Mutated VKOR leads to insufficient levels of reduced vitamin K and, consequently, vitamin K–dependent clotting factors. 5 VKOR is responsible for reducing vitamin K to its active form, which is necessary for the activation of the vitamin K–dependent clotting factors. Mutated CYP2C9 results in reduced coumarin metabolism and, subsequently, a longer half-life, thereby increasing the risk of hemorrhage with a standard dose of warfarin. These often-undiagnosed, subtle changes can increase the likelihood of a hemorrhagic complication associated with warfarin therapy.ĬYP2C9 is a microsomal enzyme partially responsible for coumarin breakdown. 5 Bleeding can result from gross abnormalities, such as hemophilia A or B, or from more subtle single nucleotide polymorphic mutations, such as those found in cytochrome P450 2C9 (CYP2C9), in vitamin K epoxide reductase, or in Factor IX propetide. Warfarin therapy can be problematic as a result of its narrow therapeutic index, highly variable dosage requirements among patients, and significant drug, dietary, and disease interactions. We review the advantages and disadvantages of these therapies and recommend Three Factor PCC with small doses of rFVIIa and with vitamin K in life-threatening situations if Four Factor PCC is unavailable. The current therapies available to emergency room physicians in the United States are fresh frozen plasma, recombinant Factor VIIa (rFVIIa), Factor Eight Inhibitory Bypassing Activity, or Three Factor PCC concomitantly administered with vitamin K. The most effective method of warfarin reversal involves the use of Four Factor Prothrombin Complex Concentrate (PCC), which is widely used throughout Europe but is unavailable in the United States. Annually the frequency of bleeding complications associated with overanticoagulation is 15% to 20%, with fatal bleeds measuring as high as 1% to 3%. It is one of the leading drugs implicated in emergency room visits for adverse drug reactions. Warfarin inhibits the activation of the vitamin K–dependent clotting factors (Factors II, VII, IX, and X) and regulatory proteins (proteins C, S, and Z). In 2004, 31 million warfarin prescriptions were dispensed in the United States. Warfarin, an oral vitamin K antagonist, is used to prevent arterial and venous thromboembolism in patients suffering from a multitude of diseases.
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