Impaired physical ability in patients with transfusion‐dependent β‐thalassaemia: Can regular physical activity be a countermeasure?

Summary

Transfusion‐dependent β‐thalassaemia (TDβT) is a genetic disorder characterised by reduced or absent β‐globin chain synthesis, resulting in chronic anaemia. Treatment consists of regular blood transfusions and chelation therapy to limit iron overload and its negative effects on organs (e.g. heart, lungs and liver). Despite improved life expectancy with transfusions and chelation therapy, TDβT patients experience poor quality of life and impaired exercise capacity (mainly due to muscle deconditioning and reduced cardiac inotropism). The aims of this review are (i) to discuss the role of organ dysfunction in the impairment of exercise capacity and reduced quality of life of TDβT patients; and (ii) to discuss physical activity as a potential therapeutic strategy to alleviate the multifactorial impact of the disease.

Regular physical activity (ΦAct) may be used as a possible therapeutic strategy to limit some symptoms of transfusion‐dependent β‐thalassaemia (TDβT). Indeed, regular ΦAct could (i) improve physical ability and reduce depression and anxiety, all of which affect quality of life; (ii) reduce oxidative stress and haemolysis and have positive effects on haemoglobin levels and cardiac function; and (iii) increase bone mineral density, limiting fragility fracture risk. In addition, regular ΦAct has been shown to increase medication adherence, which could help limit iron overload and related damage in TDβT patients.

INTRODUCTION

β‐Thalassaemia comprises group of diseases mainly present in Mediterranean and Asiatic populations, caused by genetic mutations on chromosome 11. These mutations induce a reduction (β⁺) or absence (β⁰) of β‐globin chain synthesis leading to an imbalanced α‐to‐β–globin chains ratio. In excess, α chains aggregate and damage the cell membrane, causing intramedullary apoptosis of erythroid precursors, reduction in normal haemoglobin synthesis, shorter lifespan of mature red blood cells, haemolysis and chronic anaemia. Patients receive treatment via regular blood transfusions to (i) maintain haemoglobin levels above 9 g/dL and (ii) reduce intra‐ and extra‐medullary erythropoiesis, thus avoiding organomegaly (spleen, liver and bones). ¹ , ² , ³ Other possible therapeutic strategies include haematopoietic stem cell transplantation and gene therapy (currently under development and implementation). ⁴

While transfusion‐dependent transfusion‐dependent β‐thalassaemia (TDβT) patients, benefit from increased life expectancy, the frequent transfusion can increase their risk of developing iron overload due to a deficiency of hepcidin, a hormone that inhibits iron absorption. ⁵ , ⁶ Each unit of blood contains approximately 250 mg of iron. ⁵ Because physiological pathways for iron elimination are absent and because erythropoiesis is ineffective, iron overload ⁵ is an inescapable issue for TDβT patients if left untreated. Unfortunately, the resulting iron depositions and accumulations can induce severe organ dysfunction (e.g. heart and liver).

Chelating agents (e.g. deferasirox, deferiprone and deferoxamine) are used to prevent or limit (at least partly) iron overload‐related damages. ⁷ In that sense, chelation decreases some risks (e.g. cardiomyopathy) and consequently increases survival. ⁸ Nonetheless, despite improvements in the clinical profile, exercise capacity, quality of life and overall well‐being due to transfusion and chelation therapies, ⁹ the health state of TDβT patients remains lower compared to that of healthy subjects. ¹⁰ , ¹¹ , ¹²

The multiorgan consequences related to the disease require regular medical follow‐ups (cardiology, pneumology, hepatology, rheumatology, etc.), inducing a heavy medical burden. Furthermore, regular assessment of iron stores and deposition (once a year according to the French recommendations) is essential.

This manuscript focuses on the repercussions of TDβT (outside the context of haematopoietic stem cell transplantation) on the function of organs involved in exercise and physical ability, and consequently on sedentary behaviour and quality of life of TDβT patients. This paper also proposes physical activity (ΦAct) to be potential complementary strategy in the therapeutic arsenal of patient care.

TDβT REPERCUSSIONS ON ORGANS INVOLVED IN EXERCISE CAPACITY/PHYSICAL ABILITY

TDβT patients, who often develop iron overload, may experience complications related to the dysfunction of organs, such as the lungs, heart (e.g. arrhythmias), bones (e.g. osteopaenia) and muscles (e.g. sarcopaenia), all involved in exercise capacity and exercise tolerance. Below we describe how each organ system is uniquely affected by the disease.

Pulmonary function

Pulmonary function is often impaired in TDβT, at rest and during exercise. ² , ¹³ , ¹⁴ , ¹⁵ The most common impairment is a restrictive pattern, but the prevalence is widely variable between studies (from 13.5% to 79.0%). ¹⁶ Many studies (but not all) suggest a possible implication of iron overload in the aetiology of pulmonary dysfunction. Correlations have been observed between (i) myocardial T2* and the predicted percentage of functional vital capacity or the total lung capacity (TLC), ¹⁴ and (ii) ferritin levels and restrictive parameters (diffusion capacity and TLC). ¹⁴ , ¹⁷ , ¹⁸ It is important to mention that some studies have found no correlation between iron stores and pulmonary dysfunction, ¹⁵ , ¹⁹ showing that the relationship between iron load and pulmonary function is unclear.

Pulmonary hypertension is also frequently observed in TDβT (especially in splenectomised patients). Several pathophysiological mechanisms seem to be involved, including left ventricular dysfunction, hypercoagulable state, haemolysis, chronic hypoxaemia, oxidative stress and iron (over)load. ²⁰ , ²¹ , ²²

Cardiovascular function

Cardiopathies are one of the most common causes of death in TDβT, even in patients without cardiac iron overload. ⁹ , ²³ , ²⁴ Several cardiovascular abnormalities such as bradycardia, paroxysmal atrial fibrillation episodes, important arrhythmic indexes, systolic and diastolic dysfunction, myocardial fibrosis and pulmonary arterial hypertension have been reported in TDβT patients. ²⁴ , ²⁵ , ²⁶ , ²⁷ Interestingly, previous studies have reported (i) a negative correlation between cardiac iron load and contractile reserve during exercise, ²⁸ (ii) an association between repolarisation abnormalities (QT interval prolongation, leftward shift of the T‐wave axis and ST/T wave changes) and cardiac iron load ²⁵ and (iii) a negative relationship between iron input (during the past year) and S′ waves measured by tissue Doppler imaging. ²⁹ Although these associations do not prove cause‐and‐effect relationships, iron is nevertheless known to mediate cardiac fibrosis ³⁰ and interacts with ryanodine‐sensitive calcium channels, leading to inhomogeneous myocardial contractions. ³¹ Moreover, iron induces oxidative stress and inflammation, which lead to atrial fibrillation and increased vascular resistance. ³²

Several pathophysiological mechanisms are implicated in the development of cardiovascular pathologies, including the reduction of nitric oxide availability (due to haemolysis), chronic tissue hypoxia, oxidative stress (due to diabetes mellitus, haemolysis, iron and hypoxia) and an increased hypercoagulable state (due to splenectomy), all of which increase cardiovascular resistance and remodelling. ²¹ , ²² , ³² Additionally, cardiac impairments such as reduced left atrial size and systolic dysfunction are known predictors of decreased physical ability. ³³

Anaemia and oxygen saturation

Although transfusions can increase haemoglobin concentration, TDβT patients may not systematically achieve the ‘normal’ haemoglobin levels found in healthy subjects (i.e. above 13 g/dL for males or 12 g/dL for females in adults), but rather only transiently. During the transfusion cycle (typically 3 weeks, but can range from 2 to 6 weeks), anaemia fluctuates within haemoglobin levels ranging between 8–10 and 10–12 g/dL. ³⁴ , ³⁵ Anaemia causes fatigue, which worsens towards the end of the transfusion cycle. Even at rest, TDβT patients can be subjected to arterial hypoxaemia (below 95%). ³⁴ , ³⁶ However, this is not systematic, as some studies did not find any impairment in arterial oxygen saturation. ³⁷ Independently, but a fortiori in combination, low haemoglobin levels and arterial oxygen desaturation drastically reduce oxygen transport and supply to the tissues (such as the heart and especially the active skeletal muscles), resulting in the reduction of physical ability, exercise tolerance and fatigue resistance (vide infra). ³⁸

Bones and joints

Thalassaemia bone disease, which includes osteoporosis, coarse trabeculae, joint effusion, disk degeneration, nerve compression, metaphyseal dysplasia and pain, is a common complication in TDβT. ³⁹ , ⁴⁰ Thavonlun et al. reported a prevalence of 38.4% for osteoporosis, 55.4% for osteopaenia and 20.5% for fragility fracture in TDβT patients. ⁴¹ The origin of these osseous repercussions is multifactorial and seems to implicate: bone marrow expansion caused by ineffective erythropoiesis, ⁴² iron toxicity, ⁴³ iron chelation, ⁴⁴ endocrine abnormalities (hypogonadism, hypothyroidism, diabetes mellitus and growth hormone deficiency) ⁴⁵ , ⁴⁶ , ⁴⁷ and vitamin D deficiency. ⁴⁸ , ⁴⁹ It is important to note that low ΦAct level was associated with low bone mineral density and pain severity suggesting that (i) sedentary behaviour may contribute to osteopaenia and (ii) pain could restrain ΦAct of patients. ⁵⁰ Therefore, regular ΦAct could be an interesting strategy to limit the decrease in bone mineral density and thus avoid fragility fractures (vide infra). ⁵¹

Muscles and nerves

To our knowledge, only a few studies have evaluated muscle function in TDβT patients. Among these, one study evaluated 112 patients and found that 61.6% had sarcopaenia. ⁴¹ In accordance, another study conducted on six TDβT patients showed (i) atrophy of muscle fibres, with predominance of type 1 fibres; and (ii) myopathic changes on electromyography. ⁵² Together, these studies support the notion of muscle deconditioning in TDβT patients. Along the same line, another study reported that 27.7% of TDβT patients had myopathy and 38.9% had polyneuropathy (according to criteria defined by the American Academy of Neurology, the American Association of Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation). ⁵³ The pathophysiological mechanisms may include iron overload, as shown by an association between cardiac iron and polyneuropathy/sarcopaenia, ⁵³ gonadal status ⁵⁴ and possible toxicity of iron chelators as demonstrated by (i) an association between deferasirox use and sarcopaenia ⁴¹ and (ii) a link between high dose of deferoxamine and optic/auditory neuropathy. ⁵⁵ , ⁵⁶ Furthermore, other factors such as chronic hypoxia, age, bone marrow expansion, vitamin E deficiency and oxidative stress appear to be associated with reduced neurological function. ⁵⁵ , ⁵⁷ , ⁵⁸ , ⁵⁹ However, further studies are warranted to elucidate the underlying mechanisms of the TDβT‐associated myoneural alterations and chelation therapy on muscle function and characteristics.

PHYSICAL ABILITY AND EXERCISE LIMITATIONS

Numerous studies have identified notable reductions of physical capacities in TDβT patients, indicated by low values of peak oxygen consumption (V̇O₂peak) and (so‐called) anaerobic threshold compared to healthy controls or their predicted values. ²⁸ , ²⁹ , ³⁵ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵

At the pulmonary level, Nanas et al. observed that most TDβT patients exhibited limited maximal inspired pressure (P _imax). ⁶² Because P _imax was found to be correlated with V̇O₂peak in those patients, ⁶⁰ , ⁶² at least part of the physical ability impairment of TDβT patients could be related to inspiratory muscle deconditioning.

Physical ability is directly related to the oxygen transport capacity, ⁶⁶ which depends on maximal cardiac output (maximal heart rate and maximal stroke volume) and arterial oxygen content. Concerning the factors of cardiac output, a lower stroke volume (vide infra for further discussion) and/or a limited heart rate reserve could impair O₂ transport and thus physical abilities in TDβT patients. ⁶² , ⁶³ Concerning arterial oxygen content, anaemia is a well‐known factor associated with exercise capacity limitations, ⁶⁷ , ⁶⁸ and as expected, an increase in exercise tolerance is observed after transfusion. ³⁴ , ³⁵ Studies have reported that each gramme of haemoglobin gained by transfusion allows an increase in oxygen consumption by 82.5 mL/min at maximal exercise (and 35.0 mL/min at the ‘anaerobic threshold’). ³³ , ⁵⁸ However, in TDβT patients, the degree of anaemia is not always correlated with exercise performance and does not explain exercise tolerance variability between patients, suggesting that exercise limitation is multifactorial and other pathophysiological mechanisms must be implicated (vide infra). ⁶⁰

Many studies have reported limitations in O₂ pulse (oxygen uptake/heart rate ratio) at maximal exercise, reflecting impairments of maximal stroke volume and/or oxygen extraction by the active muscles. ² , ³ , ⁶² , ⁶³ One explanation is a lower maximal stroke volume in conjunction with other adverse cardiovascular alterations. In that sense, a previous study reported that O₂ pulse was correlated with high sensitivity reactive protein C, a systemic inflammation marker, suggesting that chronic vascular inflammation was associated with alterations in cardiac response to exercise, limiting O₂ pulse. ⁶³ A second explanation would be related to skeletal muscle alterations, as a decrease in O₂ pulse may lead to a lower muscle oxygen extraction (CaO₂‐CvO₂). ⁶⁹ In deconditioned patients, defective oxygen extraction is a leitmotif due to inability of patients to take off and utilise oxygen. ⁷⁰ Additionally, V̇O₂peak of TDβT patients was found to be positively correlated with muscle mass, showing that muscle hypotrophy and/or weakness may cause impairments in V̇O₂peak and physical ability. ⁶⁰ Piatti et al. ⁶⁰ found that the greatest factor for exercise limitation in patients is muscle deconditioning, defined as early‐onset metabolic acidosis, low O₂ pulse, significant breathing reserve and normal maximum heart rate during an incremental exercise test (found in 63.0% of patients).

Regarding the multifactorial nature of exercise limitation in TDβT patients, Piatti et al. ⁶⁰ also reported that reduced cardiac inotropism due to iron deposition (in 57.4% of patients) is another important factor. For a minority of their patients (26.4%), exercise limitation was due to deficits in lung perfusion. ⁶⁰ Similarly, other studies reported that, in addition to anaemia, pulmonary and cardiac dysfunctions as well as muscle deconditioning were implicated in exercise intolerance in TDβT. ⁶⁰ , ⁶² , ⁷¹ , ⁷²

The literature has reported negative correlations between V̇O₂peak or maximal heart rate and cardiac iron burden (both, p < 0.03). ⁶³ Although weak (r ² = 0.10 and 0.08, respectively), these correlations suggest that while not all patients with poor physical ability have high iron burden, it is apparent that all patients with cardiac iron overload display poor physical ability. ⁶³

Splenectomy may also contribute to exercise capacity reduction in TDβT patients. Indeed, Nanas and colleagues observed that V̇O₂peak and the (so‐called) anaerobic threshold were lower in splenectomised compared to non‐splenectomised TDβT patients, possibly due to a more severe clinical profile (e.g. cardiac abnormalities) in the former patients. ⁶² It is not clear, however, whether these reduced physical abilities were also due to a lower exercise‐induced haemoconcentration, given a lack of spleen contraction in splenectomised patients, which has been shown in thalassaemia intermedia. ⁷³ Further studies are needed to evaluate the difference in exercise capacities and their underlying mechanisms between splenectomised and non‐splenectomised TDβT patients.

ROLE OF ΦAct IN QUALITY OF LIFE

Previous studies reported that quality of life (including several dimensions of physical and mental health) is reduced in TDβT patients. ¹⁰ , ¹² , ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ , ⁷⁸ Quality‐of‐life assessment is indeed complex, as it incorporates various factors including, but not limited to, psychosocial aspects (e.g. professional life), clinical burden, chronic fatigue, pain, as well as complications associated with the disease (e.g. splenomegaly, infertility, bone deformities and fractures and diabetes). ¹² , ⁷⁴ , ⁷⁹ , ⁸⁰

In this complexity, ΦAct nevertheless appears as an important component of quality of life. ⁷⁴ In that sense, a cross‐sectional study in TDβT patients found that ΦAct was the dimension with the lowest score on the ‘Health Promoting Lifestyle Profile’ questionnaire, which also evaluates spiritual growth, health responsibility, interpersonal relationships, stress management and nutrition. ⁷⁴

Because of anaemia, fatigue, physical deconditioning and pain, TDβT patients are prone to adopt a (hyper)sedentary lifestyle (Figure 1). ⁵⁰ , ⁸¹ , ⁸² In accordance, only 27.8% of TDβT patients undertook vigorous ΦAct (according to International Physical Activity Questionnaire). ⁶⁰ However, these sedentary behaviours are known to increase the risk of comorbidities (diabetes, cancer and hypertension), and as already mentioned, to decrease quality of life. ⁸³ , ⁸⁴ This is a vicious cycle where inactive patients worsen their physical deconditioning, fatigue, depressive symptoms and consequently quality of life. Regular ΦAct may appear as an interesting strategy to escape from this vicious cycle. As such, a previous study in TDβT patients found those who regularly performed vigorous ΦAct did not suffer from muscle deconditioning, while patients with low ΦAct levels had lower V̇O₂peak values than patients with moderate/vigorous ΦAct. ⁶⁰ One may conclude that muscle deconditioning was mainly due to low ΦAct levels, and therefore an active lifestyle may prevent physical deconditioning and exercise capacity decline in TDβT patients.

FIGURE 1.

Hypothetical mechanisms involved in quality of life and physical ability in transfusion‐dependent β‐thalassaemia. Reduced β‐globin chain synthesis leads to the precipitation of excess α chains, which causes both haemolytic anaemia and oxidative stress. Moreover, transfusion and hepcidin deficiency induce iron overload and related organ dysfunction (heart, lungs and bones). These organ dysfunctions and the muscle deconditioning caused by a sedentary lifestyle both contribute to poor physical ability and quality of life.

PERSPECTIVES: POTENTIAL BENEFITS OF REGULAR ΦAct IN TDβT

Regular physical exercise (the most often studied being endurance training) has proven benefits in multiple disease states (e.g. diabetes, metabolic syndrome, cancer, cardiac disease and obesity) by increasing physical ability and quality of life and decreasing fatigue, pain and depression. ⁸⁵ , ⁸⁶ , ⁸⁷ , ⁸⁸ , ⁸⁹ Interestingly, moderate‐intensity endurance training has also been shown to be beneficial in sickle cell anaemia, by limiting muscular hypotrophy, growing microvasculature, increasing oxidative metabolism and improving physical ability. ⁹⁰ , ⁹¹ Similar results could be expected in TDβT patients.

Because oxidative stress, which is highly prevalent in TDβT (due to degradation of the unstable haemoglobin and iron overload), aggravates haemolysis, ineffective erythropoiesis and vital organs failure, ⁹² endurance and resistance training that improve the antioxidant defences ⁹³ may serve as a possible strategy to limit some symptoms of TDβT.

Additionally, it has been shown that regular ΦAct improves bone mineral density and consequently overall health state. ⁵¹

In TDβT, endurance training (e.g. walking, cycling and swimming) may be an interesting strategy to limit iron overload‐related damage to organs. Indeed, two recent studies showed that (i) regular ΦAct reduced iron overload‐related cardiac damages on experimentally iron‐overloaded rats ⁹⁴ and (ii) mild‐intensity ΦAct alleviates iron accumulation in cardiac tissue and bones in a thalassaemic murine model. ⁹⁵ Furthermore, endurance and resistance training have been shown to increase hepcidin levels, thereby reducing iron absorption. ⁹⁶ Taken together, these three studies suggest that ΦAct may decrease iron absorption and overload, thereby reducing the risk of cardiopathy. These improvements in the regulation of iron homeostasis have the potential to increase physical ability and quality of life of TDβT patients (Figure 2).

FIGURE 2.

Potential beneficial effects of regular physical activity in transfusion‐dependent β‐thalassaemia. Regular physical activity may appear as a potential interesting strategy to limit anaemia, iron overload, muscle deconditioning and fragility fracture risk. Exercise may (i) limit iron absorption by increasing hepcidin expression, (ii) decrease oxidative stress damages (haemolysis and cardiac dysfunction), (iii) improve mental health and (iv) increase bone density. All these factors may contribute to improving patients' quality of life by improving either their physical fitness and/or their mental health.

Moreover, it cannot be excluded that regular ΦAct also could increase treatment adherence as shown in patients with severe mental disorders and hypertension. ⁹² , ⁹³ As low compliance to iron chelation is associated with higher risk of cardiac disease and endocrinopathies as well as a lower survival, ⁹⁴ regular ΦAct could help decrease the risk associated with iron (over)load.

In addition, by increasing self‐esteem, social support and self‐efficacy, ⁹⁷ ΦAct has been shown to be beneficial for depression, which has a high prevalence in TDβT (between 20% and 40%). ⁷¹ , ⁹⁵ , ⁹⁶

However, to date, only one study has evaluated the effects of 8 weeks of physical training (aquatic training, 3 sessions per week, 1 h per session) on TDβT patients, which reported a significant increase in quality‐of‐life mean score and haemoglobin levels, although a non‐significant decrease in iron levels, in the experimental group. ⁹⁸ Further studies with different experimental paradigms are necessary to investigate the feasibility and safety of endurance training and its potential beneficial effects on pathophysiology (e.g. iron overload, cardiovascular function and low bone mineral density), physical ability, mental health and quality of life in TDβT patients.

CONCLUSION

This manuscript aimed to discuss the links among organ dysfunction, poor physical ability, low ΦAct levels and poor quality of life in TDβT patients. Physical ability is reduced mainly because of cardiopulmonary dysfunctions, anaemia and muscle deconditioning. Regular ΦAct may offer a possible strategy to decrease muscle deconditioning, to increase physical ability and therefore quality of life. Further studies are needed to evaluate the safety and the benefits of regular exercise in TDβT patients. Special attention should be paid to the dose (quantity and intensity) of ΦAct to implement feasible, safe and beneficial ΦAct for TDβT patients.

AUTHOR CONTRIBUTIONS

MN and LAM designed the paper. MN, PB and LAM wrote the first draft. All authors critically revised and approved the present version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest or financial interests.

Noguer M, Berthon P, Makowski C, Messonnier LA. Impaired physical ability in patients with transfusion‐dependent β‐thalassaemia: Can regular physical activity be a countermeasure? Br J Haematol. 2025;206(1):86–93. 10.1111/bjh.19847