Does warfarin (Coumadin) decrease Protein C and S activity/antigen levels?

From the Guidelines

Warfarin (Coumadin) decreases both Protein C and Protein S activity and antigen levels, which can lead to a temporary hypercoagulable state during the initial treatment phase. This effect is due to the inhibition of vitamin K-dependent clotting factors by warfarin, and both Protein C and Protein S are vitamin K-dependent proteins 1. When a patient starts warfarin therapy, Protein C levels fall more rapidly than other clotting factors due to its shorter half-life (approximately 8 hours) 1. Protein S has a slightly longer half-life but is similarly affected.

The reduction in Protein C and S levels can create a temporary hypercoagulable state during the first few days of treatment, which is why patients at high risk for thrombosis are often bridged with heparin when starting warfarin 1. This approach is particularly important in patients with underlying Protein C deficiency, as the warfarin-induced reduction in Protein C can occasionally lead to a rare but serious complication called warfarin-induced skin necrosis.

Key points to consider:

• Warfarin decreases Protein C and S activity and antigen levels
• Protein C levels fall more rapidly than other clotting factors due to its shorter half-life
• The reduction in Protein C and S levels can create a temporary hypercoagulable state during the initial treatment phase
• Patients at high risk for thrombosis should be bridged with heparin when starting warfarin
• Testing for inherited deficiencies of Protein C and S should not be performed while a patient is on warfarin therapy, as it will give falsely low results 1.

From the FDA Drug Label

Warfarin sodium tablets and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. The resultant in vivo effect is a sequential depression of Factor VII, Protein C, Factor IX, Protein S, and Factor X and II activities. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%.

Key Points:

• Warfarin inhibits the synthesis of vitamin K dependent clotting factors, including proteins C and S.
• The resultant effect is a sequential depression of protein C and S activities.
• Therapeutic doses of warfarin decrease the total amount of active vitamin K dependent clotting factors, including proteins C and S, by approximately 30% to 50%.

Answer: Yes, coumadin (warfarin) decreases Protein C and S activity levels 2, 2.

From the Research

Effect of Coumadin on Protein C and S Activity/Antigen Levels

• Coumadin, also known as warfarin, has been shown to decrease protein C and S activity/antigen levels in several studies 3, 4, 5, 6, 7.
• The decrease in protein C antigen levels is rapid, with a significant decline observed within the first few days of warfarin therapy 3, 6.
• Protein S antigen levels do not decrease as rapidly as protein C, but functional levels of protein S are often low in patients with acute thrombus 4.
• The decrease in protein C and S activity/antigen levels may contribute to a transient prothrombotic phase during the initiation of warfarin therapy 3, 4.
• The anticoagulant activity of protein C decreases to a greater extent than either the amidolytic or immunologic levels during oral anticoagulation 7.
• Measurement of protein C anticoagulant activity may be necessary to reflect adequately the anticoagulant protection afforded by this protein, especially during stabilized warfarin treatment 7.

Comparison of Protein C and S Levels

• Protein C and S levels affect warfarin doses and predictions significantly, but not to a clinically meaningful degree 5.
• Protein C accounted for only 4.2% of the mean maintenance dose, but protein C and S levels accounted for 31% of the mean dose prediction error 5.
• The rate of protein C decrease is closer to that of factor VII than those of factors IX, X, and II 6.

Clinical Implications

• Deficiency of protein C and protein S should be considered a risk factor contributing to recurrent thrombotic disease 4.
• The function of these proteins is altered by many common clinical conditions, which have associated increased risk of thrombosis 4.
• The early decrease in protein C may contribute to the poor antithrombotic efficacy of anticoagulant therapy during the first days of treatment 6.