Complement is an elaborate system of innate immunity. Genetic variants and
autoantibodies leading to excessive complement activation are implicated in a variety of human diseases. Among them, the
hematologic disease paroxysmal nocturnal hemoglobinuria (PNH) remains the prototypic model of complement activation and inhibition.
Eculizumab, the first-in-class
complement inhibitor, was approved for PNH in 2007. Addressing some of the unmet needs, a long-acting C5 inhibitor,
ravulizumab, and a C3 inhibitor,
pegcetacoplan, have also now been approved for PNH. Novel agents, such as
factor B and
factor D inhibitors, are under study, with very promising results. In this era of several approved targeted
complement therapeutics, selection of the proper
drug must be based on a personalized approach. Beyond PNH,
complement inhibition has also shown efficacy and safety in
cold agglutinin disease, primarily with the C1s inhibitor of the classical complement pathway
sutimlimab, as well as with
pegcetacoplan. Furthermore, C5 inhibition with
eculizumab and
ravulizumab, as well as inhibition of the
lectin pathway with
narsoplimab, is being investigated in
transplantation-associated
thrombotic microangiopathy. With this revolution of next-generation
complement therapeutics, additional hematologic entities, such as
delayed hemolytic transfusion reaction or
immune thrombocytopenia, might also benefit from
complement inhibitors. Therefore, this review aims to describe state-of-the-art knowledge of targeting
complement in
hematologic diseases, focusing on (1)
complement biology for the clinician, (2) complement activation and therapeutic inhibition in prototypic
complement-mediated
hematologic diseases, (3) hematologic entities under investigation for
complement inhibition, and (4) other
complement-related disorders of potential interest to hematologists.