Blood Loss in Rivaroxaban Anticoagulated Pigs with Severe Polytrauma Is Significantly Reduced By Early Therapy with Prothrombin Complex Concentrate

Introduction: The reversal of the anticoagulant effects of rivaroxaban in severely bleeding patients remains uncertain with conflicting evidence. In this ongoing study we assessed the ability of a four-factor prothrombin complex concentrate (PCC) to reverse rivaroxaban anticoagulation in a porcine polytrauma model.

Methods: After ethical approval, rivaroxaban was infused over 30 min (1 mg/kg/h) prior to injury in anaesthetized male pigs (n=24); the sham group (n=8) received placebo. A standardized blunt liver injury and bilateral femur fractures were induced. After trauma and hemorrhagic shock, animals were resuscitated 5 min post injury with Ringer's solution and blood loss (BL) was recorded 12 min post trauma. Randomized animals (n=8/group) received a single injection of PCC (25 or 50 IU/kg), or vehicle (control). Animals were observed up to 180 min after trauma, and total BL was assessed after the observation period or animal's death. Coagulation variables included rivaroxaban plasma concentration, global coagulation assays (PT, aPTT) and thromboelastometry. For a differentiated risk assessment, thrombin generation and thrombin-antithrombin (TAT) levels, indicating the extent of coagulation activation were obtained. BL and hemodynamic variables were monitored over 3 h or until time of death. For statistical analysis, ANOVA (mean ± SD) and the log-rank test for survival were used.

Results: After infusion and prior to injury rivaroxaban levels were 666 ± 88 ng/mL. In contrast to sham animals (BL: 467 ± 56 mL), BL in in all anticoagulated animals was significantly elevated 12 min post injury (BL: 810 ± 83 mL). Anticoagulation with rivaroxaban without PCC therapy resulted in a total BL of 3111 ± 479 mL with 88 % mortality (survival time: 50-180 min; p<0.05 vs PCC treated animals and sham). The application of 25 IU/kg PCC (1497 ± 292 mL) or 50 IU/kg PCC (1468 ± 107 mL) showed a significant reduction in total BL with 100% survival and no significant difference between groups. The application of PCC was associated with a dose-depended increase in peak thrombin generation (Peak height; figure 1). D-Dimer increased after trauma in sham and PCC treated animals. However, no difference in D-Dimer concentration in the PCC 25 or 50 IU/kg group was measured post injury. Clinically and macroscopically no adverse events were observed.

Conclusions: This porcine model demonstrates a four-factor PCC may be a reasonable and safe intervention for rivaroxaban-treated patients with life-threatening haemorrhage, though these data need clinical confirmation.

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