Anemia at Altitude: Thalassemia,Sickle Cell Disease,and Other Inherited Anemias

Introduction

Anemia is one of the most common medical conditions, affecting millions of people worldwide. It is estimated that up to 5% of the world's population has a variant hemoglobin gene, with the most frequent being thalassemia and sickle cell disease (Rund and Rachmilewitz, 2005). Overall, the biggest impact of anemia for travel is reduced exercise performance—for every 1% fall in hematocrit, the VO₂max decreases by 1% and endurance by 2% (Tufts et al., 1985; Ekblom and Berglund, 1991; Gledhill et al., 1999; Burtscher, 2004). This is most likely due to decreased blood oxygen-carrying capacity. However, anemia can have other wide-ranging effects on traveling to altitude. This article will review the impact of anemia on traveling to altitude and precautions that should be taken before travel.

Thalassemia

The most common hemoglobin defect in the world is thalassemia. Adult hemoglobin comprises a multimer of four proteins—two alpha chains and two beta chains. Thalassemia syndromes occur due to genetic mutations that lead to reduced or no hemoglobin chain production (Table 1).

Given that there are four genes (two on each chromosome 16) that encode for alpha chains, there are four types of alpha-thalassemia—silent, trait, hemoglobin H disease, and hemoglobin Bart's hydrops fetalis (Piel and Weatherall, 2014). Patients with one or two alpha chains missing have minimal clinical signs with no or mild anemia and lower mean corpuscular volumes. Patients missing three chains have hemoglobin H disease. Hemoglobin H disease causes anemia due to impaired hemoglobin production and due to hemolysis caused by unpaired beta chains forming tetramers that lead to destruction of red cells. Total elimination of alpha chain production—often called hemoglobin Bart's hydrops fetalis—is incompatible with life unless diagnosed and treated prenatally. The distribution of alpha-thalassemia has been observed predominantly in Africa and Southeast Asia. The more severe forms (hemoglobin H and Bart's) are restricted to Southeast Asian patients (Piel and Weatherall, 2014).

Beta-thalassemia has three main clinical presentations (Taher et al., 2021). Thalassemia major is the lack of or greatly reduced synthesis of both beta chain genes. If hemoglobin synthesis is only moderately reduced, it is called thalassemia intermedia, and the presence of only one abnormal gene is called thalassemia trait. Patients with thalassemia major are transfusion dependent from early childhood. As the name suggests, thalassemia intermedia is associated with varying degrees of anemia, ranging from transfusion dependency to mild anemia. Trait patients are only mildly anemic, with hemoglobin in the 9–11 g/dl range.

Patients with thalassemia major are treated with aggressive transfusion therapy that both corrects the anemia and suppresses marrow production of abnormal red cells. Over time, these transfusions can lead to iron overload, which if not treated with chelation therapy can lead to end-organ damage—endocrinopathy, liver disease, and heart failure. Aggressive therapy with iron chelators can prevent these complications.

Thalassemia intermedia in patients can pose unique issues. Often it may be diagnosed later in life due to the milder nature of disease. Some can present with iron overload even without transfusions due to increased iron absorption seen with thalassemia. Those who require frequent transfusions may also be at risk for iron overload, thus requiring chelation. Some patients may require splenectomy if their splenic enlargement leads to high transfusion needs.

Due to chronic transfusion therapy, patients with thalassemia major (and intermedia requiring transfusions) who travel to altitude should have adequate exercise performance, assuming normal cardiac function. Screening with echocardiography to detect heart failure should be done if there is concern about cardiac iron overload. In addition, patients with both thalassemia types, major and intermedia, should be screened for pulmonary hypertension (Fraidenburg and Machado, 2016). Endocrinopathies are common, and osteoporosis can be an issue in older patients (Taher et al., 2021). Patients who have undergone splenectomy need to be up to date on vaccinations and should carry prophylactic antibiotics (Table 2). Asplenic patients are at risk of developing severe complications of malaria and need to rely on prophylaxis if traveling to areas where malaria is endemic.

Iron chelation therapy in patients can pose several challenges. Oral iron chelators—deferasirox and deferiprone—are used in many patients. These offer convenience, but are expensive, and (if lost or forgotten) cannot be easily replaced. Deferoxamine is still widely used, but needs to be administered subcutaneously; carrying multiple intravenous bags of drug is not feasible for most travel purposes. For short trips, a brief drug “holiday” may be the most practical approach.

Trait patients require no specific precautions. They should be advised that due to their lower baseline hemoglobin, they will have limited exercise ability compared with their peers, but there is no reason to suspect they will be more susceptible to altitude illness. Although thalassemia is often associated with increased iron stores, patients should still have their ferritin levels checked to ensure iron repletion.

Sickle Cell Anemia

Sickle cell anemia is widespread in those of African and Middle Eastern origin (Piel et al., 2017). The molecular defect for the most frequent sickling hemoglobin (hemoglobin S) is substitution of valine for glutamine at position 6 of the beta chain of hemoglobin. In hypoxic conditions, this leads to polymerization of hemoglobin S, creating long insoluble chains of hemoglobin that can lead to red cell destruction. In addition, the inflexible red cells can block blood vessels in any organ, leading to a variety of complications.

There are two clinical presentations of sickle cell—sickle cell disease and sickle cell trait. Patients with sickle cell disease may have protean manifestations of their disease (Table 2). Common to all patients is profound hemolytic anemia, with average hemoglobin in the 6–7 g/dl range. Pain crises are a frequent complication. These are attacks of severe pain in any area of the body that can last for days. Pulmonary complications are frequent, with development of pulmonary hypertension the most worrisome complication. Pulmonary hypertension may increase the risk of death 10-fold (Gladwin et al., 2004). The incidence of asthma and sleep apnea is also increased in sickle cell patients.

Treatment remains unsatisfactory. The observation that patients with increased levels of fetal hemoglobin (Hb F) have a milder disease course has led to efforts to increase Hb F production in sickle cell patients. For 20 years, the only approved agent for this purpose has been hydroxyurea, which has been shown to reduce pain crises and improve survival. Recently, three new medications have been released for sickle cell disease (Steinberg, 2020). L-glutamine was approved due to clinical trial data showing reduction in pain crises (Niihara et al., 2018). The P-selectin inhibitor crizanlizumab—administered intravenously—has also been shown to reduce episodes of veno-occlusive crisis. Finally, voxelotor can increase hemoglobin. Currently, there is much uncertainty as to when to use the agents or whether they can be combined for treatment. There is increasing interest in stem cell transplantation for patients at most risk for a shortened life span, and encouraging studies have been published recently about gene therapy.

Patients with sickle cell disease would be expected to do poorly at altitude for several reasons. First, severe anemia would limit exercise tolerance. Second, the often-present cardiopulmonary disease would also be a limiting factor—especially pulmonary hypertension. In addition, climatic conditions are thought to play a role in triggering pain crises—especially cold weather and windy conditions (Piel et al., 2017). Finally, since hypoxia promotes sickling, lower oxygen tensions would be expected to lead to more pain at altitude. Indeed, a study from Colorado showed that 20% of patients with sickle cell disease had crises when traveling above 2,000 m (Mahony and Githens, 1979). This risk of altitude is additive to the higher risk of pain crisis observed with any travel in sickle cell patients (Stankovic Stojanovic et al., 2011; Willen et al., 2014).

Patients with sickle cell disease who want to travel to altitude should start preparation early. Given that most of these patients are at least functionally asplenic, the precautions outlined in Table 3 should be undertaken. Patients with severe pulmonary hypertension (systolic pulmonary artery pressure [PASP] over 50 mmHg) should avoid altitudes over 2,000 m unless on oxygen, and those with lesser pressure should undergo careful evaluation—including assessment of PASP with simulated hypoxia—to establish risk of travel (Luks, 2009). If possible, a gradual conditioning program may be helpful in preparing for the trip and may decrease crises (Martin et al., 2015). There is increasing evidence showing that a carefully supervised exercise program can benefit patients with sickle cell disease (Gellen et al., 2018; Liem, 2018).

There are several variant forms of sickle cell anemia, which occur due to combinations of the sickle hemoglobin with other hemoglobin defects. Most common is the combination of sickle cell and beta-thalassemia. These patients tend to have fewer pain crises and are still at risk of all the serious sequelae of sickle cell disease. Another sickling hemoglobinopathy is hemoglobin SC disease, where the S beta chain is paired with hemoglobin C (da Guarda et al., 2020). Patients with hemoglobin SC often have higher hematocrit levels, but the increased viscosity seen with this condition may put them at greater risk of crisis. The Colorado study showed that 28.6% of hemoglobin SC patients had crises at altitude (Mahony and Githens, 1979). In addition, many patients with hemoglobin SC disease (and some with sickle–beta-thalassemia) will have preserved spleens into adulthood and so are at risk of splenic infarction with ascent to altitude (Githens et al., 1977).

Patients with sickle cell trait are mostly asymptomatic. The number of patients identified with sickle trait is increasing due to newborn screening, which is mandated in most states. The presence of ∼50% normal hemoglobin blocks the polymerization of the sickle hemoglobin except in the most hypoxic conditions.

Clinically, patients with sickle cell trait traveling to altitude have three concerns: risk of dehydration, sudden death, and splenic infarcts (Xu and Thein, 2019).

Trait patients may have urinary concentrating defects due to infarcts causing loss of renal tissue in the area of kidneys responsible for concentrating the urine. The concentrating defect may lead to dehydration (Sears, 1978). Hematuria is also increased in trait patients due to these small infarcts in the renal papillary area.

The most concerning trait complication has been the increased risk of sudden death reported in athletes and those in the military (Mitchell, 2018). Most reported cases have been due to hyperthermic rhabdomyolysis seen after extreme exertion in the heat (Tsaras et al., 2009). In army recruits, the risk of exercise-related death in trait recruits was 28 times higher when compared with nontrait recruits (Shaskey and Green, 2000). The pathophysiology is thought to be extreme exertion combined with dehydration, leading to vascular occlusion and then rhabdomyolysis, disseminated intravascular coagulation, organ failure, and death. A reasonable approach to prevent this dreaded complication is to avoid strenuous exercise in the heat and to stay well hydrated. The use of universal precautions concerning strenuous exercise in the heat has reduced death rates in the military among patients with sickle cell trait (Nelson et al., 2016). Trait patients also need to be aware that muscle cramps can be an early warning sign for these complications and they need to stop their activities accordingly.

Splenic infarct is a unique high-altitude complication of sickle cell trait. This was first reported in 1950 (Sullivan, 1950), with the first case series noting the triad of splenic infarction, sickle trait, and high altitude published in 1954 (Cooley et al., 1954). The altitude where infarctions have been recorded is usually over 1,500 m (Sears, 1978; Lane and Githens, 1985; Goodman et al., 2014). Splenic infarction is manifested by severe left upper quadrant pain soon—usually within 24 hours—after reaching altitude or becoming hypoxic. Vomiting is common, as is fever. On examination, a third of patients will have a palpable spleen tip (Goodman et al., 2014). In progressive cases, the pain can become severe with signs of an acute abdomen. The underlying pathophysiology is infarction of the spleen.

On reviewing the literature, white patients with sickle cell trait appear to be at increased risk of splenic infarction (Lane and Githens, 1985). In a series of 25 cases from Colorado, 41% of patients were non-Hispanic whites and 18% were Hispanic (Goodman et al., 2014). Given the rarity of trait in white patients (0.09%) (Niebuhr et al., 2017), there may be a specific predilection for infarction in this population.

Imaging with computed tomography or ultrasound can identify the infarcts. Treatment is conservative. Many patients respond to descent from altitude and pain control (Kumar et al., 2019). Patients with unremitting pain, acute abdomen, or signs of rupture should undergo splenectomy.

Given the unknown, but low, risk of splenic infarct, travel to altitude should not be precluded for trait patients—especially since there are rare reports of splenic infarctions at sea level (Gitlin and Thompson, 1989). A reasonable approach would be to recommend descent from altitude at the onset of any left upper quadrant pain and to seek medical care if pain does not remit.

Inherited Hemolytic Anemia

In general, there are three major classes of inherited hemolytic anemia: (1) membrane defects such as hereditary spherocytosis (HS); (2) hemoglobin defects such as sickle cell disease; and finally, (3) enzymatic defects, an example of which is glucose-6-phosphate dehydrogenase (G6PD) deficiency.

The inherited hemolytic anemia classes share several common traits (Haley, 2017). First, the degree of hemolysis can vary greatly. For example, patients with HS range from having severe anemia starting at birth to subtle defects only detected much later in life. Second, the degree of hemolysis can be exacerbated by internal and external stressors. For example, infection can worsen hemolysis with many hemolytic anemia disorders. Certain medications can induce hemolysis with G6PD deficiency. Third, because of increased bilirubin due to hemolysis, the incidence of gallstones is increased, which may lead to cholecystitis at an early age. Finally, due to increased demand for erythropoiesis, patients are at risk of becoming folate deficient.

One thing that is common to all hemolytic anemia disorders is release of free hemoglobin during episodes of hemolysis. This free hemoglobin binds the vasodilator, nitric oxide, which increases pulmonary artery vasoconstriction (Schaer et al., 2013). This at altitude may be detrimental as it would augment the hypoxic pulmonary artery vasoconstriction and predispose to high altitude pulmonary edema.

Membrane Defects

The membrane of the red cell is designed to be a biconcave disk to provide maximal surface area for gas exchange. A protein cytoskeleton holds the red cell in this shape. Defects in the cytoskeleton lead to an erythrocyte that is misshapen and fragile, making it prone to shedding parts of its membrane; eventually, this can lead to rupture of the red cell.

The most common membrane defect is HS with an incidence of 1:5,000 (Malec, 2020). In this anemia, parts of the erythrocyte membrane are shed, leading to red cells taking on a spherical shape. The deformed red cells do not tolerate mechanical stress (such as traversing the spleen) as well and undergo hemolysis. Most patients have compensated anemia, but stress such as infection can exacerbate hemolysis. Most patients have moderate hemolysis—perhaps due to mild cases not being diagnosed. Typical findings in moderate disease are anemia with a hemoglobin level in the 10 g/dl range and signs of hemolysis such as a high indirect bilirubin and low haptoglobin. On examination, patients may have palpable splenomegaly. The diagnosis is made by observing spherocytes in the blood smear; it is confirmed by either finding an abnormal osmotic fragility or by observing lack of eosin-5′-maleimide binding—indicating missing skeletal proteins—on flow cytometry (Malec, 2020).

In counseling for altitude travel, patients with HS should be advised of impaired exercise ability due to anemia. Patients are at risk of having increased hemolysis in the setting of infection. Patients who have been treated with splenectomy need to take precautions as outlined in the Sickle Cell Anemia section. Given the increased incidence of gallstones, patients who develop symptoms consistent with cholecystitis while traveling should be empirically treated with amoxicillin–clavulanate or moxifloxacin until they can be evacuated and assessed. While splenomegaly is common, splenic rupture is fortunately very rare.

Enzymatic Defects

The best-characterized and most common enzyme defect causing congenital hemolytic anemia is G6PD deficiency, which may affect up to 5% of the population (Luzzatto et al., 2016; Stone et al., 2020). Hemoglobin is very prone to oxidation, which leads to development of insoluble hemoglobin precipitate with resultant hemolysis as the spleen removes these aggregates. Given this, the red cell requires constant reducing power to maintain normal hemoglobin. G6PD is a key enzyme in this reducing pathway, and mutations that affect its function can lead to excess oxidation of hemoglobin, which leads to hemolysis. The vast majority of mutations in the G6PD gene lead to hemolysis only when the reducing system is stressed—as with some medications or infections (Malec, 2020). The hemolysis can be brisk and severe, leading to severe anemia. There are two major subtypes of G6PD deficiency. The Mediterranean form has a less efficient enzyme that can be overwhelmed by oxidative stress. The African type is an unstable enzyme, so if exposed to oxidative stress, the higher amount of enzyme in reticulocytes can compensate. The Mediterranean form tends to have more severe anemia with oxidative exposure. While the G6PD gene is sex linked, women are also at risk of hemolysis as enzyme activity can be variable due to the random inactivation of one X chromosome in women.

The most common trigger for hemolysis is medication (Luzzatto et al., 2016). While all agree that some drugs are highly likely to induce hemolysis, other drugs remain controversial. The antimalarials, dapsone, primaquine, and pamaquine, are definitely contraindicated in those with G6PD deficiency, while chloroquine and quinine are possibly trigger drugs (Belfield and Tichy, 2018; Dominelli et al., 2020). For antibiotics, the fluoroquinolones have been implicated as triggers for hemolysis in affected patients. Although some consider acetazolamide a risky drug, a recent study showed no issues (Dominelli et al., 2020).

Patients with known G6PD deficiency should avoid medications that can lead to hemolysis. When anyone takes a suspect medication and develops back pain and dark urine, G6PD deficiency should be suspected and the offending medication stopped. An unusual syndrome that mainly complicates the Mediterranean form is favism. This is when a patient has severe hemolysis after eating fava beans. Strangely, the patient may have previously eaten these beans with no issues.

High-Affinity Hemoglobin

A rare hemoglobin defect may predispose carriers to do better at altitude. Mutations in high-affinity hemoglobin result in decreased oxygen delivery to the tissues. This results in not only higher hemoglobin levels but also better performance with hypoxia. Studies in patients with high-affinity hemoglobin with an average hemoglobin level of 20 g/dl showed less hypoxia-induced decline in exercise performance with altitude (Hebbel et al., 1978; Dominelli et al., 2020). Less commonly detected is the low-affinity hemoglobin, which can lead to mild anemia (Yudin and Verhovsek, 2019). While there are no studies of patients with low-affinity hemoglobin at altitude, they would be expected to have impaired exercise performance both due to anemia and decreased ability for hemoglobin to load oxygen.

Summary

Inherited anemia is common, and preparation for travel to altitude requires knowledge of the natural history of anemia and its severity in the patient. Knowing the physiology of the underlying cause of the patient's anemia can provide knowledge to plan for adventure trips.