Nina Haagenrud Schultz‘s PhD thesis contains in vitro-studies of potential reversal agents of the direct-acting oral anticoagulants rivaroxaban and apixaban.


  1. A low dose of activated prothrombin complex concentrate effectively reverses anticoagulation by rivaroxaban and apixaban.
  2. Rivaroxaban might increase fibrinolytic activity but has no effect on endothelial activation or primary hemostatis.


Thesis: Oral factor Xa inhibitors: Studies on reversal of their anticoagulant effect and on their influence on primary hemostasis, endothelial function and fibrinolysis
Candidate: Nina Haagenrud Schultz
Time: November 8, 2019 at 13:15
Place: University of Oslo, Domus Medica: Runde auditorium
Link to university website


(1/2) Rivaroxaban and apixaban provides anticoagulation by inhibiting activated factor X. Reversal agents of these direct-acting oral anticoagulants could be essential in case of a life-threatening bleeding, but are not yet available in Norway. Haagenrud Schultz and co-workers show that the effects of both apixaban and rivaroxaban are reversed with the activated prothrombin complex concentrate (aPCC) FEIBA® in lower doses than currently recommended.

FEIBA® proved more effective than recombinant factor VIIa and four-factor prothrombin complex concentrate in 50 rivaroxaban-treated and 30 apixaban-treated patients. Their blood samples were spiked with the three inhibitors at 80 %, 100 % and 125 % of suggested therapeutic doses. All doses of FEIBA® were equally effective.

(3) In a case-series of three patients in urgent need of heart surgery, FEIBA® had good hemostatic effect and reversed the effect of apixaban. The treatment reduced clotting time in all patients, and there were no bleeding complications during surgery. However, one of the patient experience bleeding after the operation.

(5/4) Rivaroxaban reduces plasminogen activator inhibitor (PAI-1), thus potentially increasing fibrinolytic activity. No other markers of fibrinolytic activity or endothelial activation were affected by the treatment. Rivaroxaban possibly also causes a reduction in P-selectin but does not influence platelet aggregation or von Willebrand factor.

The studies include twelve patients with venous thrombosis assigned to temporary rivaroxaban treatment, and blood was collected both during and after the treatment period.


(1) Schultz, N. H., Tran, H. T. T., Bjørnsen, S., Henriksson, C. E., Sandset, P. M., & Holme, P. A. (2017). The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitorThrombosis journal15(1), 6.

(2) Schultz, N. H., Tran, H. T., Bjørnsen, S., Henriksson, C. E., Sandset, P. M., & Holme, P. A. (2017). 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 haemostasis1(1), 49-56.

(3) Schultz, N. H., Lundblad, R., & Holme, P. A. (2018). Activated prothrombin complex concentrate to reverse the factor Xa inhibitor (apixaban) effect before emergency surgery: a case seriesJournal of medical case reports12(1), 138.

(4) Schultz, N. H., Holme, P. A., Bjørnsen, S., Henriksson, C. E., Sandset, P. M., & Jacobsen, E. M. (2018). The impact of rivaroxaban on primary hemostasis in patients with venous thrombosisPlatelets, 1-5.

(5) Schultz, N. H., Holme, P. A., Henriksson, C. E., Mowinckel, M. C., Sandset, P. M., Bratseth, V., & Jacobsen, E. M. (2019). The influence of rivaroxaban on markers of fibrinolysis and endothelial cell activation/injury in patients with venous thrombosisThrombosis research177, 154.

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