Pathophysiology and physical activity in patients with sickle cell anemia
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1 Movement & Sport Sciences Science & Motricité 83, (2014) c ACAPS, EDP Sciences, 2014 DOI: /sm/ Pathophysiology and physical activity in patients with sickle cell anemia Xavier Waltz and Philippe Connes UMR Inserm 665, Pointe-à-Pitre, Université des Antilles et de la Guyane, Pointe-à-Pitre, Guadeloupe Laboratoire d Excellence (LABEX) GR-Ex The red cell: from genesis to death, PRES Sorbonne Paris Cité, Paris, France Institut Universitaire de France, Paris, France Laboratoire ACTES (EA 3596), Département de Physiologie, Université des Antilles et de la Guyane, Pointe-à-Pitre, Guadeloupe Received 17 June 2013 Accepted 8 September 2013 Abstract. Sickle cell anemia (SCA) is an inherited blood disorder caused by a single mutation on the β-globin gene leading to the synthesis of an abnormal hemoglobin S (HbS). Under deoxygenation, HbS may polymerize leading to red blood cell (RBC) sickling, hemolysis, vaso-occlusion and ultimately chronic organ damage. The metabolic changes occurring during a physical exercise may initiate sickling and painful vaso-occlusion. Although, few studies suggested that exercise could have beneficial effects in SCA patients, actually there is no accurate recommendation for physicians to prescribe an exercise program in this population. SCA patients are usually encouraged to exercise on a symptom-limited basis. This review discusses the basic theoretical principles that could be used for exercise training in patients with SCA. Key words: Sickle cell disease, exercise rehabilitation, exercise testing, clinical complications, physical fitness Résumé. Physiopathologie et activités physiques chez les patients drépanocytaires homozygotes. La drépanocytose homozygote (génotype SS) est une maladie génétique conduisant àlasynthèse d hémoglobine S (HbS). La polymérisation de l HbS, durant sa désoxygénation, est l élément physiopathologique primaire conduisant àlafalciformationérythrocytaire et aux complications cliniques associées àladrépanocytose homozygote. Les changements métaboliques qui ont lieu durant une activité physique peuvent initier la falciformation érythrocytaire et la survenue de crises vasoocclusives. Cependant, bien que quelques rares études suggèrent qu une activité physique pourrait être bénéfique chez ces patients, actuellement il n existe aucune recommandation précise autorisant la prescription de programmes d entraînement. Cette revue a pour objectif de présenter les principes théoriques de bases qui pourraient être utilisés pour la pratique d une activité physiquedans le cadre de cette maladie. Mots clés : Drépanocytose, réhabilitation par l exercice, tests d effort, complications cliniques, aptitude physique 1 Sickle cell anemia and the classical pathophysiological model African traditional medicine knew sickle cell anemia (SCA) for centuries. During the cold season, a part of the African population experienced chronic rheumatisms. In 1910, James Herrick was the first scientist to describe sickle red blood cells (Herrick, 1910) and the mutation causing HbS was described in 1977 by Marotta et al. (Marotta, Forget, Cohne-Solal, Wilson, & Weissman, 1977; Marotta, Wilson, Forget, & Weissman, 1977). The gene defect is a mutation of a single nucleotide (A T) on the β-globin chain, which results in the substitution of valine for glutamic acid in the sixth position of the beta chain of the hemoglobin S (HbS). The hydrophobic residues of valine at position 6 of the beta chain in hemoglobin are able to associate with the hydrophobic patch, causing HbS molecules to aggregate and form Article published by EDP Sciences
2 42 Movement & Sport Sciences Science & Motricité /1 fibrous precipitates under deoxygenated condition. Such a phenomenon is called polymerisation of HbS (Perutz & Mitchison, 1950; Stuart & Nagel, 2004) and is usually reversible on reoxygenation. However, repeated cycles of deoxygenation/reoxygenation cause red blood cell (RBC) damages leading to hemolysis and hemorheological disorders (i.e., a reduction of RBC deformability and alterations of RBC aggregation properties). After many repeated cycles of deoxygenation/reoxygenation, RBCs become and remain irreversibly sickled (Ballas & Mohandas, 2004). SCA refers to the homozygous state (HbSS) of sickle cell disease (SCD), but other frequent forms of SCD exist such as sickle-hemoglobin C disease (SC), sickle-β + thalassemia and sickle-β 0 thalassemia. More than 50 million of persons are affected by this disease worldwide (Angastiniotis, Modell, Englezos, & Boulyjenkov, 1995). When RBCs from patients with SCA become deoxygenated in the capillaries, the HbS polymerizes inducing the sickling process, which decreases the deformability of the RBCs. Rigid cells fail to move through the small blood vessels, hence blocking local blood flow in the microvasculature (Ballas et al., 2004; Jung, 2010; Marossy, Svorc, Kron, & Gresova, 2009). The abnormal rheology of the sickle RBCs contributes to tissue hypoxia, vasoocclusive crisis and ultimately organ damage. Moreover, these rigid RBCs are more fragile than normal RBCs, hence promoting hemolytic episodes and severe anemia (Embury, 1986). It is known that the percentages of HbS and fetal hemoglobin (HbF) determine the polymerization tendency and thus can modulate the severity of SCA (Platt et al., 1994). However, HbS polymerization only is insufficient to explain the extreme variable phenotypic expression of SCA and its multiple complications such as vaso-occlusive painful crisis, acute chest syndrome, pulmonary hypertension, leg ulcer, priapism, glomerulopathy and stroke (ischemic or hemorrhagic). Although SCA is a monogenic disorder, the pathophysiological mechanisms involved are complex. 2 Sickle cell anemia and the two sub-phenotypes Recently, a new model of the pathophysiology of SCA has been proposed (Gladwin & Vichinsky, 2008; Kato, Gladwin, & Steinberg, 2007) with the presence of two clinical/biological phenotypes: 1) the hemolyticendothelial dysfunction phenotype and 2) the viscosityvaso-occlusion phenotype. 1 Hemolytic-endothelial dysfunction phenotype The hemolytic-endothelial dysfunction phenotype is characterized by a high rate of hemolysis, which mainly impacts on the vascular physiology at the pre-capillary arterioles level, but also in large arteries (Connes, Verlhac, & Bernaudin, 2013; Katoet al., 2007). As a result of hemolysis, hemoglobin is released into plasma where it reacts with nitric oxide (NO) to produce methemoglobin and nitrate, resulting in abnormally high rates of NO consumption and a reduction of NO bioavailability. Moreover, the release of RBC arginase into the plasma catabolizes plasma arginine, reducing its availability. In addition, heme and heme-iron dissociate from Hb and catalyze the production of reactive oxygen species (ROS), which are potent NO scavengers (Kato et al., 2007). The increased oxidative stress aggravates hemolysis by stimulating the process of RBCs senescence, RBC phagocytosis by macrophages and extravascular hemolysis. The oxidized flippase enzyme causes a disruption of membrane phospholipid asymmetry followed by phosphatylserine exposure and membrane vesiculation resulting in a release of RBC toxic microparticles. RBC microparticles have been recently demonstrated to cause vaso-occlusion at the kidney level in a murine model of sickle cell disease (Camus et al., 2012). The drop in plasma NO content causes endothelial dysfunction, over-expression of vascular adhesion molecules and impaired vasomotor tone (Kato et al., 2005; Lin,Rodgers,&Gladwin,2005). In support of these mechanisms, plasma from patients with SCA contains cell-free ferrous oxyhemoglobin, which stoichiometrically consumes micromolar quantities of NO and abrogates forearm blood flow response to NO donor infusion (Reiter et al., 2002). These biological alterations seem to be involved in the development of pulmonary hypertension (Gladwin et al., 2004), glomerulopathy (Nebor et al., 2010), leg ulcers (Connes et al., 2013b), priapism (Kato et al., 2007), cerebral vasculopathy (Connes et al., 2013a), ischemic stroke (Bernaudin et al., 2008) and silent cerebral infarct (DeBaun et al., 2012). 2 Viscosity-vaso-occlusion phenotype Painful vaso-occlusion, acute chest syndrome and osteonecrosis would belong to the viscosity-vaso-occlusion phenotype, which takes place mainly in the post-capillary venules (Kato et al., 2007). A large epidemiological study in the United States (the Cooperative Study of Sickle Cell Disease) demonstrated that high hematocrit (Hct) increased the risks for vaso-occlusive crises (Platt et al., 1991). Because Hct is a key component of blood viscosity, it is expected that blood viscosity could be increased in patients at risk for vaso-occlusive crisis. Recently, two studies strengthen this hypothesis both in sickle cell adults (Nebor et al., 2011) and children (Lamarre et al., 2012): SCA patients with a high rate of hospitalized vasoocclusive crises had higher blood viscosity at steady state than patients with a low rate of vaso-occlusion. Moreover, blood viscosity has been reported to further increases during vaso-occlusion (Awodu et al., 2009), as a consequence of massive RBC sickling (Ballas & Smith, 1992). While blood viscosity is involved in the pathophysiology of acute painful vaso-occlusion, it seems to be less implicated in the mechanisms of osteonecrosis despite the fact that high Hct and hemoglobin levels are involved
3 Pathophysiology and physical activity in patients with sickle cell anemia 43 in this complication (Lemonne et al., 2013). This paradox is due to the fact that patients with osteonecrosis have also increased RBC deformability, which compensates for the increased Hct and lead to a relative normalization of blood viscosity. Although an increase of RBC deformability is beneficial for blood flow and tissue perfusion in healthy population, increased RBC deformability in sickle cell patients increases the risks for osteonecrosis (Lemonne et al., 2013) and acute painful vaso-occlusion (Lamarre et al., 2012). Indeed, sickle RBC with the highest deformability are very adherent to the vascular wall, thus decreasing the lumen of microvessels, slowing blood flow and initiating vascular occlusion (Kaul &Fabry,2004). Abnormal adhesion of circulating cells to the vascular wall is a common pathway shared by the two sub-phenotypes. 3 Sickle cell anemia and abnormal vascular adhesion of circulating cells In sickle cell anemia, young immature RBCs (i.e. reticulocytes), dense sickle RBCs, white blood cells and platelets have increased adhesion potential to the endothelium through the involvement of several cell membrane receptors, several endothelial or sub-endothelial matrix receptors and plasma factors (Elion, Brun, Odievre, Lapoumeroulie, & Krishnamoorthy, 2004). The recurrent ischemic-reperfusion injury, as well as local hypoxia, in SCA up-regulate several vascular adhesion receptor (VCAM-1, ICAM-1, E-selectin) in human microvascular endothelial cells (Stanimirovic, Shapiro, Wong, Hutchison, & Durkin, 1997). In addition, hypoxia/ischemia causes a large imbalance in the endothelial cell redox status through several mechanisms such as an increase in the xanthine oxidoreductase activity leading to reactive oxygen species production or a decrease of the hydroxylation of the hypoxia-inducible factor (HIF), which leads to a transcriptional activation of INOS expression and the formation of ONOO (Muruganandam, Smith, Ball, Herring, & Stanimirovic, 2000). This oxidative stress stimulates the expression of several endothelial cell adhesion molecules (Kokura, Wolf, Yoshikawa, Granger, & Aw, 1999). The chronic inflammation in SCA (Nebor et al., 2011) activates the α4β1 integrinonreticulocytes, hence promoting their adhesion to the endothelial cells (Durpes et al., 2011). The release of epinephrine under stressful situation phosphorylates Lu/BCAM, the unique eythroid receptor on mature RBCs, leading to increased vascular adhesion potential of mature RBCs on laminin (El Nemer, Colin, & Le Van Kim, 2010). Abnormal RBCs and white blood cells adhesion mainly occur in the post-capillary venules where the shear stress is low enough to allow circulating blood cells rolling and then firmly adhere to the vascular wall (Kaul, Finnegan, & Barabino, 2009). These mechanisms may initiate acute painful vaso-occlusive crises by slowing blood flow in the microvasculature (Kaul et al., 2009). The slowing of blood flow prolongs the transit time of sickle RBCs, which triggers HbS polymerization and sickling, hence promoting full vascular occlusion. Studies on atherosclerosis also clearly demonstrate that cellular adhesion to the vascular wall may occur in large arteries, mainly at the level of arterial branch points where shear stress is low and flow turbulent (Chiu & Chien, 2011; Switzer, Hess, Nichols, &Adams,2006).Thesamemechanismseemstobeinvolved in the development of stenosis in large arteries at the cerebral level in SCA (Connes et al., 2013a). 4 Sickle cell anemia, exercise intolerance and exercise risks SCA patients are characterized by a low physical fitness (decreased aerobic power and capacity as described by low maximal oxygen consumption and ventilatory thresholds, respectively) compared to healthy controls (Balayssac-Siransy et al., 2011; Callahan et al., 2002; Lonsdorfer et al., 1983;Waltzet al., 2012). Several studies have examined the mechanisms responsible for this exercise intolerance and multiple factors have been identified, such as: reduced oxygen carrying capacity related to the low hemoglobin level, functional and structural cardiac adaptations (increased stroke volume, even at very low exercise intensity) resulting from chronic anemia (Alpert, Dover, Strong, & Covitz, 1984; Braden, Covitz, & Milner, 1996), pulmonary parenchymal dysfunction caused by repeated episodes of acute chest syndrome (Castro et al., 1994), pulmonary vascular disease (Callahan et al., 2002; Delclaux et al., 2005) and peripheral vascular impairments (Callahan et al., 2002) due to frequent and repeated microvascular occlusion (i.e. vascular damages caused by RBC sickling and impaired vasodilation due to the decrease of NO bioavailability). Nevertheless, health care providers are often questioned about the possibility of SCA patients to participate in sports or physical activity. Regular physical exercise has been proven to be very beneficial from a clinical and social point of view in several chronic diseases and it could be expected to be the same in SCA. The major question faced by health care professionals and exercise physiologists involved in SCA management is the acceptable and safe level of physical activity they should recommend for their patients. Exercise and physical activity are known to cause marked metabolic changes, such as lactic acid production by active muscles. The presence of anemia is responsible for a faster transition from aerobic to anaerobic metabolism during exercise, which may stimulate the polymerization of HbS and lead RBCs to sickle and promote microvascular occlusions (Moheeb, Wali, & El-Sayed, 2007). Dehydration and local tissue hypoxia occurring during exercise may promote RBC sickling. Exposure to moderate temperature changes during exercise may also trigger vaso-occlusive crisis. Furthermore, although regular exercise may improve immune function,
4 44 Movement & Sport Sciences Science & Motricité /1 acute bouts of exercise may cause a temporary immune dysfunction with transient increase in several circulating cytokines (Gleeson, 2007;Pyne,1994) which may also initiate vaso-occlusive crisis through an activation of several adhesion molecules and circulating blood cells (Makis, Hatzimichael, & Bourantas, 2000). The genesis of reactive oxygen species during intense exercise could also promote endothelial dysfunction and RBCs alterations (Connes, Machado, Hue, & Reid, 2011). All these considerations stimulate fear from physicians about exercise recommendations in SCA patients and very few studies focused on the biological responses of exercising SCA patients. 5 Sickle cell anemia and acute biological responses to submaximal exercise Before the establishment of accurate exercise programs in SCA can be possible, there is a need to test the exercise type that SCA patients could be able to sustain without any risks of vaso-occlusive and medical complications. Barbeau et al. (2001) initially tested the effects of a 30 min cycling exercise at 60 75% of predicted maximum heart rate, repeated for three consecutive days, on several biological factors. The authors (Barbeau et al., 2001) wereabletodemonstratethat the repetition of a submaximal exercise at moderate intensity increased the plasma NO content of SCA patients, and the authors conclude that regular exercise could decrease the risk for inflammatory reaction related to exercise and could increase the vasodilatory reserve in this population. More recently, Balayssac-Syransy et al. (2011) demonstrated that a moderate exercise (50% of maximal aerobic power) during 20 min did not cause marked hemorheological alterations or clinical adverse events in a group of SCA patients, suggesting the safety and the feasibility of this kind of effort in this population. Nevertheless, the authors noted a large rise of the proportion of irreversibly dense sickle RBCs, which could become problematic for longer or more intense efforts. Using the same exercise protocol than Balayssac-Syransy et al. (2011), Faes et al. (2013) recently reported no change in NO levels, antioxidant capacity, se- and sp-selectin induced by exercise in SCA patients. These results suggest that this exercise was well tolerated by this population. Nevertheless, while the plasma concentration of VCAM-1 increased in SCA patients and in a group of healthy subjects after exercise, plasma ICAM-1 increased in SCA patients only. In addition, a wide inter-individual variability in the exerciseresponses of SCA patients for svcam-1 and sicam-1 was noted, indicating that a sub-group of SCA patients could be at greater risk for endothelial dysfunction during exercise. Waltz et al. (2012) tested the effects of a short incremental exercise (less than 15 min) conducted until the first ventilatory threshold. No further alteration in RBC deformability, blood viscosity or coagulation markers (prothrombin time and activated partial thromboplastin time) was observed in the SCA patients after exercise or in the 3 following days. Moreover, none of the SCA participants exhibited clinical complication. Of interest, it was also noted a decrease of the RBC aggregates strength level below the baseline value 2 and 3 days after the exercise bout, suggesting that RBCs from SCA patients were less sticky at that time. This is an interesting finding since increased RBC aggregates strength has been demonstrated to increase the risks for acute chest syndrome (Lamarre et al., 2012). Nevertheless, one patient involved in this exercise protocol exhibited a large decrease of the hemoglobin oxygen saturation (Waltz et al., 2012). This hypoxemic episode during the effort, if prolonged, could trigger vaso-occlusive crisis (Kirkham et al., 2001) or pulmonary hypertension (Campbell et al., 2009). We recently reported that one third of SCA children experienced a significant hemoglobin oxygen desaturation during a sixminutes walk test (Waltz et al., 2013). This hemoglobin oxygen desaturation was independently associated with a high rate of previous acute chest syndrome episodes (Waltz et al., 2013). Indeed, caution is required during exercise to avoid too large and prolonged hemoglobin oxygen desaturation in SCA patients. 6 Recommendations for physical activity in SCA patients All these findings suggest that patients with SCA could participate to physical activity of less than 20 min duration and at intensity below or equal to the first ventilatory threshold to avoid further biological alteration and clinical complication. Nevertheless, there is a large variability in the biological responses observed at exercise and there are probably some patients more at risk for acute complications than others: a large cohort study is needed to identify sub-groups of patients according to the risks encountered during physical efforts. Further studies are now needed to test the effects of a training program over several consecutive weeks on the biological and clinical profile of SCA patients to find the best modality of practice for this population. Of importance, caution is required to limit the physiological strain of the exercise, particularly if the patients do not feel good or experience breathlessness, to avoid prolonged hypoxemic episodes, which could trigger acute complications. Intensity and duration must be lowered if the patients have difficulty to breathe or to exercise. Moreover, to prevent dehydration, SCA patients should drink water during and after exercising. Hydration is particularly important in patients with hemoglobinopathies since even in the asymptomatic sickle cell trait carriers it may normalize the hemorheological profile of subjects (Tripette et al., 2010). Finally, for outdoor sports, care should be taken to prevent cold or heat stress, and SCA patients, particularly those with enlargement of the spleen, should also avoid contact sports.
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7 Pathophysiology and physical activity in patients with sickle cell anemia 47 Pyne, D.B. (1994). Exercise-induced muscle damage and inflammation: a review. Austrian Journal of Science and Medicine in Sports, 26 (3 4), Reiter, C.D., Wang, X., Tanus-Santos, J.E., Hogg, N., Cannon, R.O., 3rd, Schechter, A.N., & Gladwin, M.T. (2002). Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nature and Medicine, 8 (12), Stanimirovic, D., Shapiro, A., Wong, J., Hutchison, J., & Durkin, J. (1997). The induction of ICAM-1 in human cerebromicrovascular endothelial cells (HCEC) by ischemia-like conditions promotes enhanced neutrophil/hcec adhesion. Journal of Neuroimmunology, 76 (1 2), Stuart, M.J., & Nagel, R.L. (2004). Sickle-cell disease. Lancet, 364 (9442), Switzer, J.A., Hess, D.C., Nichols, F.T., & Adams, R.J. (2006). Pathophysiology and treatment of stroke in sicklecell disease: present and future. Lancet Neurology, 5 (6), Tripette, J., Loko, G., Samb, A., Gogh, B.D., Sewade, E., Seck, D., Hue, O., Romana, M., Diop, S., Diaw, M., Brudey, K., Bogui, P., Cissé, F., Hardy-Dessources, M., & Connes, P. (2010). Effects of hydration and dehydration on blood rheology in sickle cell trait carriers during exercise. American Journal of Physiology Heart and Circulation Physiology, 299 (3), H Waltz, X., Hedreville, M., Sinnapah, S., Lamarre, Y., Soter, V., Lemonne, N., Etienne-Julan, M., Beltan, E., Chalabi, T., Chout, R., Hue, O., Mougenel, D., Hardy-Dessources, M.D., & Connes, P. (2012). Delayed beneficial effect of acute exercise on red blood cell aggregate strength in patients with sickle cell anemia. Clinical Hemorheology and Microcirculation, 52, Waltz, X., Romana, M., Lalanne-Mistrih, M.L., Machado, R.F., Lamarre, Y., Tarer, V., Hardy-Dessources, M.D., Tressières, B., Divialle-Doumdo, L., Petras, M., Maillard, F., Etienne-Julan, M., & Connes, P. (2013). Hematological and hemorheological determinants of resting and exerciseinduced hemoglobin oxygen desaturation in children with sickle cell disease. Haematologica, 98,
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