of active site‐inhibited factor VIIa in endotoxin‐induced coagulation in humans
Author(s) -
Jilma Bernd,
Marsik Claudia,
Mayr Florian,
Graninger Monika T.,
Taylor Fletcher B.,
Ribel Mette C.,
Erhardtsen Elisabeth,
Handler Sylvia,
Eichler Hans Georg
Publication year - 2002
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2002.127740
Subject(s) - tissue factor , fibrin , medicine , pharmacodynamics , fibrinolysis , pharmacology , thrombomodulin , coagulation , sepsis , thrombin , factor vii , partial thromboplastin time , tissue factor pathway inhibitor , factor x , platelet activation , prothrombin time , thromboplastin , immunology , platelet , pharmacokinetics
Background Inhibition of the tissue factor‐factor VIIa pathway attenuated the activation of coagulation and prevented death in a gram‐negative bacteremia primate model of sepsis. This lethal animal model suggested that tissue factor also influences inflammatory cascades. Methods This trial examined the pharmacodynamic effects of active site‐inhibited factor VIIa (FFR‐recombinant factor VIIa [rFVIIa]; ASIS) on endotoxin‐induced procoagulant, fibrinolytic, and inflammatory responses in healthy humans. A double‐blind, randomized, placebo‐controlled, parallel‐group study was conducted in 12 healthy male volunteers. Subjects received a bolus infusion of 2‐ng/kg endotoxin, followed by a bolus infusion of ASIS (400 μg/kg) or placebo 10 minutes later. Results Endotoxin injection induced inflammation, activation of coagulation, and activation and subsequent inhibition of fibrinolysis. ASIS infusion completely blocked thrombin and fibrin generation, as measured by plasma levels of prothrombin fragment (no increase in the ASIS group, as compared with a 13‐fold increase in the placebo group at 4 hours; P < .01), soluble fibrin, and fibrin split product D‐dimer. ASIS did not alter endotoxin‐induced changes in the fibrinolytic system, cytokine levels, or markers of endothelial (E‐selectin, thrombomodulin) or platelet (P‐selectin) activation. Conclusions In summary, ASIS effectively and selectively attenuates tissue factor‐induced thrombin generation. Because ASIS was well tolerated, this study provides seminal data to further characterize its anticoagulant and putative anti‐inflammatory effects in critically ill patients. Clinical Pharmacology & Therapeutics (2002) 72 , 403–410; doi: 10.1067/mcp.2002.127740