Venous Thromboembolism and Anticoagulation

Venous thromboembolism (VTE) is a common condition encountered in general internal medicine practice and includes pulmonary embolism (PE) and lower-extremity deep-vein thrombosis (DVT). Knowing how to diagnose and manage VTE is crucial. See the IM Oncology rotation guide for treatment of VTE in patients with malignancy.

In section, we address the following topics:

• Diagnosis of PE

• Diagnosis of DVT

• Diagnosis of VTE in Pregnancy

• Management of VTE

• Management of Upper-Extremity DVT

• Anticoagulant Reversal

• Thrombophilia Testing

Diagnosis of Pulmonary Embolism

In patients presenting acutely, the diagnosis of PE can be made with the following steps:

Step 1: Assess the patient’s pretest probability for PE by calculating their Wells score using the Wells clinical decision rule for PE (see calculator).

Step 2: Based on the patient’s pretest probability for PE according to the Wells score, perform an initial workup as follows:

• Low-risk Wells score: Patients who have a Wells score <2 are at low risk for PE (prevalence, 1.3%) and are typically further risk-stratified using the pulmonary embolism rule-out criteria (PERC):

  • PERC criteria:

    • age <50 years

    • heart rate <100 beats per minute

    • oxyhemoglobin saturation ≥95%

    • no hemoptysis

    • no estrogen use

    • no prior DVT or PE

    • no unilateral leg swelling

    • no surgery or trauma requiring hospitalization within the prior 4 weeks

  • PERC interpretation:

    • If all eight of these criteria are met, then no further testing is needed.

    • If any of the criteria are not met, then a D-dimer measurement can be helpful; a normal value can help rule out PE and obviate the need for imaging.

• Intermediate-risk Wells score: In intermediate-risk patients (those with a Wells score of 2-6; incidence of PE, 16.2%), a D-dimer level is indicated.

  • D-dimer interpretation:

    • In patients with a negative D-dimer result, no further workup is needed.

    • In patients with a positive D-dimer, proceed to CT angiography.

  • If the D-dimer level is <0.5 µg/mL, further imaging is typically not needed. However, the full clinical picture should be taken into account for patients who fall into this group.

  • Imaging to rule out PE may be appropriate for some intermediate-risk patients, regardless of D-dimer value. This may apply to older patients, those with cardiopulmonary compromise, those with a Wells score at the upper end of the intermediate range, and other patients where the clinical evaluation raises concern for PE beyond what is reflected in the Wells score.

• High-risk Wells score:

  • Imaging (usually CT angiography) should be obtained in all high-risk patients (those with a Wells score >6; incidence of PE, 37.5%).

  • There is no role for measuring a D-dimer level in these patients, as a normal D-dimer level does not adequately rule out PE.

Note: Before using D-dimer as a screening test for VTE, remember that it is nonspecific for any coagulation occurring in the body. Thus, a patient undergoing knee replacement would be expected to have an elevated postoperative D-dimer level after surgery. Certain disease states (e.g., cancer, renal disease, and cirrhosis) are associated with chronic subclinical disseminated intravascular coagulation (DIC) that may not manifest with typical DIC signs (e.g., low fibrinogen or elevated prothrombin time [PT] or partial thromboplastin time [PTT]) but will often be associated with an elevated D-dimer level that is not clinically meaningful. Furthermore, D-dimer levels tend to increase in older people such that alternative criteria must be applied to D-dimer elevations with aging (patient age in years x 10 mcg/l is thought to represent the upper limit for that individual).

Diagnosis of DVT

In patients presenting acutely, the diagnosis of DVT can be made with the following steps:

Step 1: Assess the patient’s pretest probability of DVT by calculating their Wells score using the Wells clinical decision rule for DVT (see Medscape calculator).

Interpretation of the Wells score for DVT:

• ≤0: low risk for DVT

• 1-2: intermediate risk for DVT

• ≥3: high risk for DVT

Step 2: Based on the patient’s pretest probability of DVT according to the Wells score, perform an initial workup as describe:

• Low-risk Wells score:

  • Patients who have a Wells score ≤0 are at low risk for DVT (prevalence of DVT, 3%) and a D-dimer measurement is helpful; a normal value rules out DVT and obviates the need for imaging.

• Intermediate- or high-risk Wells score:

  • Imaging (usually ultrasonography) should be obtained in all intermediate or high-risk patients.

  • A Wells score of 1−2 indicates intermediate risk (prevalence of DVT, 16.6%) and a score ≥3 indicates high-risk (prevalence of DVT, 76.6%).

  • There is no role for measuring a D-dimer level in these patients prior to imaging as a normal D-dimer level does not adequately rule out DVT. If clinical suspicion for DVT remains after a negative ultrasonography test, then D-dimer measurement may be performed. Should the D-dimer be positive, then repeat ultrasonography is indicated in one week.

(Source: Venous Thromboembolism. BMJ 2006. Reprinted with permission.)

Diagnosis of VTE in Pregnancy

The incidence of VTE increases fourfold during pregnancy, and the above algorithms have not been tested in pregnancy. The pregnancy-adapted YEARS algorithm (shown below) can be used instead. The goal during pregnancy is minimal radiation exposure to the fetus.

• For diagnosis of PE, a ventilation-perfusion (V/Q) scan should be considered first if the patient is clinically stable and a V/Q scan is available.

• For diagnosis of DVT in pregnancy, ultrasonography remains the test of choice.

(Source: Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism. N Engl J Med 2019.)

For more detailed information regarding VTE in pregnancy, see the American Society of Hematology (ASH) VTE in Pregnancy Pocket Guide.

Management of VTE

Evidence-based guidelines from the American Society of Hematology (ASH) describe the management of VTE in three phases:

• initial management

• primary treatment

• secondary prevention

Phase 1: Initial Management

Initial management includes:

Ambulatory care vs. inpatient care: Deciding whether ambulatory care or inpatient care is most appropriate for managing the patient’s VTE:

• Inpatient care is indicated for patients with VTE and the following presentations:

  • massive DVT (including proximal deep-vein thrombosis)

  • limb-threatening DVT

  • high risk of bleeding with anticoagulation therapy

  • symptomatic PE (including when intravenous analgesics are required)

• Ambulatory care may be suitable for patients with VTE and none of the above listed presentations, at low risk for complications, and with no other conditions requiring hospitalization. In this scenario, primary treatment (phase 2) can be initiated.

Type of emergent treatment: Deciding on type of emergent treatment: Emergent treatments for VTE are anticoagulation therapy (most patients), fibrinolytic therapy (thrombolytic therapy), and inferior vena cava filter.

• Anticoagulation therapy: The first choice for most patients with VTE is with direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs).

  • No one DOAC (e.g., dabigatran, rivaroxaban, apixaban, edoxaban, or betrixaban) is recommended over another.

  • Renal or hepatic insufficiency, concomitant cancer, treatment cost, patient preference, and dosing frequency should be considered when selecting anticoagulation therapy.

  • During VKA initiation, retreatment with low-molecular-weight heparin (LMWH) for a minimum of 5 days is necessary. After 5 days, LMWH can be discontinued provided a therapeutic international normalized ratio (INR) has been achieved for 24 hours.

  • For treatment with a DOAC, the need for LMWH pretreatment varies depending on DOAC choice.

    • For patients initiating treatment with dabigatran or edoxaban, pretreatment with LMWH for up to 5 to 10 days is needed before switching to the DOAC.

    • For patients treated with rivaroxaban or apixaban, there is no need for pretreatment with LMWH, but a higher dose is administered for the first 3 weeks of rivaroxaban therapy and the first week of apixaban therapy.

  • For LMWH pretreatment, unfractionated heparin can be used instead of LMWH if there is concern for bleeding, need for quick reversal, or renal dysfunction.

  • Other anticoagulants with novel mechanisms are being investigated (e.g. factor XI inhibitors, factor Xia inhibitors, factor XII inhibitors) to reduce thrombosis risk while minimizing bleeding risk.

• Fibrinolytic therapy (thrombolytic therapy): Anticoagulation therapy alone is recommended for most patients with VTE. However, thrombolytic therapy followed by anticoagulation is recommended for patients with the following characteristics:

  • limb-threatening DVT

  • selected younger patients with symptomatic DVT involving the iliac and common femoral veins (conferring increased risk of post-thrombotic syndrome) who are at low risk for bleeding, have a preference for rapid resolution of symptoms, and accept the added risk of major bleeding associated with thrombolytic therapy

  • PE with hemodynamic compromise

  • PE with echocardiography and/or biomarkers compatible with right ventricular dysfunction but without hemodynamic compromise (submassive PE)

  Note: When thrombolytic therapy is used in patients with DVT, catheter-directed thrombolysis is recommended over systemic thrombolysis.

• Inferior vena cava (IVC) filter: In patients with a contraindication to anticoagulation, insertion of a retrievable IVC filter may be appropriate. IVC filters are not recommended in the context of trauma. (View a NEJM Quick Take video summary of a recent multicenter trial of IVCs after major trauma.)

Phase 2: Primary Treatment

Primary treatment refers to the minimal length of time a patient must be on therapeutic anticoagulation for treatment of the initial VTE before considering long-term treatment. A 3−6-month course of anticoagulation is recommended regardless of whether the VTE is provoked by a transient risk factor, a chronic risk factor, or unprovoked.

• Primary management of upper-extremity DVT differs slightly from management of other VTEs. Up to 10% of DVTs occur in the upper extremities. The most common cause is from indwelling catheters (i.e., peripherally inserted central catheter [PICC] and central venous catheters). Upper-extremity DVTs may embolize, but because of their small size relative to lower-extremity clots, they are unlikely to lead to PE or death.

(Source: Deep-Vein Thrombosis of the Upper Extremities. N Engl J Med 2011.)

Phase 3: Secondary Prevention

Secondary prevention refers to the decision to continue anticoagulation therapy following primary treatment.

• Unprovoked VTE: Indefinite anticoagulation is appropriate after primary treatment for the majority of patients with unprovoked VTE (except those who have a high risk of bleeding). However, for patients who are undecided or for whom the balance between risks and benefits is uncertain, decision-making can be aided by prognostic scores, D-dimer testing, or ultrasound assessment for residual thrombosis from an initial DVT. These patients should be referred to a hematologist.

• VTE provoked by a chronic risk factor: Indefinite antithrombotic therapy is recommended after primary treatment.

• VTE provoked by a transient risk factor: Cessation of antithrombotic therapy is recommended after primary treatment.

Depending on the clinical scenario, DOACs can sometimes be reduced to a lower dose (see EINSTEIN CHOICE and AMPLIFY-EXT trials).

Anticoagulant Reversal

Anticoagulant therapy is very effective at preventing recurrent VTE but is associated with an increased risk of bleeding. Major bleeding occurs in 1%−3% of patients treated with VKAs each year. The relative risk of major bleeding with DOACs is approximately 30% lower.

Warfarin reversal: Warfarin inhibits synthesis of the vitamin K-dependent clotting factors (II, VII, IX, X) as well as the natural anticoagulant proteins C and S. The anticoagulant effect of warfarin can be reversed multiple ways and is dependent on the urgency of the clinical situation as described in the following table:

DOAC reversal: Reversal of DOAC therapy is recommended in the following clinical settings only:

• Bleeding at a critical site where there is a high risk that the function of a vital organ will be compromised with resulting disability or death. This includes intracranial, thoracic, airway, pericardial, intra-abdominal (non-gastrointestinal), retroperitoneal, intra-articular, and intramuscular bleeding.

• Bleeding that is life-threatening.

• Major bleeding that fails to respond to initial control measures.

Factor Xa reversal: Reversal of factor Xa can be achieved by stopping the oral direct Xa inhibitor and either:

• administering 4-factor prothrombin complex concentrates (4F-PCCs)

• administering coagulation factor Xa (recombinant) such as andexanet alfa. Andexanet alfa is a recombinant form of factor Xa that binds and sequesters the anticoagulant, thus allowing homeostasis to occur using the patient’s endogenous factor Xa.

Dabigatran reversal: Stop dabigatran and administer idarucizumab.

Unfractionated heparin reversal: Heparin works by binding to and activating antithrombin III, which in turn inactivates thrombin and factor Xa. Heparin’s effect can be neutralized by stopping the infusion and administering protamine, after which the PTT must be monitored. Protamine must be used with caution because it can cause an anaphylactoid reaction. Protamine can be used to reverse the effects of low-molecular-weight heparin as well.

More detail on reversal of specific anticoagulants can be found here.

Thrombophilia Testing

Workup of unprovoked VTE should only rarely include hereditary thrombophilia testing (factor V Leiden mutation, prothrombin 20210A gene mutation, antithrombin, proteins C and S, and antiphospholipid antibodies) and should not be ordered in the acute setting (do not order in a hospitalized patient immediately after a clot or if the patient is on anticoagulation therapy). See this review and the 2023 American Society of Hematology guidelines for management of VTE and thrombophilia testing.