Secondary Thrombotic Microangiopathy (TMA) in children- A Central Role for the Glycocalyx.

Abstract

Thrombotic microangiopathy (TMA) is classically defined by the triad of haemolytic anaemia, thrombocytopenia, and organ injury, most notably kidney involvement. Secondary TMA, which arises in association with specific diseases or external triggers, is more common than primary or complement mediated TMA. Current evidence supports an important role for complement activation in the pathogenesis of secondary TMA, and emerging data highlight the contribution of the endothelial glycocalyx (eGC) to complement dysregulation at the endothelial surface. The eGC is an integrated matrix lining the luminal aspect of endothelial cells and plays a central role in maintaining endothelial homeostasis and preventing thrombosis. Its unique structure may represent a missing mechanistic link in several forms of secondary TMA that are relevant to children, including Pneumococcal associated TMA (Pneu-TMA), Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS), calcineurin inhibitors associated TMA, and hypertension associated TMA. This mini review summarises current evidence and understanding of the central role of the eGC in these conditions, and discusses the implications for future therapeutic innovation. Editor's Note Thrombotic microangiopathy (TMA) in children is not a single entity but a mechanistically heterogeneous group of disorders whose causes differ substantially from those seen in adults. Shiga toxin-producing Escherichia coli hemolytic uremic syndrome accounts for the majority of pediatric cases, yet secondary TMA as a whole, arising in the context of an underlying condition or external trigger, is far more common than primary, complement-mediated disease, and its pathophysiology has remained incompletely understood. In this timely mini review, Ma et al. propose a unifying framework centered on the endothelial glycocalyx (eGC), the sugar-rich matrix lining the luminal endothelial surface that safeguards vascular homeostasis and restrains complement activation. Injury to the eGC, with shedding of heparan sulfate and impaired complement factor H binding, provides the "second hit" that couples complement dysregulation to endothelial injury. The authors summarize how this mechanism links otherwise disparate triggers, including pneumococcal infection, Shiga toxin, calcineurin inhibitors, and severe hypertension. This perspective helps explain why complement blockade benefits only selected children with secondary TMA, and potentially reframes eGC thickness as a candidate biomarker and its restoration as a therapeutic target. Further studies are needed to define which children with secondary TMA are most likely to benefit from complement blockade (see the Pediatric Nephrology series at https://www.kidney-international.org/content/pediatric-nephrology).