Reversing direct factor Xa or thrombin inhibitors: Factor V addition to prothrombin complex concentrate is beneficial in vitro

Abstract

Background Prothrombin complex concentrate (PCC) is a human plasma‐derived mixture of partially purified vitamin K‐dependent coagulation factors (VKCF). Current therapeutic indication is treatment and perioperative prophylaxis of bleeding in acquired VKCF deficiency. Off‐label uses include treatment of direct factor Xa‐ or thrombin inhibitor‐associated bleeds, treatment of trauma‐induced coagulopathy, and hemorrhagic complications in patients with liver disease. Objective Considering PCC as a general prohemostatic drug, we argued that its clinical efficacy can benefit from supplementation with coagulation factors that are absent in the current PCC formulation. In this study, we focused on factor V. Methods We mimicked a coagulopathy in vitro by spiking whole blood or derived plasma with the direct oral anticoagulants (DOAC) rivaroxaban or dabigatran. We studied DOAC reversal by PCC and factor V concentrate (FVC) using a thrombin generation assay, thromboelastography, fibrin generation clot lysis test, and microfluidic thrombus formation under flow. Results In DOAC‐treated plasma, PCC increased the amount of thrombin generated. The addition of FVC alone or in combination with PCC caused a partial correction of the thrombin generation lag time and clotting time. In DOAC‐treated whole blood, the combination of PCC and FVC synergistically improved clotting time under static conditions, whereas complete correction of fibrin formation was observed under flow. Clot strength and clot resistance toward tissue plasminogen activator‐induced lysis were both increased with PCC and further enhanced by additional FVC. Conclusion Our in vitro study demonstrates a beneficial effect of the combined use of PCC and FVC in DOAC reversal.

Antithrombotic and prohemorrhagic actions of different concentrations of apixaban in patients exposed to single and dual antiplatelet regimens

“…APIX reduced platelet and fibrin interactions with the thrombogenic surface exposed to circulating blood. Inhibition in platelets and fibrin formation has been reported for different DOACs in previous studies from our group and others 20 , 21 , 28 , 29 . Interestingly, one of the previous studies reported a delayed fibrin formation in DOAC-treated under static conditions 29 .…”

“…Inhibition in platelets and fibrin formation has been reported for different DOACs in previous studies from our group and others 20 , 21 , 28 , 29 . Interestingly, one of the previous studies reported a delayed fibrin formation in DOAC-treated under static conditions 29 . Our present microfluidic studies with recalcified anticoagulated blood were performed for a relatively short time (3 min) to avoid clotting of the system.…”

Antithrombotic and Prohemorrhagic Actions of Different Concentrations of Apixaban in Patients Exposed to Single and Dual Antiplatelet Regimens

“…APIX reduced platelet and fibrin interactions with the thrombogenic surface exposed to circulating blood. Inhibition in platelets and fibrin formation has been reported for different DOACs in previous studies from our group and others [27,28,32,33]. Interestingly, one of the previous studies reported a delayed fibrin formation in DOAC-treated under static conditions [33].…”

“…Inhibition in platelets and fibrin formation has been reported for different DOACs in previous studies from our group and others [27,28,32,33]. Interestingly, one of the previous studies reported a delayed fibrin formation in DOAC-treated under static conditions [33]. Our present microfluidic studies with recalcified anticoagulated blood were performed for a relatively short time (3 min) to avoid clotting of the system.…”

Antidote vs. unspecific hemostatic agents for the management of direct oral anticoagulant-related bleeding in trauma

“…There are four-factor (4F-PCC), three-factor (3F-PCC) and activated PCC formulations [60,61]. The key differentiator is the inclusion of factor VII in 4F-PCC, believed to enhance hemostatic efficacy compared to 3F-PCC [62,63]. Activated PCC contains nonactivated factors II, IX, and X as well as activated factor VII.…”