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Recombinant activated protein C in pediatric sepsis.

Background The incidence of sepsis has risen 139% during the past 10 years and affects 750,000 patients annually. Mortality in adults with sepsis is 28– 50% and is associated with annual expenditures of $16 billion. Although the mortality rate in children is lower ( 10%), it is higher among infants and costs per case ($54,000) are higher than in any other age group: $1 billion for infants with sepsis; and another $622 million in children between 1 and 18 years. Sepsis induces increased coagulation and decreased fibrinolysis. Derangements in platelet function and number, prolongation of activated partial thromboplastin and thromboplastin times, abnormal fibrinogen levels and elevated levels of fibrin breakdown products are observed to varying degrees. Endotoxin or other microbial products activate macrophages and other cells. Activated cells secrete cytokines, such as tumor necrosis factorand interleukins. These in turn stimulate more cells in various organs of the body. Tissue factor production from monocytes (and perhaps endothelial cells) activates the coagulation pathway by activating Factor VII. Factor VIIa (part of the extrinsic coagulation system) activates Factor X, which then results in thrombin formation. The final step, as thrombin cleaves fibrinogen, is the deposition of fibrin and formation of a fibrin clot. Thrombin also exacerbates inflammation directly and indirectly. While clot formation is being promoted, fibrinolysis is inhibited by the release of thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1). The reactions result in a hypercoagulable state. Thrombi in the lung microvasculature may cause acute respiratory distress syndrome (ARDS). A manifestation of this response is thrombus formation in peripheral vessels, leading to ischemia and purpura fulminans. As with other hypercoagulable states, bleeding can be precipitated by consumption of coagulation factors and platelets and reduced production of hemostatic molecules. One of the endogenous proteins that regulate coagulation, protein C, is vitamin K-dependent and is synthesized in the liver. Once activated by thrombin-thrombomodulin complexes and bound to its receptor on endothelial cells, activated protein C produces antithrombotic and profibrinolytic effects. It inactivates Factors Va and VIIa, causing a decrease in thrombin formation, and it inhibits PAI-1 and TAFI, resulting in an increase in fibrinolysis. Activated protein C has antiinflammatory effects indirectly via inhibition of thrombin formation and directly by blocking cytokine formation and inhibiting nuclear factor B translocation in cells. Thus protein C is a regulator of hemostasis and the immune sequelae of sepsis. Over 80% of patients with sepsis have protein C deficiency. The degree of protein C deficiency has been correlated to both mortality and organ dysfunction. Some patients with severe sepsis may be deficient in expression of thrombomodulin and protein C receptors, which are normally found on endothelial cells, resulting in an inability to activate endogenous or exogenous circulating protein C.