A 72-year-old woman comes to the office for a routine follow-up appointment. She has no symptoms and her past medical history is insignificant. Her temperature is 36.7 C (98 F), blood pressure is 110/80 mm Hg, and pulse is 76/min and irregular. ECG shows atrial fibrillation with no ischemic changes. Anticoagulation therapy with warfarin is initiated for stroke prevention. Two days later, the patient is hospitalized with severe skin and subcutaneous fat necrosis. Drug effects on which of the following processes are most likely responsible for this patient's skin findings?
This patient has warfarin-induced skin necrosis, a rare but important complication of warfarin initiation. It is thought to be due to a transient hypercoagulable state that can occur during the first few days of warfarin therapy.
The overall anticoagulant effect of warfarin is due primarily to its inhibition of the vitamin K-dependent gamma-carboxylation of clotting factors II, VII, IX, and X ("vitamin K-dependent clotting factors"). However, warfarin also decreases carboxylation of proteins C and S, which normally exert an anticoagulant effect (through proteolysis and deactivation of factors V and VIII). Protein C has a short half-life, so its anticoagulant activity is reduced quickly when warfarin therapy is initiated, by about 50% within the first day. During this time, the vitamin K-dependent clotting factors II, IX, and X continue to exert a procoagulant effect as they have longer half-lives (factor VII has a short half-life similar to protein C).
This difference in half-lives translates into a transient hypercoagulable state:
Thrombosis and clot can interrupt blood flow to the skin and lead to skin necrosis. For this reason, overlapping coadministration of heparin ("heparin bridge") is commonly used when warfarin is initiated. The risk of warfarin-induced skin necrosis is increased in patients with a preexisting protein C deficiency, as well as in those started on a large loading dose of warfarin.
(Choice A) Warfarin affects coagulation factor carboxylation, not synthesis.
(Choice B) Factor VII inhibition by warfarin has an anticoagulant effect.
(Choice C) Warfarin does not have a major direct effect on factor XI activity that would cause skin necrosis.
(Choices D and F) Fibrinogen and prothrombin activity may be impacted downstream, but this is not the primary process affected by warfarin.
Educational objective:
Warfarin inhibits proteins C and S (natural anticoagulants present in blood), which can lead to skin necrosis, particularly in patients with protein C or S deficiency. This complication is usually seen in the first few days of warfarin therapy.