Fig 2.

Biology of complement‐mediated haemolysis in PNH on terminal complement inhibitors. (A) Initial complement activation. C3:H₂O generated by spontaneous hydrolysis of C3 (the so‐called “C3 tick‐over”) continuously initiates the complement cascade through its alternative pathway in the fluid phase. Due to the lack of CD55, PNH erythrocytes are unable to regulate complement activation on their surface, and C3bBb C3 convertase can be generated from C3 tick‐over and factor B cleavage operated by factor D. These C3 convertases generate further C3b, eventually self‐transforming into the C3bBbC3b C5 convertases. These steps are not affected by C5 inhibitors, which act downstream, making free C5 not available for the C5 convertases. (B) C3‐mediated extra‐vascular haemolysis. Terminal complement inhibitors (i.e. anti‐C5 agents) prevent the cleavage of C5 into C5a and C5b, thereby disabling the formation of the MAC and inhibiting intravascular lysis of PNH erythrocytes. Nevertheless, early steps of complement activation and upstream C5 cleavage remain uncontrolled, leading to opsonization of PNH erythrocytes with C3 fragments. C3‐opsonized erythrocytes can be recognised by C3‐specific receptors, expressed on professional macrophages in the liver and in the spleen, eventually resulting in extra‐vascular haemolysis. (C) Residual intravascular haemolysis due to pharmaco‐kinetic breakthrough. In the case of inadequate plasma levels of eculizumab (or any other anti‐C5 agent), free C5 becomes once again available for the C5 convertases. This eventually enables the terminal pathway of the complement, leading to MAC‐mediated residual intravascular haemolysis. (D) Residual intravascular haemolysis due to pharmaco‐dynamic breakthrough. During massive complement activation, C3 convertases may generate an excess of active forms of C3 (C3b), leading to the generation of “C3b‐rich” C5 convertases, which have higher affinity for C5. Thus, these high‐affinity C5 convertases may better compete with eculizumab for free C5, possibly displacing C5 from its inhibitor. This eventually enables the terminal pathway of the complement, leading to MAC‐mediated residual intravascular haemolysis. MAC, membrane attack complex; PNH, paroxysmal nocturnal haemoglobinuria.