From the Guidelines
The recommended workup and management for a patient with unprovoked thrombosis should prioritize indefinite antithrombotic therapy after completion of primary treatment, considering the high risk of recurrent VTE, as suggested by the American Society of Hematology 2020 guidelines 1. The workup for a patient with unprovoked thrombosis includes a comprehensive evaluation to identify potential underlying causes and guide management decisions. Initially, obtain a complete blood count, comprehensive metabolic panel, coagulation studies (PT/INR, aPTT), and D-dimer. Consider age-appropriate cancer screening and testing for thrombophilias such as factor V Leiden, prothrombin gene mutation, protein C and S deficiencies, antithrombin deficiency, and antiphospholipid antibodies. Imaging studies should be performed based on symptoms to confirm thrombosis location and extent.
For management, start anticoagulation immediately with low molecular weight heparin (enoxaparin 1 mg/kg twice daily or 1.5 mg/kg once daily) or direct oral anticoagulants (DOACs) such as rivaroxaban (15 mg twice daily for 21 days, then 20 mg daily), apixaban (10 mg twice daily for 7 days, then 5 mg twice daily), or edoxaban (60 mg daily after 5-10 days of parenteral anticoagulation). For patients with contraindications to DOACs, warfarin (target INR 2-3) overlapping with parenteral anticoagulation until therapeutic is appropriate.
- Key considerations for indefinite antithrombotic therapy include:
- High risk of recurrent VTE, estimated to be as high as 10% by 1 year and up to 30% by 5 to 10 years 1
- Balancing recurrence risk against bleeding risk, with periodic reassessment
- Patient's values and preferences, relating to the impact of thrombosis recurrence and bleeding
- The decision for extended therapy should be individualized, taking into account factors contributing to thrombosis recurrence risk and bleeding risk, as suggested by the guidance from the SSC of the ISTH 1. Compression stockings may help manage post-thrombotic syndrome symptoms. This approach is necessary because unprovoked thrombosis often indicates an underlying hypercoagulable state that requires both immediate treatment and long-term management to prevent recurrence.
From the FDA Drug Label
For patients with a first episode of idiopathic DVT or PE, warfarin is recommended for at least 6 to 12 months. For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is suggested The dose of warfarin should be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations.
The recommended workup and management for a patient with unprovoked thrombosis includes:
- Anticoagulation therapy: with warfarin for at least 6 to 12 months for a first episode of idiopathic DVT or PE, and indefinite treatment for patients with two or more episodes of documented DVT or PE 2
- INR monitoring: to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations
- Risk-benefit assessment: periodic reassessment of the risk-benefit of anticoagulant treatment in patients who receive indefinite therapy 2
- Apixaban: can be used as an alternative to warfarin, with a dose of 5 mg twice daily orally for 6 months, followed by 2.5 mg or 5 mg twice daily orally for extended treatment 3
From the Research
Unprovoked Thrombosis Workup
The workup and management of patients with unprovoked thrombosis involve several factors, including the mode of initial clinical presentation, patient sex, antecedent hormonal therapy use, thrombophilia, D-dimer levels, and residual vein occlusion in patients with deep vein thrombosis 4.
Recommended Testing
Testing for thrombophilia is recommended in patients with unprovoked venous thromboembolism to detect strong thrombophilias, such as antithrombin deficiency, antiphospholipid antibody syndrome, homozygous factor V Leiden, double-heterozygous factor V Leiden plus prothrombin 20210 mutation, protein C deficiency, and protein S deficiency 5.
Factors to Consider
Several factors should be considered when estimating a patient's risk for recurrent thromboembolism, including:
- Mode of initial clinical presentation (deep vein thrombosis or pulmonary embolism)
- Patient sex
- Antecedent hormonal therapy use
- Thrombophilia
- D-dimer levels
- Residual vein occlusion in patients with deep vein thrombosis 4
- Hyperpigmentation, edema or redness of either leg
- D-dimer > or = 250 microg/L while taking warfarin
- Body mass index > or = 30 kg/m(2)
- Age > or = 65 years 6
Management
The management of patients with unprovoked venous thromboembolism involves anticoagulant therapy, and the decision to extend or discontinue therapy should be based on an individualized assessment of the risks for venous thromboembolism recurrence and anticoagulant-related bleeding 7. Women with 0 or 1 risk factor (hyperpigmentation, edema or redness of either leg; D-dimer > or = 250 microg/L while taking warfarin; body mass index > or = 30 kg/m(2); or age > or = 65 years) may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism 6.
Key Considerations
- The finding of a strong thrombophilia has several clinical consequences, including decreasing the threshold to recommend long-term anticoagulation in a patient with unprovoked VTE 5
- Factor V Leiden is associated with a 2- to 3-fold increased relative risk for pregnancy loss and possibly other obstetric complications 7
- The clinical expression of Factor V Leiden is influenced by the number of Factor V Leiden alleles, coexisting genetic and acquired thrombophilic disorders, and circumstantial risk factors 7