Sickle cell disease From clinical challenges to therapeutic horizons

Sickle cell disease (SCD) is a severe hemoglobinopathy that imposes a significant global burden. There is a need for research to enhance our understanding of SCD and improve its management on a global scale. This thesis explores different aspects of the pathophysiology of SCD, management of frequently encountered complications, and potential therapeutic targets. In Chapter 2, we evaluate the risk of fluid overload following intravenous fluid therapy as treatment of vaso-occlusive crises (VOC). Chapter 3 provides the outcomes of a randomized controlled trial investigating the use of incentive spirometry in reducing the incidence of acute chest syndrome in adults hospitalized for VOC. Chapter 4 evaluates the diagnostic accuracy of D-dimer-based algorithms for excluding pulmonary embolism in SCD patients. Chapter 5 examines the potential of renal function decline rate as a marker for disease severity, exploring its utility in guiding treatment decisions for high-risk patients. In the second part of this thesis, we focus on the complex interplay between hemolysis, oxidative stress, neutrophils and free iron to deepen our understanding of SCD pathophysiology and explore potential therapeutic targets. A review of the literature concerning neutrophils as a prospective therapeutic focus in SCD is provided in chapter 6. Chapter 7 presents our study examining neutrophil characteristics of SCD patients during steady state and VOC and upon hydroxyurea and HSCT therapy. In chapter 8 we assess whether the decrease in hemolysis after treatment with voxelotor is associated with decreased neutrophil activity and less inflammatory phenotype. Chapter 9 discusses the effects of low-dose iron chelation with deferasirox on erythrocyte rheology, hemolysis and neutrophil characteristics.