Paroxysmal Nocturnal Hemoglobinuria (PNH)

Definition

PNH is a rare, potentially life-threatening acquired clonal blood disorder caused by a somatic mutation in the PIG-A gene (located on the short arm of the X chromosome). Because PIG-A is X-linked, a single mutation is sufficient to cause complete loss of function. - Goldman-Cecil Medicine

Pathophysiology

Somatic PIG-A mutation in a hematopoietic stem cell - affects all lineages (RBCs, WBCs, platelets)
PIG-A encodes an enzyme essential for synthesis of GPI (glycosylphosphatidylinositol) anchors
Without GPI anchors, cells lose surface proteins including the two key complement regulators:
- CD55 (DAF) - inhibits C3 convertase
- CD59 (protectin/MIRL) - prevents C9 polymerization and MAC assembly
Without CD55/CD59, the membrane attack complex (C5b-9) assembles freely on RBC surfaces
Result: chronic intravascular hemolysis

Red cells are classified by GPI expression:

PNH III cells - completely devoid of GPI (most sensitive to hemolysis)
PNH II cells - partial GPI deficiency
Robbins & Kumar Basic Pathology; Goldman-Cecil Medicine

Why "Nocturnal"?

Nocturnal (or early morning) hemoglobinuria occurs because CO2 retention during sleep causes mild blood acidification, which activates complement. However, most patients present with chronic anemia rather than dramatic paroxysms of dark morning urine. - Robbins & Kumar

Epidemiology

Most common between ages 10-50; mean age at diagnosis ~34 years
Female-to-male ratio approximately 1:1
Estimated prevalence ~1 per million population
Median survival after diagnosis ~20 years with modern therapy
Goldman-Cecil Medicine

Clinical Manifestations

Feature	Mechanism
Dark morning urine (hemoglobinuria)	Complement activation during sleep (acidosis)
Chronic anemia	Ongoing intravascular hemolysis
Iron deficiency	Chronic urinary iron loss (hemosiderinuria)
Thrombosis (most feared complication)	Prothrombotic release from RBC/platelet membranes + NO scavenging
Abdominal pain, dysphagia, erectile dysfunction	Free hemoglobin scavenges nitric oxide
Cytopenias (leukopenia, thrombocytopenia)	Bone marrow involvement
Aplastic anemia (in ~1/3 of cases)	Related bone marrow failure

Thrombosis is the most dangerous complication - characteristically involves unusual sites including:

Hepatic veins (Budd-Chiari syndrome)
Portal veins
Cerebral veins

Rare transformation to acute myeloid leukemia can occur. - Goldman-Cecil Medicine

Diagnosis

Key clue: Coombs-negative (DAT-negative) intravascular hemolytic anemia with iron deficiency

Gold standard: Flow cytometry demonstrating deficiency of GPI-linked proteins:

CD59 on red cells
CD24/CD57 on neutrophils
CD14 on monocytes
FLAER (fluorescent aerolysin) - binds directly to the GPI anchor; the best and most reliable reagent for leukocyte testing

Clone size correlates with degree of intravascular hemolysis. - Goldman-Cecil Medicine

Treatment

Complement Inhibitors (main therapy)

Drug	Mechanism	Dosing
Eculizumab	Anti-C5 monoclonal antibody	600 mg/week x4, then 900 mg q2 weeks
Ravulizumab	Anti-C5, longer half-life	Weight-based loading, then q8 weeks
Crovalimab	Subcutaneous C5 inhibitor	Useful in eculizumab/ravulizumab resistance
Pegcetacoplan	Targets C3 (proximal)	1080 mg SC twice weekly

Pegcetacoplan targets C3 upstream, blocking both intravascular AND extravascular hemolysis - superior anemia correction compared to anti-C5 agents, but risk of more severe breakthrough hemolysis if inadequate blockade.

Important: All patients receiving complement inhibitors must be vaccinated against Neisseria meningitidis (A, B, C) before starting therapy, and long-term oral penicillin prophylaxis is often co-prescribed. This is because C5b-9 blockade impairs defense against encapsulated bacteria.

Curative Option

Allogeneic hematopoietic stem cell transplantation (HSCT) - reserved for patients with refractory pancytopenia or bone marrow failure not responding to complement therapy

Supportive

Anticoagulation if thrombosis occurs (combined with eculizumab)
Iron supplementation for iron deficiency
Goldman-Cecil Medicine; Harrison's Principles of Internal Medicine 22E (2025)

Effect of Eculizumab - A Note

While eculizumab eliminates intravascular hemolysis, treated patients still have C3b deposition on PNH red cells, causing iatrogenic extravascular hemolysis (Coombs-positive). Pegcetacoplan (C3 inhibitor) addresses this by blocking upstream, preventing both types of hemolysis. - Harrison's 22E

Recent Evidence

A 2024 systematic review and meta-analysis (PMID: 39453029) assessed danicopan (an oral factor D inhibitor), finding it safe and effective as add-on therapy in PNH patients with residual anemia on anti-C5 therapy - representing an emerging proximal complement inhibition option.

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