Antiphospholipid syndrome (APS) is an autoimmune clotting disorder that may present catastrophically with multiple thromboses over a short period of time. In this article, we examine the case of a woman with undiagnosed APS whose first symptoms presented during a long-haul flight. A review of the literature on thrombosis at high altitudes and during long duration travel helps us understand potential treatment and prevention of the same in APS patients.
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Explore This IssueAugust 2018
A 22-year-old woman noted diffuse severe abdominal pain while traveling by plane from California to India. Each episode began with a bloating sensation that progressed to cramping pain with nausea but no emesis, no relation to food intake and eventual resolution of symptoms without intervention. Such symptoms recurred with any long flights she took, typically to and from India.
One year later, a comprehensive evaluation, including negative infectious workup, yielded the diagnosis of irritable bowel syndrome and cholelithiasis without cholecystitis. After undergoing an elective cholecystectomy, her postoperative course was complicated by renal infarction (see Figure 1A) followed by splenic (see Figure 1B), ovarian and mesenteric infarction within one week. Serologic examination was significant for elevated serum cardiolipin antibody titers, yielding a diagnosis of catastrophic antiphospholipid syndrome.
She was subsequently treated with anticoagulation in addition to plasmapheresis and rituximab. However, the question of prior symptoms then arose: Was her initial abdominal pain actually mesenteric ischemia? Could this have been prevented?
The Clinical Problem
Although vast numbers of individuals travel by air yearly, many remain unaware of the risk of deep vein thrombosis (DVT) and venous thromboembolism (VTE) posed by time spent at high altitudes with prolonged immobility, even in healthy individuals. Those with hypercoagulable conditions, such as APS, are at even greater risk. The literature describing the clotting risk with prolonged travel (typically greater than eight hours) is extensive.1 However, limited data describe a specific association between clotting risk and high altitudes in patients with APS. For this reason, we conducted a literature review to evaluate the association of high altitudes and clotting in patients with APS, in addition to management recommendations in such situations.
Individuals ascending to altitudes greater than 2,400–3,000 meters have demonstrated hypobaric hypoxia and its effects on the coagulation system, including decreased tissue oxygenation and sympathetic compensatory changes.2,3 In 2006, Peter Bärtsch, MD, described healthy mountaineers suffering from altitude-induced thrombosis and subsequent death.4 Hypoxemia activates transcription factor early growth response-I (EGR-1), which results in vascular fibrin deposition. This is amplified by a concomitant suppression of fibrinolysis by upreguation of plasminogen activator inhibitor-1.5
Additional studies have demonstrated an independent, increased risk of thrombosis with prolonged (longer than four hours) air, bus, car or train travel described by some to be equivalent to the risk of thrombosis with oral contraceptives.6-10 Further analysis of risk factors demonstrates the need to address the role of comorbidities, such as diabetes, coronary artery disease and hyperlipidemia, in having a greater risk of sudden cardiac death at higher altitudes.11
Despite published literature demonstrating the specific association between hypoxia and VTE, contrasting results have also been described.4,12-16 In a crossover study mimicking air pressure in a flight cabin by evaluating changes in hemostatic markers in individuals exposed to a hypobaric chamber for eight hours compared with normobaric normoxia, William D Toff, MD, and colleagues could not find a difference in the clotting risk between the study groups.17
The continued debate over whether thrombosis prevention is indicated in prolonged travel in the general population is based on a known incidence of VTE of one per 1,000 individuals per year and the absolute risk of thrombosis in air travel of one per 6,500 passengers.18 This—combined with the limited evidence for the utility of compression stockings and exercise, as well as the independent risk of bleeding with medicinal prophylaxis—offsets the value of thromboprophylaxis in the general low-risk population. However, such recommendations applied to individuals predisposed to clotting at baseline may be worthy of consideration.
In addition to being exposed to low atmospheric oxygen, those traveling in planes also sit for prolonged periods of time without actively moving their legs, another known risk factor for the development of a DVT. A cross-sectional comparison of incident VTE was reported in individuals exposed to seated immobility at work compared with those exposed to long-haul flights greater than eight hours in duration.19 Of 61 patients with VTE who completed the questionnaire, 21 patients reported seated immobility at work (defined as sitting for at least eight hours in one day and at least three hours consistently without standing). One of these 21 patients was subsequently diagnosed with APS and seven others with the factor V Leiden mutation, factor VIII deficiency, or prothrombin gene mutation. The criteria of the number of hours of seated immobility were chosen as such because risks of VTE begin to increase at flight duration greater than four hours, peaking beyond eight hours.20
APS is characterized by antibody formation against phospholipids or phospholipid-bound protein cofactors in the blood. Through a series of events, antiphospholipid antibodies increase the risk of arterial and venous thrombosis that typically require lifelong anticoagulation. Although recommendations for anticoagulant thromboprophylaxis have been made, no formal guidelines are set. The Sapporo classification criteria for APS implicate the diagnosis if one clinical criterion (vascular thrombosis or pregnancy morbidity) and one laboratory criterion (anti-cardiolipin antibody, anti-β2 glycoprotein-I antibody or lupus anticoagulant) are met (see Table 1).21,22
Of note, however, not every positive antiphospholipid antibody (aPLA) is clinically significant, and not every patient with positive aPLA has the same risk. Other factors, such as cardiovascular disease and recent trauma, play a role. A clinically significant anti-cardiolipin antibody greater than or equal to 40 units or anti-β2 glycoprotein-I antibody greater than or equal to 40 units is tested twice at least 12 weeks apart.23 Further, a positive lupus anticoagulant test is based on guidelines from the International Society of Thrombosis and Haemostasis.21
Buddha Basnyat, MD, and colleagues describe a young man with APS who experienced vision changes and abdominal pain while climbing at 7,000 meters in the Himalayas.24 The patient was found to have superior mesenteric vein thrombosis, as well as multiple venous sinus thromboses.
Another study of 20 volunteers on a flight from Vienna to Washington demonstrates an increased activity of clotting factor VII and VIII, suppressed fibrinolysis and reduced activated partial thromboplastin time (aPTT) measurements after the flight.25
A study of six climbers traveling in the Argentinian Andes up Aconcagua, the highest peak in South America, to an altitude of greater than 6,000 meters in 2007, found that all of them had retinal vascular engorgement and tortuosity after the climb.26 Of the two who experienced visual changes, one had an elevated aPLA. Since that report was published, ophthalmologists recommend individuals with glaucoma, age-related macular degeneration or diabetic retinopathy avoid prolonged and unnecessary high-altitude exposure without appropriate acclimatization.11
Guidelines specific to APS, travel & long-haul flights are lacking. The protective effect of low dose aspirin in individuals with clinically significant aPLA values is not supported by randomized controlled data.
Guidelines from Professional Societies
Guidelines specific to APS, travel and long-haul flights are lacking. The protective effect of low dose aspirin (ASA) in individuals with clinically significant aPLA values is not supported by randomized controlled data. Moreover, little evidence exists showing that aspirin is of great benefit for high-risk individuals while traveling. However, Maria Cesarone, MD, and colleagues concluded that enoxaparin (1 mg/kg) administered two to four hours before traveling may minimize the risk of DVT.27
Further risk stratification based on aPLA profile, age, concomitant systemic autoimmune disease and cardiovascular disease categorizes an individual to low-, moderate- or high-risk categories.20 Individuals with no medical conditions traveling fewer than eight hours or fewer than 5,000 kilometers are at low risk. Moderate-risk patients include those who are obese, pregnant, on hormone-replacement therapy or oral contraceptives, or who use tobacco and have longer travel times and distances. High-risk patients may have a history of VTE, hypercoagulable state, recent surgery or malignancy.
In the LONFLIT3 study, three high-risk groups were studied: One was given no prophylaxis, one was given ASA, and the last received low-molecular-weight heparin (LMWH; enoxaparin).27 Results revealed the group given enoxaparin developed no DVT, whereas several individuals in the other two groups did develop DVT. Several years later, the American College of Chest Physicians (ACCP) devised recommendations for those considered at high risk of VTE, which includes individuals with APS (see Table 2).28 In addition to recommending general measures for those at a low risk of clotting (e.g., minimize constrictive clothing, maximize hydration and carry out frequent calf muscle exercises [Grade 1C]), the ACCP suggests below-the-knee graduated compression stockings (Grade 2C) or a single dose of LMWH prior to flight (Grade 2C). It does not support the use of ASA for VTE prophylaxis (Grade 1B).28
Authors’ Conclusions & Recommendations
It is prudent for practitioners to consider anticoagulation for high-risk patients with APS who are traveling for long distances or at high altitudes. When deciding whether to anticoagulate a patient positive for aPLA, it is important to be attentive of clinically significant laboratory values, as well as comorbidities associated with a greater increase in the risk of clotting. Further, in individuals with known APS, consideration for a booster dose of enoxaparin (1 mg/kg) is not unreasonable two to four hours prior to travel on flights exceeding eight hours’ duration. Although our recommendations are based on a review of the literature, further research is encouraged for patients with APS to assist in preventive measures and overall improved quality of life.
Vaneet Kaur Sandhu, MD, is an assistant professor in the Division of Rheumatology at Loma Linda University, Loma Linda, Calif.
Kathleen Teves, MD, is an internal medicine resident at the University of California, Riverside, Calif.
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- Anand AC, Saha A, Seth AK, et al. Symptomatic portal system thrombosis in soldiers due to extended stay at extreme altitude. J Gastroenterol Hepatol 2005 May;20(5):777–783.
- Auerbach PS. Wilderness Medicine, 5th ed. Philadelphia: Mosby, 2007.
- Bärtsch P. How thrombogenic is hypoxia? JAMA. 2006 May 17;295(19):2297–2299.
- Yan SF, Mackman N, Kisiel W, et al. Hypoxia/hypoxemia-induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis. Arterioscler Thromb Vasc Biol. 1999 Sep;19(2):2029–2035.
- Ninivaggi M, de Laat M, Lancé MM, et al. Hypoxia induces a prothrombotic state independently of the physical activity. PLoS ONE. 2015 Oct 30;10(10):e0141797.
- Cannegieter SC, Doggen CJ, van Houwelingen HC, et al. Travel-related venous thrombosis: Results from a large population-based case control study (MEGA study). PLoS Med. 2006 Aug;3(8):e307.
- Kraaijenhagen RA, Haverkamp D, Koopman MM, et al. Travel and risk of venous thrombosis. Lancet. 2000 Oct 28;356(9240):1492–1493.
- Ferrari E, Chevallier T, Chapelier A, et al. Travel as a risk factor for venous thromboembolic disease: A case-control study. Chest. 1999 Feb;115(2):440–444.
- Rosendaal FR. Interventions to prevent venous thrombosis after air travel: Are they necessary? No. J Thromb Haemost. 2006 Nov;4(11):2306–2307.
- Georgalas I. Climbing the Himalayas more safely BMJ. 2012 Jun 13;344:e3778.
- Hoeper MM, Granton J. Intensive care unit management of patients with severe pulmonary hypertension and right heart failure. Am J Respir Crit Care Med. 2011 Nov 15;184(10):1114–1124.
- Bradford A. The role of hypoxia and platelets in air travel-related venous thromboembolism. Curr Pharm Des. 2007;13(26):2668–2672.
- Martin DS, Pate JS, Vercueil A, et al. Reduced coagulation at high altitude identified by thromboelastography. Thromb Haemost. 2012 Jun;107(6):1066–1071.
- Sabit R, Thomas P, Shale DJ, et al. The effects of hypoxia on markers of coagulation and systemic inflammation in patients with COPD. Chest. 2010 Jul;138(1):47–51.
- Schreijer AJ, Cannegieter SC, Doggen CJ, et al. The effect of flight-related behaviour on the risk of venous thrombosis after air travel. Br J Haematol. 2009 Feb;144(3):425–429.
- Toff WD, Jones CI, Ford I, et al. Effect of hypobaric hypoxia, simulating conditions during long-haul air travel, on coagulation, fibrinolysis, platelet function, and endothelial activation. JAMA. 2006 May 17;295(19):2251–2261.
- Kuipers S, Schreijer AJM, Cannegieter SC, et al. The absolute risk of venous thrombosis after air travel (WRIGHT study). J Thromb Haemost. 2005;3:P1657.
- Aldington S, Pritchard A, Perrin K, et al. Prolonged seated immobility at work is a common risk factor for venous thromboembolism leading to hospital admission. Int Med J. 2008 Feb;38(2):133–135.
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- Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb;4(2):295–306.
- Gómez-Puerta JA, Cervera R. Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun. 2014 Feb–Mar;48–49:20–25.
- Barbhaiya M, Erkan D. Primary thrombosis prophylaxis in antiphospholipid antibody-positive patients: Where do we stand? Curr Rheumatol Rep. 2011 Feb;13(1):59–69.
- Basnyat B, Graham L, Lee SD, et al. A language barrier, abdominal pain, and double vision. Lancet. 2001 Jun 23;357(9273):2022.
- Schobersberger W, Fries D, Mittermayr M, et al. Changes of biochemical markers and functional tests for clot formation during long-haul flights. Thromb Res. 2002 Oct 1;108(1):19–24.
- Ho TY, Kao WF, Lee SM, et al. High-altitude retinopathy after climbing Mount Aconcagua in a group of experienced climbers. Retina. 2011 Sep;31(8):1650–1655.
- Cesarone MR, Becaro G, Nicolaides AN, et al. Venous thrombosis from air travel: The LONGFLIT3 study—Prevention with aspirin vs low-molecular-weight heparin (LMWH) in high-risk subjects: A randomized trial. Angiology. 2002 Jan–Feb;53(1):1–6.
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