🩸 PNH Pathophysiology & Clinical Manifestations — High-Yield Pearls
🎤 Highlights from the 15th Annual Conference of the Saudi Society of Blood and Marrow Transplantation (
#SSBMT2026)
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🧬 Complement Regulation in Normal RBCs
Normal red cells express two key GPI-anchored proteins:
🛡️ CD55 (Decay-Accelerating Factor, DAF)
⛔ Inhibits formation and stability of C3 convertase.
🛡️ CD59 (Membrane Inhibitor of Reactive Lysis, MIRL)
⛔ Prevents assembly of the membrane attack complex (MAC; C5b-9).
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💥 What Happens in PNH?
Acquired mutation in PIGA → loss of GPI anchor → absent CD55/CD59.
Result:
Uncontrolled complement activation
Terminal MAC formation
Intravascular hemolysis
Nitric oxide depletion
Platelet activation
Thrombosis
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⚙️ Terminal Complement Cascade
C3 → C5 cleavage → C5b C6–C9 → MAC → RBC lysis.
Additional effects:
↑ LDH
↓ Haptoglobin
Hemoglobinuria
End-organ damage
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🧪 Nitric Oxide Scavenging
Free plasma hemoglobin binds nitric oxide.
Clinical consequences:
Dysphagia
Esophageal spasm
Abdominal pain
Erectile dysfunction
Pulmonary hypertension
Chest pain
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🩸 Why Thrombosis Occurs
Multiple mechanisms:
Platelet activation
Complement-mediated endothelial injury
NO depletion
Procoagulant microparticles
Common sites:
Hepatic veins (Budd–Chiari)
Portal vein
Mesenteric veins
Cerebral veins
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🩺 Common Symptoms of PNH
😴 Fatigue
🩸 Anemia
🌑 Dark urine / hemoglobinuria
😮💨 Dyspnea
🍽️ Dysphagia
🤕 Abdominal pain
❤️ Chest pain
🔞 Erectile dysfunction
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⚠️ Major Complications
🩸 Venous/arterial thrombosis
🫁 Pulmonary hypertension
🩺 Chronic kidney disease
🫀 Cardiac dysfunction
🧠 Neurologic events
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🔬 Key Laboratory Findings
↑ LDH (best marker of hemolysis)
↓ Haptoglobin
↑ Reticulocytes
Indirect hyperbilirubinemia
Negative DAT
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💊 Therapeutic Targets
C5 Inhibitors
Soliris® (eculizumab)
Ultomiris® (ravulizumab)
C3 Inhibitor
Empaveli® (pegcetacoplan)
Factor B Inhibitor
Fabhalta® (iptacopan)
Factor D Inhibitor
Voydeya® (danicopan)
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💎 Clinical Pearl
In PNH, thrombosis—not anemia—is the leading cause of mortality.
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❓ Board-Style MCQ
Which protein directly prevents membrane attack complex formation?
A. CD34
B. CD55
C. CD59
D. C3
✅ Answer: C. CD59
Explanation: CD59 blocks C9 polymerization and MAC assembly.
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📚 References
PNH Source for Physicians
Frontiers in Immunology Review on PNH Pathogenesis
Holt M et al. Annals of Blood. 2024.
Brodsky RA. Blood. 2014.
#PNH #ComplementBiology #Eculizumab #Ravulizumab #Iptacopan #BoneMarrowFailure #Thrombosis #Hematology #KFSHRC #SSBMT2026