(A) Model of the modified Ham (mHam) test. PIGA^null (PNH-like) TF1 cells do not express CD55 and CD59 and are therefore susceptible to complement-mediated killing. Cells are incubated with patient and control sera, then with a WST-1 cell proliferation dye reagent (Roche). Nonviable cells do not release dye because of complement-mediated killing, resulting in differences in measured absorbance. The percentage of live cells is calculated as the ratio of sample absorbance relative to its heat-inactivated control, multiplied by 100. The percentage of nonviable cells is a measure of complement activation. (B) Proposed model for APS and CAPS. Recent studies suggest that aPLs induce complement activation in patients with complement-amplifying trigger(s), such as infection, surgery, or autoimmune disease, and cause thrombosis in APS. Patients who also have a pathogenic loss-of-function mutation in a complement-inhibitory factor (e.g., CFH, CFI, CD46, or THBD) or a gain-of-function mutation of a complement-activating factor (e.g., CFB, C3) are likely to be predisposed to uncontrolled complement activation. In the setting of a complement-amplifying trigger, aPL-induced complement activation could lead to disseminated thrombosis and ischemic multiorgan failure in CAPS. PIGA, phosphatidylinositol N-acetylglucosaminyltransferase subunit A; PNH, paroxysmal nocturnal hemoglobinuria; APS, antiphospholipid syndrome; CAPS, catastrophic antiphospholipid syndrome; aPL, antiphospholipid antibody.