Venous Thromboembolism at High Altitude: Our Approach to Patients at Risk

Abstract

Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is a prevalent disorder that confers substantial cardiovascular morbidity and, in serious cases, death. VTE has a complex and incompletely understood etiopathogenesis with genetic, acquired, and environmental risk factors. As the focus of this review, one environmental risk factor, which may interact with other risk factors such as hereditary and/or acquired thrombophilias, is travel to high altitude (HA), although current evidence is limited. As guidelines do not directly address this topic, we will discuss the epidemiology of HA-VTE, review the putative mechanisms for thrombosis at HA, and discuss our clinical approach to both risk stratification and counseling, including specific pharmacologic and nonpharmacologic recommendations for patients with elevated VTE risk before they travel to HA.

Introduction

As the world population continues to expand and age, in part, owing to advances in medical care, more people than ever are traveling to high altitude (HA) destinations, both urban and rural, for reasons including business, military deployment, tourism, and recreation. As venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a disease with a prevalence similar to that of stroke (Heit, 2015), and because travel to HA may be a risk factor for VTE, it is common to encounter patients who may benefit from specialized counseling in this setting. Although definitions vary, for the purposes of this review we will define HA as 2500 m or greater, an altitude at which more frequently discussed HA diseases, including HA pulmonary edema (HAPE), HA cerebral edema (HACE), and mountain sickness occur (Hackett and Roach, 2001). Although there are well-defined risk factors for VTE such as surgery, trauma, major illness, hormones, malignancy, and thrombophilias, relatively little is known about the effects of HA on VTE risk in the general population, although limited evidence exists to suggest a causal relationship. There are a number of small studies and case reports on this topic but no large-scale research has been conducted to inform practice. Human studies on the risk of HA on VTE have largely been carried out in soldiers stationed at HA for sustained durations; whether these studies can be extrapolated to travelers and nonmilitary personnel is unknown. As such, guidelines do not address the question of how to approach a patient who may be at risk of HA-VTE. Although HA may also increase the risk of arterial thrombosis (Fagenholz et al., 2007; Chan et al., 2012), in this review we will consider this question with respect to venous thrombosis by discussing HA-VTE epidemiology, etiopathogenesis, risk factors, and a practical approach to clinical recommendations for patients with different risk profiles.

Epidemiology of High Altitude Venous Thromboembolism

Historically, major surgery or advanced terminal illness was considered to be the most important risk factors for VTE. Beginning in the 1990s, additional risk factors were identified and it appears that only 25%–50% of symptomatic VTE occur in patients during hospitalization for medical illnesses or surgery, or soon after discharge (Anderson and Spencer, 2003). VTE is now considered a major disease worldwide with epidemiological studies showing an incidence of about 1–2 per 1000 person-years, in patients of European descent; other populations may be at either an increased or decreased risk (Heit, 2015).

Although HA is not currently a well-established VTE risk factor, several lines of evidence suggest the possibility of a causal relationship, although evidence is limited and further research is warranted. Anand et al. (2001) prospectively studied Indian soldiers serving at least 1 month at HA and found an odds ratio of 30.5 for vascular thrombosis (including ischemic stroke) compared with soldiers from non-HA areas (defined as <3000 m). Another Indian study of incident DVT in two hospitals, one at 3600 m serving soldiers and the other serving civilians at a “lowland” altitude (not specified), showed a relative risk of 24.5 for DVT at HA, although the incidence of DVT at the lowland hospital was unusually low (two cases/year in a population of 70,000) (Kumar 2006). United States Air Force cadets stationed at an altitude of 2212 m were observed to have a twofold higher incidence rate of thromboembolic events than military personnel stationed at sea level; however, arterial events were included and there were significant methodological limitations in this retrospective study by Smallman et al. (2011).

Recent retrospective studies of orthopedic surgery patients by Cancienne (2017) and Damodar et al. (2018a and 2018b) have shown knee arthroscopy, total hip arthroplasty, and total shoulder arthroplasty recipients at an altitude of only 4000 feet above sea level had odds ratios for VTE within 30 days of surgery of 2.0, 1.74, and 39.5, respectively, compared with low altitude cohorts. Presti et al. (1990) reviewed 7753 autopsies performed at a HA Colorado hospital and found a ninefold increase in chronic massive thrombosis of major pulmonary arteries compared with previously reported data from other institutions, although the incidence of acute massive PE was similar. Dutta et al. (2018) described 53 Indian soldiers stationed at HA for up to 4 consecutive months who were diagnosed with PE; only 17% had a hereditary thrombophilia. Of interest, the vast majority of these patients had moved to HA from low altitude. Khalil and Saeed (2010) described 50 cases of PE in Pakistani soldiers at HA and concluded that HA was the only risk factor in 50% of affected patients. This study, and a multitude of case reports of HA-VTE, may be subject to attribution error and an overestimation of risk attributable to HA. In contrast, HAPE can mimic PE and perhaps lead to underestimation of PE at HA (Khan et al., 2003). Although data are insufficient to make conclusions about the epidemiology of HA-VTE, we speculate that HA is an independent risk factor for thrombosis, although additional research is needed.

Mechanisms of HA-VTE

Hypobaric hypoxia, which is necessarily present at HA, and factors not specific to HA such as cold ambient temperature and preceding long-distance travel may themselves contribute to HA-VTE or interact with patient-specific risk factors present before traveling to HA, thereby crossing an already lowered threshold for thrombus formation. One or more abnormalities in blood flow, the vascular endothelium, and blood coagulability (Virchow's Triad) can be accounted for by the aforementioned factors and is a useful model for understanding HA-VTE. Although research remains limited to small studies of mostly healthy individuals with a presumably low baseline VTE risk, several putative mechanisms of HA-VTE are worth discussing.

Jha et al. (2018) performed a novel genome-wide expression analysis demonstrating differential expression of hypoxia-responsive genes in patients with DVT at HA. A vastly different gene expression profile was identified in HA DVT patients compared with controls and, although the significance of differential genetic expression in the setting of hypoxia is not clear, genes involved in activation of platelets and the coagulation cascade were upregulated in response to hypoxia. Of interest, transcriptomic and proteomic examination of platelets isolated from HA-residing subjects without thrombosis identified that HA was associated with upregulation of a number of transcripts and their corresponding proteins, compared with matched subjects residing at sea level (Shang et al., 2019). Many of these upregulated proteins mediate key aspects of platelet activation and thrombosis. Tyagi et al. (2014) demonstrated in a rat model that calpain small subunit 1 is upregulated in response to hypoxia, activating calpain and leading to platelet hyper-reactivity and thrombosis. Whether these changes in the platelet molecular signature directly contribute to HA-VTE remains unknown.

Soluble prothrombotic factors are also upregulated in HA. For example, healthy volunteers exposed to hypobaric hypoxia with a simulated altitude of 2400 m were found to increase prothrombin fragments 1 and 2, thrombin–antithrombin complex (TAT), and factor VIIa activity while decreasing tissue factor pathway inhibitor activity (Bendz et al., 2000). However a study of 76 HA climbers at 5340 m showed that none had a positive d-dimer, suggesting a lack of clotting activity (Zafren et al., 2011). Gupta et al. (2017) showed that hypoxia stimulates activation of an NLRP3 inflammasome complex, mediated by HIF-1-alpha, which may precipitate thrombosis. An excellent review by Gupta and Ashraf (2012) illustrates the sometimes contradictory results of studies of clotting parameters at HA.

Probably the most well-established hematological parameter to change at HA is red blood cell mass, which invariably increases in response to hypoxia. However, a study by Kotwal et al. (2007) of 32 healthy subjects at 3500 m for 8 months showed an increase of hemoglobin to a normal mean of 16.6 g/dL from a baseline of 14 g/dL. In contrast, Dutta et al. (2018) showed a mean hemoglobin of 17.4 among 28 Indian soldiers with PE. Even if secondary polycythemia was to result from HA, it is not itself a well-defined VTE risk factor (Bhatt, 2014). Limited data suggest HA may induce endothelial dysfunction in vitro (Gertler et al., 1993) and in healthy mountaineers (Pichler et al., 2010); however, DeLoughery et al. (2004) showed that hypoxic exercise did not reduce fibrinolysis. These somewhat conflicting results may reflect differences in study populations, environments, or other factors.

Cold ambient temperature, common at HA because of decreased barometric pressure, may contribute to thrombotic risk especially in the context of other factors likely to be present at HA. Nagelkirk et al. (2012) showed increased thrombin–antithrombin III complex concentrations during cold weather exercise, without alterations in fibrinolysis. Similar evidence of cold-induced hypercoagulability was seen in other studies demonstrating increases in blood viscosity, arterial blood pressure, platelet count (Keatinge et al., 1984), erythrocyte count, hematocrit, and thromboxane B₂ (Mercer et al., 1999). Long-distance travel, by air or ground transportation, is an established although minor risk factor for VTE with a relative risk of 2.8 and a dose–response relationship of 18% higher risk for each additional 2 hours of travel according to a meta-analysis by Chandra et al. (2009). As the risk of VTE likely persists for weeks beyond the time of travel (Watson and Baglin, 2010), it could be challenging to distinguish the effects of travel, further complicated by the simulated HA environment on many commercial flights (most commercial aircraft cabins are pressurized to an equivalent altitude of ∼2000 m), from the effects of HA itself on incident VTE. Immobilization with relative compression of leg veins and subsequent venous stasis is most likely the primary mechanism of travel-associated VTE; the assertions that dehydration, economy class travel, or alcoholic beverage consumption are risk factors is not supported by current research (Schreijer et al., 2009). Most affected patients have underlying risk factors (Kahn et al., 2012) and in the LONFLIT Study, 0 of 355 low-risk subjects and 11 of 389 high-risk subjects had DVT with an average flight duration of 12.4 hours (Belcaro et al., 2001).

Schreijer et al. (2006) showed increased thrombin generation in long-distance air travelers, particularly in those with the Factor V Leiden mutation and/or women on oral contraceptives. In contrast to some studies of the hemostatic effects, hypobaric hypoxic environment (Toff et al. 2006) did not observe significant changes of coagulation, fibrinolysis, platelet activation, or endothelial cell activation in a controlled study of 73 healthy volunteers in a simulated airplane cabin. Glucocorticoids, including dexamethasone and prednisolone, which are commonly used to prevent acute mountain sickness, as a drug class may modestly increase VTE risk (Johannesdottir et al., 2013). Several case reports and observational studies of HA-VTE patients do not describe antecedent glucocorticoid use, thus possibly leading to attribution error. To summarize, there may be several contributors to VTE risk directly or indirectly related to HA travel, although none are themselves considered major provoking risk factors. VTE risk factors are additive and more than one risk factor is present in the majority of VTE cases (Cushman et al., 2004), emphasizing the complex etiopathogenesis of VTE.

VTE Risk Assessment

As there are no known validated patient characteristics that reliably predict HA-VTE, our proposed approach to risk stratification of patients traveling to HA incorporates well-established risk factors for VTE including those described in current American College of Chest Physicians (ACCP) guidelines that address travel-associated VTE: previous VTE, recent surgery or trauma, active malignancy, estrogen use, advanced age, limited mobility, severe obesity, or known thrombophilic disorder (Table 1) (Kahn et al., 2012). Other patient factors that may be associated with VTE risk during air travel include female sex (Lapostolle et al., 2009), height <165 cm or >185 cm, and BMI >25 (Kuipers et al., 2007); however, we do not routinely consider these in isolation when counseling patients. In contrast, a history of HA-VTE, and perhaps travel-associated VTE, should be considered a significant risk factor for thrombosis occurring at HA. Risk prediction models such as Caprini and Padua that have been validated in surgical and hospitalized patients include additional clinical variables that have an unknown effect on HA-VTE risk. However, in the absence of a validated risk prediction model for HA-VTE, we tend to use clinical gestalt to VTE risk stratification for patients before long-distance travel including to HA. As risk factors for VTE are likely additive, thrombosis risk probably increases as a function of the number of concurrent risk factors, although each should not necessarily receive an equal weight with respect to magnitude of risk. For example, a healthy young woman taking an oral contraceptive almost certainly has a lower VTE risk than a patient with metastatic genitourinary cancer, although both patients have a single risk factor.

Table 1.

Risk Factors to Consider Before Long-Distance Travel (>6 Hours Regardless of Mode) or Stay at High Altitude

Previous VTE

Recent surgery

Recent trauma

Active malignancy

Pregnancy

Estrogen use (oral)

Advanced age (>65 years)

Limited mobility

Obesity (BMI >30 kg/m²)

Known thrombophilic disorder

BMI, body mass index; VTE, venous thromboembolism.

A history of thrombophilia with or without thrombosis is a common reason for consultation in our practice, but in light of the high prevalence of some thrombophilias (e.g., heterozygosity for either factor V Leiden or prothrombin G20210A, with a prevalence of 2%–7% and 1%–2%, respectively) and broad confidence intervals around risk estimates for other thrombophilias, we typically risk stratify these patients in the context of other factors (e.g., estrogen use or recent surgery) (Stevens et al., 2016). There are, however, case reports of HA-VTE in association with thrombophilias including protein S deficiency (Nair et al., 2008) and antiphospholipid syndrome (Sandhu and Teves, 2018). We do not routinely screen for thrombophilia before travel to HA. Duration of travel and length of stay at HA may also influence risk, and should factor into the clinician's assessment. Specifically, travel longer than 6 hours (ACCP recommendation) and/or a stay at HA for several months may further increase HA-VTE risk (Kumar, 2006 and Anand et al., 2001).

Patient Counseling and Measures to Reduce VTE Risk

As we are unaware of any studies or guidelines regarding HA-VTE risk reduction (other than for long-distance flights that may qualify as a pseudo-HA environment), it is not currently possible to provide evidence-based recommendations for travelers to HA. As such, the following statements should be considered tentative until further data are available. With this limitation in mind, we routinely counsel at-risk patients about VTE during travel, including travel to HA. Because long-distance travel is both a well-defined VTE risk factor and frequently necessary before arrival at HA, our approach to mitigating risk of HA-VTE is mostly based on this paradigm. We do not routinely provide counseling about preventive measures to patients without VTE risk factors given the low absolute risk and limited data; for patients with risk factors (in “VTE Risk Assessment” section), both nonpharmacologic and pharmacologic measures may be considered (Table 2).

Table 2.

Approach to Applying Interventions to Reduce Venous Thromboembolism Risk

Patient characteristics	Interventions to consider
No VTE risk factors	None
VTE risk factor(s) present	Nonpharmacologic^a
VTE on anticoagulation	Continue anticoagulation

Careful consideration of pharmacologic interventions.

Nonpharmacologic measures

For long-distance travel to and from HA, in accordance with current ACCP guidelines, we recommend conservative measures including frequent ambulation, choosing an aisle seat, calf muscle exercises while seated, and the use of graduated compression stockings (GCS) for patients with one or more risk factors for VTE (Table 3) (Kahn et al., 2012). Among these interventions, only GCS use has been rigorously studied, with findings summarized in a recent Cochrane review (Clarke et al., 2016). Knee-high GCS with at least 15 mm Hg of pressure at the ankle should be used and may be safely recommended to most patients. There is no evidence to support recommendations to avoid consumption of alcoholic beverages, upgrade from economy class travel, or increase fluid intake. In our experience, patients are likely to take these measures independently; we do not dissuade them given the low likelihood of harm.

Table 3.

Nonpharmacologic Interventions That May Reduce the Risk of Venous Thromboembolism During and After Travel to High Altitude

Frequent ambulation

Choosing an aisle seat

Calf muscle exercises while seated

Graduated compression stockings

Shortest practical duration of stay at high altitude

Measures including gradual ascent to HA, supplemental oxygen, or shorter duration at HA, while employed to reduce the risk of other HA illnesses, have unknown effects on HA-VTE risk. However, for at-risk patients considering longer stays at HA we recommend the shortest practical duration given the aforementioned study suggesting an increased risk with prolonged stays of 5 or more months. GCS use while at HA is likely a safe intervention, although it has not been studied and may cause discomfort in some patients.

Pharmacologic measures

Current guidelines suggest against the use of aspirin or anticoagulants for long-distance travelers, although this is a grade 2C recommendation that implies other alternatives may be equally reasonable (Kahn et al., 2012). We are unaware of any studies of antithrombotic agents for the prevention of HA-VTE. For travel-associated VTE, only low-molecular-weight heparin (LMWH) and aspirin have been studied; neither was shown in one randomized trial to have a clinical benefit, although LMWH reduced the rate of asymptomatic DVT (Cesarone et al., 2002). With these limited data in mind, direct oral anticoagulants (DOACs), which have excellent safety and efficacy for indications including VTE prophylaxis and treatment, may be an appropriate and more convenient alternative to LMWH for certain high-risk patients traveling to HA (Table 4). However, clinicians should approach anticoagulation conservatively given the uncertain benefits and known risk of bleeding.

Table 4.

Pharmacologic Interventions That May Reduce the Risk of Venous Thromboembolism During and After Travel to High Altitude

Apixaban 2.5 mg

Dabigatran 110 mg

Edoxaban 30 mg

LMWH 40 mg or 1 mg/kg

Rivaroxaban 10 mg

Discontinuation of oral estrogen if no risk

LMWH, low-molecular-weight heparin.

The optimal timing, dose, and duration of anticoagulation in these settings are unknown. Depending on the clinical situation, we occasionally offer prophylactic dose DOACs before long-distance travel for patients who are at risk (in “VTE Risk Assessment” section), have a good understanding of the risks and benefits of anticoagulation, do not have major drug–drug interactions, and who have a low risk of major bleeding. Our preference is to use a single dose of the factor Xa inhibitors apixaban 2.5 mg, edoxaban 30 mg, or rivaroxaban 10 mg, DOACs with similar half-lives and indicated for VTE prophylaxis in other settings, immediately before departure. In our view, continuation of anticoagulation after travel to HA should be reserved for patients with the highest VTE risk, the lowest bleeding risk, and who have an excellent understanding of the risks and benefits of anticoagulation at HA—for example, a young otherwise healthy patient with a history of HA-VTE and thrombophilia, not currently on anticoagulation, who will not be engaging in activities with a high risk of traumatic bleeding such as mountaineering.

For patients taking an anticoagulant for VTE treatment or to prevent recurrent VTE, we strongly recommend continuation during travel and while at HA. Oral estrogen for contraception or hormone replacement therapy may increase VTE risk, particularly in the setting of thrombophilia; however, discontinuation before travel may have harmful effects including unintended pregnancy or worsening of gynecological disorders. For this reason we do not routinely advise female patients to discontinue estrogen and instead carefully consider other VTE prophylactic measures.

Conclusions

In conclusion, VTE may occur during travel, ascension to, or while at HA. Current risk stratification systems are imprecise for individuals considered to be at high risk and an individualized approach to counseling and management is recommended. In those deemed to be at high VTE risk, and with an acceptably low bleeding risk, we recommend consideration of pharmacologic interventions during travel to HA. Nonpharmacologic interventions, particularly GCS, may be liberally recommended because of a possible benefit and a low likelihood of harm. Addressing modifiable VTE risk factors before ascension to HA is also recommended. Further studies on the incidence and pathophysiology of HA-VTE are warranted and will likely contribute to ongoing efforts to safely and effectively prevent and treat HA-VTE.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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