Critical Care Medicine  |   January 2017
Activated Protein C Drives the Hyperfibrinolysis of Acute Traumatic Coagulopathy
Author Notes
  • From the Center for Trauma Sciences, Blizard Institute (R.A.D., M.G., D.F., C.R., C.T., K.B.) and William Harvey Research Institute, Bart’s and the London School of Medicine and Dentistry (R.P.), Queen Mary University of London, United Kingdom; Department of Hematology, Bart’s Health NHS Trust, London, United Kingdom (S.P.); and Acute Care Research, San Francisco Injury Center, University of California - San Francisco, San Francisco, California (M.C.).
  • Submitted for publication December 14, 2015. Accepted for publication September 14, 2016.
    Submitted for publication December 14, 2015. Accepted for publication September 14, 2016.×
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • R.A.D. and M.G. are co-first authors.
    R.A.D. and M.G. are co-first authors.×
  • Address correspondence to Dr. Davenport: Center for Trauma Sciences, Blizard Institute, Queen Mary University of London, 4 Newark Street, London, E1 2AT, United Kingdom. ross.davenport@qmul.ac.uk. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Clinical Science / Cardiovascular Anesthesia / Coagulation and Transfusion / Critical Care / Hematologic System / Trauma / Burn Care
Critical Care Medicine   |   January 2017
Activated Protein C Drives the Hyperfibrinolysis of Acute Traumatic Coagulopathy
Anesthesiology 1 2017, Vol.126, 115-127. doi:10.1097/ALN.0000000000001428
Anesthesiology 1 2017, Vol.126, 115-127. doi:10.1097/ALN.0000000000001428
Abstract

Background: Major trauma is a leading cause of morbidity and mortality worldwide with hemorrhage accounting for 40% of deaths. Acute traumatic coagulopathy exacerbates bleeding, but controversy remains over the degree to which inhibition of procoagulant pathways (anticoagulation), fibrinogen loss, and fibrinolysis drive the pathologic process. Through a combination of experimental study in a murine model of trauma hemorrhage and human observation, the authors’ objective was to determine the predominant pathophysiology of acute traumatic coagulopathy.

Methods: First, a prospective cohort study of 300 trauma patients admitted to a single level 1 trauma center with blood samples collected on arrival was performed. Second, a murine model of acute traumatic coagulopathy with suppressed protein C activation via genetic mutation of thrombomodulin was used. In both studies, analysis for coagulation screen, activated protein C levels, and rotational thromboelastometry (ROTEM) was performed.

Results: In patients with acute traumatic coagulopathy, the authors have demonstrated elevated activated protein C levels with profound fibrinolytic activity and early depletion of fibrinogen. Procoagulant pathways were only minimally inhibited with preservation of capacity to generate thrombin. Compared to factors V and VIII, proteases that do not undergo activated protein C–mediated cleavage were reduced but maintained within normal levels. In transgenic mice with reduced capacity to activate protein C, both fibrinolysis and fibrinogen depletion were significantly attenuated. Other recognized drivers of coagulopathy were associated with less significant perturbations of coagulation.

Conclusions: Activated protein C–associated fibrinolysis and fibrinogenolysis, rather than inhibition of procoagulant pathways, predominate in acute traumatic coagulopathy. In combination, these findings suggest a central role for the protein C pathway in acute traumatic coagulopathy and provide new translational opportunities for management of major trauma hemorrhage.