Sickle cell disease (SCD) is the most frequent genetic disease in the world, and is recognized as a public health priority in France. SCD is an autosomal recessive disorder resulting from a single mutation in the β-globin gene, leading to the production of an abnormal hemoglobin, hemoglobin S (HbS). HbS in red blood cells (RBCs) from SCD patients accounts for ~80–90% of the total hemoglobin content. In contrast to normal hemoglobin, HbS may form aggregates under deoxygenation, which results in a mechanical distortion of RBCs into a crescent-like shape. Sickled RBCs are very fragile and rigid, which may explain why HbSS patients are characterized by chronic hemolytic anemia, and may experience frequent and repeated vaso-occlusive crises.

Sleep-disordered breathing (SDB), and more particularly obstructive sleep apnea (OSA), occurs at a high frequency in SCD population (Gileles-Hillel et al., 2015; Raghunathan et al., 2018). For instance, Katz et al. (2018) and Sharma et al. (2015) reported that 22% of SCD children and 40% of SCD adults had OSA, respectively. Although OSA could act as a modulator of clinical severity in SCD, studies focusing on the associations of the two diseases are scarce (Gileles-Hillel et al., 2015; Ruhl et al., 2019). OSA may compromise respiratory gas exchange during sleep and cause oxyhemoglobin desaturation. As a result, OSA has been suspected to trigger vaso-occlusive like events (Hargrave et al., 2003; Gileles-Hillel et al., 2015; Brennan et al., 2020). However, studies focusing on the association between OSA and the frequency of vaso-occlusive like events reported inconsistent results. Katz et al. (2018) found an association between the frequency of acute chest syndrome and OSA. In contrast, a recent study performed in SCD children failed to find an association between OSA or low nocturnal oxyhemoglobin saturation (SpO2) and the frequency of vaso-occlusive like events (Willen et al., 2018). Low nocturnal oxyhemoglobin saturation has been associated with biomarkers of hemolysis and endothelial activation in SCD (Setty et al., 2003; Rotz et al., 2016), and enhanced hemolysis plays a central role in the pathophysiology of SCD (Nader et al., 2021). However, the associations between complications related to chronic hemolysis and low oxyhemoglobin saturation have not been investigated.

The aim of the present study was to investigate the associations between OSA, nocturnal oxyhemoglobin saturation and the rates of several acute/chronic complications. In addition, we tested the impact of OSA and nocturnal oxyhemoglobin saturation on several biomarkers (hematological, blood rheological, and coagulation) known to be involved in the pathophysiology of SCD, to gain further insights into the role of SDB in SCD.

Our study demonstrated that: (1) nocturnal hypoxemia and OSA were not associated; (2) nocturnal hypoxemia but not OSA was accompanied by a decrease in RBC deformability, enhanced hemolysis and more severe anemia in SCD patients and (3) nocturnal hypoxemia but not OSA was associated with a higher proportion of patients with hemolytic complications.

The hallmark of OSA is recurrent episodes of hypoxemia and arousals throughout the night (Gottlieb and Young, 2009; Dempsey et al., 2010). As a result, OSA has been suspected to trigger vaso-occlusive like events in SCD (Hargrave et al., 2003; Gileles-Hillel et al., 2015; Brennan et al., 2020). However, our study clearly showed that significant nocturnal hypoxemia may occur independently of OSA, which confirm previous findings (Whitesell et al., 2016; Worsham et al., 2017). Respiratory events from our OSA subjects were probably not sufficiently long and deep to generate hypoxemia. It could be explained by the fact that our population study is relatively young (Ware et al., 2000). Moreover, OSA was not accompanied by an increased rate of vaso-occlusive like complications, which is in agreement with the study of Willen et al. (2018). Lung function was found to be not different between OSA and non-OSA patients, as well as between hypoxemic and non-hypoxemic individuals. Indeed, the lower oxyhemoglobin saturation found in some SCD patients in this study seems to be not due to impaired lung diffusion, which is in agreement with a previous study showing no association between pulmonary function and the prevalence of nocturnal oxyhemoglobin desaturation in SCD children (Needleman et al., 1999).

Since HbS may polymerize under deoxygenation, the rheology of RBCs from SCD patients is highly sensitive to the level of blood oxygen. Boisson et al. (2021) recently demonstrated that RBC sickling may occur in some patients at oxygen tensions of 70–80 mmHg, which is in agreement with the previous finding of Nash et al. (1986) who observed RBC sickling at oxygen tension >60 mmHg. Lu et al. (2016) reported a decrease of flow velocity of RBC from SCD patients in a microfluidic device when oxygen tensions approached 70 mmHg, which was consistent with a rise in blood viscosity caused by the formation of sickled RBC. Moreover, repeated sickling—unsickling cycles when RBCs circulate from low to high oxygen tension vascular areas cause permanent damages to the membrane, which impairs the mean ability of RBCs to deform (Padilla et al., 1973). Indeed, one may suspect that significant hypoxemia would permanently change the rheology of RBC in SCD patients. Our results showed that patients with nocturnal hypoxemia had lower mean RBC deformability than patients without nocturnal hypoxemia. In addition, patients with nocturnal hypoxemia had high reticulocytes count, LDH level and bilirubin, which indicate enhanced hemolysis that would be at the origin of the lower Hb concentration in this group. The correlations found between RBC deformability and LDH levels suggest that the most rigid RBCs would be more fragile than the most deformable ones. Connes et al. (2014) have shown that dense and rigid sickle RBCs are prone to greater mechanical fragmentation when exposed to continuous shear stress, as it is the case in the blood circulation, compared to less dense and more deformable RBCs, indicating that a direct link between decreased RBC deformability and increased hemolysis exist in SCD.

Through its effects on inflammation and oxidative stress, hemolysis plays a central role in the pathophysiology of SCD and participates to the development of progressive vasculopathy and organ damages (Kato et al., 2018; Nader et al., 2021). Coagulation markers were not increased in patients with nocturnal hypoxemia but the greater monocytes and neutrophils count suggest that inflammation could be slightly increased in comparison with the non-hypoxemic group. Two main biological-clinical phenotypes would co-exist in SCD (Kato et al., 2018), with patients with the greatest hemolytic rate being prone to develop leg ulcers, priapism, glomerulopathy, pulmonary hypertension and cerebral vasculopathy, and patients with the lowest hemolytic rate having enhanced blood viscosity that would increase the risk for developing vaso-occlusive like complications, such as VOC, ACS, osteonecrosis, and retinopathy. Although this model is debated (Hebbel, 2011) and sometimes difficult to apply in African countries (Dubert et al., 2017), consistent data have been reported in European and US countries that partly support this pathophysiological scheme (Ballas, 1991; Nolan et al., 2005, 2006; Gladwin and Vichinsky, 2008; Gurkan et al., 2010; Maier-Redelsperger et al., 2010; Connes et al., 2013). Our results confirm the link already reported between oxygen hemoglobin saturation, hemolysis, and anemia (Homi et al., 1997; Quinn and Ahmad, 2005; Rotz et al., 2016) and suggest that nocturnal hypoxemia could play a key role in the development of complications from the hemolytic phenotype.

Alternatively, one could also hypothesize that a further decrease in red blood cell deformability could participate in the occurrence or strengthening of hypoxemia, as it has already been suggested in non-SCD individuals (Connes et al., 2004). Any decrease in RBC deformability has been demonstrated to impair blood flow dynamics in the pulmonary circulation of animals (Hakim, 1988) and could favor thrombosis (Gillespie and Doctor, 2021). Pulmonary thrombotic arteriopathy has been reported in SCD patients (Adedeji et al., 2001). The resulting alterations in blood flow dynamics may lead to intrapulmonary shunts (Hambley et al., 2019), a situation previously described in SCD patients (Desai et al., 2019; Hambley et al., 2019), which could cause hypoxemia of unclear etiology.

In conclusion, nocturnal hypoxemia could be responsible for changes in RBC deformability that would fragilize RBCs resulting in enhanced hemolysis that could play a significant role in the development of complications such as leg ulcers, priapism, pulmonary hypertension or glomerulopathy. The identification of nocturnal hypoxemia and its causes, other than OSA, and treatment of SDB could be helpful to decrease morbidity in SCD patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by CPP Lyon OUEST V. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.

ES and PC designed the study and performed statistical analyses and wrote the first version of the manuscript. SP, GC, AG, RF, YB, and AH recruited the patients and collected clinical data. ES, CR, PJ, CB, VP, and PC performed biological analyses. ES, LP-D, and TP performed sleep-related measurements. PC is the guarantor of this study. All authors read and approved the manuscript before submission.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.