Beyond Terminal Blockade: A Mechanism-Based Approach to Complement Inhibitor Selection in Paroxysmal Nocturnal...

Complement inhibitor selection in paroxysmal nocturnal hemoglobinuria (PNH) can no longer be reduced to a binary class-level decision. Terminal C5 inhibitors provide durable control of intravascular hemolysis (IVH) and the most mature evidence for thromboembolic risk reduction, supporting their continued primacy in patients with high thrombotic risk or established venous thromboembolism. Persistent anemia during C5 inhibition is mechanistically heterogeneous. Before it is ascribed to extravascular hemolysis (EVH) or bone marrow failure (BMF), the adequacy of terminal complement inhibition should be confirmed, as incomplete IVH suppression may contribute to residual hemolysis in some patients. Among patients with confirmed terminal suppression, persistent anemia is driven primarily by C3-mediated EVH in a subset of patients, whereas in others it arises from underlying BMF or a combination of both. Differentiating among these mechanisms is a prerequisite for escalation decisions rather than an optional refinement. The proximal complement inhibitors pegcetacoplan (C3), iptacopan (Factor B), and danicopan (Factor D) address EVH-driven anemia but have not been evaluated in trials powered for thrombosis prevention, creating an asymmetry in the evidence base that demands explicit clinical reasoning. This review proposes a phenotype-driven longitudinal management strategy stratifying treatment decisions by dominant disease mechanism, thrombotic risk, and practical treatment context. Diagnostic approaches to differentiating EVH‑dominant, BMF‑dominant, and overlap phenotypes in the relevant patient subsets, comparative evidence across inhibitor classes, and mechanism-based escalation strategies are addressed in sequence, alongside high-risk clinical scenarios and an evidence-gap analysis to guide future research.