Given the lack of conclusive evidence, epidemiological and pathophysiological studies were undertaken by the World Health Organization to assess the risk of travel-related deep vein thrombosis (DVT).

Results from a population-based case-control study (involving people with a history of venous thromboembolism [VTE]) found the relative risk of VTE to double after a long-haul journey (greater than 4 hours), regardless of the mode of transport. In a retrospective cohort study of healthy individuals, the relative risk was increased four-fold for flights over 4 hours but the absolute risk remains extremely low — calculated to be 1 event per 4600 long-haul flights. In both studies, the relative risk was found to increase by risk factors such as obesity, extremes of height, factor V Leiden mutation, and oral contraceptive use.

The risk of venous thrombosis and air travel was examined in the WRIGHT (World Health Organization Research Into Global Hazards of Travel) project [Department for Transport, 2005; WHO, 2007]. This is a multi-centred multi-study project funded by the UK Department of Transport and the European Commission.

• Phase I: assessed the risk of VTE with air travel and determined the magnitude of the risk. The results were published in 2007.
• Phase II: is examining the effect of preventive measures to reduce the risk of travel-related VTE. This phase is currently ongoing.

Risk of VTE with travel (phase 1)

• A population-based case-control study (the Multiple Enviromental and Genetic Assessment [MEGA] study [Cannegieter et al, 2006]) involving 1906 adults presenting to six anticoagulant clinics with a first VTE (their partners were used as the control group) found:
• Long-haul journeys (4 hours or more) increased the risk of venous thrombosis two-fold compared to not travelling, regardless of the mode of transport (by plane, bus, car or train) (odds ratio [OR] 2.1, 95% CI 1.5 to 3.0). The risk was not clearly related to increased duration of travel (when comparing journey times of 4–8 hours with 8–12 hours, and over 12 hours).
• The risk of venous thrombosis was higher when long-haul travel was combined with the following risk factors:
• Factor V Leiden mutation: (OR 8.1, 95% CI 2.7 to 24.7 for non-air travel, and OR 13.6, 95% CI 2.9 to 64.2 for air travel).
• Obesity: (OR 1.4, 95% CI 1.2 to 1.7 for a body mass index [BMI] of 25–30 kg/m², and OR 1.7, 95% CI 1.4 to 2.1 for a BMI over 30 kg/m²).
• Oral contraceptive use: the OR for non-air travel was estimated to be around 20. The OR increased to around 40 for air travel.
• People of extreme heights: when compared to non-travelling people of average height, the risk of venous thrombosis is increased for people taller than 1.90 metres who travelled by plane (OR 6.8, 95% CI 0.8 to 60.6) or by bus, car, or train (OR 4.7, 95% CI 1.4 to 15.4). For people with a height less than 1.60 metres, the risk was only increased for air travel (OR 4.9, 95% CI 0.9 to 25.6).
• Earlier and smaller studies had also found an increased risk of travel-related deep vein thrombosis (DVT) with the presence of risk factors (such as obesity, oral contraceptive use, previous DVT, recent trauma, varicose veins, cardiac disease, thrombophilia, pregnancy, and cancer) [Kesteven and Robinson, 2001; Arya et al, 2002; Hughes et al, 2003; Jacobson et al, 2003; Martinelli et al, 2003; Paganin et al, 2003], as did the following study.
• A large retrospective cohort study looked at the risk of employees from international companies and organizations undertaking long-haul flights (4 hours or more), developing travel-related venous thrombosis. A total of 267,241 flights were included for analysis, of which 86,748 were longer than 4 hours.
• For flights over 4 hours, the relative risk of VTE was 3.45 (95% CI 2.3 to 5.1).
• However, the absolute risk of VTE was found to be only 1 event per 5944 flights (95% CI 1/3433 to 1/12714).
• This increased with duration of flight (up to one event per 1000 flights lasting 12 hours or longer), and if multiple journeys were taken in the 4-week exposure.
• Given that the study was based on a cohort of employees who were generally young and healthy, the absolute risk is likely to be higher in the general population.
• In a subsequent publication of this study (updated to 314,762 flights) [Kuipers et al, 2007b]:
• The absolute risk of venous thrombosis was found to be 1 per 4,656 flights.
• As in the MEGA study, the incidence rate of venous thrombosis was higher for women taking oral contraceptives (both at baseline and after long distance flights), people of extreme height (taller than 185 cm or shorter than 165 cm), and for people with a BMI greater than 25 kg/m².
• Passengers under 30 years of age were found to have a higher risk than older passengers. The authors attributed this to 'attribution of susceptibles' (where susceptible individuals are likely to develop a disease shortly after the start of a risk factor). The youngest employees were most likely to be 'new frequent travellers'.
• The risk of venous thrombosis increased with the number of flights per employee. The incidence rate tripled after exposure to five or more long-haul flights when compared to people exposed to only one or two long-haul flights. With each extra flight, the risk increased 1.4-fold (95% CI 1.2 to 1.6).
• The absolute risk of venous thrombosis for flights shorter than 4 hours was one event in 106,667 flights, compared to one event in 1264 flights for flights longer than 16 hours. For each extra hour of flight duration, the incidence rate ratio increased 1.1-fold (95% CI 1.1 to 1.2).
• The risk of venous thrombosis was highest within the first 2 weeks after a long-haul flight and gradually decreased with time, returning to the baseline risk after 8 weeks.
• In a retrospective cohort study involving 2499 Dutch commercial pilots (response rate: 73% of current members and 33% of past members):
• Six people were diagnosed with VTE, an incidence of 0.3 per 1000 person-years (95% CI 2.2 to 13.1).
• When adjusted for age and sex difference, this rate was no different from the general Dutch population. No association was found between the number of hours flown.
• There is a possibility of under-reporting due to the possible effects that a history of venous thrombosis might have on the participants' careers.
• Results from patho-physiological studies indicate increased coagulation markers after air travel in some individuals, particularly in people with factor V Leiden mutation who are also taking oral contraceptives.