The Health Outcome
Venous thromboembolism (VTE) is a multifactorial disease resulting from the interaction between genetic and environmental risk factors (1). Genetic risk factors involve abnormalities causing inherited thrombophilia, such as deficiencies of the anticoagulants antithrombin, protein S, protein C, and the gain-of-function mutations in genes encoding coagulation factor V (factor V Leiden) and prothrombin. Environmental risk factors include cancer, recent surgery, pregnancy, use of oral contraceptives, and prolonged immobilization.
Air travel has recently been suggested as a possible risk factor for VTE. In the 1960’s, Homans observed an association between air or surface travel and VTE; this was recently confirmed by two case-control studies (2-4). Another case-control study of air travel failed to confirm such an association (5).
The Finding
Martinelli et al. conducted a case-control study to establish whether air travel is a risk factor for VTE, and to investigate the interaction between air travel and thrombophilia. They also evaluated the interaction between air travel and oral contraceptive use (a common and independent risk factor for VTE). Cases were patients who attended the Thrombosis Center between January 1, 1999 to September 30, 2001 for thrombophilia screening, if they had a first and documented episode of proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in the last 24 months. Age ranged from 20-70 years old, and those with malignant diseases were excluded from the study. The controls were subjects who volunteered to be screened for thrombophilia in the same period as patients. This included friends or partners of the entire population of patients referred to the Thrombosis Center , with exclusion criteria being a history of thrombosis and malignant disease.
There were 210 patients in the study (107 males and 103 females), and 210 controls (115 male and 95 female) selected according to matching criteria. Cases and controls were matched on such factors as age, gender, education level, and BMI. Thrombophilia screening included: 1) DNA analysis for the 1691 guanine-to-adenine substitution in coagulation factor V gene (FVL) and for the 20210 guanine-to-adenine substitution in the prothrombin gene, 2) Measurement of plasma levels of anticoagulants antithrombin, protein C, and protein S, 3) Presence of antiphospholipid antibodies (lupus anticoagulant and anitcardiolipin antibodies), 4) Measurement of plasma levels of fasting and post-methionine load total homocysteine.
In 100 cases, no environmental risk factors for VTE were reported (48%). Air travel was reported by 31 cases (15%) and 16 controls (8%), with an OR of 2.1 (95% CI 1.1-1.4). The odds ratio associated with long distance flights was 3.0 (95% CI 0.9-9.5). The most common transient risk factor observed was oral contraceptive use, with 61% of cases and 27% of controls reporting use. Thrombophilia was present in 102 cases (49%) and 26 controls (12%) with an OR of 6.7 (95% CI 4.1-10.9). The distribution of thrombophilia was similar in cases who developed VTE after air travel (58%) and in those who did not fly before the event (47%).
In general, the interaction between air travel, thrombophilia, and oral contraceptive use in determining VTE is significant. Compared with the reference group (who did not fly or have thrombophilia), there was a 6-fold increased risk for those with thrombophilia, a 2-fold increased risk in those who flew, and a 16-fold increased risk for those with both risk factors. Compared with the reference group (who did not fly or use oral contraceptives), there was a 4-fold increased risk for OC users, a 2-fold increased risk for those who flew, and 14-fold increased risk for those with both risk factors. Adjusted measures were reportedly not significantly different from crude measures.
Public Health Implications
The findings from this study are significant, but more research must be conducted to assess interaction among thrombophilia, OC use, and VTE. Though literature has both confirmed and refuted the association between air travel and VTE, the association is still widely discussed. Two previous studies regarding the association between VTE and travel did not differentiate air travel from surface travel, and also involved referral bias (3,4). In the Ferrari et al. study, the control group was inappropriately selected (3). A third study avoided referral bias, but failed to show an association between DVT and air travel (5). This may have been due to low numbers of both cases and controls (both 2%) with exposure to air travel the month preceding the visit. Also, this study included individuals with malignant disease and the mean age was 63. The current study selected controls by ruling out thrombosis by using a structured, validated questionnaire. Also, cases with lower-limb DVT were limited to those with proximal thrombi, avoiding potential misclassification by inaccurate ultrasonographic assessment of distal thrombosis. In a randomized trial of compression stockings to reduce DVT, false-positive results could not be ruled out (7).
Though results of this study are significant, wide confidence intervals implicate instability of the risk estimates. The authors speculate this is due to the small number of controls exposed to air travel. It has been suggested that simple behavioral modifications (adequate hydration, limitation of alcohol, leg exercise, and elastic stockings) may help prevent VTE in low and high risk individuals. One study has been conducted to evaluate the effectiveness of prophylaxis of high risk individuals, leaning in favor of a single dose of low-molecular-weight heparin instead of aspirin (6). More such studies must be conducted to determine feasibility and utility of prophylactic measures. The use of anticoagulants is a common treatment for severe cases, but it is not without risk of excess bleeding. Inability to clot can become problematic (especially during surgery or trauma), and often calls for a cost-benefit approach to such therapy.
References
- Martinelli I. Risk factors in venous thromboembolism. Thromb Haemost. 2001; 86:395-403.
- Homans J. Thrombosis of the deep leg veins due to prolonged sitting. N Engl J Med. 1954; 250:148-149.
- Ferrari E., et al. Travel as a risk factor for venous thromboembolic disease: a case-control study. Chest. 1999;115:440-444.
- Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius Study. Arch Intern Med. 2000;160:3415-3420.
- Kraaijenhagen RA., et al. Travel and risk of venous thrombosis. Lancet. 2000;356:1492.
- Cesarone MR., et al. Venous thrombosis from air travel: the LONFLIT3 Study: prevention with aspirin vs low-molecular-weight heparin (LMWH) in high-risk subjects: a randomized trial. Angiology. 2002;53:1-6.
- Scurr J., et al. Frequency and prevention of symptomless deep-vein thrombosis in long-haul flights: a randomized trial. Lancet. 2001;357:1485-1489.
