From the Guidelines
Protein C deficiency is associated with the highest risk of deep vein thrombosis (DVT) due to its significant impairment of the body's natural anticoagulation system. Deficiencies in antithrombin III, protein C, and protein S are all associated with increased risk of DVT, but protein C deficiency carries the highest risk 1. When protein C is deficient, the body cannot effectively inactivate factors Va and VIIIa, leading to excessive coagulation and thrombus formation. This condition increases DVT risk 7-10 fold compared to the general population. Some key points to consider:
- Protein C deficiency can be inherited or acquired, and it significantly impairs the body's natural anticoagulation system 1.
- Patients with protein C deficiency often require long-term anticoagulation therapy, typically with warfarin, direct oral anticoagulants (DOACs), or low molecular weight heparin depending on clinical circumstances 1.
- When initiating warfarin in these patients, protein C levels can temporarily decrease further, potentially causing warfarin-induced skin necrosis, so heparin bridging is often recommended during warfarin initiation 1.
- Screening for protein C deficiency should be considered in patients with unprovoked DVT, especially those with family history of thrombosis or thrombosis at young age 1.
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 protein deficits associated with a higher risk of DVT are:
- Deficiency of Protein C
- Deficiency of Protein S
- Deficiency of antithrombin 2
From the Research
Protein Deficit and Risk of DVT
- Antithrombin deficiency is a significant risk factor for deep vein thrombosis (DVT) 3, 4, 5, 6, 7
- Studies have shown that patients with antithrombin deficiency have a higher risk of venous thromboembolism (VTE) compared to those without the deficiency 3, 5, 6, 7
- The risk of VTE is increased in patients with antithrombin deficiency due to enhanced thrombin generation and a prothrombotic plasma fibrin clot phenotype 6
- Antithrombin activity is crucial for the effectiveness of enoxaparin prophylaxis, and low antithrombin activity is associated with reduced responsiveness to enoxaparin and increased risk of VTE 7
Mechanisms of Antithrombin Deficiency
- Antithrombin deficiency can be inherited or acquired, with acquired deficiency occurring in various medical conditions such as sepsis, liver dysfunction, and major surgery 3, 5
- Microvascular leakage and endothelial loss are potential mechanisms of antithrombin depletion, leading to increased thrombotic risk 5
- Antithrombin deficiency is associated with reduced fibrin clot permeability and prolonged clot lysis time, contributing to the prothrombotic state 6
Clinical Implications
- Patients with antithrombin deficiency require careful management, including long-term anticoagulation and/or thromboprophylaxis, especially in high-risk situations such as surgery and pregnancy 3, 4
- Antithrombin concentrates can be used for treatment and prevention of acute venous thrombosis in patients with antithrombin deficiency 3, 4
- Ex vivo antithrombin supplementation may improve responsiveness to enoxaparin prophylaxis and reduce the risk of VTE 7