title: Enhancement of fibrinolytic potential in vitro by anticoagulant drugs targeting activated factor X, but not by those inhibiting thrombin or tissue factor.
abstract: Tissue factor-induced coagulation leads to the generation of a small amount of thrombin, resulting in the formation of a fibrin clot. After clot formation, thrombin generation continues resulting in the activation of thrombin activatable fibrinolysis inhibitor, leading to downregulation of fibrinolysis. In this study, the effect of anticoagulant drugs targeting different steps in the coagulation cascade on clot formation and subsequent breakdown was investigated using a plasma-based clot lysis assay. All drugs tested significantly delayed clot formation; only those drugs targeting activated factor X (FXa) (tissue factor pathway inhibitor, fondaparinux, and low molecular weight heparin) accelerated fibrinolysis. Anticoagulant drugs targeting tissue factor (active site-inactivated recombinant activated factor VII) or thrombin (hirudin and d-phenylalanyl-l-prolyl-l-arginyl chloromethyl ketone) did not affect clot lysis time. In accordance with these findings, it was shown that total thrombin generation, as quantified by the endogenous thrombin potential, was only affected by anticoagulant drugs targeting FXa when all drugs were used in a concentration resulting in doubling of clotting time. Induction of hyperfibrinolysis by anticoagulant drugs directed against FXa might be beneficial as increased clot breakdown might facilitate thrombolysis or prevent re-occlusion. On the other hand, the induction of hyperfibrinolysis by these compounds might increase the risk of bleeding complications.
authors.affiliation: Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Centre, Utrecht, The Netherlands. j.a.lisman@azu.nl
authors.forename: Ton
authors.initials: T
authors.lastname: Lisman
authors.forename: Jelle
authors.initials: J
authors.lastname: Adelmeijer
authors.forename: H Karel
authors.initials: HK
authors.lastname: Nieuwenhuis
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D005167:Factor VII / Q000494:pharmacology; D015942:Factor VIIa; D065427:Factor Xa Inhibitors; D005342:Fibrinolysis / Q000187:drug effects*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D009391:Nephelometry and Turbidimetry; D009844:Oligosaccharides / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D009844:Oligosaccharides; C064764:PENTA; D011994:Recombinant Proteins; D005167:Factor VII; D013925:Thromboplastin; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone