Genetic Modifiers and the Pathophysiology of Leg Ulcers in Sickle Cell Disease: A Scoping Review Protocol

Sickle Cell Disease (SCD) is the most widely distributed single-gene disorder globally and serves as a prototype condition for studying chronic inflammatory diseases. It is characterized by recurrent painful vaso-occlusive crises, progressive organ damage, and a wide spectrum of clinical complications. Despite decades of research and the World Health Organization’s recognition of SCD as a major public health concern, the disease continues to receive inadequate attention, particularly in Sub-Saharan Africa where the burden and severity are highest. Emerging evidence highlights the complexity of SCD pathophysiology, involving interactions between hemolysis, inflammation, vascular dysfunction, and genetic modifiers that influence disease expression and outcomes. This review protocol aims to map existing evidence on the biological and genetic mechanisms underlying SCD complications, with specific emphasis on leg ulcer development and the role of genetic modifiers. By synthesizing available literature, this scoping review will identify knowledge gaps, clarify current understanding, and inform future research directions and targeted interventions for improved patient outcomes.