Correct Answer: D. Deficiency of CD 55 and CD 59
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells characterized by deficiency of complement-regulatory proteins on the cell surface. The pathophysiology hinges on loss of GPI-anchored proteins, particularly CD55 (decay-accelerating factor, DAF) and CD59 (membrane inhibitor of reactive lysis, MIRL). These proteins normally protect cells from complement-mediated lysis by inhibiting C3 and C5 convertases and preventing membrane attack complex (MAC) formation. In PNH, mutations in the PIG-A gene (phosphatidylinositol glycan anchor biosynthesis class A) prevent GPI-anchor synthesis, leading to absent or severely reduced CD55 and CD59 expression on red blood cells, white blood cells, and platelets. Without these protective proteins, the alternative complement pathway proceeds unopposed, causing intravascular hemolysis (not extravascular), particularly during sleep or stress when complement activation increases. The hemolysis is triggered by complement activation via the alternative pathway, and the classic presentation includes dark urine (hemoglobinuria), thrombosis (due to platelet activation), and cytopenias. Indian textbooks (Robbins, Harrison) emphasize that CD55 and CD59 deficiency is the molecular hallmark of PNH, making option D the discriminating and correct answer. This is why flow cytometry detecting absent CD55/CD59 on blood cells is the gold standard diagnostic test in Indian clinical practice.
Why the other options are wrong
A. Extravascular haemolysis — This is wrong because PNH causes intravascular hemolysis, not extravascular. The complement-mediated lysis of RBCs occurs directly in the circulation due to unopposed MAC formation, resulting in hemoglobinuria and hemoglobinemia. Extravascular hemolysis (spleen/liver) occurs in conditions like autoimmune hemolytic anemia or hereditary spherocytosis, not PNH. This is a classic NBE trap pairing hemolysis with the wrong mechanism. B. Inherited defect in PIG-A — This is wrong because PNH is an acquired disorder, not inherited. Although the molecular defect involves somatic mutations in the PIG-A gene (which is X-linked), these mutations occur in hematopoietic stem cells during life, not germline mutations. The defect is clonal and acquired, making it non-heritable. Patients do not pass PNH to offspring. This option confuses the molecular mechanism with inheritance pattern—a common NBE trap. C. Microcytic anaemia — This is wrong because PNH typically presents with normocytic anemia due to intravascular hemolysis, not microcytic anemia. Microcytic anemia suggests iron deficiency or thalassemia. While chronic hemolysis in PNH can lead to iron loss (hemoglobinuria), the primary anemia is hemolytic and normocytic. This option mischaracterizes the hematologic phenotype and is a distractor for students unfamiliar with hemolytic anemia classification.
High-Yield Facts
- CD55 and CD59 deficiency is the molecular hallmark of PNH; these are GPI-anchored complement-regulatory proteins.
- PIG-A mutations are somatic (acquired), not germline; PNH is an acquired clonal disorder of hematopoietic stem cells.
- Intravascular hemolysis is the mechanism in PNH; dark urine (hemoglobinuria) and hemoglobinemia are cardinal signs.
- Flow cytometry detecting absent CD55/CD59 on blood cells (RBCs, WBCs, platelets) is the gold standard diagnostic test.
- Thrombosis is a major complication of PNH due to platelet activation and complement-mediated endothelial damage.
- Eculizumab (C5 inhibitor) is the standard treatment in India; it prevents MAC formation and reduces hemolysis.
Mnemonics
PNH = GPI Gone GPI-anchor synthesis defective (PIG-A mutation) → Proteins (CD55, CD59) Not anchored → Hemolysis intravascular. Remember: no GPI = no CD55/CD59 = complement unchecked = hemolysis. CD55 & CD59: Complement Brakes CD55 = DAF (stops C3 convertase). CD59 = MIRL (stops MAC). Both missing in PNH = complement accelerator stuck on = intravascular hemolysis. Use when recalling why hemolysis occurs.
NBE Trap
NBE pairs "PIG-A defect" with "inherited" to trap students who confuse somatic mutations with germline inheritance. Also, "hemolysis" is paired with "extravascular" to test whether students know PNH causes intravascular (not extravascular) lysis.
Clinical Pearl
In Indian practice, a patient presenting with dark urine, thrombosis, and cytopenias should raise suspicion for PNH. Flow cytometry showing absent CD55/CD59 on blood cells confirms the diagnosis and guides eculizumab therapy—a life-changing intervention that prevents complement-mediated hemolysis and thrombosis in these rare but critically ill patients.
_Reference: Robbins Ch. 12 (Red Blood Cell Disorders); Harrison Ch. 108 (Hemolytic Anemias)_