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"paroxysmal nocturnal hemoglobinuria"[MeSH Terms]

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Here is a comprehensive overview of Paroxysmal Nocturnal Hemoglobinuria (PNH):

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Definition

PNH is a rare, acquired clonal blood disorder caused by a somatic mutation in the PIG-A gene (on the X chromosome) in a hematopoietic stem cell. This gene encodes an enzyme essential for synthesis of GPI (glycosylphosphatidylinositol) anchors, which tether numerous proteins to the cell membrane. Loss of GPI anchors means GPI-linked complement regulatory proteins are absent from the surface of red cells, white cells, and platelets - rendering them vulnerable to complement-mediated destruction. - Goldman-Cecil Medicine, p. 1692

Pathophysiology

The PIG-A mutation occurs in a single hematopoietic stem cell; all clonal progeny (RBCs, WBCs, platelets) are affected
X-linked location of PIG-A means a single mutation on the active X chromosome suffices (lyonization)
~150 different PIG-A mutations have been identified
The GPI-anchored proteins lost include:
- CD59 (protectin / MIRL - membrane inhibitor of reactive lysis) - the most important; inhibits C3 convertase and prevents C9 polymerization (MAC formation)
- CD55 (DAF - decay-accelerating factor) - antagonizes C3/C5 convertase complexes
- C8-binding protein (homologous restriction factor)
- Also: CD14, CD16a, CD24, CD58, acetylcholinesterase, leukocyte alkaline phosphatase
Without CD59 and CD55, the membrane attack complex (C5b-9) assembles unopposed on cell surfaces → intravascular hemolysis

Three types of PNH RBCs (based on sensitivity to complement lysis):

Type	GPI Deficiency	Sensitivity to Lysis
Type I	Normal	Normal
Type II	Partial	3-5x normal
Type III	Complete (no GPI)	15-25x normal

Henry's Clinical Diagnosis and Management, p. 693; Robbins & Kumar Basic Pathology, p. 606

Why PNH Clones Expand

Most normal individuals have a small number of PIG-A-mutant bone marrow cells that remain harmless. They are thought to expand (producing clinical PNH) only when they gain a selective advantage - most commonly in the setting of autoimmune attack against GPI-linked antigens (explaining the strong association with aplastic anemia). PNH clones also upregulate anti-apoptotic genes that make them resistant to immune attack. - Robbins, Cotran & Kumar Pathologic Basis of Disease

Epidemiology

Incidence: ~2-5 per million/year; prevalence ~1 per million
Age: most common between 10-50 years (mean ~34, median ~40 years)
No sex preference (F:M ratio ~1:1)
No family history typical (acquired, not inherited)
Median survival after diagnosis: ~20 years
Goldman-Cecil Medicine, p. 1692

Clinical Features

Feature	Details
Hemoglobinuria	Dark/brown urine on waking - but classic in only 25%; most have chronic hemolysis without dramatic hemoglobinuria
Hemosiderinuria	Almost always present - leads to chronic urinary iron loss and iron deficiency
Anemia	Normocytic (usually mild-moderate), but can become microcytic/hypochromic due to iron deficiency; often DAT-negative
Thrombosis	Leading cause of death; ~40% of patients; affects unusual venous sites (hepatic = Budd-Chiari, portal, cerebral, mesenteric veins) in 85% of thrombotic events
Abdominal pain	~1/3 of patients; from NO scavenging by free hemoglobin
Dysphagia	Smooth muscle dystonias due to NO depletion
Erectile dysfunction	Same mechanism (NO scavenging)
Pancytopenia	Neutropenia in ~3/5, thrombocytopenia in ~2/3 at some time
Aplastic anemia	~1/3 evolve into; 50-60% of aplastic anemia patients have subclinical PNH clones
AML transformation	Rare

Goldman-Cecil Medicine, p. 1692; Henry's Clinical Diagnosis, p. 693

Triggers of hemolytic crises: infection, surgery, transfusion, contrast dyes, severe exercise, acidosis, hypoxia, fever.

Diagnosis

Suspect PNH when:

Acquired, Coombs-negative (DAT-negative) intravascular hemolytic anemia
Especially if concurrent iron deficiency (from hemosiderinuria)
Unusual site thrombosis (Budd-Chiari, portal vein)

Gold standard: Flow cytometry demonstrating GPI-deficient cells

Flow cytometry in PNH - Panel A shows normal RBCs with CD55+/CD59+ staining; Panel B shows a PNH patient with a large red population of CD55-/CD59- (GPI-deficient) RBCs

Flow cytometry: Panel A (normal) - all RBCs are CD55+/CD59+. Panel B (PNH patient) - large red cluster in the lower-left quadrant represents the GPI-deficient PNH clone lacking both CD55 and CD59. - Robbins, Cotran & Kumar Pathologic Basis of Disease

Test both neutrophils/monocytes (CD24, CD57, CD14) and RBCs (CD59)
FLAER (fluorescent aerolysin variant) - binds directly to the GPI anchor on leukocytes; most reliable reagent for PNH diagnosis
Clone size correlates with degree of hemolysis
Old tests (Ham's acidified serum test, sucrose hemolysis test) are obsolete

Treatment

Complement Inhibitors (First-Line where available)

Drug	Mechanism	Notes
Eculizumab (anti-C5)	Humanized mAb blocking C5 cleavage, prevents MAC formation	Introduced 2007; abolishes/reduces transfusion requirement; reduces thrombosis; but causes iatrogenic extravascular hemolysis (PNH RBCs now opsonized by C3, Coombs-positive)
Ravulizumab (anti-C5)	Long-acting anti-C5	Less frequent dosing than eculizumab
Pegcetacoplan (anti-C3)	Proximal complement inhibitor (C3 level)	Prevents both intravascular AND extravascular hemolysis; more complete anemia correction; risk of more severe breakthrough hemolysis if blockade is incomplete

Meningococcal vaccination mandatory before starting anti-C5 therapy (risk of Neisseria meningitidis)

Supportive Treatment

Folic acid supplements (at least 3 mg/day) - mandatory
Iron supplementation - check serum iron periodically (lost in urine)
Transfusions (washed/filtered RBCs) - as needed
Anticoagulation - for all patients with prior thrombosis or thrombophilic risk factors
Thrombolysis (tPA) - for thrombotic complications not otherwise resolving
Glucocorticoids: NOT indicated long-term (no benefit, significant side effects); short course only if inflammatory exacerbation

Bone Marrow Transplantation (BMT)

Only curative option
Consider for: young patients with severe PNH, PNH-aplastic anemia syndrome (AA), HLA-identical sibling available
Anti-C5 therapy has no effect on underlying bone marrow failure (BMF)
Immunosuppression (ATG + cyclosporine) is an alternative for PNH-AA patients
Harrison's Principles of Internal Medicine 22E, p. 849-850; Goldman-Cecil Medicine, p. 1692

PNH Categories (WHO)

Classic PNH - hemolysis dominant; large clone
PNH in the setting of another bone marrow disorder (AA, MDS) - cytopenias predominant; clone often small
Subclinical PNH - PIG-A mutant cells detectable but no hemolysis or thrombosis

Key Associations to Remember

PNH + Aplastic Anemia: very common overlap (50-60% of AA patients have subclinical PNH clones)
Budd-Chiari syndrome in a young patient = think PNH
DAT-negative hemolysis + iron deficiency = think PNH
Free hemoglobin scavenges NO → smooth muscle dystonia (abdominal pain, dysphagia, erectile dysfunction)
CD59 deficiency on platelets → phosphatidylserine externalization → prothrombinase complex formation → thrombosis

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