Paroxysmal Nocturnal Hemoglobinuria (PNH)

Summary

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal stem cell disorder caused by a somatic mutation in the X-linked PIGA gene, impairing glycosylphosphatidylinositol (GPI) anchor synthesis. This leads to the loss of surface complement regulators CD55 and CD59, leaving erythrocytes vulnerable to unchecked terminal complement-mediated (MAC) intravascular hemolysis (typically normocytic, MCV 80–100 fL, or microcytic from iron loss).

Clinical presentation features the classic triad of Coombs-negative intravascular hemolysis (dark morning urine/hemoglobinuria), pancytopenia (bone marrow failure), and atypical venous thrombosis (e.g., Budd-Chiari syndrome). Peripheral blood smear shows non-specific normocytic or polychromatic RBCs without spherocytes. Diagnosis is confirmed via peripheral blood flow cytometry showing absent CD55/CD59 or FLAER binding on blood cells. Treatment relies on C5 terminal complement inhibitors (eculizumab or ravulizumab), which mandate prior meningococcal vaccination; allogeneic HSCT is the only curative option.

Overview

What is PNH?

• PNH = a rare, acquired clonal disorder of the hematopoietic stem cell producing intravascular hemolysis, thrombosis, and bone marrow failure.
• It is the only acquired intrinsic (membrane) cause of hemolytic anemia — every other intrinsic cause (hereditary spherocytosis, G6PD deficiency, sickle cell) is inherited.
• Epidemiology: ~1–5 per million per year; typically young adults (median 30–40 y); strongly linked to aplastic anemia (a PNH clone is detectable in up to 25% of cases) and MDS.
• Name decoded: Paroxysmal (episodic attacks) · Nocturnal (mild respiratory acidosis during sleep activates complement) · Hemoglobinuria (free Hb in urine → dark morning urine).

Pathophysiology

Pathophysiology – one missing anchor

1. Acquired somatic PIGA mutation (an X-linked gene, but the mutation is not inherited) arises in a single stem cell, which then expands as a clone — favored when the marrow is under immune attack (explains the aplastic-anemia link).
2. PIGA performs the first step of GPI-anchor biosynthesis → without it, GPI-anchored surface proteins cannot attach.
3. Loss of the complement regulators CD55 (DAF) and CD59 (MIRL) from blood cells.
4. Unchecked complement assembles the MAC (C5b–9) on the patient's own RBCs → chronic intravascular hemolysis → free hemoglobin in plasma and urine.

The same anchor defect drives the other two pillars: free hemoglobin scavenges nitric oxide (NO) → smooth-muscle dystonia and platelet activation (thrombosis), while the underlying stem-cell injury reduces all lineages (pancytopenia).

Clinical Presentation – The Classic Triad

Anchor the picture to the triad "HAT" — Hemolysis, Aplastic marrow, Thrombosis.

1. Intravascular hemolysis

• Fatigue, pallor, jaundice.
• Hemoglobinuria — dark/cola-colored urine, classically in the first morning sample.
• Chronic urinary iron loss → iron deficiency; high cell turnover → folate deficiency.

2. Atypical (venous) thrombosis — leading cause of death

• Venous thrombosis at unusual sites:
  • Hepatic veins → Budd-Chiari syndrome (abdominal pain, ascites, hepatomegaly) — the classic exam clue.
  • Portal, mesenteric, splenic, and cerebral (sagittal sinus) veins.

3. Bone marrow failure

• Pancytopenia: anemia + thrombocytopenia (bleeding) + leukopenia (infections).
• May evolve to aplastic anemia or, rarely, AML.

Smooth-muscle dystonia (NO depletion)

• Esophageal spasm / dysphagia, abdominal pain, and erectile dysfunction — all from free-hemoglobin scavenging of nitric oxide.

Diagnostic Approach

Step 1 – Confirm intravascular hemolysis (initial labs)

• Serum: markedly ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, ↑ reticulocytes; CBC shows normocytic anemia (microcytic if iron-deficient) ± pancytopenia.
• Direct antiglobulin test (Coombs): NEGATIVE — the key to excluding autoimmune hemolytic anemia.
• Urine: hemoglobinuria (dipstick positive for blood, no RBCs on microscopy) and chronic hemosiderinuria (specific for chronic intravascular hemolysis).

Step 2 – Confirm with flow cytometry (gold standard)

• Peripheral-blood flow cytometry showing absent CD55 and CD59 on RBCs and WBCs — the diagnostic gold standard.
• FLAER (fluorescent aerolysin) binds the GPI anchor directly — more sensitive, best applied to granulocytes/monocytes.
• Historical tests (name-recognition only): Ham (acidified-serum) test and sugar-water (sucrose) test.

Differential diagnosis

Separate PNH from the other hemolytic anemias with one or two clinical clues — the matrix below is the highest-yield consolidation:

When the picture is dominated by pancytopenia, also consider aplastic anemia (hypocellular marrow; can coexist with PNH), MDS (dysplasia, older patients), and acute leukemia (blasts on smear).

Management

Supportive care (all patients)

• Folate and iron replacement (high turnover + urinary iron loss).
• Transfusion for symptomatic anemia.
• Anticoagulation for any thrombotic event (and prophylaxis in high-risk patients).

Targeted therapy – terminal complement inhibition

• Eculizumab — humanized anti-C5 monoclonal antibody; blocks MAC formation → dramatically reduces hemolysis, transfusion requirement, and thrombosis risk.
  • Key adverse effect: Neisseria meningitidis infection (terminal complement is needed to lyse Neisseria) → give meningococcal vaccination ≥2 weeks before starting, ± penicillin prophylaxis.
• Ravulizumab — longer-acting anti-C5 (every-8-week dosing); same role.

Curative therapy

• Allogeneic HSCT — the only curative option; reserved for severe marrow failure, refractory thrombosis, or malignant transformation.

Complications & High-Yield Pearls – نقاط مهمة للامتحانات

Complications

• Thrombosis — the leading cause of death (hepatic/Budd-Chiari, portal, mesenteric, cerebral veins).
• Chronic kidney disease — renal hemosiderin deposition from chronic hemoglobinuria.
• Pulmonary hypertension — chronic NO depletion.
• Iron-deficiency anemia — ongoing urinary iron loss.
• Aplastic anemia, and rarely MDS/AML transformation.
• Meningococcal sepsis — iatrogenic, from terminal complement-inhibitor therapy.

Mnemonics

High-yield pearl

Key Points for Exams – نقاط مهمة للامتحانات

• PNH = the only acquired membrane defect causing hemolytic anemia.
• PIGA mutation (X-linked but somatic — not inherited) → no GPI anchor → no CD55/CD59 → uncontrolled complement → intravascular hemolysis.
• Classic triad: Coombs-negative intravascular hemolysis + atypical thrombosis + pancytopenia.
• Most feared scenario: Budd-Chiari syndrome in a young patient with cytopenias and dark morning urine.
• Labs: ↑ LDH, ↓ haptoglobin, ↑ reticulocytes, negative Coombs, positive urine hemosiderin.
• Diagnosis: flow cytometry (absent CD55/CD59 ± FLAER); Ham & sucrose tests are historical.
• Treatment: Eculizumab/ravulizumab (anti-C5) — vaccinate against Neisseria meningitidis first; HSCT is curative.
• Leading cause of death: thrombosis.