Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

Abstract

Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the β‐globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso‐occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell‐derived microparticle (MP) generation is also involved in the vaso‐occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US‐FDA‐approved therapy to prevent painful vaso‐occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L‐glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.

<p>Patient-Reported Outcomes and Economic Burden of Adults with Sickle Cell Disease in the United States: A Systematic Review</p>

“…1 It is also characterized by recurrent vaso-occlusion that involves multicellular adhesions between multiple blood cells, as well as progressive vascular and organ damage. [2][3][4] In the United States (US), SCD is the most common inherited blood disorder, affecting approximately 100,000 patients, and an additional 3.5 million have the sickle cell trait. 1 The population of adult patients with SCD is growing due to early diagnosis of the disease and improved quality of patient care.…”

Polymerization of deoxygenated sickle hemoglobin in the presence of fractionated leaf extracts of Anacardium occidentale, Psidium guajava, and Terminalia catappa

“…HbS aggregation and polymerization are pivotal primary events leading to the distortion of sickle erythrocyte morphology and presentation of pathophysiologic indicators of SCD (Vekilov 2007;Uzunova et al 2010;Piccin et al 2019). In search of remedies for SCD, using in vitro models, previous empirical studies have demonstrated the capability of varieties of herbal extracts to control and impede HbS aggregation and polymerization (Okpuzor et al 2008;Uwakwe and Nwaoguikpe 2008;Chikezie et al 2010; Chikezie 2011; Imaga 2013; Dash Pauline et al 2013;Nurain et al 2017).…”

“…It implied, therefore, that the physicochemical properties of phytocomponents from the fractionated leaf extracts of A. occidentale, P. guajava, and T. catappa had direct bearing on their capacities to alter the process leading to HbS aggregation and polymerization. Since intra-erythrocytic HbS aggregation and polymerization are pivotal to the pathogenesis and pathophysiology of SCD (Uzunova et al 2010;Piccin et al 2019), the use of chemical agents that covalently modify HbS molecules has been suggested to be an important approach to impede dHbS-M aggregation and polymerization (Park et al 2003;Eaton and Bunn 2017;Kassa et al 2019). Covalent modification of HbS molecules by carbamylation using isothiocyanates, acetylation using methyl acetyl phosphate (MAP), and Snitrosylation of Cys-beta93 has been reported (Xu et al 1999;Park et al 2003;Chikezie, 2011;Jana et al 2018).…”

Repurposing pyridoxamine for therapeutic intervention of intravascular cell-cell interactions in mouse models of sickle cell disease

“…HU exhibits its clinical benefit through multiple mechanisms, including inducing HbF production, lowering the number of circulating leukocytes and reticulocytes, increasing NO production, and reducing phosphatidylserine exposure. 38 , 39 Given the synergistic effect, pyridoxamine is likely to act distinctly from HU without compromising the beneficial effect, providing evidence that pyridoxamine could be a supplement to HU therapy for patients with SCD.…”