Which factor deficiency predisposes to thrombus formation and pulmonary embolism (PE)?

Factor Deficiencies That Predispose to Thrombus Formation and Pulmonary Embolism

Antithrombin deficiency is the most significant factor deficiency that predisposes to thrombus formation and pulmonary embolism, with a 14-fold increased risk of venous thromboembolism. 1

Primary Thrombophilic Factor Deficiencies

• Antithrombin deficiency is a strong risk factor for venous thromboembolism (VTE) and pulmonary embolism (PE), with affected individuals having an annual VTE risk of 1.2% compared to 0.07% in non-deficient individuals 1
• Type I antithrombin deficiency (quantitative deficiency) carries a significantly higher risk than Type II (qualitative deficiency), with a sevenfold greater risk of VTE (hazard ratio: 7.3) 2
• Protein C deficiency is another important factor deficiency that predisposes to thrombosis, as it impairs the natural anticoagulant system that normally inactivates procoagulant factors Va and VIIIa 3
• Protein S deficiency similarly increases thrombosis risk as it functions as a cofactor for activated Protein C in the inactivation of factors Va and VIIIa 3

Mechanism of Thrombosis in Factor Deficiencies

• Antithrombin normally functions as a serine protease inhibitor (SERPIN) that irreversibly inhibits thrombin by covalently binding to its enzymatic active site 3
• When antithrombin is deficient, there is inadequate inhibition of thrombin and other coagulation factors (Xa, IXa), leading to unchecked thrombin generation and increased fibrin formation 4
• The natural anticoagulant system (antithrombin, protein C, protein S) normally confines hemostatic plugs to sites of vessel wall injury and prevents pathologic thrombus formation 3
• Deficiencies in these natural anticoagulants disrupt this balance, allowing thrombi to form more readily and potentially embolize to the lungs 3

Clinical Significance and Risk Assessment

• Antithrombin deficiency is considered to be a rare condition, but should be seriously considered in patients with unexplained thrombotic episodes below age 40, recurrent DVT or PE, and a positive family history 3
• Mild antithrombin deficiency (activity <5th percentile of normal) increases recurrent VTE risk by 1.5-fold compared to normal antithrombin levels 5
• More severe antithrombin deficiency (<70% activity) increases recurrent VTE risk by 3.7-fold 5
• The annual recurrence risk without long-term anticoagulant therapy is 8.8% for antithrombin-deficient patients compared to 4.3% for non-deficient VTE patients 1

Management Implications

• For patients with a first episode of DVT or PE who have documented deficiency of antithrombin, protein C or protein S, treatment with warfarin for 6 to 12 months is recommended, and indefinite therapy is suggested for idiopathic thrombosis 6
• The dose of warfarin should be adjusted to maintain a target INR of 2.5 (range 2.0-3.0) for all treatment durations 6
• Warfarin should be used with caution in patients with known or suspected deficiency in protein C mediated anticoagulant response, as tissue necrosis can occur in these patients 6
• Concomitant anticoagulation therapy with heparin for 5-7 days during initiation of warfarin therapy may minimize the incidence of tissue necrosis in patients with protein C or protein S deficiency 6

Common Pitfalls and Caveats

• Factor XII deficiency, unlike other factor deficiencies, is associated with thrombosis risk despite being a contact activation factor 3
• Not all patients with inherited thrombophilias develop thrombosis; these deficiencies often need to interact with acquired risk factors (surgery, immobilization, pregnancy, oral contraceptives) before thrombosis occurs 3
• Testing for thrombophilia should be considered in patients with unexplained thrombotic episodes, especially those occurring at a young age, in unusual sites, or with recurrence 3
• The risk associated with these deficiencies varies between individuals, making personalized risk assessment crucial 6