Am Fam Physician. 2022;105(4):377-385
Author disclosure: No relevant financial relationships.
Venous thromboembolism (VTE) recurrence rates are three times higher in patients with chronic or no risk factors compared with those who have transient risk factors after stopping anticoagulation therapy. In patients with unprovoked VTE, age-appropriate screening is sufficient evaluation for occult malignancy. Thrombophilia evaluation should be considered only in selected patients because routine evaluation has not been shown to improve outcomes. Patients with VTE should receive three months of anticoagulation therapy. The context of the initial VTE, risk of bleeding and recurrence, and patient preference should be considered when determining whether to continue treatment beyond the initial three months. There is growing evidence regarding the use of risk assessment models to determine risk of recurrence, but this has not been incorporated into guidelines. All pregnant patients with a prior VTE should receive postpartum prophylaxis for six weeks. Antepartum prophylaxis should be used in pregnant people with a history of unprovoked or hormonally induced VTE. High-risk patients undergoing surgery may require extended VTE prophylaxis postoperatively.
Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep venous thrombosis (DVT), occurs in 300,000 to 600,000 people (1 to 2 per 1,000) and accounts for up to 100,000 deaths annually in the United States.1 Literature has traditionally categorized VTE as provoked (i.e., at least one identifiable risk factor) or unprovoked (i.e., no identifiable risk factors), but newer literature distinguishes patients with VTE as having transient (i.e., reversible) or chronic risk factors.
| Clinical recommendation | Evidence rating | Comments |
|---|---|---|
| Perform only age-appropriate cancer screening to detect occult malignancy in patients with VTE.10,22,23 | A | NICE guidelines, one randomized controlled trial, one meta-analysis |
| Do not routinely test for thrombophilia in patients with provoked VTE. Routine testing in patients with unprovoked VTE is discouraged.10,26,27 | A | NICE guidelines, one randomized controlled trial, one meta-analysis |
| Patients with VTE due to a transient risk factor (provoked) can stop anticoagulation after three months of treatment.30 | C | CHEST guidelines |
| Patients with VTE due to chronic risk factors or with no identifiable risk factors (unprovoked) should continue anticoagulation indefinitely unless they are at high risk of bleeding.10,30 | C | NICE and CHEST guidelines |
| Recommendation | Sponsoring organization |
|---|---|
| Do not test for protein C, protein S, or antithrombin III levels during an active clotting event to diagnose a hereditary deficiency. These tests are not analytically accurate during an active clotting event. | American Society for Clinical Pathology |
| Do not do workup for clotting disorder (order hypercoagulable testing) for patients who develop a first episode of deep venous thrombosis from a known cause. | Society for Vascular Medicine |
| Do not test for thrombophilia in adult patients with venous thromboembolism caused by major transient risk factors (e.g., surgery, trauma, prolonged immobility). | American Society of Hematology |
Patients with a provoked VTE due to a transient risk factor have only a 3.3% risk of recurrence in the first year after stopping anticoagulation, whereas patients with an unprovoked VTE have a 10.3% risk of recurrence. The recurrence risk for patients with provoked VTE does not increase significantly after the first year, but the risk for patients with unprovoked VTE increases more than 30% after 10 years.2–5 The mortality rate for unprovoked recurrent VTE is 3.8% (95% CI, 2.0% to 6.1%), ranging from 5% to 13%.4,6,7 This article aims to help physicians assess risks and benefits of prolonged anticoagulation therapy and address considerations in specific populations to reduce the risk of recurrent VTE.
Risk Factors
Performing a thorough medical history and confirming the context of the initial VTE are foundational to identifying risk factors for VTE recurrence. An important unmodifiable risk factor is biologic sex. Several studies have shown a higher risk of recurrence in men with provoked VTE (1.4-fold increase) and unprovoked VTE (1.8-fold increase).4,8,9 Risk factors for VTE are listed in Table 1.10–14
| Chronic or potentially persistent risk factors Antiphospholipid antibody syndrome Autoimmune disease (e.g., collagen vascular disease, rheumatoid arthritis) Body weight < 110 lb (50 kg) or > 264 lb, 9 oz (120 kg); body mass index > 30 kg per m2 Chronic immobilization Chronic infections Heart failure Inflammatory bowel disease Male sex Malignancy Medication use (especially hormone therapy, combined oral contraceptives, testosterone, and heparin) Myeloproliferative disorders Nephrotic syndrome Recurrent pregnancy loss Major transient risk factors Hospitalization > three days with limited mobility Hospitalization for COVID-19 treatment Immobilization (leg injury limiting mobility or bed rest for ≥ three days) Surgery (general anesthesia lasting > 30 minutes) Trauma Minor transient risk factors Hospitalization < three days Oral contraceptives or hormone therapy Pregnancy Presence of a major risk factor one to three months before initial venous thromboembolism Prolonged travel (≥ two hours; highest risk with air travel > four hours or car travel > eight hours in a 24-hour period) Surgery (general anesthesia < 30 minutes) |
The location of the VTE is important because a proximal DVT has up to 4.8 times the risk of recurrence as a distal DVT (e.g., below the knee).4,15–17 In one study, patients with VTE of an iliac vein had twice the risk of recurrence as those with VTE in femoral or distal locations.15 In a meta-analysis of patients with an initial VTE, patients with a distal DVT had only a 1.9% risk of recurrence in the first year after stopping anticoagulation.4 The risk of VTE recurrence is higher in patients who have a central PE compared with a noncentral PE.18
Elevated d-dimer levels posttreatment in unprovoked VTE predict an increased recurrence risk (hazard ratio [HR] = 1.27).16 A study evaluating patients with unprovoked VTE found that those with low d-dimer levels (less than 250 μg per L) three weeks after completing anticoagulation therapy had a 3.7% probability of recurrence in two years, whereas those with high levels (250 μg per L or more) had an 11.5% probability of recurrence.19
Evaluation for Malignancy
Up to 20% of VTEs occur in patients with cancer,20,21 and malignancy is associated with higher rates of recurrence. Specific cancers with higher recurrence rates include brain, myeloproliferative, ovarian, lung, and gastrointestinal (noncolorectal) cancers, as well as any advanced cancer. Stage IV pancreatic cancer has the highest association with recurrence, with an HR of 6.38.5
Guidelines do not recommend additional testing for occult malignancy beyond age-appropriate screening. Additional testing has not been shown to improve outcomes and is not cost-effective.10,22,23 Blood tests (e.g., complete blood cell count, complete metabolic panel, prothrombin time), physical examination, and history are sufficient to identify abnormalities that may prompt further evaluation for malignancy. An abnormal location of thrombosis (e.g., splanchnic or cerebral vein), family history of cancer, recurrence while on anticoagulation, or additional symptoms (e.g., weight loss) may warrant further evaluation or hematology referral.24,25 Splanchnic or cerebral vein thrombosis should prompt evaluation for myeloproliferative disorder.25
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