Direct thrombin inhibitors, but not the direct factor Xa inhibitor rivaroxaban, increase tissue factor‐induced hypercoagulability in vitro and in vivo. (19th June 2014)

• Record Type: Journal Article
• Authors: Perzborn, E.; Heitmeier, S.; Buetehorn, U.; Laux, V.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 12:Number 7(2014:Jul.)
• Page Start: 1054
• Page End: 1065
• Publication Date: 2014-06-19
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.12591
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth12591-abs-0001"> <title>Summary</title> <sec id="jth12591-sec-0001" sec-type="section"> <title>Background</title> <p>Increased hypercoagulability has been reported with low doses of direct thrombin inhibitors but not with direct factor Xa inhibitors.</p> </sec> <sec id="jth12591-sec-0002" sec-type="section"> <title>Objectives</title> <p>To compare the effects of rivaroxaban with those of melagatran and dabigatran on thrombin generation (TG) and tissue factor‐induced hypercoagulability and to explore the possible involvement of the thrombin–thrombomodulin/activated protein C system.</p> </sec> <sec id="jth12591-sec-0003" sec-type="section"> <title>Methods</title> <p>In normal human plasma and in protein C‐deficient plasma, TG was investigated <italic>in vitro</italic> in the presence and absence of recombinant human soluble thrombomodulin (rhs‐TM). TG was determined by calibrated automated thrombography and an ELISA for prothrombin fragments 1+2 (F<sub>1+2</sub>). In an <italic>in vivo</italic> rat model, hypercoagulability was induced by tissue factor; levels of thrombin–antithrombin (TAT) and fibrinogen and the platelet count were determined.</p> </sec> <sec id="jth12591-sec-0004" sec-type="section"> <title>Results</title> <p>Rivaroxaban inhibited TG in a concentration‐dependent manner. In the absence of rhs‐TM, melagatran and dabigatran also inhibited TG concentration dependently. However, in the presence of rhs‐TM, lower concentrations of melagatran (119–474 nmol L<sup>–1</sup>) and dabigatran (68–545 nmol L<sup>−1</sup>) enhanced endogenous thrombin potential, peak TG, and F<sub>1+2</sub> formation in normal plasma but not in protein C‐deficient plasma. <italic>In vivo</italic>, rivaroxaban dose‐dependently inhibited TAT generation, whereas melagatran showed a paradoxical effect, with an increase in TAT and a small decrease in fibrinogen and platelet count at lower doses.</p> </sec> <sec id="jth12591-sec-0005" sec-type="section"> <title>Conclusion</title> <p>Low concentrations of the direct thrombin inhibitors melagatran and dabigatran enhanced TG and hypercoagulability, possibly via inhibition of the protein C system. In contrast, rivaroxaban reduced TG and hypercoagulability under all conditions studied, suggesting that it does not suppress this negative‐feedback system.</p> </sec> </abstract>