Longitudinal Dynamics of Angiopoietin-1, Angiopoietin-2 and Soluble Thrombomodulin During Recovery from Paediatric Cerebral Malaria in Ghana.

Cerebral malaria (CM) remains a leading contributor to paediatric mortality and long-term neurocognitive sequelae in sub-Saharan Africa, driven by a complex interplay between Plasmodium falciparum sequestration and host endothelial dysfunction. Clinical recovery is typically defined by parasite clearance and neurological improvement; however, the temporal relationship between vascular restoration and symptomatic resolution remains inadequately characterized. This study aimed to delineate the recovery kinetics of angiopoietin imbalance and soluble thrombomodulin (sTM) in CM and determine whether these pathways resolve in a coordinated or sequential manner. In this prospective longitudinal cohort study, we assessed 30 Ghanaian children with CM, 30 with uncomplicated malaria (UM) and 34 age-matched healthy controls. Serial measurements of angiopoietin-1 (ANG1), angiopoietin-2 (ANG2) and sTM were performed with CM at admission, coma recovery, and on days 7 and 14 thereafter, and UM at presentation and on days 7 and 14. Among CM cases, abnormal ANG2:ANG1 ratios increased from 10% at admission to 53% at coma recovery, then declined to ≤12% by day 14 thereafter. Abnormal sTM levels decreased more gradually, from 71% to 15% over the same period, suggesting a temporal dissociation between functional endothelial stabilization and structural endothelial repair. UM displayed milder, transient sTM elevations, which resolved more rapidly. These findings reveal a lag between clinical stabilization and biomarker normalization, suggesting a post-treatment window of microvascular vulnerability. Concurrent monitoring of ANG and sTM may provide complementary mechanistic insights into malaria pathophysiology and inform risk stratification, longitudinal monitoring, and the development of endothelial-targeted adjunctive therapies for paediatric malaria.