The pharmacologic effect of warfarin is to inhibit the synthesis of the four coagulation factors and protein C and S, resulting in a decrease in their plasma levels according to their half-life. Protein C has the shortest half-life (8 h), and its plasma level falls the most quickly. Factor VII has the shortest half-life of the coagulation factors, about 7 h, and plasma levels fall thereafter. Factor II has the longest half-life, about 60 h, and its plasma levels fall the most slowly after the start of warfarin therapy. The phase delay between the fall in protein C (an antithrombotic protein) and the fall in the affected four coagulation factors (thrombotic proteins) results in a transient state of increased thrombogenesis that lasts for about 24 to 36 h. This potential hypercoagulable state is reduced but not eliminated by initiating warfarin therapy with 5-mg/d doses.5 For patients in whom sudden intravascular thrombosis can be fatal (e.g., those with a prosthetic heart valve), anticogulation should be ensured with heparin [or perhaps a low-molecular-weight (LMW) product] before starting oral warfarin. Thus, a noncompliant patient with a prosthetic heart valve who has stopped oral anticoagulants should not simply be discharged with instructions to restart warfarin.
There also appears to be rebound during warfarin withdrawal. During the first 4 days, factors VII and IX increase more rapidly than proteins C and S, resulting in an imbalance between provokers and inhibitors of coagulation. 6 This potential hypercoagulable condition appears to exist biochemically for about 4 days during warfarin withdrawal. However, prospective studies have shown no increased incidence of clinical episodes of thrombosis with sudden termination of warfarin therapy compared to gradual tapering. The thromboembolic events that occur in patients after warfarin discontinuation are related more to the underlying condition than to the method of termination.
The two major complications of warfarin therapy are major bleeding episodes and skin necrosis. Bleeding is usually related to the degree of anticoagulation and can be prevented by laboratory monitoring with dose adjustments. Reversal with vitamin K-, or factor replacement may be necessary for major hemorrhage. Skin necrosis occurs primarily in patients with protein C deficiency. This complication usually develops 3 to 8 days after starting treatment and is due to thrombosis of small cutaneous vessels. Warfarin in contraindicated in pregnancy because it is teratogenic and causes fetal hemorrhage.
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