W. E. Plautz1, M. R. Dyer2, S. Haldeman2, M. Rollins-Raval3, J. S. Raval3, J. L. Sperry2, B. S. Zuckerbraun2, M. D. Neal2 1University Of Pittsburgh,School Of Medicine,Pittsburgh, PA, USA 2University Of Pittsburgh,Department Of Surgery,Pittsburgh, PA, USA 3University Of North Carolina At Chapel Hill,Department Of Pathology,Chapel Hill, NC, USA
Introduction: Increases in plasma von Willebrand Factor (vWF) levels, accompanied by decreases in its respective metalloprotease ADAMTS13, have been demonstrated in diseases of microvascular injury. We hypothesized that following severe trauma, a burst of ultra-large vWF is released into the bloodstream by damaged endothelium, resulting in a dysregulation of the circulating vWF multimeric composition. We further hypothesized that impaired ADAMTS13 activity would be insufficient to cleave the burst of ultra-large vWF, facilitating organ injury.
Methods: 37 severe trauma patients from a randomized control trial (RCT) on the use of pre-hospital plasma were analyzed for antigen levels of plasma vWF at 0- and 24-hours after admission. Circulating vWF multimeric composition from both time points was determined by vertical agarose gel electrophoresis, followed by a quantitative structural analysis of vWF multimeric length. ADAMTS13 antigen, activity, and antibody levels were obtained by ELISA and FRETS-73 analyses, and the circulating vWF multimeric composition at both 0- and 24-hours was evaluated for a dependence on ADAMTS13 activity. Finally, multivariate analyses were performed with data abstracted from the RCT database and electronic medical records to identify further dependences.
Results: VWF levels were increased in severe trauma patients when compared to healthy controls at presentation (189% (110-263) vs. 95% (74-120)) and persisted through 24-hours (213% (146-257) vs. 132% (57-160)). Ultralarge-vWF forms were elevated at both 0- and 24-hours when compared to pooled normal plasma ((10.0% (8.9-14.3) and 11.3% (9.1-21.2), respectively, vs 0.6%), while the proportion of small multimers concomitantly decreased. The largest vWF forms within trauma patient plasma circulated at 33±4 dimers vs 18±1 dimer in length within pooled normal plasma and were sustained through 24-hours. Trauma patient ADAMTS13 activity was decreased at 0-hours (66% (47-86) vs. 100% (98-100)) and at 24-hours (72.5% (56-87.3) vs 103% (103-103)) when compared to healthy patients, with antigen levels showing congruent trends. Furthermore, within the trauma patient population, the circulating vWF composition demonstrated a significant plasticity within its small multimeric forms at 24-hours that was dependent upon ADAMTS13 activity (Decreased ADAMTS13 Activity: 20.4% (15.0-22.7) vs Normal Activity: 25.8% (22.7-35.2)). ADAMTS13 activity independently predicted the development of coagulopathy, correlating with presentation INR (ρ =-0.63), activated clotting time of thromboelastography (TEG) (ρ=-0.36), and TEG maximum amplitude (ρ=0.36). ADAMTS13 activity also closely correlated with injury severity (ISS) (ρ=-0.34) and blood product transfusion (ρ =-.45).
Conclusion: Severe traumatic injury dysregulates ADAMTS13 and its target, vWF, contributing to a distorted vWF multimeric profile, persistently altered hemostasis, and the development of coagulopathy.