Complement-mediated hemolytic anemias can either be caused by deficiencies in 
regulatory complement components or by autoimmune pathogenesis that triggers 
inappropriate complement activation. In paroxysmal nocturnal hemoglobinuria 
(PNH) hemolysis is entirely complement-driven. Hemolysis is also thought to be 
complement-dependent in cold agglutinin disease (CAD) and in paroxysmal cold 
hemoglobinuria (PCH), whereas warm antibody autoimmune hemolytic anemia (wAIHA) 
is a partially complement-mediated disorder, depending on the subtype of wAIHA 
and the extent of complement activation. The pathophysiology, clinical 
presentation, and current therapies for these diseases are reviewed in this 
article. Novel, complement-directed therapies are being rapidly developed. 
Therapeutic terminal complement inhibition using eculizumab has revolutionized 
the therapy and prognosis in PNH but has proved less efficacious in CAD. 
Upstream complement modulation is currently being investigated and appears to be 
a highly promising therapy, and two such agents have entered phase II and III 
trials. Of these, the anti-C1s monoclonal antibody sutimlimab has shown 
favorable activity in CAD, while the anti-C3 cyclic peptide pegcetacoplan 
appears to be promising in PNH as well as CAD, and may also have a therapeutic 
potential in wAIHA.