Coagulation inhibitor replacement during sepsis: Useless?

Objective: Because coagulatory activation in sepsis is triggered mainly by tissue factor release from endothelial cells and blood monocytes during their activation via proinflammatory cytokines, inhibition of coagulation by exogenous administration of coagulation inhibitors has been proposed. These strategies should allow us to prevent and treat excessive coagulatory activation, thereby potentially preventing sepsis-induced organ dysfunction. Potential therapies include the natural coagulation inhibitors antithrombin, activated protein C, and tissue factor pathway inhibitor, as well as direct thrombin inhibition by recombinant hirudin. Data Sources: A limited review of the published literature using all sources was undertaken. Study Selection: Selected clinical and experimental studies with coagulatory inhibitors were analyzed. Conclusions:The biological properties of coagulatory activation during sepsis (coagulation as a protective mechanism to control the septic focus, e.g., fibrin deposition during peritonitis) are not completely understood. Therefore, one has to be careful when administering coagulatory inhibitors, especially because patients with multiple organ dysfunction syndrome often do not show the widespread fibrin deposition in nutritive blood vessels that have been seen experimentally. How might these patients benefit from thrombin inhibition? Coagulatory activation per se seems unlikely to directly cause deterioration of organ function, although it is involved in generalized endothelial activation with consecutive mediator release and increased leukocyte-endothelial cell interaction. Antagonism of inflammatory mediators and, consecutively, endothelial cell activation might be a better target in adjunctive sepsis therapy, with improvement in septic microcirculatory disturbances. Administration of natural pleiotropic coagulation inhibitors that are documented positive effects on the microcirculation, (such as activated protein C, antithrombin) seems to be promising.