Laboratory Monitoring of Complement Activation in Gene Therapy: Analytical Pitfalls and Clinical Interpretation

Complement activation is a consistent and predictable biological response to adeno-associated virus gene therapy, particularly after high-dose systemic administration. Early postdose laboratory changes, including mild thrombocytopenia, modest reductions in C3 and C4, and low-level elevations in complement activation markers, are commonly observed and generally reflect expected pharmacodynamic effects rather than toxicity in isolation. However, a subset of individuals progresses to complement-mediated endothelial injury and thrombotic microangiopathy, a rare but potentially severe complication. Despite increasing recognition of complement biology in gene therapy safety, laboratory monitoring practices remain inconsistent, and interpretation of complement biomarkers is often fragmented. Reliance on isolated measurements may obscure early pathologic trajectories, while functional assays are sensitive to preanalytical variability. Emerging data suggest that alternative pathway amplification governs severity across diverse initiating mechanisms and distinguishes self-limited complement activation from sustained endothelial injury. This article proposes a laboratory-centered framework that integrates complement biomarkers with hematologic and renal indices, emphasizing serial trends over isolated values. Standardized interpretation of complement testing is essential for early recognition of pathologic escalation and for maintaining patient safety as gene therapy expands across clinical settings.