Deep Vein Thrombosis and Pulmonary Embolism

Introduction

Deep vein thrombosis (DVT) is a condition in which a blood clot develops in the deep veins, usually in the lower extremities. A pulmonary embolism (PE) occurs when a part of the DVT clot breaks off and travels to the lungs, which can be life-threatening. Venous thromboembolism (VTE) refers to DVT, PE, or both. VTE is often recurrent and can lead to long-term complications (e.g., post-thrombotic syndrome after a DVT or chronic thromboembolic pulmonary hypertension after a PE).

Extended periods of limited mobility are inherent to long-distance travel and can increase a traveler's risk for VTE. An association between VTE and air travel was first reported in the early 1950s; since then, long-distance air travel has become more common, leading to increased concerns about travel-associated VTE.

Pathogenesis

Virchow's classic triad for thrombus formation is venous stasis, vessel wall damage, and a hypercoagulable state. Prolonged, cramped sitting during long-distance travel interferes with venous flow in the legs, creating venous stasis. Seat-edge pressure to the popliteal area of the legs can aggravate venous stasis and contribute to vessel wall damage. Coagulation activation can result from an interaction between air cabin conditions (e.g., hypobaric hypoxia) and individual risk factors for VTE. Studies of the pathophysiologic mechanisms for the increased risk of VTE after long-distance travel have not produced consistent results, but venous stasis appears to play a major role. Other factors specific to air travel might increase coagulation activation, particularly in travelers with preexisting risk factors for VTE.

Incidence

The annual incidence of VTE in the general population is estimated to be 0.1% but is greater in subpopulations with risk factors for VTE (Box 7.3.1). The actual incidence of travel-related VTE is difficult to determine because there is no national surveillance for VTE and no consensus on the definition of travel-associated VTE, particularly regarding duration of travel and period of observation after travel.

Studies estimating the incidence of air travel-associated VTE have used various criteria to determine risk factors and outcomes. For example, investigators have defined long-distance air travel as lasting anywhere from >3 hours to >10 hours. Although no standard definition exists, >4 hours is most often used. Post-flight observation period is similarly inconsistent and ranges from "hours after landing" to ≥8 weeks; 4 weeks, however, is most common. Finally, study outcomes range from asymptomatic DVT to symptomatic DVT/PE to severe or fatal PE. In general, the incidence of air travel-associated VTE appears to be low. For flights >4 hours, 1 study reported an absolute risk for VTE of 1 in 4,656 person-flights; another reported an absolute risk of 1 in 6,000 person-flights.

Box 7.3.1

Risk factors

People who travel on long-distance flights generally are healthier and therefore at lower risk for VTE than the general population. Five prospective studies conducted to assess the incidence of DVT after travel >8 hours among travelers at low to intermediate risk for VTE yielded an overall VTE incidence of 0.5%. For flights <4 hours, the risk of symptomatic VTE is negligible.

Studies indicate that long-distance air travel might increase a person's overall risk for VTE by 2- to 4-fold, but the data are inconsistent. While some studies found that long-distance air travel increased the risk of VTE occurring, others either found no definitive evidence of increased risk or found that risk increased only if ≥1 additional VTE risk factors were present. Magnitude of risk correlates with duration of travel and with preexisting risk factors for VTE. Risk decreases with time after air travel and returns to baseline by 8 weeks; most air travel-associated VTE occurs within the first 1–2 weeks after the flight. A similar increase in risk for VTE is noted with other modes of long-distance travel (bus, car, or train), which implies that increased risk is due mainly to prolonged limited mobility rather than to the air cabin environment.

Most travel-associated VTE occurs in travelers with preexisting risk factors for VTE (Box 7.3.1). The combination of air travel with preexisting individual risk factors might synergistically increase risk. Some studies have shown that 75%–99% of people who developed travel-associated VTE had ≥1 preexisting risk factors; one study showed that 20% had ≥5 risk factors. For travelers without preexisting risk factors, the risk of travel-associated VTE is low.

For air travelers, height appears to be an additional risk factor; people <1.6 m (5 ft, 3 in) and those >1.9 m (6 ft, 3 in) tall were at increased risk. Because airline seats are higher than car seats and cannot be adjusted to a person's height, air travelers <1.6 m (5 ft, 3 in) tall might be more prone to seat-edge pressure to the popliteal area. Air travelers >1.9 m (6 ft, 3 in) tall are also at increased risk, possibly because taller travelers have less leg room.

Clinical presentation

Signs and symptoms of DVT/PE are nonspecific. Typical signs or symptoms of DVT in the extremities include pain or tenderness, swelling, warmth in the affected area, and redness or discoloration of the overlying skin. The most common signs or symptoms of acute PE include unexplained shortness of breath, pleuritic chest pain, cough or hemoptysis, and syncope.

Diagnosis

Imaging studies are needed for diagnosis. Duplex ultrasonography is the standard imaging procedure for DVT diagnosis. Computed tomographic pulmonary angiography is the standard imaging procedure for diagnosis of PE. Ventilation-perfusion scan is the second-line imaging procedure.

Treatment

Anticoagulant medications commonly are used to treat DVT or PE; anticoagulants also are used for VTE prophylaxis. Bleeding can be a complication of anticoagulant therapy. The most frequently used injectable anticoagulants are unfractionated heparin, low molecular weight heparin (LMWH), and fondaparinux. Oral anticoagulants include apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban, and warfarin.

Air travel after VTE

The International Air Travel Association (IATA) and the British Thoracic Society (BTS) each provide guidelines on the time frame that should elapse between a DVT or PE and the intended flight.

International Air Travel Association guidelines

The IATA 2020 Medical Manual states that travelers with a recent DVT of the legs may fly once they are asymptomatic and stable on anticoagulants. Travelers with a recent PE may travel after ≥5 days if anticoagulation is stable and the partial pressure of oxygen (PAO₂) is normal on room air. However, the time frame is subject to change following medical assessment (e.g., right ventricular function).

British Thoracic Society guidelines

The BTS 2022 Clinical Statement on air travel for passengers with respiratory disease states that air travel should be delayed for 2 weeks after a diagnosis of DVT or PE.

Preventive measures

Graduated compression stockings and pharmacologic prophylaxis

Graduated compression stockings (GCS) appear to reduce asymptomatic DVT in travelers and are generally well tolerated. Decisions regarding use of pharmacologic prophylaxis for long-distance travelers at high risk should be made on an individual basis. When the potential benefits of pharmacologic prophylaxis outweigh the possible adverse effects, anticoagulants rather than antiplatelet drugs (e.g., aspirin) are recommended. There is no formally recommended dose for LMWH, but enoxaparin 40 mg or 1 mg/kg SC about 4 hours before the flight has been suggested. Direct oral anticoagulants (DOACs) are much more convenient than LMWH injections, but currently there is no evidence base for their use for the prevention of travel-associated VTE, so any use of DOACs for the prevention of travel-associated VTE would be off-label. People at increased risk should be evaluated with enough time before departure so that they understand how to take or administer the medication. Healthcare professionals should evaluate whether the traveler could have adverse effects from the combination of pharmacologic prophylaxis with other medications they are taking.

Hydration

There is no evidence for an association between dehydration and travel-associated VTE. Furthermore, no direct evidence exists to support the concept that frequent hydration or avoiding alcoholic beverages has a protective effect. However, dehydration could theoretically promote hyperviscosity of the blood, which could increase the risk of VTE, and alcohol consumption may induce diuresis, as well as promote immobility. Therefore, maintaining hydration is reasonable and unlikely to cause harm, but it cannot be recommended specifically to prevent travel-associated VTE.

In-flight mobility and seat assignment

Immobility while flying is a risk for VTE. Indirect evidence suggests that maintaining mobility could prevent VTE. In view of the role that venous stasis plays in the pathogenesis of travel-associated VTE, recommending frequent ambulation and calf muscle exercises for long-distance travelers is reasonable.

An aisle seat also might be a protective factor to reduce the risk of developing VTE. In one study, travelers seated in window seats experienced a 2-fold increase in general risk for VTE compared with passengers in aisle seats; travelers with a body mass index ≥30 kg/m² who sat in window seats had a 6-fold increase in risk. Conversely, aisle seats are reported to have a protective effect compared with window or middle seats, probably because travelers are freer to move around.

Society guidelines

The American College of Chest Physicians (ACCP) and the American Society of Hematology (ASH) each provide guidelines on the prevention of VTE in long-distance travelers.

American College of Chest Physicians guidelines

For long-distance travelers (>6 hours travel) at increased risk of VTE, the ACCP recommends frequent ambulation, calf muscle exercise, sitting in an aisle seat, and using properly fitted below-the-knee GCS that provide 15–30 mmHg of pressure at the ankle during travel (grade 2C: weak recommendations, low or very low-quality evidence). For long-distance travelers not at increased risk of VTE, use of GCS is not recommended. ACCP advises against the use of aspirin or anticoagulants to prevent VTE in long-distance travelers.

American Society of Hematology guidelines

For long-distance travelers (>4 hours travel) at substantially increased VTE risk (e.g., recent surgery, prior history of VTE, postpartum, active malignancy, or ≥2 risk factors, including combinations of the above with hormone replacement therapy, obesity, or pregnancy), the ASH guidelines suggest GCS or prophylactic LMWH. If GCS or LMWH is not feasible, ASH suggests using aspirin rather than no VTE prophylaxis. For travelers without risk factors, ASH advises against using GCS, LMWH, or aspirin for VTE prophylaxis.