In the summer of 2019, according the American Automobile Association (AAA), 706 million Americans traveled by automobile; 57.9 million traveled by air; and 64.3 million traveled by rail, cruise ship, or other mode of transportation.1  Prolonged travel has been considered a risk factor for venous thromboembolism (VTE) since the first association of travel with VTE was reported in the 1950s.2  Associated provoking risk factors for VTE occur on a spectrum, from entirely unprovoked, to events that occur in association with major provoking events such as orthopedic surgery or malignancy.3  So how and where does travel-associated thrombosis fit in this framework? And what was the risk of VTE in the millions of U.S. travelers mentioned above? In this Mini Review, we will sail through the pertinent guidelines, fly through diagnostic pitfalls, and cruise through the optimal treatment of travel-associated VTE.

What is the definition of travel-associated VTE and how risky is traveling?

“Travelers’ thrombosis” is a frequently used term4 ; however, the duration of travel and timeframe of VTE in relation to travel is up for debate. ASH clinical practice guidelines indicate that travel time must be more than four hours and that VTE should occur within four weeks of travel.5  However, the British Committee of Standard Hematology (BCSH) uses a duration of eight weeks following a trip to attribute the VTE to travel, if travel duration was three hours or more.6  In a meta-analysis of 14 studies, travel increased the risk of VTE by two- to 2.8-fold, with an 18 to 26 percent increase in risk with every additional two hours of travel.7 

How does the method of transportation influence VTE risk?

It is commonly thought that air travel is the method most associated with VTE, based on numerous publications discussing this topic. The term “economy class syndrome,” most often ascribed to air travel in current times, was not originally used in this context. The original report by Drs. Symington and Stack in 1977 describes eight patients with travel durations of three to 24 hours — three traveling by automobile, three by plane, one by rail, and one by combination rail and ship travel. Circumstances unique to air travel — dehydration due to reduced humidity,8  and relative hypoxia — have been hypothesized to stimulate the coagulation cascade promoting venous thrombosis.9  In reality, all modes of travel (air, car, bus, or train) increase the risk of VTE similarly.10  One study demonstrated a slightly lower risk when flying business or first class11  in comparison to flying economy class, but in the New Zealand Air Traveller’s Thrombosis study, the proportion of business and economy class passengers who developed thrombosis was similar.12  Therefore, “travelers’ thrombosis” is the most appropriate term4  and provides important insights into the pathophysiology, with immobilization as a common factor among all forms of transport.10  Interestingly, prolonged boating (e.g., cruise ships, submarines, sailing) in the modern day might not actually be included in this definition (it has not been well described in the literature), perhaps owing to a lesser degree of confinement or more frequent ambulation. Whether space travel may pose a risk for VTE is a fascinating yet unanswered question, with only one reported case of a spontaneous internal jugular vein thrombosis.13 

How do additional risk factors play a role while traveling?

Overall risk (OR) for travel-associated VTE is low (0.02%).6  Passenger-related factors that increase the risk of VTE are important to consider.13  Oral contraceptive use is associated with a 20-fold increase in risk of developing VTE while traveling.10  Similarly, obesity with body mass index greater than 30 kg/m2 increases the odds of VTE (OR, 1.7; 95% CI, 1.4-2.1). Factor V Leiden increases risk of VTE by eight times during travel, and recent surgery increases the risk of VTE by 20 times.14  These data demonstrate that risk of travel-related VTE is higher in individuals with preexisting risk factors. Hence, patients with travel-associated VTE should have a proper evaluation to exclude any other underlying additional risk factors.

How is travel-associated VTE treated?

In general, upfront management of travel-associated VTE is treated in the same way as any other VTE episode. Recommendations regarding long-term anticoagulation must be individualized based on a complete assessment of all contributing factors, with shared decision-making taking into consideration medication cost, patient preference, frequency and necessity of travel, and bleeding-risk assessment. A full understanding of the travel history, especially when it is the only potential VTE risk factor, is important. The previously mentioned definitions of travel-associated VTE, based on the minimum duration of travel of four hours, do not imply that all travel-associated VTE should be treated the same. A 12-hour travel duration is not the same as “a three hour tour.” Most travel (4-8 hours) cannot even be considered a major (> 10-fold increase in risk) or even minor (3-10–fold increase in risk) transient VTE risk factor as defined by the International Society for Thrombosis and Haemostasis.3  Additionally, prolonged travel with multiple breaks for ambulation should decrease the emphasis on this as a provoking factor.

What VTE prophylaxis is recommended for patients planning prolonged travel?

In passengers with no history of VTE and without known risk factors, who are traveling for more than four hours, general, non–evidence-based recommendations are to maintain hydration, mobilize as much as possible, use calf muscle exercises, and avoid prolonged sitting with the legs crossed.15  ASH recommends no mechanical or pharmacologic VTE prophylaxis (including aspirin) in patients without risk factors. Since travel-associated thrombosis likely has more to do with patient-specific factors, we do not overemphasize the impact of traveling “economy class.”

In passengers at higher risk (recent surgery; history of VTE; postpartum women; active malignancy; or combination of above with obesity, hormonal replacement therapy, or pregnancy), ASH recommends use of graduated compression stockings (GCS) or pharmacologic VTE prophylaxis with low-molecular-weight heparin (LMWH). In these travelers, if mechanical or pharmacologic VTE prophylaxis is not feasible, aspirin is recommended instead of no VTE prophylaxis.5  For high-risk travelers (prior history of VTE, recent trauma or surgery, malignancy, pregnancy, estrogen use, advanced age, limited mobility, obesity, or known thrombophilic disorder), the American College of Chest Physicians guidelines only recommend GCS and no anticoagulant or aspirin use.16  The BCSH conversely, recommends GCS for intermediate-risk travelers (postpartum women, previous unprovoked or travel-related VTE) and GCS with or without anticoagulation for high-risk (recent major surgery, active malignancy) travelers on a journey of more than eight hours. In contrast to the ASH guidelines, in select and appropriate patients, our practice is to use prophylactic-dose direct oral anticoagulants (DOACs) instead of LMWH injections owing to the ease of administration, avoidance of security checkpoint concerns, overwhelming patient preference, and overall strong body of literature for prevention in other settings.

Passengers who are already on anticoagulation for other reasons should continue to take their prescribed dose of anticoagulant while they are traveling. No additional precautions are needed for these individuals from a VTE prevention standpoint.2  For patients on long-term prevention with a low-dose DOAC, we do not routinely increase their dose during travel. In patients with post-thrombotic syndrome and/or venous insufficiency, we recommend use of GCS to avoid symptomatic worsening of their edema during travel, as we find that postflight anxiety about increased swelling can be prevented, leading to a more enjoyable vacation.

References

References
1.
Casselano
J
.
AAA Forecasts Americans will take 700 million trips this summer
.
AAA Newsroom. 2019. Last accessed Sep 24, 2020
. Article
2.
Czuprynska
J
,
Arya
R.
Annotation: travel and thrombosis
.
Br J Haematol
.
2020
;
188
:
838
-
843
.
3.
Kearon
C
,
Ageno
W
,
Cannegieter
SC
, et al.
Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH
.
J Thromb Haemost
.
2016
;
14
:
1480
-
1483
.
4.
Johnston
RV
,
Hudson
MF
,
Aerospace Medical Association Air Transport Medicine Committee. Travelers’ thrombosis
. Aviat Space Environ Med.
2014
;
85
:
191
-
194
.
5.
Schünemann
HJ
,
Cushman
M
,
Burnett
AE
, et al.
American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients
.
Blood Adv
.
2018
;
2
:
3198
-
3225
.
6.
Watson
HG
,
Baglin
TP
.
Guidelines on travel-related venous thrombosis
.
Br J Haematol
.
2011
;
152
:
31
-
34
.
7.
Chandra
D
,
Parisini
E
,
Mozaffarian
D
.
Meta-analysis: travel and risk for venous thromboembolism
.
Ann Intern Med
.
2009
;
151
:
180
-
190
.
8.
Schwarz
T
,
Siegert
G
,
Oettler
W
, et al.
Venous thrombosis after long-haul flights
.
Arch Intern Med
.
2003
;
163
:
2759
-
2764
.
9.
Schut
AM
,
Venemans-Jellema
A
,
Meijers
JCM
, et al.
Coagulation activation during air travel is not initiated via the extrinsic pathway
.
Br J Haematol
.
2015
;
169
:
903
-
905
.
10.
Cannegieter
SC
,
Doggen
CJM
,
van Houwelingen
HC
, et al.
Travel-related venous thrombosis: results from a large population-based case control study (MEGA study)
.
PLoS Med
.
2006
;
3
:
e307
.
11.
Schreijer
AJM
,
Cannegieter
SC
,
Doggen
CJM
, et al.
The effect of flight-related behaviour on the risk of venous thrombosis after air travel
.
Br J Haematol
.
2009
;
144
:
425
-
429
.
12.
Hughes
RJ
,
Hopkins
RJ
,
Hill
S
, et al.
Frequency of venous thromboembolism in low to moderate risk long distance air travellers: the New Zealand Air Traveller’s Thrombosis (NZATT) study
.
Lancet
.
2003
;
362
:
2039
-
2044
.
13.
Kuipers
S
,
Cannegieter
SC
,
Doggen
CJM
, et al.
Effect of elevated levels of coagulation factors on the risk of venous thrombosis in long-distance travelers
.
Blood
.
2009
;
113
:
2064
-
2069
.
14.
Kuipers
S
,
Venemans
A
,
Middeldorp
S
, et al.
The risk of venous thrombosis after air travel: contribution of clinical risk factors
.
Br J Haematol
.
2014
;
165
:
412
-
413
.
15.
Symington
IS
,
Stack
BH
.
Pulmonary thromboembolism after travel
.
Br J Dis Chest
.
1977
;
71
:
138
-
140
.
16.
Kahn
SR
,
Lim
W
,
Dunn
AS
, et al.
Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines
.
Chest
.
2012
;
141
:
e195S
-
e226S
.

Competing Interests

Dr. Pasha and Dr. Houghton indicated no relevant conflicts of interest.