M. R. Dyer1, W. Plautz1, M. A. Rollins-Raval2, J. S. Raval2, B. S. Zuckerbraun1, M. D. Neal1 1University Of Pittsburgh,Surgery,Pittsburgh, PA, USA 2University Of North Carolina At Chapel Hill,Pathology And Laboratory Medicine,Chapel Hill, NC, USA
Introduction: ADAMTS13 is metalloprotease that binds and cleaves von Willebrand factor (VWF), which is a critical regulator of thrombus formation. ADAMTS13 deficiency has been implicated as the cause of idiopathic thrombotic thrombocytopenia purpura (TTP) but is also closely associated with other diseases of microvascular injury. Trauma is a leading cause of mortality worldwide and is characterized by a unique trauma-induced coagulopathy (TIC), with a pathophysiology that is incompletely understood. We sought to evaluate a possible link between ADAMTS13 activity and coagulopathy in trauma patients.
Methods: Plasma samples from an ongoing randomized trial in trauma patients were obtained for analysis. Plasma from healthy individuals served as controls. Fluorescence resonance energy transfer analysis (FRET) was utilized to determine the activity level of ADAMTS13 in circulation. ADAMTS13 antigen and antibody levels were determined by enzyme-linked immunosorbent assays (ELISA). FRET activity levels, ADAMTS13 antigen, and antibody levels were compared between trauma patients and healthy controls using Mann-Whitney U tests. FRET activity levels were correlated with laboratory markers of coagulopathy (INR, Thromboelastography (TEG) maximum amplitude value, TEG activated clotting time, and blood product requirement) by determining the Spearman correlation coefficient.
Results: 70% of trauma patients had abnormal ADAMTS13 activity on FRET analysis (normal >80% IU/ml). Compared to healthy controls, the ADAMTS13 activity in plasma is significantly lower in trauma patients (96% vs. 66% IU/ml, p=0.0013). Correspondingly 81% of trauma patients displayed depressed levels of circulating ADAMTS13 compared to healthy controls, and overall levels of circulating ADAMTS13 were significantly lower in trauma patients (0.96 vs. 0.47 ug/ml, p=0.0019). There was no difference in circulating antibodies against ADAMTS13 between trauma patients and healthy controls. Interestingly, ADAMTS13 activity was found to be significantly correlated with injury severity score in trauma patients (ISS) (r=-0.34, p<0.05). Next, ADAMTS13 activity levels were correlated to markers of coagulopathy. Strikingly, ADAMTS13 activity was closely correlated with admission INR (r=-0.6250, p<0.001), admission TEG activated clotting time (r=-0.36, p<0.05), and admission TEG MA (r=0.36, p<0.05). Finally, ADAMTS13 activity significantly correlated with overall blood product transfusion requirements in trauma patients (r=-0.46, p<0.05).
Conclusion: Trauma results in several derangements in the normal clotting process. We now present evidence that circulating levels and enzymatic activity of ADAMTS13, a key regulator in normal hemostasis, are decreased following severe trauma. The decreased activity was found to be significantly correlated with markers of coagulopathy and may represent a novel insight into potential mechanisms of TIC.