Name: Activated Protein C

Drotrecogin alpha (activated)

Xigris - Eli Lilly & Co., Indianapolis, IN

Description/Contents: Drotrecogin alpha (activated) is a recombinant form of human activated protein C (APC) that is manufactured as an inactive zymogen and is enzymatically activated by cleavage with thrombin, then purified using monoclonal antibodies. APC exerts an anticoagulant effect, along with its co-factor protein S, by inactivating Factors Va and VIIIa, two critical pro-coagulants that lead to thrombin formation. Thrombin binds to thrombomodulin on endothelial cells at – and adjacent to – the site of vascular injury which stimulated the coagulation process. Thrombomodulin serves as a cofactor for the conversion of protein C, present in the plasma, by thrombin to activated protein C.

APC also inhibits tumor necrosis factor production by monocytes, blocks leukocyte adhesion to selectins and limits thrombin-induced microvascular damage. Discovery of an APC-resistant state, hereditary Factor V Leiden, which leads to increased susceptibility to thrombosis, has led to extensive laboratory testing and an occasional diagnosis of APC-resistance in some cases of thrombophilia or venous thrombosis.

• APC is approved by the FDA for use in severe sepsis, based on the finding that it decreased mortality and the development of DIC in high-risk patients (defined by APACHE II scores >25) by about 20%. Although there are documented instances of familial protein C deficiency, the only approved indication currently is the acquisition of deficiency in the presence of severe sepsis. It is not approved for pediatric use.

Dosage and Administration: Hematologic consultation is always recommended before starting therapy. APC should be administered intravenously at 24 ?g/kg/hr for a total of 96 hours. Dosage adjustment should not be based on clinical or laboratory parameters. For detailed information on dosage and administration, see package insert.

APC interferes with the measurement of aPTT. Coagulopathy in treated patients should be assessed using the prothrombin time (PT) test and/or the INR.

Contraindications and Adverse Reactions: APC therapy increases the risk of bleeding and is contraindicated in patients with active internal bleeding, recent spinal or cranial surgery or trauma, presence of an epidural catheter or an intracranial neoplasm or mass lesion.

Bleeding is the most common adverse reaction associated with APC. There is no antidote for APC, however, it has a short half-life. Bleeding and /or overdose is treated by cessation of infusion and monitoring and treatment of bleeding.

Alternative Therapy: Currently none. Standard support for severe sepsis is part of the treatment regimen.

Moll S, Roberts HR. Overview of anticoagulant drugs for the future. Seminars in Hematology 39:145-157, 2002.

Gerson WT, Dickerman JD, Bovill EG, Golden E. Severe acquired protein C deficiency in purpura fulminans associated with DIC: treatment with protein C concentrate. Pediatrics 91: 418, 1993.

Kraus M. The anticoagulant potential of the protein C system in hereditary and acquired thrombophilia: pathomechanisms and new tools for assessing its clinical relevance. Sem Thromb Hemost 24:337-354, 1998.

Transfusion Guidelines

Plasma Guidelines	Antithrombin III Guidelines
Platelet Guidelines	Activated Protein Guidelines
Red Cell Guidelines	Factor IX Guidelines
Cryoprecipitate Guidelines	Factor VIII Guidelines
AICC/Porcine Factor VIII Guidelines	IVIG Guidelines Coagulation Factor VII Guidelines

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