What is the recommended workup and treatment for a patient with a history of thrombosis or at high risk of thrombotic events due to conditions such as cardiovascular disease, cancer, or genetic disorders?

Procoagulant Workup and Management

Initial Laboratory Evaluation

For patients with thrombosis or at high risk for thrombotic events, routine thrombophilia testing is NOT recommended, as it rarely changes management and does not justify indefinite anticoagulation in asymptomatic carriers. 1

Essential Initial Tests

• Complete blood count with platelet count to identify thrombocytopenia and rule out myeloproliferative neoplasms 1
• Renal function (creatinine clearance) to guide LMWH or DOAC dosing 1
• Liver function tests to identify coagulopathy from hepatic dysfunction 1
• Age-appropriate cancer screening, as 20% of VTE occurs in cancer patients 1

When to Consider Thrombophilia Testing

Testing may be considered only in patients with first unprovoked VTE when results would directly influence duration of anticoagulation 2, 1. However, prospective studies demonstrate that heterozygous prothrombin G20210A mutation does not increase recurrence risk 2.

Common pitfall: Avoid reflexive thrombophilia panels. The EGAPP Working Group found that routine testing for Factor V Leiden and prothrombin mutations does not improve outcomes in most patients with idiopathic VTE 2.

Risk Stratification by Clinical Context

Cancer-Associated Thrombosis

For active cancer with VTE, use DOAC (apixaban or rivaroxaban) or LMWH as first-line treatment. 1

• LMWH is strongly preferred over unfractionated heparin for initial treatment 2, 1
• Continue anticoagulation indefinitely while cancer remains active 1
• For incidental DVT or PE in cancer patients, therapeutic anticoagulation is recommended if no contraindications exist 1
• Extended anticoagulant therapy is preferred over 3 months of treatment in patients with low or moderate bleeding risk 2

Special consideration for intracranial malignancies: Standard anticoagulation with LMWH is recommended, as symptomatic intracranial hemorrhage rates are only 0-7% 1. However, a history of lobar intracerebral hemorrhage suggesting cerebral amyloid angiopathy is an absolute contraindication 1.

Unprovoked VTE

Treat with anticoagulation for at least 3 months, then evaluate for extended therapy based on bleeding risk. 2

• First unprovoked PE with low or moderate bleeding risk: Extended anticoagulant therapy is suggested over stopping at 3 months 2
• First unprovoked PE with high bleeding risk: Stop at 3 months 2
• Second unprovoked VTE with low bleeding risk: Extended anticoagulation is strongly recommended 2
• Second unprovoked VTE with moderate bleeding risk: Extended anticoagulation is suggested 2

The recurrence rate without continued anticoagulation is approximately 20% within 5 years and 30% within 10 years 2.

Inherited Thrombophilia with Documented DVT

Patients with ischemic stroke or TIA with established inherited thrombophilia should be evaluated for deep vein thrombosis. 2

• If DVT is present, anticoagulate for 6-12 months for first episode with documented deficiency of antithrombin, protein C, protein S, Factor V Leiden, or prothrombin 20210 gene mutation 3
• Indefinite therapy is suggested for idiopathic thrombosis 3
• In the absence of venous thrombosis, long-term anticoagulants or antiplatelet therapy is reasonable 2
• Patients with recurrent thrombotic events may be considered for long-term anticoagulation 2

Myeloproliferative Neoplasms

Risk stratification determines treatment intensity. 2

• High-risk patients (age >60 years and/or prior thrombosis): Cytoreductive therapy with hydroxyurea plus low-dose aspirin (81-100 mg/day) 2, 4
• Low-risk patients with JAK2 mutation (age ≤60 years, no prior thrombosis): Aspirin (81-100 mg/day) for vascular symptoms or observation 2, 4
• Very low-risk patients (age ≤60 years, no JAK2 mutation, no prior thrombosis): Observation unless symptomatic 2

Critical caveat: Screen for acquired von Willebrand syndrome before initiating aspirin in patients with platelet counts >1,500 × 10⁹/L to avoid bleeding complications 4.

Antiphospholipid Antibody Syndrome

The WARSS/APASS trial found no difference between warfarin (INR 1.4-2.8) and aspirin (325 mg) for secondary stroke prevention in APL antibody-positive patients 2. However, patients with both lupus anticoagulant and anticardiolipin antibodies had higher event rates (31.7%) compared to those negative for both (24.0%) 2.

Anticoagulant Selection

First-Line Agents by Clinical Context

Non-cancer patients: DOAC is preferred over warfarin due to ease of use 1

Cancer patients: DOAC (apixaban/rivaroxaban) or LMWH as first-line treatment 2, 1

Mechanical heart valves: Warfarin is required, with target INR varying by valve type and position 1, 3:

• St. Jude Medical bileaflet valve in aortic position: INR 2.0-3.0 (target 2.5) 3
• Tilting disk valves and bileaflet mechanical valves in mitral position: INR 2.5-3.5 (target 3.0) 3
• Caged ball or caged disk valves: INR 2.5-3.5 (target 3.0) plus aspirin 75-100 mg/day 3

Severe renal impairment (CrCl <30 mL/min): Unfractionated heparin due to shorter half-life, reversibility with protamine, and hepatic clearance 2

Warfarin Dosing

• Initial dosing: Start with 2-5 mg daily, with lower doses for elderly, debilitated patients, or those with CYP2C9 and VKORC1 genetic variations 3
• Maintenance: Most patients require 2-10 mg daily 3
• Target INR for VTE: 2.0-3.0 (target 2.5) for all treatment durations 2, 3

Common pitfall: Avoid large loading doses, which increase hemorrhagic complications without providing more rapid protection 3.

Duration of Anticoagulation

Provoked VTE (Surgery/Trauma)

3 months of anticoagulation 5

Unprovoked VTE

At least 3 months, then reassess for extended therapy 2, 5

• Extended therapy is preferred in patients with low or moderate bleeding risk 2
• Reassess continuing use at periodic intervals (e.g., annually) 2

Permanent Risk Factors

Indefinite anticoagulation for active cancer, prolonged immobilization from medical diseases, antiphospholipid syndrome, and carriers of multiple thrombophilic abnormalities 5

Special Populations

Thrombocytopenic patients with hematologic malignancies: 6

• Platelets ≥50-<100 × 10⁹/L: Therapeutic dose LMWH
• Platelets ≥30-<50 × 10⁹/L: 50% dose reduction
• Platelets <30 × 10⁹/L: Discontinue LMWH; consider IVC filter with prophylactic LMWH and platelet transfusion for acute VTE

Fall risk: Fall risk alone does not contraindicate anticoagulation—a patient would need to fall 295 times per year for subdural hemorrhage risk to exceed stroke prevention benefit 1.