A model for thrombin protection against endotoxin

Thrombin enhances the barrier function of rat microvascular endothelium in a PAR-1-dependent manner

“…Although these results challenge the prevalent understanding of thrombin as a widespread edemagenic proinflammatory agent, they are consistent with the evolving understanding of thrombin as a complex multifunctional molecule with both pro-and anticoagulant and pro-and anti-inflammatory roles (42,43). A potential vasoprotective role for thrombin in the microcirculation was suggested in a previous study of thrombin inhibition with hirudin in a septic hamster model (19).…”

“…Increased vascular permeability is a cardinal feature of acute inflammation and can become a clinically prominent feature in the pathobiology of inflammatory vascular diseases such as acute lung injury and the sepsis syndrome. Although studies have supported a role for thrombin in mediating increased vascular permeability in sepsis, antecedent thrombin infusion has provided a significant survival benefit in endotoxin-infused dogs (43) and thrombin inhibition has exacerbated LPS-induced microvascular dysfunction (19). Furthermore, thrombin inhibition in PAR-1 receptor knockout models has failed to lead to an improvement in survival in animal models of sepsis.…”

Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells

“…In support of a primarily antiinflammatory role for thrombin under normal physiological conditions, it is known that the infusion of a low concentration of thrombin to primates exhibits a protective effect by increasing the concentration of APC in circulation without increasing the markers of platelet activation (30). Similarly, a low concentration of thrombin has been demonstrated to block the lethal inflammatory effect of endotoxin (31). Noting that both fast and slow forms of thrombin can effectively activate protein C (32), but only the fast form of thrombin can optimally activate PAR-1 (32), it is possible that the colocalization of TM with EPCR and PAR-1 in the lipid rafts can tip the balance of thrombin in favor of interaction with TM, thereby mediating the PAR-1-dependent cellular signaling effects through the protective APC pathway under physiological conditions.…”

Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia

“…18 Fourth, infusion of low concentrations of thrombin in dogs significantly protected the animals from endotoxininduced mortality. 19 The infused thrombin likely resulted in augmented activation of endogenous PC by the TM-thrombin complex, thus potentially increasing endogenous APC levels. Fifth, both antithrombin III and tissue-factor pathway inhibitor failed to demonstrate a significant reduction in 28-day mortality in phase 3 clinical trials.…”

“…First, animal studies have shown that natural anticoagulants, in particular the components of the PC pathway (eg, thrombomodulin [TM] and PC/APC), can reduce mortality associated with septic shock. 15,16 Second, a recent large clinical trial (recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS]) demonstrated that treatment with recombinant human APC (rhAPC) reduced relative all-cause 28-day mortality by 19.4% in patients with severe sepsis as compared to patients treated with placebo. 17 Third, although a study of 184 in-hospital patients with meningococcemia found increased morbidity in heterozygous FV Leiden carriers, there was a trend toward reduced mortality in FV Leiden carriers compared with noncarriers.…”