What is the approach to investigating recurrent unprovoked Deep Vein Thrombosis (DVT)?

From the Guidelines

To investigate recurrent unprovoked deep vein thrombosis (DVT), a comprehensive approach is needed, starting with a complete blood count, coagulation profile, and D-dimer testing, as well as thrombophilia testing and imaging studies, as recommended by the American Society of Hematology 2020 guidelines 1. When investigating recurrent unprovoked DVT, it is essential to consider the potential for underlying hypercoagulable states and anatomical abnormalities. The following steps should be taken:

• Begin with a complete blood count, coagulation profile (PT, PTT, INR), and D-dimer testing to assess for any abnormalities in blood clotting.
• Order thrombophilia testing, including Factor V Leiden mutation, prothrombin gene mutation, protein C and S deficiency, antithrombin deficiency, antiphospholipid antibodies, and homocysteine levels, which should be performed at least 2-3 weeks after stopping anticoagulation therapy to avoid false results 1.
• Consider JAK2 mutation testing if there's evidence of myeloproliferative disorders.
• Imaging should include a comprehensive duplex ultrasound of the affected limb to confirm the new DVT and assess for post-thrombotic syndrome.
• CT venography or MR venography may be needed to evaluate proximal veins not well visualized by ultrasound.
• Screen for occult malignancy with age-appropriate cancer screenings, comprehensive metabolic panel, and consider CT chest/abdomen/pelvis if clinically indicated, as approximately 10% of unprovoked DVTs are associated with underlying cancer 1.
• Evaluate for anatomical abnormalities like May-Thurner syndrome (left iliac vein compression) or other venous compression syndromes. The investigation is crucial because recurrent unprovoked DVT often indicates an underlying hypercoagulable state that requires identification for proper management and may necessitate indefinite anticoagulation therapy, as suggested by the American Society of Hematology 2020 guidelines 1.

From the FDA Drug Label

Approximately 90% of patients enrolled in AMPLIFY had an unprovoked DVT or PE at baseline. In the AMPLIFY-EXT study, patients were stratified according to their index event of PE (with or without DVT) or DVT (without PE). However, patients who had experienced multiple episodes of unprovoked DVT or PE were excluded from the AMPLIFY-EXT study.

To investigate for recurrent unprovoked DVT, consider the following key points:

• Patient history: Assess for previous episodes of unprovoked DVT or PE.
• Risk factors: Evaluate for ongoing risk factors such as immobilization, history of cancer, active cancer, and known prothrombotic genotype.
• Symptom assessment: Monitor for symptoms of recurrent VTE, such as nonfatal DVT or nonfatal PE.
• Treatment consideration: Consider anticoagulant therapy, such as apixaban, for patients with unprovoked DVT or PE, as shown in the AMPLIFY and AMPLIFY-EXT studies 2.

From the Research

Investigation for Recurrent Unprovoked DVT

To investigate for recurrent unprovoked Deep Vein Thrombosis (DVT), several factors and tests should be considered:

• Patient features such as gender, and associated conditions like cancer or recent surgery, provide essential information on the risk for recurrence after anticoagulant treatment discontinuation 3.
• D-dimer levels and residual thrombosis at the time of anticoagulant treatment discontinuation have been indicated as predictors of recurrent VTE 3.
• The risk for recurrent venous thromboembolism can be estimated through a two-step algorithm, considering the features of the patient and the initial event, as well as D-dimer levels and residual thrombosis 3.

Anticoagulant Treatment

Anticoagulant treatment is effective in reducing the recurrence rate of venous thromboembolism (VTE), but it is associated with an increased risk for bleeding complications:

• All patients with acute VTE should receive oral anticoagulant treatment for three months, after which the decision for withdrawal or indefinite anticoagulation should be made based on the patient's intrinsic risk for recurrent VTE and bleeding complications 3.
• Alternative strategies for secondary prevention of VTE, such as the use of low molecular-weight heparin or direct-acting oral anticoagulants like apixaban or rivaroxaban, may be considered 4, 5, 6.

Management of Recurrent VTE

In cases of recurrent VTE, it is essential to investigate and understand the cause of the breakthrough event:

• The most common underlying disease resulting in recurrence on treatment is cancer, and subtherapeutic drug levels can be caused by poor adherence, interactions with other drugs or food, or inappropriate dosing 7.
• Improving management of anticoagulants and avoiding further recurrences is crucial, although the management of further anticoagulation after a breakthrough event is often based on minimal or no clinical trial evidence 7.