What is the effect of Warfarin (Coumadin) on Protein C levels?

From the Guidelines

Warfarin initially decreases Protein C levels more rapidly than other vitamin K-dependent clotting factors, which can potentially create a temporary hypercoagulable state. Protein C is a natural anticoagulant with a short half-life of approximately 6-8 hours, while other clotting factors have longer half-lives ranging from 24-72 hours. When warfarin therapy is initiated, the quick depletion of Protein C before other procoagulant factors are affected can disrupt the balance between pro- and anticoagulant proteins. This imbalance explains why patients starting warfarin therapy require bridging with heparin or low molecular weight heparin for at least 5 days and until the INR is therapeutic (typically 2-3) for two consecutive days. This approach prevents paradoxical thrombosis and rare complications like warfarin-induced skin necrosis, which occurs in approximately 0.01-0.1% of patients, particularly those with underlying Protein C deficiency, as reported in studies such as 1 and 1.

The pathogenesis of warfarin-induced skin necrosis is uncertain, but an association with protein C deficiency has been reported, as well as less commonly, protein S deficiency, as noted in 1. Clinicians should be vigilant for signs of skin necrosis (painful red lesions that progress to necrotic areas) during the first week of warfarin therapy, especially in high-risk patients. Key points to consider include:

• Warfarin's effect on protein C levels and the potential for a temporary hypercoagulable state
• The importance of bridging with heparin or low molecular weight heparin when initiating warfarin therapy
• The risk of warfarin-induced skin necrosis, particularly in patients with underlying protein C deficiency
• The need for careful monitoring of patients during the initial stages of warfarin therapy, as highlighted in studies such as 1 and 1.

In terms of management, a reasonable approach for patients who develop warfarin-induced skin necrosis and require further anticoagulant therapy is to restart warfarin at a low dose, while therapeutic doses of heparin are administered concurrently, and gradually increase warfarin over several weeks, as suggested in 1. This approach should avoid an abrupt fall in protein C levels before reduction in levels of factors II, IX, and X occurs.

From the FDA Drug Label

CLINICAL PHARMACOLOGY 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 half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively. The resultant in vivo effect is a sequential depression of Factor VII, Protein C, Factor IX, Protein S, and Factor X and II activities.

The effect of Warfarin on Protein C levels is a decrease in its production due to the inhibition of vitamin K-dependent clotting factors. Warfarin lowers Protein C levels by inhibiting its synthesis, with Protein C having a half-life of approximately 8 hours 2.

• Key points:
  • Warfarin inhibits the synthesis of vitamin K-dependent clotting factors, including Protein C.
  • The half-life of Protein C is approximately 8 hours.
  • Warfarin decreases the production of Protein C, leading to lower levels.

From the Research

Warfarin Effect on Protein C Levels

• Warfarin decreases protein C levels, with one study showing a decrease to 56.9% +/- 15.3% of normal levels 3
• Protein C and protein S levels affect warfarin doses and predictions significantly, but not to a clinically meaningful degree 3
• The relationship between warfarin-induced skin necrosis and level of anticoagulation was investigated, and it was found that warfarin therapy required an INR of greater than 3.5 to avoid skin necrosis in patients with homozygous protein C deficiency 4

Diagnosis of Protein C Deficiency in Warfarinized Patients

• Serial measurement of protein C, factor II, and factor X at various INR levels showed a correlation between suppression of these vitamin K-dependent factors and degree of anticoagulation 5
• There was a distinguishable difference in protein C level, protein C: factor II, and protein C: factor X ratio in warfarinized protein C deficient patients when compared with warfarinized patients who were not protein C deficient 5
• Comparison of observed over expected protein C and protein S ratios with normal ranges successfully identified known protein C and protein S deficient patients who were taking warfarin at the time of testing 6

Treatment of Protein C Deficiency

• Low molecular weight heparin (LMWH) is an effective form of long-term therapy for homozygous protein C deficient patients with measurable protein C levels 4
• Vitamin K antagonists and low-molecular-weight heparins are preferred over direct oral anticoagulants (DOACs) for treating protein C or S deficiency until more robust data are available about using DOACs in these patients 7