Travel-Related VTE: What is the Risk and How Can it be Prevented?

Author: Selim Sikander Kabir, MBBS, FCUCP, FRNZCG.
Selim Sikander Kabir is a Director and Medical Officer at Medicross Urgent Care Clinic in New Plymouth, New Zealand, and an Executive Committee Member of The College of Urgent Care Physicians.

Abstract
Prolonged travel has long been known to be associated with venous thromboembolism (VTE) with potential cost to health running into billions of dollars. A review was done of the current literature to assess the risk and incidence of VTE with prolonged travel, especially long flights, and to find means to prevent them. The review showed that long- haul passengers with no risk factors for VTE were unlikely to be more prone to develop thrombosis than the background population (Level of evidence I). The review further suggested that use of graduated compression stockings was adequate as prophylaxis in most cases (Level IC) with additional pharmaceutical means for those travellers at high risk of developing VTE (Level IC and 2B).

Introduction
The presentation to our clinic of a few long-haul travellers with calf pain/swelling who were concerned about the possibility of deep vein thrombosis (DVT) and anecdotal evidence of occurrence in travellers raised the need for further study into this problem.

Prolonged travel, especially long-haul flights, has been associated with VTE and may be an important safety issue that needs to be addressed.¹ Travel-related VTE was first described in 1954 when 5 cases were presented: 2 after long flights, 2 after prolonged travel by car, and 1 after prolonged sitting in a theatre.^2-5 By 2009, there were more than 2 billion air travellers of whom more than 300 million are long-haul passengers.^3,6,8 In 1977, a series of 8 patients with VTE occurring shortly after flying economy class was reported and the term “economy class syndrome” was coined, which erroneously implies this condition does not occur in Business or First Class or by other means of travel.^1,2 At a recent meeting of experts, the term was changed to “traveler’s thrombosis”.^2,7,9

Incidence and Risk
To estimate the risk of VTE after travel, various studies were undertaken with conflicting results. The reported incidence of DVT in a general population is 1 to 2 persons per 1000 population per year.⁵ In general, it was noted that there was no increase in VTE among travellers with low risk of DVT^{2, 6, 10-12} but among those already at risk of DVT, incidence of VTE varies between 4% to 6 % after long-distance travel.^{1, 2, 4-11, 13, 14} In this group, risk of VTE is raised 2- to 4-fold^{1, 7-9} although a 1% incidence of DVT was noted in some studies.^{13, 14}

It was impossible to determine the risk of travel-related VTE^{5, 14, 15} because large studies did not include routine surveillance of VTE, but rather, relied on retrospective report, had a strong volunteer bias¹⁴, and in many cases, included passengers who were already using compression stockings or taking aspirin.¹³

To demonstrate an extra 40 cases of travel-related VTE, it has been estimated that a sample size of more than 160,000 travellers and controls combined would be needed.¹⁶ Another author noted that 2500 travellers needed to be studied to show a significant increase in VTE among travellers compared to controls, based on a power calculation with a 1 per 1000 incidence of DVT in the general population and extrapolation to a 24-hour flight.⁵ These studies revealed a trend towards higher VTE rates with a travel dose response curve.^{3, 6-8, 13-17} A higher clinical risk of VTE also was associated with higher VTE rates.^{13, 14, 17}

Long-distance bus travel has been noted to induce activation of the coagulation system.⁷ In general, various studies did not show any major difference between the various modes of travel^{4, 7, 17} but Adi and colleagues found in his review of articles that although there was a small increase in risk of DVT associated with all forms of travel, land travel puts individuals at more risk of DVT than does air travel.³ Nowadays, it is generally accepted that long-distance travel is a risk factor for VTE, especially among those already at danger of developing DVT.

Categories of increased risk of VTE have been classified as follows.^{9, 15, 16}
Minor Risk: Travellers aged >40; very tall (>190 cm), very short (30); previous or current leg swelling from any cause; recent minor leg injury or minor body surgery (within 3 days); extensive varicose veins.

Moderate Risk: Among those with recent heart disease, myocardial infarction within the last 6 weeks, uncontrolled heart failure with left ventricular ejection fraction 20% to 40%¹⁵; pregnant or on any hormone medication, particularly oral contraceptives and hormone replacement therapy (HRT); recent major leg injury or leg surgery; family history of DVT, polycythaemia.

Substantial Risk: Previous or current VTE; known clotting tendency (thrombophilia has been noted to substantially increase [by 16 times] the risk of VTE) ⁸, Factor V Leiden mutation, prothrombin G20210A mutation, antithrombin III, protein C and protein S deficiencies ^{3, 4}; recent major surgery or stroke (within 6 weeks); current malignant disease or chemotherapy; paralysed lower limb(s).

Travel time, too, has been suggested in evaluation of risk factors, with travel of less than 5000 km or less than 8 hours being considered as low risk and travel greater than 5000 km or more than 8 hours tending to substantially increase risk of VTE in the presence of other risk factors.¹⁵

The LONFLIT studies showed a substantial effect of seat location on development of VTE. Nineteen thrombotic events were seen in the high-risk group (4.8%) of which, 18 (94.7%) occurred in passengers sitting in window or central seats. ¹⁸

To address the issue of economy class versus business class travel and thromboembolic complication, the BEST study was undertaken. ^{5, 7, 12} The study was inconclusive because there were dissimilar numbers between the two groups and they were not all scanned. The study did not show any significant difference in VTE incidence. ^{7, 8, 12}

In the 19th century, Professor Virchow described the three major influences predisposing to development of thrombus: 1. alteration or reduction in blood flow; 2. damage or abnormality of the vessel wall; and 3.

hypercoagulability or changes in blood viscosity. These factors are generally considered to be brought about in travellers by immobility and cramped seating; dehydration secondary to decreased fluid intake, diuretic effect of alcohol, tea, coffee and low humidity; and relative hypoxia and the hypobaric state. ^{4, 5, 7-9, 15, 16}

Reduction in blood flow and damage to the vessel wall is thought to be a possible consequence of the front edge of the seat compressing the veins and damaging the endothelium. ^{4, 5, 7, 16} This effect is made worse by repeated crossing of legs. ⁵ A review of data from various studies on the effect of cramped seating initiating thrombosis are inconclusive. It has been demonstrated, however, that cramped seating reduces blood volume flow through the popliteal vein by more than 40%. ⁷

Changes in blood viscosity are presumed to be secondary to hemoconcentration and hyperviscosity, leading to a hypercoagulable state. This happens as a result of dehydration due to decreased water intake and increased fluid loss. ¹ Increased fluid loss occurs due to low humidity, which is below 10% in aircraft, ⁷ and to the diuretic effect of alcohol, tea and coffee ^{5, 8, 15, 16}, with increased concentration of platelets ⁵ and possible activation of erythropoietin. ¹⁵ Development of edema in the leg with passage of fluid from the vessels also leads to intravascular hemoconcentration and is a possible casual factor for activation of coagulation. ⁷ These findings are not conclusive and it has been demonstrated that fluid loss alone may not explain coagulation activation during travel. ⁷ One study suggests that the degree of insensible water loss is insufficient for pronounced dehydration and calls into question the degree of diuresis promoted by the consumption of alcohol and caffeinated drinks. ⁷

Relative hypoxia and a hypobaric state is said to produce a transient activation of coagulation in the first few hours. ¹⁶ Commercial flights usually travel at altitudes of 7010 to 12,498 meters above sea level, but the passenger cabin is pressurised to an altitude of 1524 to 2438 meters. ⁸ Most healthy passengers tolerate this altitude. The partial pressure of arterial oxygen (PaO2) drops from 95 mm Hg to 60 mm Hg with a 3% to 4 % drop in oxyhaemoglobin saturation.⁸ The decrease in PaO2 interferes with fibrinolysis and activates the coagulation cascade.^{1, 5, 15, 16} Hypoxia also tends to cause vasodilatation with increased capillary permeability, resulting in increased edema and subsequent hemoconcentration with possible activation of the coagulation pathway.¹⁶

Preventive Measures
With the general acceptance that long-distance travel is a risk factor for VTE, especially among those already at risk of DVT, various recommendations have been made for prevention of travel-related VTE. Interventional trials on this topic are scarce and the published data have limited validity.⁷ Recommendations for decreasing risk of travel-related VTE rely more on common sense than evidence and mainly are based on outcomes from epidemiologic studies.

General Measures. Airlines already provide advice to travelers on methods to reduce stasis and circulatory problems, which is drawn from common sense and indirect conclusions rather than direct evidence.¹⁴ This guidance includes^{1, 7, 8, 14} staying well hydrated by drinking at least 250 mL of water every 2 hour, reducing intake of alcohol and caffeinated drinks., avoiding storage under seat to increase leg space, and avoiding constrictive clothes. Airlines also advise travelers to change positions frequently or walk through the cabin and do periodic calf muscle exercise for 3 minutes every hour to reduce venous stasis.

Graduated Compression Stockings. A prospective study was done involving 422 controls and 411 travelers wearing compression stocking.¹⁸ Twenty-two cases of DVT were seen in 19 passengers in the control group (4.5%) and 1 DVT was detected in the group that wore stockings (0.24%). This is a significant decrease by 18.75 times, having a P value >0.02.

A meta-analysis of studies using compression stockings showed 2 cases of VTE in 1,237 travellers wearing compression stockings compared with 46 VTEs in 1,245 travellers who did not wear any.⁸ Another meta-analysis of 2,821 participants in 9 trials showed a 90% reduction in the stocking group from 10 to 30/1,000 control passenger to 1 to 3/1,000 stocking passengers.¹⁰ Another author showed a significant decrease in DVT with a 95% Confidence Index of 0.01-0.23.¹⁶ It is to be noted that there are very low overall event rate and in fact, some trials had 0 events. Further, in some trials, one group had a small number of events while the other group had none, leading to assumptions being made.¹⁰

Use of compression stockings is now recommended to all travellers prone to immobility and especially those at moderate to substantial risk of developing travel-related VTE, with quality of evidence being rated as Grade 1C.^{1, 5, 7-11, 14-16, 18}

Aspirin. There is no clear evidence that aspirin is useful for VTE prophylaxis. Evidence is good that aspirin is effective in preventing thrombosis on the arterial side but its use for prevention on the venous side remains controversial.⁷ The LONFLIT3 study did not show any significant benefit for use of aspirin (P <0.05).^{1, 18} In that study, there was only 1 less case of DVT in the aspirin group than in the controls (3.6% vs 4.82%) and the authors concluded that aspirin had very limited effect.

Aerospace industry guidelines advise use of aspirin for VTE prophylaxis in travellers with moderate risk,⁹ but that view is not held by others. The American College of Chest Physicians (ACCP) does not recommend aspirin for VTE prophylaxis¹⁵ and that view seems to be shared by a number of authors.^{1, 7, 8, 14-16, 18}

Low molecular weight heparin(LMWH)/enoxaparin. Use of anticoagulants for thrombo-prophylaxis of VTE is growing although there are no definite guidelines.⁷ LMWH is used as prophylaxis for VTE in other clinical settings. It has been found to be an effective and safe method to prevent VTE post-surgery and in acutely ill medical patients.⁷ A number of small randomized, controlled trials (RCTs) have shown the benefit of using LMWH as prophylaxis in moderate-to-high-risk groups, but its use in groups other than those at high risk remains controversial.⁸ The LONFLIT3 study showed a trend in benefit that was not considered to be statistically significant (P<0.002). There was no DVT in the enoxaparin group compared to 4 in the control group but the total number of participants was small.¹ They had used a single dose of LMWH at 1000 units/ 10 kg subcutaneously given 2 to 4 hours before travel.

The ACCP guidelines suggest use of LMWH prophylaxis in travellers at substantial risk of VTE.^{7, 15} They have rated the quality of evidence for use of LMWH for prevention of travel-related VTE as Grade 2B.^{5, 7, 8}

Factor Xa inhibitors and thrombin antagonists. New agents such as fondaparinux, rivaroxaban, bivalirudin, and dabigatran (now available in New Zealand) have been shown to reduce incidence of VTE in high-risk individuals.^{5, 7, 14} In a small study with 92 controls and 94 individuals a high-risk group who received intervention, VTE occurred in 7.6% of the controls and none of those who received intervention (P<0.05).¹⁴ It is still too early to recommend use of these agents for travel-related thromboprophylaxis.⁷ Although development of oral thromboprophylaxis is a milestone in medicine, care must be taken to investigate these drugs further and to ensure that they are not misused by long-distance travelers.⁷

Therefore, the following measures have been suggested for prevention of VTE in long-distance travellers at various risk levels:

• Low Risk – Avoid constrictive clothing around waist and lower extremities, avoid dehydration, move around the cabin or stop the vehicle and walk about and do calf-stretching exercise. Some authors have suggested that compression stockings be considered in this group.^{5, 8, 9, 15, 16} The quality of evidence has been rated as 1C.
• Moderate Risk – Low-risk measures along with use of graduated compression stocking and travel in an aisle seat. The quality of evidence is rated as 1C and 2B.
• High Risk – Moderate-risk measures along with use of LMWH or Factor Xa inhibitors or thrombin antagonist. The quality of evidence is rated as 1C and 2B.

Experts estimate that more than 2,000 high-risk travellers need to be treated with anticoagulants to prevent one VTE. Therapy has its own attendant risks, although they are small.¹⁴ Therefore, some researchers tend to favor use of compression stockings over anticoagulation, with the latter being prescribed only if stockings cannot be used or additional prophylactic measures are deemed necessary.^{1, 14}

The reviews of VTE are possibly not representative of the incidence of the condition and the risks that can occur. It is impossible to precisely determine the risk of travel-related VTE because travellers tend to be healthier with fewer risk factors.¹⁴ Most of the large studies included no routine surveillance of VTE, but rather, VTE was mainly identified from retrospective record review. Outcomes were different for the various studies, with some having DVT as an endpoint, some pulmonary embolism (PE), some both DVT and PE, and some any thromboembolic event. It was noted that these studies were also prone to volunteer bias.^{13, 14} Most studies enrolled volunteers who tended to be healthier than the non-volunteers, thus compounding the “healthy traveler effect.”

Some of the studies used strong research methods to establish the diagnosis of VTE and to evaluate the effects of intervention. Objective diagnostic tests were used to confirm the diagnosis. Interventions were assessed with RCTs to reduce the bias for conclusions about the efficacy of the treatment.

Conclusion
Long-distance travellers who have pre-existing risk factors for VTE tend to be at increased risk of developing VTE, whereas long-distance travellers with no risk factors are no more prone to developing VTE than is the background population.

Along with pre-existing risk factors of VTE, additional risk factors are flights over 8 hours duration, cramped seats with immobility, use of window or center seats, increased alcohol or caffeine intake and low water intake. Other factors that may play a part include low humidity and the hypoxic and hypobaric atmosphere in the aircraft.
To prevent development of VTE, travelers are advised not to wear tight or constrictive clothing, to avoid window or center seats if possible, keep their leg space free, avoid dehydration by drinking 250 mL water every 2 hours, walk around the cabin or stop the vehicle and stretch for about 3 minutes every hour, and to do calf stretches. Use of graduated compression stockings is recommended for passengers with pre-existing risk factors, especially if travel is for more than 6 hours. For travelers at high risk of VTE, additional pharmaceutical means may be advised—mainly LMWH. Use of Factor Xa inhibitors or thrombin antagonist is still under review.

There are more than 2 billion air travelers, of whom 300 million are long-haul travelers.⁸ If 20% to 35% of them are at moderate to high risk of VTE, that would mean that 2 to 3.5 million travelers could have DVT and some of them would also have PE. If the average cost for a “small limited” DVT is 10,000 Euro (approximately $17,000)¹⁸ per case, the total cost of flight-related DVT could be as high as 35 to 60 billion New Zealand dollars. Better education of travellers, improved seating, mobilization, active prophylaxis using compression stockings, and avoidance of uncomfortable situations such as long waits and sitting at airports would go a long way toward reducing incidence of DVT by 85% to 90%.¹⁸
References

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