Memorandum by the WRIGHT Project Scientific
Executive Committee
THE WRIGHT PROJECT
In March 2001, the World Health Organization
(WHO) convened an international meeting on air travel and venous
thrombosis at which experts on venous thrombosis (VT) and representatives
of airline companies, the International Air Transport Association
(IATA), the International Civil Aviation Organization (ICAO),
the European Commission and consumer groups participated. The
objectives were to review the scientific information concerning
air travel and VT, identify gaps in knowledge and develop priority
areas for research. It was concluded that a link probably existed
between air travel and venous thrombosis and that similar associations
possibly existed for other forms of travel. It was decided to
set up a set of studies, consisting of:
— Epidemiological studies to determine
whether there is a link between air travel and venous thrombosis
the absolute risk if such a link exists and the size of the problem.
These studies would also provide clues to other aetiological factors;
— Special studies using intermediate
end-points in groups of volunteers to examine isolated independent
environmental and behavioural risk factors;
— A prospective intervention study
involving passengers, using objective diagnostic methods and examining
various preventive measures.
The WRIGHT project (WHO Research Into Global
Hazards of Travel) was funded by the United Kingdom Department
for Transport and Department Health and the European Commission.
Both the epidemiological and the pathophysiological
substudies were completed in Phase I. A substudy, elaborated in
the original protocol, into methods of prevention has been deferred
to Phase II.
SUMMARY OF
RESULTS OF
WRIGHT -PHASE I
Population-based case control study
As an extension of a very large population-based
case-control study (MEGA: Multiple Environment and Genetic Assessment
of risk factors for venous thrombosis), we examined the effect
of all modes of travel on the risk of a first thrombosis. The
study included 1906 patients aged less than 70 years, presenting
with a first venous thrombosis along with the same number of matched
controls (n=3,812 in total). The combined effect of travelling
and the risk factors for thrombosis (factor V Leiden, prothrombin
20210A mutation, body mass index [BMI] and height) was assessed.
Travelling for more than four hours increased
the risk of VT 2-fold (odds ratio 2.1, 95% CI 1.5 to 3.0), compared
to not travelling. The risk of flying was similar to the risk
of travelling by car, bus or train. Travel by car, bus or train
led to a high risk of thrombosis in individuals with factor V
Leiden mutation (relative risk 8.1, 95% CI 2.7 to 24.7), those
who were more than 1.90m tall (relative risk 4.7, 95% CI 1.4 to
15.4) and those who used oral contraceptives (estimated relative
risk >20). These synergistic effects were more apparent with
air travel. In addition, people shorter than 1.60 metres had an
increased risk of VT after air travel only (relative risk 4.9,
95% CI 0.9 to 25.6). Obese individuals with a BMI of more than
30kg/m2 had an increased risk. The more pronounced risk increase
observed after air travel compared to ground travel for some of
these risk factors may suggest an effect of flight-related factors,
which are absent during travel by other modes of transport.
Retrospective cohort study among employees of
international organisations
This was a retrospective cohort study among
employees of international companies and organisations. Data concerning
the occurrence of VT, risk factors for VT and habits during air
travel were linked to the organisation's travel database. Exposure
was defined as four weeks after a flight of four hours or longer.
A total of 315,762 flights were included in the analysis, of which
100 208 were of more than four hours duration. The incidence of
VT after a flight was 3.2/1,000 persons per year (95% CI 2.0 to
4.7), compared with 1.0/1,000 per year (95% CI 0.7 to 1.5) in
the non-exposed time. This yielded a relative risk of VT after
a more than four-hour flight of 3.2 (95% CI 1.8 to 5.6) in this
population. The absolute risk of VT per flight in this population
was 1/4,656. The absolute risk was greater if multiple journeys
were taken in the four-week exposure period, and increased with
duration of flight, up to one per 1,200 for flights of 16 hours
or longer. Again, higher risks were found for women who used oral
contraceptives, and in individuals who were short, tall or overweight.
Hypobaric hypoxia study
The study was conducted between September 2003
and November 2005 in the United Kingdom whereby a single-blind
crossover design was used to compare the effects of prolonged
sitting in a hypobaric hypoxic environment with those of sitting
for the same period in a normobaric normoxic environment. 73 healthy
volunteers participated in the study and were assigned to one
of three groups (Group I: individuals between the ages of 18 and
40 years without known risk factors for VT, n=49; Group II: women
between the ages of 18 to 40 years who were taking a combined
oral contraceptive pill, n=12; Group III: individuals aged 50
years or older, n=12). Significant changes in several markers
of coagulation activation and fibrinolysis were observed during
the normobaric exposure, attributed to prolonged sitting and circadian
variation. However, no significant difference was observed in
the overall change of any marker between the normobaric and the
hypobaric exposures.
Travel and non-travel immobility study
This study aimed to disentangle the possible aetiological
factors involved in the promotion of the postulated hypercoagulability
occurring during flight. The study used a crossover design in
which volunteers were exposed to an eight-hour flight and to two
control situations comprising immobility on the ground and daily
activity. The study was conducted between 24 May and 10 July 2004
with healthy volunteers, many of whom had risk factors for thrombosis
such as the factor V Leiden mutation or oral contraceptive use.
All participants were exposed to an eight-hour flight, an eight-hour
movie marathon and eight hours of their usual daily activities,
with at least two weeks between each exposure situation. Blood
samples were drawn before, during, and after each exposure. Seventy-one
healthy volunteers aged 18-40 years took part in the study, 15
men and 56 women, of whom 26 were asymptomatic carriers of the
factor V Leiden mutation; 30 women used oral contraceptives (15
with and 15 without the mutation). After the flight, median thrombin-antithrombin
(TAT) complex increased by +30.1%, while it decreased by ¸2.1%
after the cinema and by ¸7.9% after the daily life situation.
This was most evident in the group with factor V Leiden who used
oral contraceptives. We found a high-response in TAT values in
17% of the individuals after air travel (3% for movie marathon;
1% in daily life). The high-responders were mainly women with
the factor V Leiden mutation who used oral contraceptives. A high-response
in all parameters (prothrombin fragment 1 and 2 (F1+2), TAT and
D-dimer) was found in four individuals (6.3%) after the flight
and not in either of the two control situations.
Unresolved questions
Although many issues have been resolved in WRIGHT
Phase I, some questions are still unanswered and new ones have
been raised, which relate to the underlying mechanism of air travel-related
thrombosis, and to modes of prevention.
Hypobaric hypoxia is one of the factors that
travellers will encounter during air travel but not during ground
travel. The results of the hypobaric chamber studies with healthy
volunteers predominantly without risk factors for VT failed to
demonstrate any association between hypobaric hypoxia and prothrombotic
alterations in the haemostatic system. However, the travel and
non-travel immobility study, which included a high proportion
of individuals with risk factors, suggested that some flight-specific
factor may interact with pre-existing risk factors and result
in increased coagulation activation in susceptible individuals
over and above that related to immobility. Further study will
be required to determine the identity of the culpable factor.
In view of the substantial number of people
undertaking long-haul air travel and the fact that many travellers
will have one or more known or unknown risk factors for thrombosis,
air travel-related VT is an important public health issue. There
is a clear need for travellers to be given appropriate information
regarding the risks and for further studies to identify effective
preventive measures. At the moment, there is a complete lack of
data on the efficacy and safety of methods to prevent air travellers'
thrombosis. Hence, guidelines are contradictory, illustrated by
a study, also performed within the WRIGHT project, among 1,600
professionals employed in the field of thrombosis and haemostasis.
Travelling to Sydney for a conference in this field, 80% of the
respondents used preventive measures. The form of prophylaxis
varied widely, from exercise to the use of anticoagulant medication
by 10% of the delegates.
To date, no studies on the optimal prevention
of clinical thrombosis have been performed, mainly because they
will require large sample sizes, as the condition is relatively
infrequent in an average flying population. To solve this, some
investigators have performed intervention trials with asymptomatic
thrombosis as endpoint. Asymptomatic clots can be found by ultrasound
scans of the legs, and as they are much more frequent than symptomatic
events (3% of passengers), the sample sizes can be much reduced.
Whilst useful in showing that clots form often during air travel,
and that prevention is possible, the clinical relevance of these
studies is uncertain. In designing preventive studies it therefore
makes most sense to target those individuals who are increased
risk.
CONCLUSION
Several studies were performed during Phase
I of the WRIGHT project to investigate the magnitude of the risk,
the effect of other factors on the risk and the mechanism by which
air travel leads to VT. The findings of the epidemiological studies
indicate that the risk of VT increases by approximately three-fold
after a long-haul flight. This increased risk applies to other
forms of travel (such as car, bus or train) where travellers are
exposed to prolonged seated immobility. The risk increases with
the duration of travel and with multiple flights within a short
period. The incidence of VT after a long-haul flight was estimated
to be one in several thousand travellers. Obesity, height, use
of oral contraceptives and the presence of prothrombotic blood
abnormalities or variant were identified as contributors to the
increased risk of travel-related VT. The pathophysiological studies
supported these findings.
Two billion people per annum travel by air.
The results from the WRIGHT project indicate that over 150,000
of them will develop venous thrombosis, of whom 7,500 will suffer
a fatal pulmonary embolism. While the risks and risk groups have
now been clearly identified, there is no clarity about effective
and safe prevention. For this reason it is essential that prevention
study of the type proposed for Phase II of the WRIGHT Project
is carried out and that future passengers will be adequately informed
about their risk and the optimal mode of prevention of travel-related
venous thrombosis.
18 July 2007
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