Hereditary haemolytic anaemias represent the most prevalent group of genetic disorders worldwide and have a substantial impact on global health. Current treatments are few and primarily supportive. Recent studies suggest a crucial and overlapping role of metabolic impairment of red blood cells in these diseases, extending beyond the primary genetic defect. Pyruvate kinase activators enhance glycolysis, thereby targeting this shared metabolic impairment by increasing ATP production and improving cellular homeostasis. The first pyruvate kinase activator has been approved for the treatment of pyruvate kinase deficiency. Clinical trials evaluating pyruvate kinase activators in other haemolytic disorders, including thalassaemia, sickle cell disease, and red blood cell membrane disorders have provided evidence of clinical efficacy by ameliorating haemolytic anaemia and improving other disease-related outcomes, while maintaining a generally favourable safety profile. Ongoing preclinical and translational research continues to provide further insights into other potential indications for pyruvate kinase activators.

Sickle cell disease is a genetic red blood cell disorder, affecting millions of people globally. This Seminar provides a comprehensive update on the disease, emphasising its complex pathophysiology involving sickle haemoglobin polymerisation, vaso-occlusion, haemolysis, and inflammation that lead to acute, life-threatening complications and progressive organ damage. We review the spectrum of the most frequent acute manifestations-vaso-occlusive crises, acute chest syndrome, stroke, and infections-alongside chronic complications affecting virtually all organ systems. Recent advances include expanded implementation of hydroxyurea in low-resource settings and the optimisation of hydroxyurea protocols, refined transfusion therapy, improved haematopoietic stem cell transplantation outcomes with alternative donor strategies, and gene therapies now approved for clinical use. Additionally, new drugs are being evaluated in clinical trials globally. We examine successful implementation strategies in low-income and middle-income countries using point-of-care diagnostics and integrated care models. Controversies and challenges include the management of sickle haemoglobin-C and haemoglobin S/β+ variants, cerebrovascular complication prevention, hydroxyurea use in pregnancy, and the transition from paediatric to adult care.

In sub-Saharan Africa, the burden of diabetes and hypertension is high, alongside a high prevalence of HIV. Whether these conditions can be managed in an integrated way in the community is unknown. We aim to compare integrated community-based care with integrated facility-based care for people with HIV, diabetes, and hypertension in Tanzania and Uganda.