Reversing Rivaroxaban Anticoagulation as Part of a Multimodal Hemostatic Intervention in a Polytrauma Animal Model

Abstract

Background Life-threatening bleeding requires prompt reversal of the anticoagulant effects of factor Xa inhibitors. This study investigated the effectiveness of four-factor prothrombin complex concentrate in treating trauma-related hemorrhage with rivaroxaban-anticoagulation in a pig polytrauma model. This study also tested the hypothesis that the combined use of a low dose of prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate could improve its subtherapeutic effects. Methods Trauma (blunt liver injury and bilateral femur fractures) was induced in 48 anesthetized male pigs after 30 min of rivaroxaban infusion (1 mg/kg). Animals in the first part of the study received prothrombin complex concentrate (12.5, 25, and 50 U/kg). In the second part, animals were treated with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid or plus tranexamic acid and fibrinogen concentrate. The primary endpoint was total blood loss postinjury. The secondary endpoints (panel of coagulation parameters and thrombin generation) were monitored for 240 min posttrauma or until death. Results The first part of the study showed that blood loss was significantly lower in the 25 U/kg prothrombin complex concentrate (1,541 ± 269 ml) and 50 U/kg prothrombin complex concentrate (1,464 ± 108 ml) compared with control (3,313 ± 634 ml), and 12.5 U/kg prothrombin complex concentrate (2,671 ± 334 ml, all P < 0.0001). In the second part of the study, blood loss was significantly less in the 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate (1,836 ± 556 ml, P < 0.001) compared with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid (2,910 ± 856 ml), and there were no early deaths in the 25 U/kg prothrombin complex concentrate, 50 U/kg prothrombin complex concentrate, and 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate groups. Histopathologic analyses postmortem showed no adverse events. Conclusions Prothrombin complex concentrate effectively reduced blood loss, restored hemostasis, and balanced thrombin generation. A multimodal hemostatic approach using tranexamic acid plus fibrinogen concentrate enhanced the effect of low doses of prothrombin complex concentrate, potentially reducing the prothrombin complex concentrate doses required for effective bleeding control. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

In vitro reversal of direct factor Xa inhibitors: Direct comparison of andexanet alfa and prothrombin complex concentrates Cofact and Beriplex/Kcentra

“…In contrast, a correlation between thrombin generation improvement and bleeding correction was evident in a similar study with edoxaban‐anticoagulated individuals 15 . Also, in an animal bleeding model of rivaroxaban‐treated pigs that underwent complex traumatic injury followed by PCC treatment, correction of hemostasis coincided with improvement of thrombin generation 30 . In the same polytrauma model, andexanet alfa rapidly restored thrombin generation and significantly reduced total blood loss in apixaban‐treated animals 31 .…”

“… 15 Also, in an animal bleeding model of rivaroxaban‐treated pigs that underwent complex traumatic injury followed by PCC treatment, correction of hemostasis coincided with improvement of thrombin generation. 30 In the same polytrauma model, andexanet alfa rapidly restored thrombin generation and significantly reduced total blood loss in apixaban‐treated animals. 31 We observed in our in vitro experiments that andexanet alfa increased peak thrombin and velocity index to above normal, irrespective of the presence of FXaI.…”

Coagulopathy management of multiple injured patients – a comprehensive literature review of the European guideline 2019

“…In vitro data showed that idarucizumab reduced plasma concentrations of dabigatran ( 143 ) and that andexanet alfa lowered the concentrations of FXa-inhibitors but did not normalize VEM ( 143 ). In a porcine trauma model, PCC effectively reduced blood loss, restored haemostasis, and balanced thrombin generation despite previous rivaroxaban intake ( 144 ). However, outcome data remain inconclusive.…”

Coagulation Management after Trauma in the Presence of Direct Oral Anticoagulants

“…The authors administered increasing doses of prothrombin complex concentrate (PCC; 12.5, 25, and 50 U/kg) along with combinations of PCC plus tranexamic acid and fibrinogen concentrate, and determined total blood loss and survival over 4 h. In comparison to controls (saline), treatment with PCC 25 and 50 U/kg and PCC 12.5 U/kg plus tranexamic acid and fibrinogen concentrate reduced bleeding and achieved 100% survival versus 0% in controls. 1 The important findings of this study include the following. First, the impact of a high rivaroxaban plasma concentration on rotational thrombelastometry (ROTEM) showed a prolonged extrinsically activated clotting time, while maximum clot formation was unaltered.…”

“…In this issue of the Journal, the article by Rayatdoost et al provides novel data from an established polytrauma pig model. 1 In brief, a high rivaroxaban plasma concentration (approximately 400 ng/ ml) was established in anesthetized pigs before inflicting a standardized major trauma of blunt liver injury and bilateral femur fractures. The authors administered increasing doses of prothrombin complex concentrate (PCC; 12.5, 25, and 50 U/kg) along with combinations of PCC plus tranexamic acid and fibrinogen concentrate, and determined total blood loss and survival over 4 h. In comparison to controls (saline), treatment with PCC 25 and 50 U/kg and PCC 12.5 U/kg plus tranexamic acid and fibrinogen concentrate reduced bleeding and achieved 100% survival versus 0% in controls.…”