The complement system can be activated via three pathways. The membrane attack complex (MAC) is assembled by the terminal complement components. Paroxysmal nocturnal hemoglobinuria (PNH) occurs due to somatic mutation in PIG-A gene, leading to deficiency of GPI-anchored proteins. The two GPI-anchored complement regulatory proteins whose absence leads to hemolysis in PNH are:

• A Factor H and Factor I, which are soluble plasma proteins inhibiting the alternative pathway
• B C1 inhibitor and clusterin, which block C1q activation and MAC assembly
• C CR1 (CD35) and CR3 (CD11b/CD18), which are opsonin receptors preventing hemolysis
• D CD55 (DAF, decay accelerating factor) and CD59 (protectin/MIRL), which normally accelerate decay of C3 convertases and block MAC assembly respectively ✓

Explanation

In PNH, the PIG-A mutation prevents synthesis of GPI anchors, depleting all GPI-anchored proteins from affected blood cell clones. The two critically relevant GPI-anchored complement inhibitors are CD55 (DAF, decay-accelerating factor), which accelerates decay of both classical and alternative pathway C3 convertases (C3bBb and C4b2a), and CD59 (protectin), which blocks polymerization of C9 into the pore-forming MAC on the cell membrane. Without these, complement activation on the RBC surface proceeds unchecked, forming MAC and causing complement-mediated intravascular hemolysis. Eculizumab (anti-C5 monoclonal antibody) treats PNH by blocking MAC formation upstream of CD59.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.