A Critical Review on Sickle Cell Disease: Pathophysiology, Clinical Burden, and Therapeutic Advances

Abstract

Sickle cell disease (SCD) is a monogenic haemoglobin disorder caused by a point mutation in the β-globin gene, resulting in the production of haemoglobin S, which polymerises under deoxygenated conditions to distort erythrocytes into characteristic sickle shapes. The consequences of this structural abnormality extend far beyond haemolysis, encompassing vaso-occlusion, endothelial activation, chronic organ dysfunction, and profound psychosocial burden. Despite representing one of the most prevalent genetic disorders worldwide, SCD has historically received comparatively little research investment relative to the scale of suffering it causes. The past decade has witnessed a remarkable acceleration in the understanding of SCD pathophysiology and an equally striking transformation in its therapeutic landscape. The regulatory approvals of L-glutamine, lentiviral gene therapy, and CRISPR-Cas9–based gene editing represent genuine milestones in clinical haematology, whilst the post-authorisation withdrawals of crizanlizumab and voxelotor have underscored the critical importance of clinical over surrogate endpoints in trial design and regulatory evaluation. Nevertheless, the overwhelming majority of affected individuals — concentrated in sub-Saharan Africa, South Asia, and the Middle East — continue to lack access even to hydroxyurea (hydroxycarbamide), let alone to curative options. This critical review synthesises contemporary evidence on the molecular pathophysiology, clinical spectrum, diagnostic strategies, and therapeutic advances in SCD, with particular attention to the growing divide between the scientific frontier and the realities of global care delivery. Persistent gaps in evidence are identified, and areas requiring urgent research and policy action are discussed.