ACTIVATED PROTEIN C. Activated protein C (APC) is generated from the protein C precursor via proteolytic cleavage by thrombin.

Protein C is a vitamin-K dependent plasma protein zymogen and it acts as a major physiological anticoagulant (Esmon, 1992). Activation of protein C converts it into a serine protease which occurs on the endothelial surface in the presence of a thrombin-thrombomodulin complex. APC inhibits the coagulation of blood by direct

proteolytic inactivation of FVIIIa and Va. The inactivation of FVa by APC effectively shuts down thrombin formation (Gresele, 1998). This inhibition of blood coagulation occurs in the presence of protein S, which is a non-enzymatic cofactor, as well as negatively charged phospholipids. Griffin, Fernandez, Gale & Mosnier (2007) reported that mild or sereve genetic deficiency of protein C is linked with increased risk for venous thrombosis or neonatal purpura fulminans respectively. Furthermore, mutations that result in the resistance of factor Va to APC inactivation is also implicated in increased risk of thrombosis (Gale, Xu, Pellequer, Getzoff & Griffin, 2002). Liaw et al. (2006) also reported that impaired

proteolytic cleavage of protein C is observed in patients with inflammation and sepsis.

Schematics showing the activation and function of APC

Severe sepsis is characterized by acute organ dysfunction and it is the result of an inflammation due to excessive stimulation of the immune system by bacteria or other microorganisms. Angus et al., (2000) reports that approximately 750,000 people develop sepsis per year in the United States alone, of which 225, 000 are fatal cases. The mortality rate is speculated to be between 30 50% irrespective of the fact that advances has been made in treatment of patients. The concentration of APC in the plasma is 40 pM while that of protein C is 70 nM (Gruber & Griffin, 1992). Promising results have been obtained in animal models and clinical studies demonstrating the use of APC for treating a host of thrombotic disorders as well as providing a strong rationale for development of clinical trials of APC in ischemic stroke (Cheng, 2003; Griffin, Zlokovic, & Fernandez, 2002). APC in its purified form has been shown to be effective against venous thrombosis in rats and septic shock in baboons (Yamashita, Matsuoka, Funatsu, & Yamamoto, 1994). In 2003, deKleijn et al., reported the outcome of a clinical trial which showed that protein C concentrate resulted in dosedependent, albeit transient increase, of plasma Activated Protein C leading to subsequent improvement in haemostasis. The observation that APC may exhibit a profibrinolytic

property has also strengthened its choice as an antithrombotic agent (Gresele, 1999). The use of recombinant human APC for the treatment of severe sepsis has gained the approval of global regulatory agencies. Recombinant human activated protein C known as drotrecogin alfa (activated) was used in a phase III (PROWESS) clinical trial. The result showed reduced mortality among patients treated with activated drotrecogin alfa (Bernard, 2001). Drotrecogin alpha (activated) is currently available for the treatment of severe sepsis in over 50 countries. A major drawback in APC therapy is its ability to induce bleeding as a result of its anticoagulant activity. In the PROWESS tial, this was the major side effect during the 4-day infusion period (Bernard, 2003).

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