PNH symptoms are driven by complement-mediated hemolysis
In PNH, uncontrolled complement activity driven by the alternative pathway leads to hemolysis of RBCs lacking the complement-regulatory proteins CD55 and CD59.1,5
Factor B, Factor D, and C3 are components of the proximal complement system required for the generation of C3 convertase in an amplification loop that results in both IVH and EVH.
In the terminal pathway, C5 triggers the membrane attack complex (MAC) resulting in IVH.9,10
Breakthrough hemolysis can be caused by incomplete blockade of complement (pharmacokinetic breakthrough) or due to infection or inflammation (pharmacodynamic breakthrough)10-13
EVH is not addressed by, and is a potential consequence of, terminal complement inhibition1,4,11
Bone marrow failure is also associated with hemolysis14
*DAT, direct antiglobulin test. Performed in patients treated with a C5 inhibitor.
EVH is not addressed by, and is a potential consequence of, terminal complement inhibition1,4,11
Preliminary studies suggest terminal complement inhibition induces C3 fragment deposition on PNH RBCs. The C3 fragments trigger destruction of the cells by macrophages, making EVH a potential consequence of terminal complement inhibition.1,4,11
One in vivo study (N=56) found no evidence of C3 on the RBCs of untreated patients, but found C3 on PNH RBCs of all 41 patients treated with a terminal complement inhibitor11
In another in vivo study, 68% of patients (21/31) treated with a terminal complement inhibitor were DAT positive, while 8% of untreated patients (3/39) tested positive in a DAT4
Additional studies are needed to further understand the impact of terminal complement inhibition on EVH