Trauma and Hemorrhage: Functional Characterization of Acute Traumatic Coagulopathy

BACKGROUND: Trauma is the leading cause of death in individuals under the age of 44. Acute traumatic coagulopathy (ATC) occurs when severe injury is combined with shock and results in a hypocoagulable state resulting in increased bleeding, increased resuscitation requirements and worsened outcomes including a 4-fold increase in mortality. Our group has implicated protein C activation as a likely mechanism for ATC. We have evaluated whether activated protein C (APC) induces coagulopathy through cleavage of factor (f)V/Va by systematically evaluating 4 groups of increasing level of traumatic coagulopathy.

METHODS: From a large cohort of plasma samples collected from trauma patients at time of admission to a major level 1 trauma sample, 80 plasma samples distributed equally between the following trauma severity groupings were selected: Group 1: ISS ≤ 15 and BD > -6 (less injured, no shock); Group 2: ISS ≤ 15 and BD ≤ -6 (less injured, with shock); Group 3:ISS > 15 and BD > -6 (more injured, no shock); Group 4:ISS > 15 and BD ≤ -6 (more injured, with shock). Each plasma sample was evaluated for plasma composition (functional activity of fII, fV, fVII, fVIII, fIX, fX, antithrombin, tissue factor pathway inhibitor, protein C), plasmin-antiplasmin complex (PAP), α-thrombin-antithrombin complex (TAT), and mathematically modeled thrombin generation. Quantitative Western blot analyses were performed using an anti-fV antibody directed at the fV heavy chain (residues 307-506). Intact fV levels were quantified via densitometry to determine whether levels were the within range characterizing healthy individuals and the presence of APC derived and other degradation products assessed via mobility comparison to purified standards. Demographic, resuscitation, and outcomes data were collected in parallel.

RESULTS: All data were quantitated and evaluated for having concentrations above and/or below the normal range for each analyte. For PAP, Groups 3 (18/20) and 4 (17/20) had a greater percentage of individuals over Groups 1 (5/20) and 2 (6/20) that were above the normal range. Groups 3 (12/20) and 4 (12/20) also had a higher percentage of detectable α-TAT over Groups 1 (5/20) and 2 (2/20). For fV antigen, Group 4 had 16/20 individuals that were below the lower limit of normal. Groups 1, 2 and 3 were all similar with 5/20 below the limit of normal but had 3-5/20 above the upper limit of normal. Products associated with activated protein C were found (fV 30kD fragment) but also other cleavage products not associated with APC were observed. There was more fV fragmentation in Group 4, with the 30kD fragment being detected in 10 individuals. No detectable fV 30kD fragments were detected in either Groups 1 or 2. In terms of the overall plasma composition there is a large variation in functional activity, especially fVIII. Group 4 showed a pattern of all factors reduced except for TFPI versus Groups 1,2, 3. These pro and anticoagulant differences between individuals results in heterogenous modeled thrombin generation profiles with the majority all being procoagulant versus a normal control. Group 4 had a higher percentage of individuals that had a prolonged clot time and a pattern towards diminished thrombin generation.

CONCLUSIONS: These data suggest that the combination of injury and shock were associated with altered PAP, TAT and functional activity changes of the plasma composition resulting in hemorrhagic thrombin generation profiles. In addition the most severely injured and shocked patients had less fVa activity, less intact fV and increased degradation of fV/fVa suggesting the presence of increased APC activity in mediating ATC.