In this population-based case-control study, long-distance traveling increased the risk of venous thrombosis 2-fold. Travel by air increased the risk to the same extent as travel by car, bus, or train. The risk was highest in the first week after traveling. As venous thrombosis is a disease in which many factors (genetic and acquired) interact [21
], we identified groups with additional risk factors in which the risk was further increased. This was the case for individuals with factor V Leiden, obese people (BMI > 30 kg/m2
), and short (only for travel by air) and tall people, as well as for women using oral contraceptives. Some of these synergistic effects were more apparent for air travel.
Although the studies that have been published so far have not yielded entirely consistent results, those that did report an increased risk of venous thrombosis in air travelers showed similar risk estimates of a 2- to 3-fold increased risk (even in one with asymptomatic events only [4
]). The occurrence of venous thrombosis was highest in the first week after travel, and slowly declined afterwards, a pattern that was also described in a recent record-linking study from Australia [1
], supporting a causal relation.
As a possible mechanism for an extra risk in travelers who fly, an effect of hypobaric hypoxia on the coagulation system was postulated, which has already been studied a number of times, mainly in hypobaric chambers, with unclear results so far. Our study showed an increased risk in all types of travel, which suggests that the increased risk of flying is caused mainly by immobilization. Additionally, the risk is further increased in short and tall people, who are likely to experience more immobilization and venous compression than other travelers. However, as some of our findings were more pronounced for air travel, we cannot exclude an additional effect of hypobaric hypoxia, possibly in risk groups only. This possibility is supported by a recent study of our group [22
] in which we found that thrombin generation occurred in some healthy volunteers after flying for 8 h but happened to a far lesser extent after being immobilized for 8 h in a cinema. The high response in the fliers was associated with the presence of risk factors for thrombosis, i.e., oral contraceptive use, the factor V Leiden mutation, and the combination of the two. This finding indicates an effect of an additional factor in an airplane, such as hypobaric hypoxia, to which mainly individuals with risk factors respond.
None of the studies published so far have systematically studied the effect of traveling in combination with other risk factors, with the exception of the study by Martinelli et al. [3
]. In an analysis of 210 patients, they found a 16-fold increased risk for patients who traveled by air and had some form of thrombophilia, as well as a 14-fold increased risk in women who flew and used oral contraceptives, findings that confirm both the results of the present study and our finding of activated coagulation in individuals with risk factors after flying [22
The finding that taller and shorter people had an increased risk of venous thrombosis after traveling should be interpreted with some caution, as the numbers were small in these strata. On the other hand, it is biologically plausible: very tall people are subjected to even more cramped seating than average-height individuals, and very short people's feet may not touch the floor, which would lead to extra compression of the popliteal veins. Interestingly, the increased risk for short people was only found in people who traveled by air. This may have to do with the fact that seats in cars are generally lower, and more individually adjustable, than those in airplanes.
As the diagnosis of DVT is usually more unambiguous than that of PE [23
], as was the case in our study population as well, we repeated the analysis using only DVT as the outcome of interest (97% objectively diagnosed). In this analysis, despite using smaller numbers, most findings were either similar or appeared more evident, and inconsistencies that were found when using both DVT and PE as endpoints disappeared.
To our knowledge, this is the first large population-based case-control study in which the effect of travel on the risk of venous thrombosis has been studied. Because the control individuals were closely matched, being partners of the cases, and couples tend to travel together, only the cases and control individuals who had not traveled together could be used for the analysis. Also because of this design, the effect of sex and age could not be studied. It has to be noted, however, that for all other research questions on the effect of genetic and acquired risk factors on the risk of venous thrombosis, this design has no limitations and the close matching of cases and controls renders confounding by, for instance, lifestyle and socioeconomic class less likely than in previous unmatched studies (see also Protocol S1
). Another advantage of this approach is the minimization of recall bias, as the cases and controls would generally fill in the questionnaire together.
Many questions are still left unanswered that necessitate more research. First of all, our study results apply only to people younger than 70 y of age. Furthermore, it is likely that other characteristics exist that also increase the risk—person-specific (e.g., other drug use), behavioral (e.g., use of sleeping pills or alcohol consumption), and flight-specific (e.g., class or seating)—that need to be identified. These further variables are part of our ongoing study as part of the World Health Organization Research Initiative into the Global Hazards of Travel (WRIGHT study). For those who have an increased risk, such as oral contraceptive users and individuals with factor V Leiden, prevention may be warranted. Prevention may vary from simple measures, such as exercises during the flight, to measures that carry a risk themselves, such as anticoagulants. Specific studies are needed to assess the efficacy of these measures and their risk–benefit ratio.
It can be concluded that the risk of venous thrombosis is 2-fold increased for all travelers and to the same extent for all modes of travel. In individuals who use oral contraceptives, are carriers of the factor V Leiden mutation, or are particularly tall, short, or obese, this risk is considerably higher, to such an extent that studies into the efficacy of prophylactic measures are required.