Association of endotheliopathy and coagulopathy biomarkers with survival in a swine model of isolated uncontrolled hemorrhage.

BACKGROUND

Hemorrhage is the leading cause of preventable death on and off the battlefield that leads to coagulation dysfunction and endotheliopathy. To improve understanding of the nature and timing of these pathologies, we sought to profile markers of coagulopathy and endotheliopathy between survivors and non-survivors in a swine model of uncontrolled hemorrhage.

STUDY DESIGN AND

METHODS

Anesthetized Yorkshire cross-bred swine (n = 39) were subjected to a 45 s uncontrolled bleed following a 6-mm laceration to the femoral artery. Following applications of various hemostatic dressings, anesthetized swine were monitored up to 24 h with periodic blood sampling. Serum/plasma was assayed for coagulopathy and endotheliopathy biomarkers and compared between survivors (24 h post-hemorrhage) and non-survivors.

RESULTS

The injury resulted in a 62% mortality with 95% succumbing to injury within ~3 h. Hyaluronan and heparan sulfate were elevated in the fatality groups at 1 h (p < .05) and 2 h (p < .05), respectively. The fatality group at 1 h exhibited reduced plasminogen activator inhibitor-1 (PAI-1, p < .001) and elevated tissue plasminogen activator (p < .01) and D-Dimer (p < .05) relative to survivors. Survivors experienced significant elevations in C-reactive protein (p < .0001), PAI-1 (p < .0001), heparan sulfate (p < .0001), E-selectin (p < .0001), and vascular cell adhesion molecule-1 (p < .01) compared to baseline.

DISCUSSION: These results suggest that acute fatalities undergo hyperfibrinolysis followed by glycocalyx shedding. Survivors may experience longer term complications due to delayed/on-going inflammation and/or endothelium activation. This characterization of severe hemorrhage provides insights into the nature and progression of coagulopathy and endotheliopathy that emulate clinical findings which can be used for evaluating future therapeutics to reduce preventable deaths.