A 36-year-old woman with mitral valve prolapse comes to the office due to dyspnea and is found to have severe mitral valve regurgitation. Two weeks later, the patient undergoes elective mechanical mitral valve replacement. Continuous heparin infusion and oral warfarin are initiated following the procedure. Coagulation studies during admission are as follows:
| Postoperative day | 1 | 2 | 3 | 4 |
| INR | 1.1 | 1.5 | 1.8 | 2.1 |
| PTT(seconds) | 72 | 76 | 74 | 78 |
The patient achieves the goal of INR ≥2.5 on postoperative day 5 and heparin infusion is discontinued. Which of the following likely caused the delay in achieving therapeutic INR in this patient?
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Warfarin is a vitamin K antagonist that blocks epoxide reductase in the liver, leading to impaired vitamin K recycling. This depletes the reduced form of vitamin K, which is required for gamma carboxylation of vitamin K–dependent clotting factors (II, VII, IX, and X). In the absence of gamma carboxylation, vitamin K–dependent clotting factors cannot bind calcium or phospholipid membranes to induce coagulation.
Because warfarin inhibits gamma carboxylation of new vitamin K–dependent clotting factors, therapeutic efficacy is delayed until preexisting clotting factors in the plasma are consumed. Although INR tends to slowly increase in the first few days of administration due to the short half-life of factor VII (4-6 hours), full therapeutic effect does not typically occur for 3 days due to the long half-life of factor II.
Warfarin also inhibits gamma carboxylation of the proteins C and S. Because these proteins exert an anticoagulant effect, the initiation of warfarin can be associated with an initial procoagulant state. However, once preexisting vitamin K–dependent clotting factors are consumed, an anticoagulant effect is established.
(Choice B) Anti-platelet factor 4/heparin antibodies cause heparin-induced thrombocytopenia, which typically arise 5-10 days after heparin initiation. This condition is marked by thrombocytopenia and a high risk of arterial and venous thrombosis, but would not result in a delay in therapeutic INR following warfarin administration.
(Choice C) Total body vitamin K is sufficient for several weeks; it does not contribute to a delay in warfarin efficacy. However, increased intake of foods rich in vitamin K (eg, green leafy vegetables) can lead to subtherapeutic INR due to increased vitamin K availability in the liver.
(Choice D) Warfarin is metabolized by the hepatic cytochrome P450 2C9 enzyme. Because many other medications induce or inhibit this enzyme, warfarin is susceptible to a wide range of drug interactions. However, the delay in achieving therapeutic INR is primarily due to the presence of preexisting clotting factors.
(Choice E) Warfarin reaches maximal plasma concentration approximately 90 minutes after administration. The delay in efficacy is due to the presence of preexisting clotting factors.
Educational objective:
Warfarin blocks epoxide reductase, which lowers the reduced form of vitamin K in the liver; this prevents gamma carboxylation of vitamin K–dependent clotting factors (II, VII, IX, and X). Because warfarin only blocks the generation of new clotting factors, therapeutic effect is delayed 3-5 days until preexisting clotting factors are consumed.