COAGULATION INHIBITOR SUBSTITUTION DURING SEPSIS

This review presents the rationale for and main results of coagulation inhibitor substitution during experimental and human sepsis. Activati on of the contact system induces activation of the classical complemen t pathway with generation of anaphylatoxins, of the kinins pathway and of fibrinolysis. Physiologic inhibition depends on the C1-inhibitor ( C1-Inh.). Septic patients exhibit a relative deficiency of biologicall y active C1-Inh. Substitution with concentrations of C1-Inh has been s afely performed and preliminary results are consistent with a possible beneficial effect on hypotension and vasopressor requirement in septi c shock. The extrinsic pathway is the main initial coagulation process involved in sepsis-induced DIG. Endothelial and monocyte generation o f tissue factor (TF) is activated by bacterial products and endotoxin. Activation of TF is counteracted by a specific tissue factor pathway inhibitor (TFPT). The potential for TFPI substitution to inhibit the a ctivation of the coagulation cascade in sepsis requires further study. Thrombin generation is inhibited by antithrombin III (ATIII) and the protein C-protein S system. During sepsis, ATIII is consumed and degra ded by elastase. Animal studies have shown that DIC and death were pre vented by high doses of ATIII concentrates. Although a significant red uction in the duration of biological symptoms of DIC has been reported in most human studies, the usefulness of ATIII substitution in human sepsis is still debated. None of the studies was able to document a st atistically significant reduction in mortality. Protein C is activated by thrombomodulin and, with its cofactor protein S, inhibits factors Va and VIIIa. The free level of protein S depends on the level of the C4b binding protein (C4bBP), an acute-phase complement regulatory prot ein. During sepsis, protein C activity is significantly reduced, eithe r by acute consumption or by thrombomodulin down-regulation, and incre ased levels of plasma C4bBP inhibit protein S. Infusion of activated p rotein C and protein S substitution both protect animals from the leth al effects of bacteria. Combining these different coagulation inhibito rs should be carefully studied before its use in septic patients is re commended.