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. 2016 Jul:96:181-9.
doi: 10.1016/j.freeradbiomed.2016.04.023. Epub 2016 Apr 20.

Post-translational oxidative modification of fibrinogen is associated with coagulopathy after traumatic injury

Nathan J White  1 , Yi Wang  2 , Xiaoyun Fu  2 , Jessica C Cardenas  3 , Erika J Martin  4 , Donald F Brophy  4 , Charles E Wade  3 , Xu Wang  5 , Alexander E St John  5 , Esther B Lim  5 , Susan A Stern  5 , Kevin R Ward  6 , José A López  2 , Dominic Chung  2
Affiliations

Post-translational oxidative modification of fibrinogen is associated with coagulopathy after traumatic injury

Nathan J White et al. Free Radic Biol Med. 2016 Jul.

Abstract

Victims of trauma often develop impaired blood clot formation (coagulopathy) that contributes to bleeding and mortality. Fibrin polymerization is one critical component of clot formation that can be impacted by post-translational oxidative modifications of fibrinogen after exposure to oxidants. In vitro evidence suggests that Aα-C domain methionine sulfoxide formation, in particular, can induce conformational changes that prevent lateral aggregation of fibrin protofibrils during polymerization. We used mass spectrometry of plasma from trauma patients to find that fibrinogen Aα-C domain methionine sulfoxide content was selectively-increased in patients with coagulopathy vs. those without coagulopathy. This evidence supports a novel linkage between oxidative stress, coagulopathy, and bleeding after injury.

Keywords: Coagulopathy; Fibrinogen; Hemorrhage; Methionine sulfoxide; Oxidative stress; Trauma.

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Figures

Figure 1
Figure 1
Associations between fibrinogen Aα-M476(SO)% and international normalized prothrombin time ratio (INR), thrombin time, and Reptilase time measured in plasma. R=Pearson product moment correlation coefficient.
Figure 2
Figure 2
Increased Aα-MSO476 sulfoxide content is associated with fibrin polymerization impairment by reptilase activation at low levels corresponding to those found in trauma patients. Other oxidative modifications of fibrinogen are also possible after exposure to HOCL, but were not investigated.
Figure 3
Figure 3. Fibrinogen methionine sulfoxide content is preferentially-increased in coagulopathic trauma patients and is associated with important clinical variables
(A) Mean Aα-M476(SO)% is increased under coagulopathic conditions (INR>1.2) in trauma patients when detected directly in plasma. (B) Albumin M353(SO)% is not increased in the same plasma sample. Fibrinogen Aα-M476(SO)% was also negatively associated with base excess as a clinical marker of metabolic shock severity (C), and positively associated with injury severity measured using the Injury Severity Score (D) Bars= Mean and StdDev. R=Pearson product moment correlation coefficient. (Richmond Cohort)
Figure 4
Figure 4. Viscoelastic clot formation parameters by Aα-M476(SO)% in Emergency Department trauma patients
Whole blood viscoelastic clot formation measured in the Emergency Department using rapid TEG are compared by Aα-M476(SO)% quartile measured by UPLC-MS/MS-MRM. Percent clot lysis (LY30%) was significantly increased in the highest Aα-M476(SO)% quartile compared to all other quartiles. Points are individual measurements and bars represent median and interquartile range. P values= nonparametric Wilcoxon Rank Sums test.
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