Breakthrough Hemolysis in PNH: Insights from Clinical Trials

Breakthrough hemolysis remains a clinically meaningful complication for patients with PNH receiving complement inhibitors; reported rates have shifted as trials refine event reporting, so BTH frequencies must be interpreted in the context of each trial’s definition.

Definitions vary across studies, and that heterogeneity alters apparent event frequency and severity—changing how outcomes are compared and how counseling and monitoring are framed.

Trial definitions typically combine biochemical and clinical triggers: LDH thresholds are commonly paired with hemoglobin drops, transfusion requirements, or recurrent hemolytic symptoms. Frequently used cut points include LDH elevations (often ≥1.5×ULN) and hemoglobin declines (commonly ≥2 g/dL); whether one or multiple elements are required directly affects event classification.

Pooled and trial-specific reports put incidence at roughly 10–15% over six months for several terminal complement inhibitors, with lower rates described for agents with longer dosing intervals and some proximal inhibitors. Common precipitants in reported series include infection, missed or delayed dosing, and surgical stress, so observed incidence varies by follow-up duration, agent class, and clinical context.

Management strategies supported by trial data emphasize verification of adherence and infusion timing, adjustment of dosing intervals or supplemental dosing, prompt use of transfusion and acute rescue therapies, and consideration of anticoagulant prophylaxis during severe episodes. Operational measures—reliable scheduling and rapid access to rescue therapy—are repeatedly linked with fewer severe BTH events in trial reports.

Patients at higher risk include those with suboptimal baseline responses, a history of BTH, or recent complement-amplifying events; monitoring should prioritize rising LDH, significant hemoglobin drops, and new or worsening hemolytic symptoms. Teams can focus operationally on targeted monitoring, scheduling resilience, and defined rapid-rescue pathways to reduce BTH-related harm.