Abstract
BackgroundThe mechanisms of trauma induced coagulopathy (TIC) are considered multifactorial. Amongst others, however, shedding of the endothelial glycocalyx resulting in increased concentrations of glycocalyx fragments in plasma might also play a role. Thus, we hypothesized that shedded glycocalyx components affect coagulation and may act as humoral mediators of TIC.MethodsTo investigate effects of heparan sulfate, chondroitin sulfate, syndecan-1, versican, and thrombomodulin we added these fragments to in vitro assays of whole blood from healthy volunteers to yield concentrations observed in trauma patients. Platelet function, whole blood coagulation, and fibrinolysis were measured by standard coagulation tests, impedance aggregometry (IA), and viscoelastic tests (VET). To assess dose-response relationships, we performed IA with increasing concentrations of versican and VET with increasing concentrations of thrombomodulin.ResultsIntrinsically activated clotting times (i.e., activated partial thromboplastin time and intrinsically activated VET with and without heparinase) were unaffected by any glycocalyx fragment. Thrombomodulin, however, significantly and dose-dependently diminished fibrinolysis as assessed by VET with exogenously added rt-PA, and increased rt-PA-induced lysis Indices after 30 (up to 108% of control, p < 0,0001), 45 (up to 368% of control, p < 0,0001), and 60 min (up to 950% of control, p < 0,0001) in VET. Versican impaired platelet aggregation in response to arachidonic acid (up to − 37,6%, p < 0,0001), ADP (up to − 14,5%, p < 0,0001), and collagen (up to − 31,8%, p < 0,0001) in a dose-dependent manner, but did not affect TRAP-6 induced platelet aggregation. Clotting time in extrinsically activated VET was shortened by heparan sulfate (− 7,2%, p = 0,024), chondroitin sulfate (− 11,6%, p = 0,016), versican (− 13%, p = 0,012%), and when combined (− 7,2%, p = 0,007).ConclusionsGlycocalyx components exert distinct inhibitory effects on platelet function, coagulation, and fibrinolysis. These data do not support a ‘heparin-like auto-anticoagulation’ by shed glycosaminoglycans but suggest a possible role of versican in trauma-induced thrombocytopathy and of thrombomodulin in trauma-associated impairment of endogenous fibrinolysis.
Highlights
The mechanisms of trauma induced coagulopathy (TIC) are considered multifactorial
In line with the first experimental series, platelet function after activation with thrombin receptor activator peptide-6 (TRAP-6) remained unaltered. The data from this in vitro study suggest a possible role for endothelial glycocalyx components as mediators in TIC since different glycocalyx fragments showed distinct dose-dependent effects on fibrinolysis, platelet function, and tissue factor-induced clotting time
Our results do not support relevant heparin-like effects of the examined glycocalyx fragments, at least not in concentrations commonly found in trauma patients [10]
Summary
The mechanisms of trauma induced coagulopathy (TIC) are considered multifactorial. In up to one third of trauma patients, hemorrhagic shock is complicated by trauma-induced coagulopathy (TIC), an independent risk factor for mortality [2]. The etiology of TIC is considered multifactorial [3] and alterations in platelet function [4], coagulation [5], and fibrinolysis [6] have been suggested to play major roles. Fibrinolysis, in particular, may be massively increased, leading to hyperfibrinolytic bleeding, or is endogenously suppressed, leading to ‘fibrinolysis shutdown’. Both conditions are associated with an increased mortality [7]. The mediators leading to acquired platelet dysfunction, alterations in thrombin generation, and the frequently observed pro- or antifibrinolytic states (hyperfibrinolysis vs. lysis shutdown) are largely unknown
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