Coagulopathy In Trauma Patients Is Accompanied By Oxidation Of a Methionine Residue In The αC Domain Of Fibrinogen and Abnormal Fibrin Polymerization

Introduction The concentration of clottable fibrinogen in plasma decreases rapidly after severe traumatic injury and resuscitation, a reduction associated with both greater transfusion requirements and mortality. Fibrinogen is very sensitive to oxidative modification by oxidants generated during ischemia and inflammation, including hypochlorous acid and peroxynitrite, which both can oxidize methionine to methionine sulfoxide. Here, we investigated the potential of this mechanism to contribute to the coagulopathy of trauma. Methods We obtained plasma, clinical data, and outcomes from a biorepository of trauma patients presenting to the Emergency Department of a local Level I trauma center. Subjects with plasma INR ≥1.3 were defined as being coagulopathic while those with INR Results Trauma patients who were coagulopathic (N=31) required more blood products in the first 24 hours of care compared to non-coagulopathic subjects (N=30) (mean PRBC: 3.9 vs. 0.5 units, p < 0.001; mean plasma transfused: 3.2 vs. 0.2 units, p < 0.001; and mean platelets transfused: 0.8 vs. 0.2 units, p=0.008) and were more likely to die (29% vs. 10% mortality, ChiSqr Likelihood Ratio p=0.056). Methionine sulfoxide was selectively increased in coagulopathic trauma patients at position 476 in the alpha C domain compared to controls [mean(SEM) 1.8(0.1)% vs. 2.5(0.1)%, p=0.003] and this low-level of oxidation was confirmed to be associated with an increasing reptilase time in vitro. Mean thrombin time (16 vs. 17.8 sec, p = 0.01) and reptilase times (18.2 vs. 23.7 sec, p Conclusions The level of oxidation of methionine residues in fibrinogen was increased in coagulopathic trauma patients presenting to the Emergency Department. Even at low levels, this modification was associated with altered fibrin polymerization suggesting that it may contribute mechanistically to coagulopathy by altering fibrin alpha C domain dimerization during the lateral aggregation of fibrin monomer. Disclosures: White: Stasys Medical Corp: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties; Vidacare Corp: Honoraria; NIH: Research Funding; Coulter Foundation: Research Funding; Washington State Life Sciences Discovery Fund: Research Funding.