History
The syndrome was first described nearly 150 years ago by Rudolf Virchow, the German medical pioneer. In 1940, during the Battle of Britain, an increase in pulmonary embolism was observed in London. Those affected were found to have slept upright in deck chairs while huddled in air raid shelters. When the deck chairs were removed and cots provided, the incidence of pulmonary embolism returned to normal. Immobilization in the seated position was thus identified as a major risk factor.

Later studies corroborated this belief, although many other risk factors have since been identified. In 1988, Cruickshank and colleagues at ICI Pharmaceuticals in Macclesfield (U.K.) noted a cluster of pulmonary embolism cases among economy class fliers. The authors hypothesized that cramped quarters in economy class accommodations limited the activity of passengers while seated and decreased the likelihood of walking about the cabin while in flight. They postulated that the inactivity led to a clot in the legs. When the clot broke loose, it followed the circulation to the arterial bed of the lungs, where it blocked oxygenation of the blood. The authors coined the term economy class syndrome to describe the process brought on by immobility. It actually can occur just as easily in business class or even first class seats.

Biology
The deep veins of the calves appear to be the most common starting point for thrombosis. Once a clot begins to form, it attaches to the wall of a vein. The clot is a trigger for further clotting and, if conditions are right, the primary clot enlarges. The attachment of the clot to the inner lining of a vein damages the lining, and the vein becomes inflamed, swollen, warm, and tender. It also releases factors that promote more clotting. The greater the extent of clotting, the greater the extent of inflammation.

Figure 1. Birth of a thrombus. Under conditions of stress, a clot or thrombus can form in a leg or pelvic vein, typically in the low-pressure area behind a valve (bottom outset). If the vein dislodges, it passes through the right side of the heart (top outset) and along the pulmonary artery to the lungs (middle outset). If the clot blocks an early arterial branch point in the lung, blood cannot enter the pulmonary capillaries to become oxygenated. This condition could lead to death.

If the thrombus remains in the calf, then the major risk appears to be the venous inflammation, or thrombophlebitis. If the thrombosis extends to the larger vessels of the thighs and pelvis, however, the likelihood of it dislodging and becoming an embolus increases (Figure 1 at right).

Once a clot is embolized, it is carried by the blood flow through the right side of the heart and into the arterial bed of the lungs. A single small embolism poses little threat to life. Several small emboli or a single large embolism can, however, be life-threatening. An embolism large enough to obstruct the pulmonary artery bifurcation—the point where the artery splits, forming the right and left pulmonary arteries—can lead to sudden death.

Whether a clot forms and enlarges is determined by a balance between thrombogenic (clot-promoting) and thrombolytic (clot-dissolving) factors. Thrombogenic factors include stasis, hypoxia, damage to the blood vessel lining and other tissues, and various disease states. Stasis, the slowing or even cessation of blood flow, is promoted by gravity and constriction of the venous system by tight clothing, furniture, or the position of the body, all of which can create pressure points. It is also promoted by lower blood flow during periods of inactivity, when the muscular action that normally compresses the blood in the low-pressure venous system, and thus increases venous flow, is absent. Clotting in the deep veins of the lower part of the body is believed to begin in the vicinity of the valves, which prevent retrograde flow in veins and which are points of minimal blood flow. Tissue damage also triggers clotting in veins, because damaged tissues release substances that initiate clotting at various points in the coagulation system.

Thrombosis in the veins of the lower extremities is more likely to lead to thrombophlebitis than pulmonary embolism. Research suggests that silent (asymptomatic) thrombosis in the lower extremities may be relatively common. Whether thrombi are small and silent or enlarge and embolize may hinge on thrombolytic forces. The blood coagulation system has several pathways for dissolving clots, for, as we have seen, a clot in the wrong place, of the wrong size, or at the wrong time can be dangerous.

Consider a small clot that forms in the deep veins of the calf because of a seating position that constricts blood flow. If the person moves or changes position, the clotting trigger is removed. But although the trigger is now absent, the clot remains, and it releases factors that identify it as clot. These factors trigger the blood’s lytic systems, which act to dissolve clots. If, however, the clot is caused by the release of factors from damaged tissue, then the continued release of those factors creates more clots, overwhelming the lytic system. Once the damage is repaired, however, the release of tissue-damage factors ceases, and the thrombolytic system breaks down the clot. The factors favoring clot creation and those favoring clot breakdown are continually in opposition.

Secondary risk factors Several factors increase the likelihood of developing deep vein thrombosis and may aggravate and facilitate the onset of economy class syndrome. Here is a partial list: clothing or furniture that restricts blood flow obesity medications such as estrogen, and some cancer chemotherapeutic agents cancer, stroke, hypertension, some types of heart disease, and some inflammatory disorders trauma (including burns) to, or surgery on, the legs and pelvic organs dehydration, especially when associated with alcohol intake blood and coagulation disorders.

Risks
Although other factors contribute to clotting (see box at right), immobility is the primary trigger for deep vein thrombosis in economy class syndrome. The central role of immobility is highlighted by the increased prevalence of clotting in those who have a paralyzed lower limb. An individual with one immobile leg suffers more clotting in the paralyzed appendage than in the mobile leg. It must be noted that immobility without the legs dependent, such as when we sleep, rarely leads to deep vein thrombosis.

The incidence of venous thromboembolism is 1 or 2 per 1000 people per year. The syndrome is almost unheard of before the age of 20, and its incidence rises with age. Some researchers assert that in a healthy person, venous thromboembolism from seated immobility is unlikely without a secondary risk factor.

Diagnosis and treatment
The diagnosis of venous thromboembolism is not straightforward; nor is the diagnosis of pulmonary embolism simple. Thrombosis in a vein leads to inflammation, which may cause only minimal symptoms. Venous thrombosis in the calves is commonly taken to be nothing more than a sprain or bruise of the calf muscles. A significant number of pulmonary emboli occur without warning of trouble in the lower extremities. Similarly, having embolized to the lung, a clot may produce few symptoms that are diagnostic of pulmonary embolism, which are variable and range from nothing more than a dry cough, shortness of breath, or fever and chest pain, to collapse and sudden death. Thus, a high index of suspicion remains the cornerstone of diagnosis, as venous thrombosis and pulmonary embolism can mimic many other conditions.

There are no simple or inexpensive tests to detect venous thrombosis or pulmonary embolism. The most accurate tests for both conditions are invasive and carry a degree of risk. Treatment of venous thromboembolism consists of anticoagulant therapy, rest, and heating and elevation of the affected extremity. Pulmonary embolism can be treated with anticoagulant therapy and hospitalization when there is no respiratory compromise. If the embolism compromises respiration, however, thrombolytic agents are used to dissolve it quickly. Thrombolytic therapy has a risk of bleeding complications. Long-term anticoagulant therapy (3–6 months) is prescribed after the occurrence of pulmonary embolization, to prevent recurrent venous thrombosis.

Recommendations
Authorities stress that prevention of venous thrombosis and pulmonary embolism is simpler, cheaper, and safer than the diagnosis and treatment of the conditions. Given that physicians know many of the predisposing causes, prevention should be the byword. For those in good health, the simple precaution of moving the legs frequently while traveling may be sufficient to eliminate the risk of venous thromboembolism. Since the death of the British victim, several airlines have placed notices in their in-flight literature advising activity throughout the flight.

Suggested reading

1. Simpson, K. Shelter deaths from pulmonary embolism. Lancet 1940, 2, 744.
2. Cruickshank, J. M.; Gorlin, R.; Jennett, B. Air travel and thrombotic episodes: The economy class syndrome. Lancet 1988, 2, 497–498
3. Carter, C. J. The natural history and epidemiology of venous thrombosis. Prog. Cardiovasc. Dis. 1994, 36, 423–438.