Inflammation, sepsis, and coagulation

The molecular links between inflammation and coagulation are unquestioned. Inflammation promotes coagulation by leading to intravascular tissue factor expression, eliciting the expression of leukocyte adhesion molecules on th e intravascular cell surfaces, and down regulating the fibrinolytic and pro tein C anticoagulant pathways. Thrombin, in turn, can promote inflammatory responses. This creates a cycle that logically progresses to vascular injur y as occurs in septic shock. Most complex systems are regulated by product inhibition. This inflammation-coagulation cycle seems to follow this same p rinciple with the protein C pathway serving as the regulatory mechanism. Th e molecular basis by which the protein C pathway functions as an anticoagul ant is relatively well established compared to the mechanisms involved in r egulating inflammation. As one approach to identifying the mechanisms invol ved in regulating inflammation, we set out to identify novel receptors that could modulate the specificity of APC in a manner analogous to the mechani sms by which thrombomodulin modulates thrombin specificity. This approach l ed to the identification of an endothelial cell protein C receptor (EPCR). To understand the mechanism, we obtained a crystal structure of APC (lackin g the Gla domain). The crystal structure reveals a deep groove in a locatio n analogous to anion binding exosite 1 of thrombin, the location of interac tion for thrombomodulin, platelet thrombin receptor and fibrinogen. Thrombo modulin blocks the activation of platelets and fibrinogen without blocking reactivity with chromogenic substrates or inhibitors. Similarly, in solutio n, EPCR blocks factor Va inactivation without modulating reactivity with pr otease inhibitors. Thus, these endothelial cell receptors for the protein C system share many properties in common including the ability to be modulat ed by inflammatory cytokines. Current studies seek to identify the substrat e for the APC-EPCR complex as the next step in elucidating the mechanisms b y which the protein C pathway modulates the response to injury and inflamma tion. (C) 1999 Ferrata Storti Foundation.