Myths and Realities: Airline Travel and Deep Venous Thrombosis-Does Economy Class Syndrome Really Exist?

November 26, 2014


By Matthew Weiss, MD

Peer Reviewed

Background:

The number of worldwide air travelers is expected to surpass 3.3 billion by 2015 and possibly double by 2030 [1]. These changes will likely be driven by international markets, where growth rates were twice that of domestic U.S. flights during the past two years [2]. With more passengers taking to the skies and enduring longer international and transoceanic flights, the general practitioner is increasingly asked to advise on the risk of travel-associated venous thromboembolism (VTE). Accordingly, it is essential that the medical community appropriately educates travelers regarding their risk of venous thromboses and complications and recommends evidence-based preventative strategies. The savvy traveler may already know the benefits of compression stockings, but how should physicians respond to the question of adding aspirin (ASA) or the need for heparin injections? This review attempts to answer these questions by addressing the relevant pathophysiology, epidemiology, and data and recommendations regarding VTE prevention in travelers – economy class or otherwise.

Physiology:

As far back as 1856 Rudolf Virchow proposed the triad of pathogenic influences leading to the development of venous thromboses that have since bore his name: blood flow stasis, vascular endothelial damage, and blood hypercoagulability [3]. While many inherited conditions (Factor V Leiden or protein C or S deficiencies, etc.) may contribute to prothrombotic states via one of these three mechanisms, acquired hypercoagulable states (surgery, obesity, active malignancy, estrogen use, etc.)are much more common. In fact, over half of patients in the general population presenting with VTE have at least one acquired risk factor [4]. As a subgroup of the general population, all travelers departing on prolonged flights are – at a minimum – predisposed to increased periods of blood flow stasis secondary to prolonged cramped seating, possible dehydration, and hypobaric hypoxia. These conditions, in addition to passenger-specific conditions (obesity, age, inherited thrombophilias etc.), account for the roughly three-fold higher incidence of VTE in non-high risk patients compared to the general population incidence of 1-3 per 1,000 per year [5].

Blood flow stasis and subsequent coagulation activation have been known to stem from prolonged recumbence and reduced calf muscle pump function (as well as suspected popliteal vein compression and endothelial damage from the seat edge) since at least 1940 when Simpson reported an increase in fatal pulmonary emboli (PE) following prolonged sitting in World War II air raid shelters [6]. Historical data also show a two-thirds reduction in venous blood flow velocity in normal seated volunteers [7]. More contemporary studies demonstrate that 85-100% of VTE occur in passengers in non-aisle seats, while passengers developing severe PE during one randomized trial were identified having not left their seats during travel, further corroborating the stasis-VTE association [8-10]. Of note, there are no specific data to suggest that roomier business-class travel decreases what was formerly known as “economy-class syndrome.” However, known data regarding window-seat based incidence of deep vein thrombosis (DVT) [8-10], do tend to suggest that roomier business-class seating may indeed confer benefit.

Commercial airliners are routinely pressurized to an altitude of roughly 8,000 feet, a pressure at which travelers are subjected to hypobaric hypoxia and potential dehydration secondary to decreased cabin humidity. Both of these factors are theorized to contribute to the increased incidence of VTE in airborne travelers. Dehydration is posited to predispose to hypercoagulability and hyperviscosity, although supporting data are highly inconsistent [11-12]. Meanwhile, the current literature also does little to support any clinical relevance to the minimal levels of hypoxia experienced by passengers on commercial planes with even the most sensitive of tests (D-dimer measurements) remaining unchanged, suggesting that hypoxia during airline travel does not activate even sub-clinical coagulation.

Epidemiology:

Despite a heterogenous and incomplete data set, multiple generalized conclusions can be drawn from the available prospective, observational cohort studies on travel-related VTE and PE. These studies demonstrate a low incidence of VTE of less than 6% with the exception of one oulier study reporting a 10% incidence [13, 14]. In fact, the overall flight-associated VTE risk, including both low- and high-risk travelers, is less than that of “low-risk” surgical patients of whom 2% develop DVTs [15]. Secondly, symptomatic thrombosis is quite rare, with multiple studies demonstrating an incidence of <1% [16, 17]. Thirdly, while in the generalized outpatient population up to one-half of venous thrombi present as pulmonary emboli, in patients with recent air travel, symptomatic PE was low, less than 0.5 per million passengers, and was directly related to length of travel. Multiple studies suggest >8 hours flight duration was associated with a significant increase in incidence of PE [10, 18, 19]. Finally, nearly all studies indicate that passenger-specific risk factors are important, as most passengers presenting with VTE had additional risk factors for thrombosis present aside from recent air travel [15, 16].

Interventions:

Behavioral, mechanical and, pharmacological methods of VTE/ DVT/ PE prophylaxis have been assessed in randomized clinical trials addressing both low-risk and high-risk fliers. Multiple trials examined the role of compression stockings in VTE prevention on long-haul flights, typically greater than 6 or 8 hours in duration [13, 20, 21]. Collectively the data show a reduction in incidence of VTE in low- and high-risk patients with compression stocking use compared to controls (RR 0.165 – 0.054 in high-risk patients). Notably in low-risk patients there were no events (VTE) in the intervention group compared to 10% incidence of events in the control with a 3% incidence of adverse effects (phlebitis in intervention group) [13]. Compression stocking use appears to therefore offer protection without increased side effects in patients with predisposing risk factors.

The most recent studies of high-risk patients undergoing long-haul travel have examined behavioral modifications (standing and moving legs for 5 to 10 minutes every hour, avoiding luggage under the seat in front, and drinking water regularly) combined with pharmacologic prophylaxis (ASA or low-molecular-weight heparin [LMWH]) versus behavior modifications alone. In one well-organized study of 250 subjects, the incidences of any DVT was 4.8% in the control group, 3.6% for ASA (400mg for 3 days; p<0.05), and 0% for enoxaparin (one dose at 1mg/kg; p<0.002). Of note, DVT was asymptomatic in 60% of patients and 13% of patients in the ASA group developed mild transient gastrointestinal symptoms [9]. A subsequent consensus position from the American College of Chest Physicians adds upon these data advising against the use of ASA alone as VTE prophylaxis in any group given its inferior efficacy compared with LMWH and increased risk of avoidable adverse events as demonstrated in clinical trials [22].

Notably, from a physiologic standpoint, there is an important distinction between anti-platelet and anticoagulant agents and their relative efficacies. Whereas ASA is a well-known means of primary and secondary prevention for arterial thrombi (indicated for coronary artery disease and cerebrovascular accidents), it is an inefficient means of VTE prophylaxis. Arterial and venous thrombi are both composed of platelets and fibrin, but the proportions differ. Arterial thrombi are platelet-rich because of the high shear in the injured artery typically at a site of plaque rupture and subsequently exposed thrombogenic material. In contrast, venous thrombi rarely form at sites of obvious vascular disruption (surgical sites and venous catheters aside), instead favoring valve cusps and sites prone to stasis. In these low-shear sites, venous thrombi form with higher proportions of fibrin and fewer platelets. Accordingly, one can understand the physiologic benefit of anticoagulant drugs like LMWH or warfarin in VTE prophylaxis compared with anti-platelet agents such as ASA or clopidogrel.

Conclusions:

With patients and the mainstream media evermore focused on flight-associated VTE, it is important to understand the true risk factors and incidence of the disease as well as judicious means of prevention. How does one interpret or respond in an evidence-based manner to a British Airways in-flight magazine article suggesting exercise for prevention of VTE because it “…helps your blood from becoming sluggish, something which can happen if you sit…” [23]? What about a recommendation from a Harvard Medical School webpage recommending ASA use prior to air travel [24]? Based upon the above review one can safely acknowledge and recommend the following:

1. The overall incidence of flight-related VTE is relatively infrequent, especially in non high-risk patients (those with prior DVT, a known coagulation disorder, severe obesity, neoplastic disease or large varicosities).

2. There is no suggested benefit from anti-VTE prophylaxis the prevention of symptomatic DVTs in low-risk travelers.

3. Based on physiologic understanding of hemostasis and coagulation, there is little reason not to encourage adequate hydration and frequent mobilization for VT prevention during long-haul flights greater than 6 hours for VTE prevention; however, well-researched data to support this claim does not exist.

4. ASA is not recommended to take aspirin to prevent flight-associated VTE, even in high-risk patients, as the supporting data currently available are weak (stemming mainly from one trial), and associated with a high percentage of adverse gastrointestinal effects.

5. Based on reasonable data available today, it is recommended that high-risk patients undergoing long-haul air travel for greater than 6hours, air travel consider compression stockings use and/or one time dosing of enoxaparin (1mg/kg) prior to the flight to prevent VTE.

Further research is needed to confirm and extend the data presented here. To date, there have been few large, high-power studies investigating flight-associated VTE; follow-up periods have been brief (days to weeks); and other means of prolonged travel (rail, bus) have not been investigated. Future research should address these issues.

Commentary by David Green, MD, PhD, Assistant Professor and Director of the Anticoagulation Service at Tisch Hospital

Air travel is uncommonly associated with VTE but is an important trigger given the enormous number of travelers. Other weak-acting thrombophilic risk factors include obesity and estrogen-containing contraceptive hormones (OCP). The weak-acting risk factors (hormones, pregnancy, factor V Leiden, prothrombin gene mutation, obesity, smoking) account for more of the total VTE burden than strong-acting risk factors (major orthopedic surgery, malignancy, protein C or S or antithrombin deficiency, antiphospholipid syndrome) because they occur much more frequently in the population. For example, OCP may be the most important cause of VTE in women of childbearing age. The optimal approach to prophylaxis for air travel is unknown. In the LONFLIT-3 study, weight-adjusted LMWH was more effective than ASA in the prevention of VTE in high-risks travelers on flights longer than 10 hours [9]. In the ASA group, 13% reported mild gastrointestinal side effects, although they were given 400 mg of ASA daily, which is significantly higher than the dose required to maximally inhibit platelet aggregation. Presumably, low-dose ASA (81 mg) would be better tolerated.

The role of ASA on the venous side is controversial. Yet, platelets are probably an important bystander in VTE. Perhaps this explains why ASA has proven activity in postoperative VTE prophylaxis and secondary prevention of VTE, although less effective than anticoagulation. Indeed, ASA was widely used in practice even before recent studies were published that supported its efficacy in secondary prevention. Injectable anticoagulants are costly and cumbersome, and not everyone is willing or able to self-inject. The optimal role of the novel anticoagulants remains unclear, but they also are being used in practice for travel prophylaxis. The current data do not allow for meaningful consensus guidelines with respect to air travel prophylaxis, so we must individualize our approach. Injectable anticoagulants (LMWH or fondaparinux) are a reasonable approach for the highest-risk group (history of VTE, hypercoagulable states) for long flights (greater than 6 hours). For lower-risk travelers, low-dose ASA and elastic compression stockings can be considered.

Dr. Matthew Weiss is a 3rd year resident at NYU Langone Medical Center

Peer Reviewed by David Green, MD, PhD, Assistant Professor, Director Anticoagulation Service Tisch Hospital, NYU Langone Medical Center\

Image courtesy of Wikimedia Commons

References:

1. Thomas, G. “IATA projects 3.3 billion air travelers by 2014.” http://atwonline.com/aeropolitics/iata-projects-33-billion-global-air-travelers-2014.

2. International Civil Aviation Organization, A United Nations Specialized Agency. “Annual Passenger Total Approaches 3 Billion According to ICAO 2012 Air Transport Results.” December 18, 2012. http://www.icao.int/Newsroom/Pages/annual-passenger-total-approaches-3-billion-according-to-ICAO-2012-air-transport-results.aspx.

3. Virchow, R. “Thrombose und Embolie. Gefässentzündung und septische Infektion.” Gesammelte Abhandlungen zur wissenschaftlichen Medicin. 1856.

4. Ferrari, E. Clinical epidemiology of venous thromboembolic disease. Results of a French Multicentre Registry. European Heart Journal, 1997;18 685-691. http://eurheartj.oxfordjournals.org/content/18/4/685.abstract.

5. Chandra D. Meta-analysis: travel and risk for venous thromboembolism. Ann Intern Med. 2009;151(3):180. http://annals.org/article.aspx?articleid=744631.

6. Simpson K. Shelter deaths from pulmonary embolism. The Lancet. 1940;348:416.

7. Wright H.P. Effect of posture on venous velocity, measure with 24NaCl. British Heart Journal. 1952;14:325-330.

8. Belcaro, G. Prevention of edema, flight microangiopathy and venous thrombosis in long flights with elastic stockings. A randomized trial: The LONFLIT 4 Concorde Edema-SSL Study. Angiology. 2002;53:635-645. http://ang.sagepub.com/content/53/6/635.abstract.

9. Cesarone M.R. Venous thrombosis from air travel: the LONFLIT 3 study – prevention with aspirin vs low-molecular-weight heparin (LMWH) in high-risk subjects: a randomized trial. Angiology. 2002;53:1-6. http://ang.sagepub.com/content/53/1/1.abstract.

10. Lapostolle, F. Severe pulmonary embolism associated with air travel. New Eng J Med. 2001;345:779-783. http://www.nejm.org/doi/full/10.1056/NEJMoa010378.

11. Landgraf, H. Economy class syndrome: rheology, fluid balance, and lower leg edema during a simulated 12-hour long distance flight. Aviation Space and Environmental Medicine. 1994;65:930-935. http://www.ncbi.nlm.nih.gov/pubmed/?term=7832736.

12. Schobersberger, W. Changes of biochemical markers and functional tests for clot formation during long-haul flights. Thrombosis Research. 2002;108:19-24. http://www.thrombosisresearch.com/article/S0049-3848(02)00347-X/abstract.

13. Scurr, J.H. Frequency and prevention of symptomless deep-vein thrombosis in long-haul flights: a randomized trial. The Lancet. 2001;357:1485-1489. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)04645-6/abstract.

14. Chee, Y-L. Air travel and thrombosis. British Journal of Haematology. 2005;130:671-680.

15. Anderson, F. Risk factors for venous thromboembolism. Circulation. 2003;107:1-9-1-16. http://circ.ahajournals.org/content/107/23_suppl_1/I-9.abstract.

16. Schwarz, T. Venous thrombosis after long-haul flights. Archives of Internal Medicine. 2003;163:2759-2764. http://archinte.jamanetwork.com/article.aspx? articleid=757492.

17. Hughes, R.J. Frequency of venous thromboembolism in low to moderate risk long distance air travellers: the New Zealand Air Traveller’s Thrombosis (NZATT) study. The Lancet. 2003;362:2039-2044. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)15097-0/abstract.

18. Clerel, M. Thromboembolic syndrome from prolonged sitting and flights of long duration: experience of the Emergency Medical Service of the Paris Airports. Bulletin de l Academie Nationale de Medecine. 1999;183:985-997.

19. Perez-Rodriguez, E. Incidence of air travel-related pulmonary embolism at the Madrid-Barajas airport. Archives of Internal Medicine. 2003;163:2766-2770. http://archinte.jamanetwork.com/article.aspx?articleid=757503.

20. Belacro, G. Venous thromboembolism from air travel: the LONFLIT study. Angiology. 2001;52:369-374. http://ang.sagepub.com/content/52/6/369.abstract.

21. Belacro, G. Prevention of venous thrombosis with elastic stockings during long-haul flights: the LONFLIT 5 JAP study. Clinical and Applied Thrombosis/ Hemostasis. 2003;9:197-201. http://cat.sagepub.com/content/9/3/197.abstract.

22. Geerts W.H. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:338S-400S.

23. Calder, S. “Exercise your constitutional rights in the air.” The Independent. Jan. 13, 2001.

24. Air travel health tips. Harvard Medical School Family Health Guide. 2004. http://www.health.harvard.edu/fhg/updates/update0604c.shtml.

 

2 comments on “Myths and Realities: Airline Travel and Deep Venous Thrombosis-Does Economy Class Syndrome Really Exist?

  • Avatar of Chelle Taylor
    Chelle Taylor on

    One cannot dispute the fact that airlines, simply as an “acceptable risk” money saving measure, under-pressurize airliner passenger cabins nor can we dispute the fact that they also maintain an 02 level far below “room air” of 19-21%. Perfectly healthy young men and women who would normally have oxygen saturations of 99% or higher can dip into the mid to low 90’s during long flights, so people at any kind of cardio-pulmonary risk will naturally sat out far lower…often dangerously so. I am a healthy runner with no identified risk factors, a non-smoker with ideal lab values and on no hormonal medications. Even my ankles swell after long flights during which I get up and walk frequently while wearing Rx high compression stockings and premedicating with short term low dose ASA. I find your conclusions suspicious and far too friendly to airlines who knowingly engage in unsafe practice simply to save money. Of course doctors can afford to fly first class, so this isn’t as “much” of an issue for you, is it.

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