Venous thromboembolism (VTE) is a frequently encountered clinical condition with an increasing incidence.¹ Patients can present across the clinical spectrum from an asymptomatic incidental finding on imaging to limb threatening ischemia or cardiogenic shock. In those that survive the initial presentation, the risk of mortality is elevated for decades.² Thus, patients with VTE warrant a thoughtful evaluation in both the acute and chronic setting. The focus of this article will be on the assessment of the etiology of the VTE and considerations for chronic anticoagulation.

Echocardiography in patients with more severe presentations with pulmonary embolism (PE) can be helpful for acute risk stratification, but also for a baseline assessment of right ventricular function and the presence of pulmonary hypertension. Lower extremity ultrasound can also be considered in patients with a PE; though results are unlikely to change management for most in the acute setting, it can serve as a baseline assessment and assist in determining recurrent versus chronic deep vein thrombosis (DVT) if patients develop new symptoms in the future.

After initial risk stratification and decision regarding need for advanced therapy is complete, focus can transition to assessment of the potential etiology of the VTE and choice of long-term anticoagulation. All patients without contraindication should receive anticoagulation for a minimum of 3 months regardless of the underlying etiology. Direct oral anticoagulants (DOAC) are the guideline recommended first-choice medications for patients with VTE and offer high efficacy, ease of administration and overall improved bleeding profile compared to vitamin K antagonists.³ Vitamin K antagonists may be preferred in certain patient populations, including those with significant renal dysfunction, antiphospholipid antibody syndrome or with difficulty obtaining insurance coverage for a DOAC. Recent data suggests DOACs may also be suitable for VTE treatment in the setting of active malignancy;⁴ however, low molecular weight heparin remains the standard of care for such patients. Inferior vena cava filters should not be routinely placed as they significantly increase the risk of subsequent DVT,⁵ but are appropriate for patients with contraindication to anticoagulation or in select patients who are extremely ill with a PE with concern for life-threatening consequences if a recurrent PE occurred (e.g., persistent hypotension/cardiogenic shock and/or significant hypoxemia with mechanical respiratory support despite advanced therapies or limited safe advanced therapeutic options).

Assessment for underlying thrombophilia should generally be delayed to the outpatient setting as some results are difficult to interpret in the setting of acute thrombosis or while receiving anticoagulation, and tests results rarely influence initial anticoagulation choice. An outpatient visit also affords more opportunity to discuss the implications of such testing with the patient after they have had the chance to recover from the acute event. One caveat to this is testing for antiphospholipid antibodies as there is limited current data available for DOACs in this condition. Testing for antiphospholipid antibodies can be considered in the acute setting in those where there is increased suspicion, such as in patients with a concomitant rheumatologic disease or concomitant arterial and venous thromboses.

As patients transition to outpatient care, understanding of the underlying cause of the VTE becomes essential as it is vital in determining the appropriate duration of anticoagulation. After the initial phase of anticoagulation, the goal of treatment is to reduce the risk of recurrent VTE. Central to this assessment is categorization of the VTE as provoked or unprovoked. Common provoking factors are listed in Table 1. In the majority of patients with a transient provoking risk factor, a limited course of anticoagulation is appropriate. Thrombophilia testing is not indicated in patients with a clearly provoked VTE as traditional risk factors are much more common and the likely etiology than a thrombophilia.⁶

Table 1: Provoking Factors for Venous Thromboembolism

Advanced age (>60 years old) Obesity Recent hospitalization for medical or surgical issue (within 90 days) Recent trauma or surgery (within 90 days) Prior history of VTE Malignancy Estrogen therapy Pregnancy/postpartum Chronic inflammatory diseases (e.g. rheumatologic disease, inflammatory bowel disease) Chronic medical conditions (e.g. heart failure, chronic kidney disease, chronic obstructive pulmonary disease, infection, atherosclerosis) Venous obstructive processes (e.g. May-Thurner syndrome, thoracic outlet syndrome, tumor compression) Indwelling central venous catheter or pacemaker Heparin-induced thrombocytopenia

Thrombophilia testing has traditionally been performed in a greater proportion of patients than necessary and the reflexive instinct to send a "hypercoagable panel" should be avoided. Inherited thrombophilias (Table 2) are associated with an increased risk of initial VTE event; however, the more prevalent thrombophilias are not associated with risk of recurrent VTE, and the remaining less common are only modestly associated with recurrent events.⁷ Negative thrombophilia testing can also lead to a false sense of comfort to discontinue anticoagulation. Prior studies have demonstrated that the risk of recurrent VTE is unchanged regardless of thrombophilia testing and results of testing should not alter duration of anticoagulation.⁸ Multiple risk scores for the evaluation of risk of recurrent VTE do not incorporate thrombophilia testing.^9,10 Testing for inherited thrombophilias can be considered in those with an unprovoked VTE and a first-degree female relative of child bearing age, particularly those with a family history of VTE. Estrogen-based contraceptive agents are associated with an exponentially elevated risk of VTE in the presence of a concomitant thrombophilia and should be avoided.¹¹

Table 2: Thrombophilias

Thrombophilia	Initial VTE Risk	Recurrent VTE Risk
Antiphospholipid* antibody	2-11x†	↑↑†
Factor V Leiden heterozygote	3-4x	-
Factor V Leiden homozygote	11x	-
Prothrombin gene mutation heterozygote	4x	-
Prothrombin gene mutation homozygote	7x	-
Compound factor V Leiden + prothrombin gene mutation heterozygote	20x	-
Antithrombin deficiency	16x	4x
Protein C deficiency	8x	3x
Protein S deficiency	7x	↑**

All patients, regardless of whether the event was provoked or unprovoked, should undergo a thorough history and physical examination for possible malignancy. New malignancy is diagnosed at a higher rate following a VTE, particularly in those with an unprovoked VTE;¹² however, prior studies did not demonstrate a benefit to a more aggressive malignancy evaluation than age-appropriate cancer screening alone.¹³ Patients that exhibit particular signs or symptoms concerning for malignancy should undergo further evaluation.

D-dimer measurement after the initial course of anticoagulation is complete is performed by some, with cessation of therapy if it is normal. Though a persistent elevation in D-dimer is associated with a higher rate of recurrence,¹⁴ follow-up studies demonstrated the risk of recurrence remained elevated in those with a negative D-dimer, thus it is of limited value when determining duration of anticoagulation in most cases.¹⁵

Anatomic variables also warrant consideration in some circumstances. Patients with unprovoked left lower extremity DVT, particularly those involving the left iliac or common femoral vein, should be evaluated for left common iliac artery compression by the right common iliac artery, May-Thurner syndrome. Patients may have a prior history of swelling in the left lower extremity or unilateral varicose veins; however, acute DVT may be the initial presentation of May-Thurner syndrome in some patients. Upper extremity DVT are most commonly associated with venous catheters or permanent pacemakers; however, when any upper extremity DVT appears to be unprovoked, evaluation for venous thoracic outlet syndrome, also known as effort thrombosis or Paget-Schroetter syndrome when a DVT occurs, should be considered. Clues for possible thoracic outlet obstruction include a history of repetitive upper extremity activities such as lifting or throwing and/or the presence of prominent superficial veins in the upper chest. If there is clinical suspicion for thoracic outlet syndrome, such an evaluation should occur in the acute setting as catheter-based intervention may offer improved outcomes when performed early in the presentation.¹⁶

Evaluation of splanchnic and cerebral vein thrombosis is beyond the scope of this article, but warrant specific consideration for thrombophilia and malignancy assessment, particularly myeloproliferative disorders and paroxysmal nocturnal hemoglobinuria in those with unprovoked splanchnic vein thrombosis.

The risk of recurrent VTE in patients with an unprovoked VTE can be 30-50% over 10 years, with highest risk in the first several years after the event.^17,18 Patients with an unprovoked VTE and are at a low risk of bleeding should be considered for indefinite anticoagulation. In those patients that are candidates for DOACs, many can be reduced to half-dose of apixaban or rivaroxaban after 6-12 months with studies demonstrating similar efficacy to full-dose anticoagulation with a lower rate of bleeding complications.^19,20 Though not as elevated as patients with unprovoked VTE, the risk of recurrence is also high in those with an initial provoked event; 20% over 10 years.^17,18 The standard of care remains a limited duration of anticoagulation in patients with provoked VTE, though recent data suggests a benefit of extended duration, low-dose anticoagulation in this patient subpopulation as well.²⁰ Prolonged anticoagulation in all patients with VTE must incorporate an individual patient's risk of recurrence versus the risks of ongoing anticoagulation, along with their personal preferences of continued therapy. Patients on long-term anticoagulation should be evaluated in clinic at least yearly to reassess the risk-benefit ratio of continued therapy, screen for bleeding complications and intermittently undergo assessment of renal function and hemoglobin. Repeat assessment with lower extremity venous ultrasound or computed tomography pulmonary angiograms to assess changes in clot burden are not indicated unless new symptoms arise. A follow up echocardiogram can be performed to evaluate improvement in right ventricular function and pulmonary artery pressure; however, such results are unlikely to change management unless a patient has persistent symptoms.

VTE will continue to be a commonly encountered disease state that requires thoughtful evaluation in both the acute and chronic phases. Future studies with a growing emphasis on precision medicine may give further insight into the optimal long-term management of patients with VTE.

References

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2. Sogaard KK, Schmidt M, Pedersen L, Horvath-Puho E, Sorensen HT. 30-year mortality after venous thromboembolism: a population-based cohort study. Circulation 2014;130:829-36.
3. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: Chest guideline and expert panel report. Chest 2016;149:315-52.
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9. Tosetto A, Iorio A, Marcucci M, et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012; 10:1019-25.
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11. Vandenbroucke JP, Rosing JR, Bloemenkamp KW, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 34:1527-35.
12. Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. N Engl J Med. 2000;342:1953-8.
13. Carrier M, Lazo-Langner A, Shivakumar S, et al. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med 2015;373:697-704.
14. Douketis J, Tosetto A, Marcucci M, et al. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of d-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med 2010;153:523-31.
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16. Molina JE, Hunter DW, Dietz CA. Paget-Schroetter syndrome treated with thrombolytics and immediate surgery. J Vasc Surg 2007;45:328-34.
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18. Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first and recurrent venous thromboembolism: A population-based cohort study in patients without active cancer. Thromb Haemost 2014;112:255-63.
19. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708.
20. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017;376:1211-22.

Keywords: Ambulatory Care, Angiography, Antibodies, Antiphospholipid, Anticoagulants, Antiphospholipid Syndrome, Arthritis, Rheumatoid, Atherosclerosis, Central Venous Catheters, Cerebral Veins, Contraceptive Agents, Early Detection of Cancer, Echocardiography, Estrogens, Femoral Vein, Fibrin Fibrinogen Degradation Products, Heart Failure, Hemoglobins, Hemoglobinuria, Paroxysmal, Heparin, Low-Molecular-Weight, Heterozygote, Homozygote, Hospitalization, Hypertension, Pulmonary, Hypotension, Iliac Artery, Incidence, Incidental Findings, Inflammatory Bowel Diseases, Insurance Coverage, Lower Extremity, May-Thurner Syndrome, Mutation, Myeloproliferative Disorders, Neoplasms, Obesity, Outpatients, Pacemaker, Artificial, Physical Examination, Postpartum Period, Pregnancy, Protein C Deficiency, Protein S Deficiency, Prothrombin, Pulmonary Artery, Pulmonary Disease, Chronic Obstructive, Pulmonary Embolism, Pyrazoles, Pyridones, Renal Insufficiency, Chronic, Risk Factors, Shock, Cardiogenic, Standard of Care, Thoracic Outlet Syndrome, Thrombocytopenia, Thrombophilia, Tomography, Upper Extremity Deep Vein Thrombosis, Varicose Veins, Vena Cava Filters, Venous Thromboembolism, Venous Thrombosis, Ventricular Function, Right, Vitamin K, Vascular Diseases

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