Splenectomy revisited in Wiskott-Aldrich syndrome in the era of HSCT and gene therapy: a bridge, a rescue, or simply obsolete?

Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency caused by mutations in the WAS gene, classically presenting with microthrombocytopenia, eczema, and recurrent infections, with an incidence of approximately 1 per 100, 000 live births. At the mechanistic level, deficiency of the WAS protein (WASp) disrupts actin cytoskeleton remodeling across hematopoietic cells, impairing immune synapse formation, T-cell receptor signaling, natural killer cell cytotoxicity, B-cell activation, and dendritic cell migration. Concurrently, these cytoskeletal defects compromise megakaryocyte proplatelet formation, producing structurally fragile platelets that are rapidly cleared by the spleen and further targeted by immune-mediated destruction, culminating in thrombocytopenia. This pathophysiological basis explains the historical use of splenectomy to control life-threatening bleeding in refractory cases, as removal of the spleen reduces platelet sequestration and destruction, leading to reliable increases in platelet counts, often exceeding 150 × 109/L, and improved bleeding outcomes. However, the durability of this response is phenotype-dependent, with sustained benefit more common in X-linked thrombocytopenia and relapse occurring in up to 56% of classical WAS cases within the first year. Despite these hematologic benefits, splenectomy does not correct the underlying immune defect and is limited by a substantial risk of overwhelming infection, necessitating lifelong antibiotic prophylaxis, vaccination, and often immunoglobulin replacement. Consequently, with the advent of hematopoietic stem cell transplantation (HSCT) and gene therapy as curative approaches, the role of splenectomy has markedly declined and is now largely restricted to specific scenarios, including as a bridge to HSCT in severe thrombocytopenia, a rescue option when definitive therapies are inaccessible, and a post-HSCT intervention for persistent thrombocytopenia due to mixed donor chimerism. Nonetheless, global disparities in access to HSCT and gene therapy (driven by donor availability, financial constraints, and health system limitations), preserve a limited but important role for splenectomy in resource-constrained settings, underscoring the need for standardized, evidence-based guidelines to ensure its use only when the anticipated benefits outweigh the risks.