Oral factor Xa inhibitors: Studies on reversal of their anticoagulant effect and on their influence on primary hemostasis, endothelial function and fibrinolysis
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- Institutt for klinisk medisin [10718]
Abstract
Direct-acting oral anticoagulants (DOACs) were recently introduced for clinical use before a specific reversal strategy had been developed. In spite of their short half-life, a reversal strategy may be lifesaving in case of major bleeding or when urgent surgery is required. An antidote for activated factor X (FXa) inhibitors is not yet available in Norway. We have performed in vitro-studies with potential reversal agents of the FXa inhibitors rivaroxaban and apixaban and a case series where the effect of apixaban was reversed with the activated prothrombin complex concentrate (aPCC) FEIBA® in three patients in need of urgent heart surgery. Furthermore, the effect of rivaroxaban other parts of hemostasis other than the coagulation system was investigated. We found that aPCC, in a lower dose than recommended in current guidelines, was more effective in reversing the anticoagulation effect of both rivaroxaban and apixaban than recombinant FVIIa and four-factor prothrombin complex concentrate (PCC). aPCC 25-30 IU/kg also had a good hemostatic effect in two out of three apixaban-treated patients assessed both clinically, and by laboratory assays. No influence of rivaroxaban on platelet aggregation, von Willebrand factor or markers of endothelial activation was found. However, after measurements of fibrinolytic markers, we detected a reduction of plasminogen activator inhibitor (PAI-1) in samples with peak concentrations of rivaroxaban. In conclusion, aPCC may be a potential reversal agent of FXa inhibitors. Furthermore, rivaroxaban may increase fibrinolytic activity by reducing the level of PAI-1.List of papers
Paper I. Schultz NH, Tran HTT, Bjørnsen S, Henriksson CE, Sandset PM, Holme PA. The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor. Thrombosis Journal 2017 Feb 20; 15:6. DOI: 10.1186/s12959-017-0129-1. The paper is included in the thesis. Also available in DUO at: http://urn.nb.no/URN:NBN:no-57088 |
Paper II. Schultz NH, Tran HTT, Bjørnsen S, Henriksson CE, Sandset PM, Holme PA. The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII in apixaban-treated patients in vitro. Research and Practice in Thrombosis and Haemostasis 2017; 1(1):49-56. DOI: 10.1002/rth2.12015. The paper is included in the thesis. Also available at: https://doi.org/10.1002/rth2.12015 |
Paper III. Schultz NH, Lundblad R, Holme PA. Activated prothrombin complex concentrate (aPCC) to reverse FXa inhibitor (apixaban) effect before emergency surgery - a case series. Journal of Medical Case reports 2018; 12(1):138. DOI: 10.1186/s13256-018-1660-9. The paper is included in the thesis. Also available in DUO at: http://urn.nb.no/URN:NBN:no-64301 |
Paper IV. Schultz NH, Holme PA, Bjørnsen S, Henriksson CE, Sandset PM, Jacobsen EM. The impact of rivaroxaban on primary hemostasis in patients with venous thrombosis. Platelets 2018; Dec 20:1-5 [Epub ahead of print]. DOI: 10.1080/09537104.2018.1557618. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1080/09537104.2018.1557618 |
Paper V. Schultz NH, Holme PA, Bratseth V, Henriksson CE, Mowinckel M, Sandset PM, Jacobsen EM. The influence of rivaroxaban on markers of fibrinolysis and markers of endothelial cell activation in patients with venous thrombosis. Thrombosis Research 2019 Mar 14; 177:154-156. DOI: 10.1016/j.thromres.2019.03.010. The paper is included in the thesis. Also available at: https://doi.org/https://doi.org/10.1016/j.thromres.2019.03.010 |