Anticoagulation Considerations for Travel to High Altitude

Abstract

DeLoughery, Thomas G. Anticoagulation considerations for travel to high altitude. High Alt Med Biol 16:181–185, 2015.—An increasing percentage of the population are on anticoagulation medicine for clinical reasons ranging from stroke prevention in atrial fibrillation to long term prevention of deep venous thrombosis. In recent years, several new direct oral anticoagulants have entered the market. The key questions that should be kept in mind when approaching a potential traveler on anticoagulation are: 1) why is the patient on anticoagulation? 2) do they need to stay on anticoagulation? 3) what are the choices for their anticoagulation? 4) will there be any drug interactions with medications needed for travel? and 5) how will they monitor their anticoagulation while traveling? Knowing the answers to these questions then can allow for proper counseling and planning for the anticoagulated traveler's trip.

Introduction

An increasing number of potential travelers are on anticoagulation medications for a variety of clinical reasons. Adding to this complexity is the rising number of anticoagulation options now available. This review will first examine the current anticoagulants on the market, evaluate indications for anticoagulation, and thrombotic risks of altitude. Knowing these facts then can allow for proper counseling and planning for the anticoagulated traveler's trip.

Overview of Anticoagulants

Currently there are two major classes of anticoagulation therapy: vitamin K antagonists, which have been used for patient care for almost 70 years, and the new class of direct oral anticoagulants.

Warfarin is the prototype vitamin K antagonist. Vitamin K is an essential cofactor for the conversion of the amino acid glutamate to gamma-carboxyglutamic acid in certain coagulation proteins (factors II, VII, IX, and X). Warfarin blocks the recycling of vitamin K, leading to decreased production of these proteins. The metabolism of warfarin is extremely variable, being modified by both genetic and environmental factors such as diet and medications. For example, warfarin is metabolized by several cytochromes, including 2C9, which leads to the potential of multiple drug interactions. Daily doses of warfarin can range from 1 to 25 mg, and because of its variability, therapy must be frequently monitored. The prothrombin time, reported as international normalized ratio (INR), is the standard test for monitoring warfarin therapy. Goal INR range for most indications is 2.0–3.0, except for some patients with high thrombotic risk mechanical cardiac valves where the range is 2.5–3.5

Due to variable warfarin doses that stem from food and drug interactions, as well as the need for frequent monitoring, direct oral anticoagulants have been developed. (Table 1). This class of anticoagulant functions by directly inhibiting coagulation enzymes and has the virtue of stable pharmacokinetics, leading to fixed dosing and few drug interactions. All the direct oral anticoagulants have been shown to be effective in the prevention of deep venous thrombosis in lower limb orthopedic surgery, stroke prevention in atrial fibrillation, and treatment of venous thromboembolic disease.

Table 1.

Direct Oral Anticoagulants

	Apixaban	Dabigatran	Edoxaban	Rivaroxaban
Action	Anti-Xa	Anti-IIa	Anti-Xa	Anti-Xa
Bioavailability	66%	6.5%	45%	80–100%
Onset to peak action (hours)	1–3	2–3	1–1.5	2.5–4
Half-life (hours)	8–15	12–14	9–11	5–9
Renal excretion (%)	∼25	80	33	∼66
Dose-prophylaxis	2.5 mg BID	150 mg/day 220 mg/day	15 mg/day	10 mg/day
Therapeutic	5 mg BID	150 mg BID	60 mg/day	20 mg/day
Renal dosing	Contraindicated with CrCl<15 mL/min	75 mg BID if CrCl<30 mL/min and contraindicated CrCl<15 mL/min	30 mg/day if CrCl 30–60 mL/min	15 mg/day CrCl 50–15 mL/min
Drug interaction	Azole antifungals (except fluconazole) or HIV-protease inhibitors; reduce dose to 2.5 mg BID	Dronedarone, ketoconazole	Verapamil, quinidine, erythromycin, azithromycin, clarithromycin, ketoconazole or itraconazole; reduce dose by 50%	Azole antifungals (except fluconazole) or HIV-protease inhibitors

The first direct anticoagulant was the thrombin inhibitor dabigatran. Generation of thrombin is the pivotal step in coagulation as it leads to both creation of the fibrin thrombus and activation of multiple coagulation factors. Dabigatran is dosed at 150 mg BID. The most significant nonbleeding side effect of dabigatran is dyspepsia, which is seen in 15% of patients. Of the new anticoagulants, dabigatran is the most renally cleared and should be used with caution in patients with creatinine clearance less than 50 mL/min.

Rivaroxaban was the first of the direct Xa inhibitors approved. Factor Xa leads to the generation of thrombin, so inhibition leads to anticoagulation by suppression of thrombin generation. Rivaroxaban is dosed daily at 20 mg/day (15 mg daily with creatinine clearance 50–15 mL/min). Apixaban, another Xa inhibitor, is the least renally cleared direct oral anticoagulant. It is dosed at 5 mg BID unless the patient has two or more risk factors: weight less 60 kg, age over 80, or creatinine greater than 1.5 mg/dL, when the dose is 2.5 mg BID. Edoxaban is the latest Xa inhibitor on the market and is dosed at 60 mg daily, but is approved only for patients with creatine clearances less than 95 mL/min.

Except for dyspepsia with dabigatran, studies have shown no other side effects for the direct oral anticoagulants except bleeding. Meta-analysis shows that the direct oral anticoagulants are associated with lower rates of major and fatal bleeding when compared with warfarin (Chai-Adisaksopha et al., 2014). The most feared complication of anticoagulation—intracranial hemorrhage—is also significantly reduced with the use of direct oral anticoagulants.

While there are currently no reversal agents for the direct oral anticoagulants, studies have shown no difference in outcomes in patients who bleed while taking these agents compared to those who bleed on warfarin (Majeed et al., 2013; Held et al., 2015; Piccini et al., 2014) To provide an extra level of reassurance about safety, there are currently several antidotes in development. For dabigatran, there is a monoclonal antibody, idarucizumab, that specifically neutralizes this agent (Hobl and Jilma, 2015). For the Xa inhibitors, andexanet is being developed, which is a recombinant factor Xa analog that inhibits factor Xa blockers but does not promote coagulation (Lu et al., 2013). Clinical studies have shown that both of these antidotes are effective at reversing the anticoagulant effect of the newer agents.

Indication for Anticoagulation

For most patients there are three major reasons to be anticoagulated. One is for short- or long-term secondary prevention of venous thrombosis. Patients with a first provoked venous thrombosis, such as by surgery or estrogen, require only 3 months of anticoagulation. For idiopathic or more than one thrombosis, indefinite anticoagulation is recommended (Kearon et al., 2012).

The second reason is prevention of cardiac embolization, most often due to atrial fibrillation. The risk of embolic stroke is 5% per year which is diminished to 1% or less with anticoagulation. There are several scoring systems available to risk stratify an individual patient's stroke risk, such as CHADS2, but for most patients with atrial fibrillation, anticoagulation is recommended for stroke prevention (January et al., 2014).

Finally, patients with mechanical heart valves require aggressive anticoagulation to prevent embolic strokes or valve thrombosis. Anticoagulation choices in these patients are challenging. The direct oral anticoagulants are contraindicated because the only study of their use in valves showed excess rates of bleeding and thrombosis (Eikelboom et al., 2013). The use of heparin requires strong compliance, leaving warfarin as the only practical choice.

Thrombotic Challenges of Altitude

While going to altitude has been perceived as a prothrombotic stimulus, it is still unclear whether this is due to physiological changes of altitude on coagulation or other risk factors. Changes in coagulation have been studied extensively, with most studies showing no consistent prothrombotic changes with hypoxia ( DeLoughery et al., 2004; Zafren et al., 2011; Gupta and Ashraf, 2012). A recent study using thromboelastography, which assays whole blood coagulation, actually demonstrated hypocoagulation at altitude, providing further evidence against increased coagulation (Martin et al., 2012).

More implicated in the thrombosis risk are other features of travel to altitude, including long airplane flights, immobility, and dehydration. Airplane travel in particular is a thrombosis risk factor, with a relative risk of 2–3 (Cannegieter, 2012). The risk rises after 6 hours of travel and is most marked after 10–12 hours. The pathogenesis appears to be many hours of immobility leading to venous stasis. Additional prothrombic risk factors, such as inherited thrombophilia or estrogens, add to this risk (Christiansen et al., 2005). Despite the risk of under-anticoagulation, the risk of thrombosis for anticoagulated patients when traveling appears low, with one study showing a risk of 0.9% of thrombosis during travel (Ringwald et al., 2014b). Bleeding was more common in this study (6.5%), but most cases were minor—bruising and hematuria. Only 0.5% had gastrointestinal bleeding, the most severe complication reported.

Pretravel Considerations

Assessment of the patient on anticoagulation consists of asking the follow questions:

1. Why is the patient on anticoagulation?

2. Do they need to stay on anticoagulation?

3. What are the choices for their anticoagulation?

4. Will there be any drug interactions with medications needed for travel?

5. How will they monitor their anticoagulation while traveling?

Why is the patient on anticoagulation?

This, as noted above, will help determine choices for anticoagulation. For instance, if the patient has mechanical cardiac valves, then warfarin is the only option for anticoagulation.

Do they need to stay on anticoagulation?

The pre-travel consultation is an excellent opportunity to review the need for long-term anticoagulation. As an example, many patients with provoked thrombosis were indefinitely anticoagulated because they had factor V Leiden or another inherited thrombophilia. Current data show these are at best a weak risk factor for recurrence and are not alone an indication for long-term anticoagulation.

What are the choices for their anticoagulation?

For patients on direct oral anticoagulation, the simplest option would be to continue the drug. For warfarin patients, there are the options of changing to another agent or continuing the warfarin. Currently, except for heart valve patients, the option of changing to a direct oral anticoagulant would be the simplest option as it eliminates the need for monitoring or concerns about food and drug interactions (Ringwald et al., 2014a). Several protocols exist for changing patients onto and off these new agents (Table 2).

Table 2.

Conversion from Warfarin to Direct Oral Anticoagulants

Drug	To direct oral anticoagulant: Stop warfarin and start new drug when	Back to warfarin
Apixaban	INR is less than 2.0	Start warfarin for 3 days and then stop apixaban
Dabigatran	INR is less than 2.0	Start warfarin for 3 days and then stop dabigatran
Edoxaban	INR is less than 2.5	Cut edoxaban dose by 50% when starting warfarin and stop edoxaban when INR is over 2.0
Rivaroxaban	INR is less than 3.0	Start warfarin for 3 days and then stop rivaroxaban

Source: Manufacturer's Prescribing information, http://depts.washington.edu/anticoag/home/.

Will there be any drug interactions with medications needed for travel?

The traveler may be started on new medications or have to take agents such as antibiotics during the trip. Table 3 lists the potential interactions of agents used in travel medicine and warfarin. While not strictly a drug interaction, there is often concern about giving vaccinations to patients on anticoagulants. The approach our clinic employs is to use the smallest needle possible and apply direct pressure to the vaccination site for 5 minutes.

Table 3.

Warfarin Drug Interactions

Drug	Warfarin interaction?
Acetazolamide	No
Atovaquone/Proguanil	Yes: raises INR
Azithromycin	Yes: raises INR
Chloroquine	No
Ciprofloxacin	Yes: raises INR
Dexamethasone	Yes: raises INR
Doxycyline	Yes: raises INR
Levofloxacin	Yes: raises INR
Mefloquine	No
Primaquine	No
Proguanil	Yes: raises INR
Trimethoprim-Sulfamoxole	Yes: raises INR

How will they monitor their anticoagulation while traveling?

For short trips of a week or 10 days, monitoring is not required. For longer trips, the INR should be checked due to changes in diet and the stress of travel. Websites such as http://www.anticoagulationeurope.org/files/files/booklets/GettinganINRtestabroad.pdf list INR clinics in various countries. More practical are point of care INR machines, which allow easy access and frequent INR checks. The size and operation of these machines are similar to glucose monitors. The downside of this convenient INR monitoring is the need to travel with the machine and reagents. Also, patients need to be comfortable measuring and adjusting their INR so self-management should start a month or so before any travel. A suggested nomogram for self-monitoring is given in Table 4.

Table 4.

Maintenance Warfarin Adjustment Nomogram

International Normalized Ratio (INR)	Dose change
1.1–1.4	Day 1: Add 10%–20% total weekly dose (TWD)^*
	Weekly: Increase TWD by 10%–20%
	Return: 1 week
1.5–1.9	Day 1: Add 5%–10% of TWD
	Weekly: Increase TWD by 5%–10%
	Return: 2 weeks
2.0–3.0	No change
	Return: 4 weeks
3.1–3.9	Day 1: Subtract 5%–10% TWD
	Weekly: Reduce TWD by 10%–20%
	Return: 2 weeks
4.0–5.0	Day 1: No warfarin
	Weekly: Reduce TWD by 10%–20%
	Return: 1 week
>5.0	Stop warfarin until INR <3.0
	Decrease TWD by 20%–50%
	Return daily

TWD, total weekly dose.

From: DeLoughery TG: Oral anticoagulants. In: Goodnight SH, Hathaway WE, eds: Disorders of Hemostasis and Thrombosis: A Clinical Guide, New York, 2001, McGraw-Hill Professional, pp 533–566.

Warfarin Management

The key to warfarin management is a consistent level of dietary vitamin K and avoidance of drug interactions—both made difficult by travel. One aid to INR stability is the intake of a consistent amount of vitamin K, as low levels of dietary consumptions lead to erratic INRs due to lack of a “buffer.” Many patients accomplish this by eating a salad a day or even taking a 75–150 μg vitamin K supplement (Gebuis et al., 2011). If the traveler needs to be on a new medication for travel, it is prudent to start it several weeks before travel to ensure no idiosyncratic drug interactions with warfarin or to allow for adjustment of the warfarin dose if there are drug interactions such as with Atovaquone/Proguanil (Ringwald et al., 2009). For agents in the prevention of altitude illness, there is no warfarin interaction with acetazolamide but a potential one with dexamethasone. If dexamethasone is required during travel, a short course of 1–2 days should not potentiate the INR.

Given the above risk factors for travel inducing supratherapeutic INRs, the only study on this issue showed surprisingly that altitude was a risk factor for subtherapeutic INRs, especially for patients with atrial fibrillation (van Patot et al., 2006). This study alone with all the potential for unstable INR highlights the importance of close monitoring.

The Anticoagulated Traveler

For the trip, the traveler should have an abundant supply of their agent packed in their carry-on luggage. For patients at very high risk of thrombosis, such as patients with mechanical cardiac valves, it may be prudent to have a separate traveling companion carry a small supply of drug in case the traveler loses their pills. The traveler should wear an alert bracelet identifying the type of anticoagulation they are taking.

An unsettled issue is what activities are safe for anticoagulated travelers. A recent thorough review of this subject showed very little evidence-based data on this subject (Hawkins et al., 2013). A common sense approach would be to avoid engaging in activities that involve exposure to high risk of injury, such as extreme rock climbing, and to wear seat belts in all vehicles and helmets when skiing, bicycling, etc.

If the anticoagulated traveler becomes severely injured, there are few options for drug reversal. Currently, prothrombin complex concentrates are used to reverse warfarin and direct oral anticoagulants, but are not available outside of major hospitals. In theory, since the concentrates are stored at room temperature, these could be taken with the traveler, but given the need for intravenous delivery and the cost of approximately $5000, this would not seem practical. For patients on warfarin, oral vitamin K (5–10 mg) can be used to lower the INR, but this can take hours. Another issue with remote altitude travel is the management of anticoagulant travelers with minor head injuries, as most protocols call for brain imagining, which would require evacuation (Hawkins et al., 2013). This highlights the need to wear helmets and avoid activities that may lead to head injury.

Conclusion

Patients should not be denied travel experience just because they are anticoagulated, but they need to be aware of the special challenges posed by these medications. Counseling at the pre-travel clinic visit can help mitigate these issues.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist.

References

Cannegieter

SC.

(2012). Travel-related thrombosis. Best Pract Res Clin Haematol, 25:345–350.

Chai-Adisaksopha

, Crowther

, Isayama

, and Lim

. (2014). The impact of bleeding complications in patients receiving target-specific oral anticoagulants: A systematic review and meta-analysis. Blood, 124:2450–2458.

Christiansen

, Cannegieter

, Koster

, Vandenbroucke

, and Rosendaal

. (2005). Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA, 293:2352–2361.

DeLoughery

, Robertson

, Smith

, and Sauer

. (2004). Moderate hypoxia suppresses exercise-induced procoagulant changes. Br J Haematol, 125:369–372.

Eikelboom

, Connolly

, Brueckmann

, Granger

, Kappetein

, Mack

, Blatchford

, Devenny

, Friedman

, Guiver

, Harper

, Khder

, Lobmeyer

, Maas

, Voigt

, Simoons

, and Van de Werf

. (2013). Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med, 369:1206–1214.

Gebuis

, Rosendaal

, van Meegen

, and van der Meer

. (2011). Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: A dose-finding study. Haematologica, 96:583–589.

Gupta

, and Ashraf

. (2012). Exposure to high altitude: A risk factor for venous thromboembolism?. Semin Thromb Hemost, 38:156–163.

Hawkins

, Caudell

, DeLoughery

, and Murray

. (2013). Participation of iatrogenically coagulopathic patients in wilderness activities. Wildern Environ Med, 24:257–266.

Held

, Hylek

, Alexander

, Hanna

, Lopes

, Wojdyla

, Thomas

, Al-Khalidi

, Alings

, Xavier

, Ansell

, Goto

, Ruzyllo

, Rosenqvist

, Verheugt

, Zhu

, Granger

, and Wallentin

. (2015). Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: Insights from the ARISTOTLE trial. Eur Heart J, 36:1264–1272.

10.

Hobl

, and Jilma

. (2015). Towards the development of specific antidotes: Idarucizumab for reversal of dabigatran effects. Thromb Haemostasis, 113:1162–1163.

11.

January

, Wann

, Alpert

, Calkins

. Cigarroa

, Cleveland

Jr , Conti

, Ellinor

, Ezekowitz

, Field

, Murray

, Sacco

, Stevenson

, Tchou

, Tracy

, and Yancy

CW.

(2014) 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation, 130:e199–e267.

12.

Kearon

, Akl

, Comerota

, Prandoni

, Bounameaux

, Goldhaber

, Nelson

, Wells

, Gould

, Dentali

, Crowther

, and Kahn

. (2012). Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 141:e419S–e494S.

13.

, DeGuzman

, Hollenbach

, Karbarz

, Abe

, Lee

, Luan

, Hutchaleelaha

, Inagaki

, Conley

, Phillips

, and Sinha

. (2013). A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med, 19:446–451.

14.

Majeed

, Hwang

, Connolly

, Eikelboom

, Ezekowitz

, Wallentin

, Brueckmann

, Fraessdorf

, Yusuf

, and Schulman

. (2013). Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation, 128:2325–2332.

15.

Martin

, Pate

, Vercueil

, Doyle

, Mythen

, and Grocott

. (2012). Reduced coagulation at high altitude identified by thromboelastography. Thromb Haemostasis, 107:1066–1071.

16.

Piccini

, Garg

, Patel

, Lokhnygina

, Goodman

, Becker

, Berkowitz

, Breithardt

, Hacke

, Halperin

, Hankey

, Nessel

, Mahaffey

, Singer

, Califf

, and Fox

. (2014). Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: Results from the ROCKET AF Trial. Eur Heart J, 35:1873–1880.

17.

Ringwald

, Grauer

, Eckstein

, and Jelinek

. (2014a). The place of new oral anticoagulants in travel medicine. Travel Med Infect Dis, 12:7–19.

18.

Ringwald

, Lehmann

, Niemeyer

, Seifert

, Daubmann

, Wegscheider

, Salzwedel

, Luxembourg

, Eckstein

, and Voeller

. (2014b). Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis. Travel Med Infect Dis, 12:258–263.

19.

Ringwald

, Strobel

, and Eckstein

. (2009). Travel and oral anticoagulation. J Travel Med, 16:276–283.

20.

van Patot

, Hill

, Dingmann

, Gaul

, Fralick

, Christians

, Honigman

, and Salman

. (2006). Risk of impaired coagulation in warfarin patients ascending to altitude (>2400 m). High Alt Med Biol, 7:39–46.

21.

Zafren

, Feldman

, Becker

, Williams

, Weiss

, and DeLoughery

. (2011). D-dimer is not elevated in asymptomatic high altitude climbers after descent to 5340 m: The Mount Everest Deep Venous Thrombosis Study (Ev-DVT). High Alt Med Biol, 12:223–227.