PB0488 - Targeted Factor V replacement during major trauma haemorrhage

Background: Factor Va (FVa) critical to thrombin generation, in a massive haemorrhage protocol (MHP) can only be supplemented as Fresh Frozen Plasma. It is unknown whether FFP can sufficiently maintain FV during MHP and ongoing bleeding in trauma.

Aims: Characterise the temporal changes of FV in trauma patients

Determine the efficacy of Factor Va replacement in a murine model of Acute Traumatic Coagulopathy (ATC).

Methods: Trauma patients at a trauma centre were included with blood samples collected on admission and after transfusion of 4, 8 and 12 RBC units for FV assay.

In a preclinical model of ATC three groups (n=10) were infused with vehicle, rhFVa (resistant to aPC), or hFVa 30 minutes after haemorrhage. Animals were euthanased at 60 minutes to collect terminal blood samples for biomarkers of coagulation, fibrinolysis and FVa degradation.

Results: 207 trauma patients were included (Table 1). Admission FV was 41% lower in MHP patients compared to those without major injury and RBC transfusion < 4 units (60u/dL vs 102u/dL, p< 0.0001). Despite MHP, FV levels decreased to 36u/dL (8U RBC) and 32u/dL (12U RBC). Patients who died early ( < 12hrs) had significantly lower FV at baseline than survivors (27u/dL vs 60 u/dL).

Compared to vehicle, mice infused with rhFVa or hFVa had significantly higher median survival rates at 60 minutes (44% vs 80% vs 88%). There was at least a three-fold increase in plasmin-antiplasmin levels in the vehicle group compared to rhFVa/hFVa (208ng/ml vs 70ng/ml vs 31ng/ml, p< 0.0001) but with no difference in ROTEM clot strength. Plasmin degradation of hFVa was observed in both intervention groups but only aPC mediated degradation was seen in rhFVa animals.

Conclusion(s): FV in bleeding trauma patients is low on admission and not corrected by current MHP therapy. FVa replacement in addition to balanced resuscitation may represent a novel therapy for trauma haemorrhage.