There is emerging evidence that the change from a normal quiescent endothelium to endothelial cell activation, glycocalyx damage, junctional disruption and ultimate endothelial cell injury reflects a progression from reversible to irreversible endothelial damage. In the present study, we investigated different endothelial derived molecules as surrogate markers for glycocalyx damage, endothelial cell activation, endothelial junction disruption and endothelial cell injury, to reveal the influence of progressive endothelial disruption on outcome in OHCA patients. Interestingly, we found that biomarkers reflecting endothelial damage were independently associated with shock degree whereas biomarkers reflecting endothelial activation and junctional disruption were independently associated with patient demography and/or other endothelial biomarkers. The finding that sE-selectin, sVE-cadherin and thrombomodulin were inter correlated supports the notion that endothelial activation, junctional disruption and cell injury are linked at the biologic level. Finally, we found that high circulating thrombomodulin was an independent predictor of increased mortality. In accordance with previous studies, higher age, male gender, high catecholamine levels and shock were all associated with high thrombomodulin levels. The strong predictive value of thrombomodulin supports the notion that patients with the most severe form of endothelial injury have the poorest outcome. The finding that post-CA therapeutic hypothermia may attenuate the anoxic brain injury and improve outcome, emphasizes that therapeutic interventions applied after ROSC can be beneficial. Given this, we infer that interventions aiming at protecting and/or restoring the endothelium, administered at the earliest possible, may be able to alleviate the downstream endothelial damage and the ensuing PCAS, and thereby improve patient outcome. A randomized clinical trial to test this hypothesis is currently underway. The present study had several limitations. First, the observational GYKI 53655 hydrochloride nature of study does not allow independent evaluations of the cause-and-effect relationships suggested. Second, the IV heparin injection to STEMI OHCA patients makes it impossible to differentiate between potential effects of the STEMI itself vs. heparin on glycocalyx damage. Third, the study was a post hoc sub-study of the TTM trial, a randomized multicenter trial, where we only investigated patients included at a single site. Given this, the present findings should be considered hypothesis- generating and the p-values as explorative in nature. Coagulation and fibrinolytic cascades may be important components of the pathogenic process GR 127935 hydrochloride leading to pre-eclampsia, eclampsia or HELLP syndrome. One proposed mechanism is that excessive release of plasminogen activator inhibitor type 1, a key down-regulator of endogenous fibrinolytic activity, from activated endothelium promotes spiral arterial or intervillous thrombosis that reduces placental perfusion.