High sCD40L levels early after trauma are associated with enhanced shock, sympathoadrenal activation, tissue and endothelial damage, coagulopathy and mortality

Abstract

DenmarkTo cite this article: Johansson PI, Sørensen AM, Perner A, Welling KL, Wanscher M, Larsen CF, Ostrowski SR. High sCD40L levels early after trauma are associated with enhanced shock, sympathoadrenal activation, tissue and endothelial damage, coagulopathy and mortality. J Thromb Haemost 2012; 10: 207-16.Summary. Background: Severe injury activates the sympathoadrenal, hemostatic and inflammatory systems, but a maladapted response may contribute to a poor outcome. Soluble CD40L is a platelet-derived mediator that links inflammation, hemostasis and vascular dysfunction. Objectives: To investigate the association between the sCD40L level and tissue injury, shock, coagulopathy and mortality in trauma patients. Methods: A prospective, observational study of 80 trauma patients admitted to a Level I Trauma Center. Data on demography, biochemistry, Injury Severity Score (ISS) and 30-day mortality were recorded and admission plasma/serum analyzed for sCD40L and biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments [hcDNA], Annexin V, thrombomodulin and syndecan-1), coagulation activation/inhibition (PF1.2, TAT-complex, antithrombin, protein C, activated protein C, sEPCR, TFPI, von Willebrand factor [VWF], fibrinogen and factor [F] XIII), fibrinolysis (D-dimer, tissue plasminogen activator [tPA] and plasminogen activator inhibitor-1 [PAI-1]) and inflammation (interleukin-6 [IL-6] and sC5b-9). We compared patients stratified by median sCD40L level and investigated predictive values of sCD40L for mortality. Results: High circulating sCD40L was associated with enhanced tissue and endothelial damage (ISS, hcDNA, Annexin V, syndecan-1 and sTM), shock (pH, standard base excess), sympathoadrenal activation (adrenaline) and coagulopathy evidenced by reduced thrombin generation (PF1.2), hyperfibrinolysis (D-dimer), increased activated partial thromboplastin time (APTT) and inflammation (IL-6) (all P < 0.05). A higher ISS (P = 0.017), adrenaline (P = 0.049) and platelet count (P = 0.012) and lower pH (P = 0.002) were associated with higher sCD40L by multivariate linear regression analysis. High circulating sCD40L (odds ratio [OR] 1.84 [95% CI 1.05-3.23], P = 0.034), high age (P = 0.002) and low Glasgow Coma Score (GCS) pre-hospital (P = 0.002) were independent predictors of increased mortality. Conclusions: High early sCD40L levels in trauma patients reflect tissue injury, shock, coagulopathy and sympathoadrenal activation and predict mortality. As sCD40L has pro-inflammatory activity and activates the endothelium, sCD40L may be involved in trauma-induced endothelial damage and coagulopathy.

Effect of acute hypobaric hypoxia on the endothelial glycocalyx and digital reactive hyperemia in humans

“…Increased levels of catecholamines, syndecan-1 and soluble thrombomodulin in patients with severe trauma, acute myocardial infarction and sepsis are associated with increased mortality (Johansson et al, 2011, 2012, 2013; Ostrowski et al, 2013a,b). In the present study, short-term hypobaric hypoxia did not induce significant increases in circulating catecholamines indicating that an effect on the endothelium from symphathetic outflow was negligible.…”

The pathophysiology of trauma-induced coagulopathy

“…By measuring the difference between KaolinTEG and HeparinaseTEG in samples taken from 77 trauma patients on ED arrival, a recent study found that four of these patients (5.2%) had evidence of a high degree of autoheparinization, which appeared mechanistically linked to endothelial glycocalyx degradation [27 && ]. This group had higher ISS [median IQR, 31 (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37) vs. 17 (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)], lower haemoglobin level (median, 5.8 vs. 8.4 mmol/l) and received more transfusions during the first 1 h (median, 5 vs. 0) and 24 h (median, 10 vs. 0; all P < 0.05). Using almost the same patient cohort, another group have published fascinating data demonstrating an association between tissue hypoperfusion, neurohormonal activation and markers of endothelial disruption [28 & ,29 & ].…”

Mechanisms of trauma-induced coagulopathy

“…36 This relationship may be mediated by products of endothelial or platelet activation, such as soluble vascular endothelial growth factor receptor 1 or soluble CD40 ligand, both of which have been shown to be predictive of shock, coagulopathy, and mortality in trauma patients. 37,38 Although specific mechanisms of shock-induced endothelial activation and dysfunction have not yet been elucidated, there is emerging evidence that disruption of the endothelial glycocalyx barrier (indicated by syndecan-1 release) plays an important role in the endothelial response to traumatic shock. Haywood-Watson et al found elevated plasma syndecan-1 concentration in severely injured trauma patients in hemorrhagic shock.…”