Cytoprotective 3K3A-activated protein C and plasma: A comparison of therapeutics for the endotheliopathy of trauma

BACKGROUND Both healthy plasma and cytoprotective aPC (3K3A-aPC) have been shown to mitigate the endotheliopathy of trauma (EoT), but optimal therapeutics remain unknown. Our aim was therefore to determine optimal therapies to mitigate EoT by investigating the effectiveness of 3K3A-aPC with and without plasma-based resuscitation strategies. METHODS Electric cell-substrate impedance sensing (ECIS) was used to measure real-time permeability changes in endothelial cells. Cells were treated with a 2-μg/mL solution of aPC 30 minutes prior to stimulation with plasma taken from severely injured trauma patients (ISS > 15 and BD < −6) (TP). Healthy plasma, or plasma frozen within 24 hours (FP24), was added concomitantly with TP. Cells treated with thrombin and untreated cells were included in this study as control groups. RESULTS A dose-dependent difference was found between the 5% and 10% plasma-treated groups when human umbilical vein endothelial cells were simultaneously stimulated with TP (μd, 7.346; 95% confidence interval [CI], 4.574–10.12). There was no difference when compared with TP alone in the 5% (μd, 5.713; 95% CI, −1.751 to 13.18) or 10% group (μd, −1.633; 95% CI, −9.097 to 5.832). When 3K3A-aPC was added to plasma and TP, the 5% group showed improvement in permeability compared with TP alone (μd, 10.11; 95% CI, 2.642 to 17.57), but there was no difference in the 10% group (μd −1.394; 95% CI, −8.859 to 6.070). The combination of 3K3A-aPC, plasma, and TP at both the 5% plasma (μd, −28.52; 95% CI, −34.72 to −22.32) and 10% plasma concentrations (μd, −40.02; 95% CI, −46.22 to −33.82) had higher intercellular permeability than the 3K3A-aPC preincubation group. CONCLUSION Our data show that FP24, in a posttrauma environment, pretreatment with 3K3A-aPC can potentially mitigate the EoT to a greater degree than FP24 with or without 3K3A-aPC. Although further exploration is needed, this represents a potentially ideal and perhaps superior therapeutic treatment for the dysregulated thromboinflammation of injured patients.