Abstract
ObjectivesAcquired coagulopathy may be associated with bleeding risk. Approaches to restore haemostasis include administration of coagulation factor concentrates, but there are concerns regarding potential prothrombotic risk. The present study assessed the prothrombotic potential of four-factor prothrombin complex concentrate (4F-PCC) versus activated PCC (aPCC) and recombinant factor VIIa (rFVIIa), using three preclinical animal models.MethodsThe first model was a modified Wessler model of venous stasis-induced thrombosis in rabbit, focusing on dilutional coagulopathy; the second model employed the same system but focused on direct oral anticoagulant reversal (i.e. edoxaban). The third model assessed the prothrombotic impact of 4F-PCC, aPCC and rFVIIa in a rat model of ferric chloride-induced arterial thrombosis.ResultsIn the first model, thrombi were observed at aPCC doses ≥10 IU/kg (therapeutic dose 100 IU/kg) and rFVIIa doses ≥50 μg/kg (therapeutic dose 90 μg/kg), but not 4F-PCC 50 IU/kg (therapeutic dose 50 IU/kg). The impact of 4F-PCC (up to 300 IU/kg) on thrombus formation was evident from 10 minutes post-administration, but not at 24 hours post-administration; this did not change with addition of tranexamic acid and/or fibrinogen concentrate. 4F-PCC-induced thrombus formation was lower after haemodilution versus non-haemodilution. In the second model, no prothrombotic effect was confirmed at 4F-PCC 50 IU/kg. The third model showed lower incidence of thrombus formation for 4F-PCC 50 IU/kg versus aPCC (50 U/kg) and rFVIIa (90 μg/kg).ConclusionsThese results suggest that 4F-PCC has a low thrombotic potential versus aPCC or rFVIIa, supporting the clinical use of 4F-PCC for the treatment of coagulopathy-mediated bleeding.
Highlights
A coagulopathic state may result from systemic disorders causing a reduction in coagulation factors
Thrombi were observed at activated Prothrombin complex concentrates (PCCs) (aPCC) doses 10 IU/kg and recombinant factor VIIa (rFVIIa) doses 50 μg/kg, but not 4F-PCC 50 IU/kg
The impact of 4F-PCC on thrombus formation was evident from 10 minutes post-administration, but not at 24 hours post-administration; this did not change with addition of tranexamic acid and/or fibrinogen concentrate. 4F-PCCinduced thrombus formation was lower after haemodilution versus non-haemodilution
Summary
A coagulopathic state may result from systemic disorders causing a reduction in coagulation factors (e.g. trauma). The coagulation response is modulated in patients who are in receipt of anticoagulation therapy (e.g. vitamin K antagonists [VKAs] or direct oral anticoagulants [DOACs]) at a level sufficient to prevent a thrombotic event. In both cases, there is an associated bleeding risk [1,2]. Fresh frozen plasma (in conjunction with red blood cells) is one recommendation for the initial management of patients with massive traumatic haemorrhage [2], but it is not routinely recommended in guidelines on anticoagulation reversal, partly due to the fact that its clotting factor content is lower than typical levels in whole blood [5,6]. Tranexamic acid (TXA) is a further option, with early administration recommended in the initial management of bleeding and coagulopathy [2,3]
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