Platelet dysfunction during trauma involves diverse signaling pathways and an inhibitory activity in patient-derived plasma

Background Trauma-induced coagulopathy (TIC) occurs in about 25% of injured patients and accounts for about 10% of deaths worldwide. Upon injury, hemostatic function may decline due to vascular dysfunction, clotting factor deficiencies, hyperfibrinolysis, and/or platelet dysfunction. We investigated agonist-induced calcium signaling in platelets obtained over time from trauma patients. Methods Platelets from trauma patients and healthy donors were monitored via intracellular calcium mobilization and flow cytometry markers (α2bβ3 activation, P-selectin display, and phosphotidylserine exposure) following stimulation with a panel of agonists [ADP, U46619, convulxin, PAR-1/4 activating peptides, iloprost] used in isolation or in pairwise tests. Furthermore, healthy donor platelets were tested in heterologous plasma isolated from healthy subjects and trauma patients. Results When exposed to agonists over the first 24 hr post-injury, trauma patient platelets mobilized less calcium in comparison to healthy platelets. Partial recovery of platelet activity was observed in about a third of patients after 120 hr, although not fully obtaining healthy baseline function. Flow cytometry markers of trauma platelets were similar to healthy platelets prior to stimulation, but were depressed in trauma platelets stimulated with ADP or convulxin. Also, washed healthy platelets showed a significant reduction in calcium mobilzation when reconstituted in plasma from trauma patients, relative to healthy plasma, at all plasma doses tested. Conclusion Platelet dysfunction in trauma patients included poor response to multiple agonists relevant to hemostatic function. Furthermore, the inhibitor effect of patient plasma on healthy platelets suggests that soluble plasma species may downregulate endogenous or transfused platelets during trauma. Level of evidence Prognostic/Epidemiological, Level III *Corresponding Author: Scott L. Diamond, 1024 Vagelos Research Laboratories, University of Pennsylvania, Philadelphia, PA, 19104, USA. Tel: +1(215)-573-5702, Fax: +1(215)-573-6815. e-mail: sld@seas.upenn.edu Author Contact Information:vernic@seas.upenn.edu, antonio.davila@uphs.upenn.edu, steve.balian@uphs.upenn.edu, carrie.sims@uphs.upenn.edu Conflict of Interest and Source of Funding: This study was supported by NIH U01 HL131053 (S.L.D.), NIH UM1 HL120877 (TACTIC Consortium, S.L.D.) and 5T32HL007954-18 (C.C.V.). We would like to thank the dedicated team of clinical research coordinators and research assistants at PARC for their ability to enroll trauma patients and obtain samples around the clock. Otherwise, no conflicts to disclose. © 2018 Lippincott Williams & Wilkins, Inc.

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