EPIDEMIOLOGY, CLINICAL FISIOPATHOLOGY AND THERAPEUTIC STRATEGIES IN PATIENTS WITH SICKLE CELL DISEASE

Sickle cell disease (SCD, SS, Sb0/+ and SC genotypes) is a worldwide distributed invalidating hereditary red cell disorder with a negative impact on patients’ quality of life (QoL). In the last two decades, the distribution of SCD is deeply changed due to voluntary migration fluxes from endemic areas for SCD to Europe and North America.1 The 2021 global disease burden study (GBD) highlights that number of patients living with SCD is globally increased compared to previous GBD studies and the total deaths of patients with SCD are markedly higher when compared to healthy population especially in low-incoming countries.1 In addition, SCD becomes an emergency health problem for migrants and refugees from endemic areas for SCD, who are vulnerable subjects exposed to discontinuation of treatments, delay identification, severe acute or organ complication related to the disease (WHO Regional Office for Europe: Migration and health: key issue; 2017). A recent survey involving Italian comprehensive centers for hemoglobinopathies demonstrated that the distribution of SCD is spread throughout Italy, with high number of patients in the Northern Italian regions together with the historical Italian endemic areas for SCD (Sicily and Calabria) (Figure 1a).2 Notably, a recent real-world study highlighted that patients with mild SCD phenotype might frequently access to emergency department (ED) for acute sickle cell related events more to the comprehensive centers for hemoglobinopathies. This represents a subgroup of SCD patients unrecognized and undertreated, who will then develop severe sickle cell organ complication at adult age.3 SCD is characterized by the presence of the pathologic hemoglobin S (HbS), which shows peculiar biochemical properties, and polymerizes when deoxygenated. Studies of the kinetics of HbS polymerization following deoxygenation have shown that the kinetics of polymer formation is a high order exponential function of hemoglobin concentration.4 Pathophysiological studies have shown that the dense, dehydrated red cells play a central role in acute and chronic clinical manifestations of sickle cell disease, in which intravascular sickling in capillaries and small vessels leads to vaso-occlusion and impaired blood flow. However, the persistent membrane damage associated with HbS polymerization also favors the generation of distorted rigid cells and further contributes to vaso-occlusive events and cell destruction in the peripheral circulation. Thus, SCD is characterized by chronic hemolytic anemia 2/3 as extravascular hemolysis and 1/3 as intravascular hemolysis.5 This latter sustains the large amount of plasma free heme and free Hb, contributing to the inflammatory vasculopathy that characterized SCD. Indeed, studies on both mouse models and patients with SCD have highlighted the high bio complexity of SCD, which involves sickle red cells but also neutrophils, abnormally activated vascular endothelial cells associated with a cytokine storm and different plasma soluble factors. Acute VOCs worsen SCD inflammatory vasculopathy with increased expression of pro-adhesion molecules such as vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) or selectins. These are important in both recruitment and adhesion of both neutrophils and sickle red cells to the abnormally activated vascular endothelial surface into the microcirculation. In addition, recent evidence indicate that free heme also participates to abnormal activation of complement alternative pathways and relative reduction of ADAMST13 bioactivity establishing the contribution of sickle cell related microangiopathy to the complexity of inflammatory vasculopathy in patients with SCD.4,6 Thus, the two main clinical manifestations of sickle cell disease are the chronic hemolytic anemia and the acute vaso-occlusive events (VOCs). Although SCD is a monogenic disorder, it might be considered a multiorgan disease. Indeed, spleen, bone marrow, brain, lung are target organs for SCD. This is related to their functional anatomy characterized by sluggish circulation, high levels of oxygen extraction, low pH, which all favor HbS polymerization and microthrombi formation (RBCs and neutrophils).7 Thus, acute sickle cell VOCs make SCD patient high utilizers of ED when compared to other severe hemoglobinopathies such as transfusion dependent thalassemia. VOCs is a pathophysiologic definition of acute sickle cell related events, which is dominated by pain in the presence/ absence of signs of organ involvement (e.g: abdominal, neurologic manifestations). The early recognition and treatment of VOCs is crucial to reduce more severe complication such as the acute chest syndrome (ACS). This is still a challenge for ED physicians and hematologists in non-endemic areas for SCD. The guidelines from the American society of hematology as well as good practice from different European countries highlight the importance of an effective and early treatment of sickle cell related pain within 30 min from the triage similarly to acute myocardial infarction or renal colic.8,9 Studies in different settings have demonstrate that the presence of hospital dedicated clinical pathways shared with the ED as well as their time-to-time refresh strategy allow to improve the clinical management of pain during acute VOCs in patients with SCD. This is extremely important since sickle cell related pain has three different origins: neuropathic, nociceptive, and idiopathic pain. This requires a multimodal analgesia, which is based on the use of molecules with different mechanism of action, allowing to target different types of pain and to reduce their possible adverse events. Of note, in adult patients with SCD, the PiSCES study reported that (i) the mean pain did not differ by sex, age or genotype; (ii) the pain crises are more frequent in depressed or older patients (≥45 years of age); and (iii) the most common pain sites are: lower back, knee/shin and hip.10 In addition, sociocultural factors and the physicians concern on possible drug addiction might represent additional barriers to effective pain management in patients with SCD in ED. Transfusion strategies still represent the corner stone in clinical management of acute sickle cell events with the final objective to rapidly and efficiently reduce the amount of HbS and the circulating dense red cells. This might be obtained by either simple transfusion or exchange therapy (manual or automatized) and it should be considered in clinical management of severe VOCs and/or in presence of signs of sickle cell related organ sufferance. Growing evidence highlight the clinical relevance of the combination of erythro-exchange and therapeutic plasma exchange in severe VOC resistant to erythro-exchange. We will discuss the main data supporting this tandem transfusion approach, ensuring a rapid removal of plasmatic pro-inflammatory cytokines as well as of free heme and free Hb. Outside acute sickle cell related events, transfusion of RBCs might be also used as prophylaxis of sickle cell cerebrovascular disease in pediatric population of in clinical management of chronic organ damage such as sickle cell cardiomyopathy or kidney disease. On steady state, hydroxyurea (HU) is the goal standard chronic treatment of both pediatric and adult patients with SCD. Different studies have identified a post-HU era based on the increased survival rate of patients with SCD as well as on the HU beneficial effects on VOCs, ACS and on patients’ hospitalization rates. As shown in Figure 1b, HU has a multimodal action, targeting different key checkpoints in the pathogenesis of sickle cell related clinical manifestations. This makes HU still a successful and powerful molecule to treat SCD.4 However, the biocomplexity of SCD requires the identification and development of new therapeutic strategies for personalized treatment of patients with SCD. Progress in the knowledge of the pathogenesis of SCD has allowed to identify new pharmacologic targets and to develop new therapeutic options to treat SCD (Figure 1b). These might be divided into: (i) molecules targeting erythroid metabolism such as the pyruvate kinase (PK) activator or L-glutamine; (ii) agents activating HbF expression; (iii) molecules targeting the hemolysis-vascular endothelial axis. We will discuss the results of the main clinical studies phase 1-2 and 3 with these pathophysiology-based agents and their main outcomes (Table 1).4 Curative treatments such as hematopoietic stem cell transplantation and cell therapies will be discussed in another section of the present meeting. In conclusion, SCD is a problem of healthcare systems, requiring the dissemination of the knowledge on clinical management and new therapeutic options. The therapeutic portfolio for SCD is constantly developing. This allows to consider new agents in dynamic combination with HU throughout the patients’ journey towards personalized medicine in a patient centered vision. Figure 1. a. Distribution of hemoglobinopathies (green) and sickle cell disease (SCD, red) in Italy based on 2019 survey. Upper panels. Distribution of patients with either hemoglobinopathies or SCD per 100,000 inhabitants by regions in Italy. Lower panel. Distribution by age and sex for SCD patients; the gray bars identify the age distribution of general Italian population in 2019 (modified from Gianesin B et al Haematologica 110: 1211, 2025). b. Schematic diagram of the mechanisms of action of pathophysiology based new therapeutic options for treatment of sickle cell disease and sickle cell vasculopathy as well as for hydroxyurea (HU, in yellow). PK: pyruvate kinase; HbF: fetal hemoglobin; PS: phosphatidyl-serine; MP: microparticles; ET-1: endothelin-1, IL1b: interleukin-1, TNF-a: tumor necrosis factor-alpha; NO: nitric oxide (modified from Matte A et al Exp Opinion Invest Drug 29: 23, 2020). Table 1. Completed clinical studies on novel treatme