Is warfarin better than Direct Oral Anticoagulant (DOAC) for a patient with Deep Vein Thrombosis (DVT) and protein C deficiency?

From the Guidelines

For patients with DVT and protein C deficiency, DOACs are preferred over warfarin due to their advantages in terms of reduced risk of harm and similar magnitude of benefit, as recommended by the latest guidelines 1. When considering anticoagulation therapy for patients with deep vein thrombosis (DVT) and protein C deficiency, the choice between warfarin and direct oral anticoagulants (DOACs) is crucial.

• The latest guidelines from the Chest journal, published in 2021, provide a strong recommendation for the use of DOACs such as apixaban, dabigatran, edoxaban, or rivaroxaban over vitamin K antagonists (VKAs) like warfarin for the treatment of VTE, including DVT 1.
• This recommendation is based on moderate-certainty evidence, but the panelists placed a high value on avoiding potential harm, leading to a strong recommendation.
• The advantages of DOACs over warfarin include reduced risk of warfarin-induced skin necrosis, which can occur due to the rapid decrease in protein C levels before anticoagulation is achieved.
• Additionally, DOACs do not require routine monitoring, have fewer food and drug interactions, and do not cause protein C depletion, making them a safer choice for patients with protein C deficiency.
• If warfarin must be used, it should be initiated with concurrent heparin or low molecular weight heparin (LMWH) coverage for at least 5 days and until the international normalized ratio (INR) is therapeutic, with a slow dose escalation approach.
• The duration of anticoagulation for these patients is typically indefinite, given their persistent thrombotic risk, and genetic testing for family members should be considered, as protein C deficiency is hereditary.

From the FDA Drug Label

For patients with a first episode of DVT or PE who have documented deficiency of antithrombin, deficiency of Protein C or Protein S, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels (>90th percentile of normal), treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis

• The FDA drug label does not compare warfarin to DOAC for patients with DVT and protein C deficiency.
• No direct comparison is made between warfarin and DOAC in the provided drug label.
• The label only provides recommendations for warfarin treatment in patients with DVT and protein C deficiency, but does not discuss DOAC as an alternative option 2.

From the Research

Comparison of Warfarin and DOACs for Patients with DVT and Protein C Deficiency

• The choice between warfarin and direct oral anticoagulants (DOACs) for patients with deep vein thrombosis (DVT) and protein C deficiency is complex and depends on various factors, including the severity of the deficiency and the patient's individual risk profile 3, 4.
• Historically, warfarin was the mainstay anticoagulant agent for managing patients with thrombotic disorders caused by protein C or S deficiency, but DOACs have shown superiority over warfarin in patients with venous thromboembolism in many landmark trials 3.
• However, there is limited data on the use of DOACs in patients with protein C deficiency, and some studies suggest that DOACs may not be as effective as warfarin in preventing recurrent thrombotic events in these patients 5, 6.
• A case series study found that apixaban was effective in preventing recurrent thrombotic events in patients with inherited thrombophilia, including protein C deficiency, without safety concerns 3.
• Another study found that rivaroxaban may pose an increased risk for recurrent thromboembolism in low-risk antiphospholipid syndrome patients compared to warfarin, but the results should be cautiously applied to DOACs besides rivaroxaban 5.

Protein C Deficiency and Thrombosis Risk

• Protein C deficiency is a rare autosomal dominant disorder that increases the risk of recurrent venous thromboembolism (VTE) and is associated with a high risk of thrombotic events 7, 4.
• Severe protein C deficiency can present in the neonatal period with purpura fulminans and severe disseminated intravascular coagulation, often with concomitant VTE, while mild protein C deficiency may be asymptomatic but can involve recurrent VTE episodes 4.
• The management of acute thrombotic events in severe protein C deficiency typically requires replacement with protein C concentrate while maintaining therapeutic anticoagulation, and long-term management involves anticoagulation with or without a protein C replacement regimen 4.

DOACs in Hypercoagulable Disorders

• The safety and efficacy of DOACs for the acute treatment and secondary prevention of VTE in select patients with hypercoagulable disorders, including protein C deficiency, is highly dependent on the type of hypercoagulable disease state 6.
• Current trials support the use of edoxaban, rivaroxaban, and apixaban for the treatment of cancer-associated thrombosis, but the use of DOACs in patients with antiphospholipid syndrome and hereditary thrombophilia should be avoided at this time due to limited data and potential increased risk of recurrent thromboembolism 5, 6.