Air Travel and Venous Thromboembolism

Bo Eklof, MD, PhD

Alerted by the worrying reports in the media on air travel-related venous thromboembolisms (ATVT) during long-distance flights, the World Health Organization (WHO) arranged a meeting of experts in Geneva, Switzerland on March 12 and 13th, 2001 in order to do the following:

• review the available scientific information,
• define the extent of the problem,
• identify priority areas for research,
• find possible solutions if, indeed, a problem exists,
• attempt to reach a consensus of pragmatic strategies for prevention based on currently available evidence.

The meeting was organized by Shanthi Mendis (Sri Lanka), a cardiologist and coordinator for cardiovascular diseases at WHO's headquarters in Geneva. Nine researchers were invited to present available scientific information under the chairmanship of professor Fred Paccaud, an epidemiologist at the University of Lausanne, Switzerland. In addition, representative were present from the following organizations: fifteen major international airlines; the International Air Travel Association (IATA), a trade organization to which most international airlines belong; the International Civil Aviation Organization (ICAO), a WHO agency; the European Commission; the Aviation Health Institute (UK); the Airlines Medical Directors Association; the Japan Aeromedical Research Center (Japan); and various other WHO groups.

Here are brief summaries of the presentations of the nine expert participants (with one expert presenting two papers):

Paul Giangrande, MD. Hematologist. Oxford, UK. "Air travel and thromboembolism: Is there a link?" There is an association between travel and venous thromboembolisms but the overall risk is low. Prospective studies are required to establish the precise incidence of individuals who have been identified with risk factors. Studies are also required to evaluate the benefit and possible risks of preventive measures which have been proposed - exercise, stockings, aspirin and heparin.

Emile Ferrari, MD. Cardiologist. Hospital Pasteur, Nice, France. "Travel as a risk factor for venous thromboembolic disease." In a case-controlled study of 160 patients admitted for deep vein thrombosis (DVT), 25% had a history of recent travel, 2 by train, 9 by airplane, and 28 by car. The odds ratio for travel related DVT was 4 (p<0.0001), leading to the conclusion that travel alone can produce DVT.

Roderik Kraaijenhagen, MD. Vascular internist. University of Amsterdam, The Netherlands. "Travel and risk of venous thromboembolism." In another prospective case-controled study of 1911 patients which were investigated for the suspicion of DVT or pulmonary embolism (PE), 32 patients with DVT and 104 controls had a history of prolonged travel with an odds ratio for travel related DVT of 0.96. Very few patients had traveled by airplane. Their conclusion was that the results did not lend support to the widely accepted assumption that long traveling time is a risk factor for venous thrombosis. However, Harry Buhler, MD, from the same institution showed an extension of this study. When patients traveled more than 10 hours they did have an increased risk to develop DVT.

John Scurr, MD. Vascular surgeon. Middlesex and University College. London, UK. "Traveller's thrombosis _ Is there a link between long haul flying and deep vein thrombosis?" This was a prospective, randomized study of 200 passengers, not yet published, where 10% of those without stockings developed asymptomatic calf vein thrombosis, while not one of the passengers with stockings developed DVT. Four percent of those with stockings, however, developed superficial thrombophlebitis in varicose veins.

Patrick Kesteven, MD. Hematologist. University of Newcastle, UK. "Air travel and venous thromboembolism: gaps in current knowledge". The author concluded - based on his own study and that of the literature - that the association between travel and thrombosis is real. Most cases with DVT have other risk factors for DVT. The incidence of traveler's thrombosis amongst patients with DVT ranged from 3.2% to 17.3%. The incidence of traveler's thrombosis in northeast England was 0.4 cases/10,000 population annually.

Bo Eklof, MD. Vascular surgeon. Straub Clinic and Hospital and the University of Hawaii, USA. "High priority research areas to confirm association and identify possible preventive measures for venous thromboembolic disease associated with air travel." Research on predisposing risk factors for ATVT show that these factors influence the Virchow triad for the development of thrombosis: endothelial lesion, hypercoagulability and stasis. The risk factors were divided into patient related internal risk factors and cabin related external risk factors. Patient related risk factors were: older than 60 years, obesity, previous DVT/PE, recent surgery or injury, pregnancy or less than two months post partum, malignancy, cardio-respiratory disease, other chronic disease, estrogen medication (oral contraceptive pill/hormone replacement therapy), varicose veins, and thrombophilia. Ninety-two percent of these patients with ATVT had at least one of these risk factors with an average of 3 risk factors.

Cabin related risk factors were: immobilization, coach position, low air pressure with relative hypoxia and dehydration due to low humidity. There were objections from some airlines representatives regarding the existence of dehydration. Several research projects on incidence and prevention were suggested.

Charles Forbes, MD. Hematologist. University of Dundee, UK, "Some considerations for prevention of venous thrombosis while flying." None of the preventive measures have any evidence base whatsoever. However, risk stratification may be the basis for advice that should be followed.

William Toff, MD. Hematologist. University of Leicester, UK. "Research: Priorities and future directions." There is a sound theoretical basis to infer an association between air travel and an increased risk of venous thromboembolism. The priorities for future research should be: confirming the apparent association between air travel and DVT, quantifying the strength of the association in subjects with and without intrinsic predisposition to determine the appropriate methods to stratify risk, identifying culpable factors in the flight environment, exploring the mechanistic basis of the association, and identifying and evaluating effective preventive measures for subjects at risk.

The confirmation and quantification of the postulated association between air travel and venous thromboembolism will require a large-scale epidemiological study. Studies of culpable factors in the flight environment (cabin related external risk factors), in particular hypobaria, hypoxia and dehydration could be studied in a hypobaric chamber. A collaboration with the Royal Air Force in the Midlands of the UK is already underway. The efficacy of therapeutic interventions should be assessed either in the hypobaric chamber or during long-haul flights. Interventions to be considered would include exercise programs, use of compression stockings, aspirin and low molecular weight heparin.

Frits Rosendaal, MD. Clinical epidemiologist. University of Leiden, The Netherlands. "Thrombosis related to long-distance flights: Considerations for research." Venous thrombosis in the general population occurs in 1 per 1,000 individuals per year with a steep age-gradient from 1/100,000 in children, 1/10,000 in adults aged 20-50 years, 1/1,000 in those aged 50-70 years to 1/100 in the very old. Case fatality is 1-10%, and is also age dependent. Research into the association between long-distance flights and thrombosis is relevant to establish the precise risk. Only then can the various recommendations to prevent the conditions be accurately evaluated, and will it be possible to avoid recommendations that may be counterproductive.

Bo Eklof MD, PhD (see above). This is preliminary, unpublished data presented with permission from the first author, Gianni Belcaro. In 355 low risk and 389 high risk passengers traveling economy class for 12 hours, no one in the low risk group developed DVT, while 2.7% in the high risk group did. In a prospective, randomized study involving 833 high risk passengers with the same flight conditions as in the first study, half the group used below knee compression stockings. There were 4.5% DVT in the no stocking group compared with 0.24% in the stocking group. These three studies clearly indicate a high incidence of DVT associated with long-distance air flights with a significant reduction by the use of below knee compression stockings.

Shanthi Mendis, MD, the organizer of the meeting, conducted a comprehensive search of the literature. There were no grade 1 or 2 evidence (meta-analysis or large prospective, randomized studies), so the evidence is limited to grade 3-5 (case-control studies, retrospective studies and expert opinion) including the two published case-control studies that were presented at this meeting. Of these two studies, one indicated a strong association between travel and thrombosis, the other did not find any such association.

A report was finally agreed upon which contains the collective views of the international experts, including discussions with the representatives of the airlines and from WHO. Based on the weight of evidence, the summary position at this point was:

• An association probably exists between air travel and venous thrombosis.
• Such an association is likely to be small, and mainly effects passengers with additional risk factors.
• Similar links may exist for other forms of travel,
• The available evidence does not permit an estimation of actual risk, and therefore public health recommendations cannot be made at the present time.

The representatives of the airlines agreed that an association probably exists, that there are insufficient data on which to make recommendations, and consequently, are committed to support further research. Ideally, such research should be an international epidemiological study involving multi-centers and include a large prospective cohort study. Such a study will likely provide clues to other etiological factors. Also helpful will be studies seeking intermediate endpoints in groups of volunteers examining isolated independent environmental and behavioral risk factors and interventional studies involving passengers prospectively and using objective diagnostic methods and examining various interventional modes.

It was the unanimous view of the group that these studies should be undertaken as soon as possible, under the auspices of WHO and supported by an independent scientific committee in close collaboration with IATA and ICAO.

In the meanwhile there are insufficient scientific data on which to make specific recommendations except, perhaps, for exercising the legs during travel. At the present time, in particular in view of the recognized side-effects, indiscriminate use of pharmacological agents cannot be recommended.

Bo Eklof MD, PhD, Straub Foundation, Straub Clinic and Hospital, 888 S. King Street, Honolulu, HI 96813. Tel: 808-522-3293. Fax 808-522-4523, Email beklof@straub.net