Paroxysmal Nocturnal Hemoglobinuria (PNH)

Content of This Page

1- Introduction, Definition

2- Pathophysiology

3-Clinical Features

4- Investigations

5-Management

6- Prognosis

Introduction

PNH is a rare acquired clonal disorder of haematopoietic stem cells characterized by:

  • Deficiency of GPI (glycosylphosphatidylinositol)-anchored proteins on cell surfaces

  • Leading to complement-mediated intravascular haemolysis

It is non-malignant, but life-threatening due to risks of thrombosis and bone marrow failure.

© image from Wikimedia Commons

Pathophysiology

  • Mutation in PIGA gene → defective GPI anchors

  • GPI is needed to attach protective proteins (like CD55 and CD59) to red cell membranes

  • Loss of these proteins → red cells become hypersensitive to complement lysis

  • Leads to intravascular haemolysis, especially at night (when pH drops) → haemoglobinuria

Clinical Features

Classic triad:

  1. Intravascular haemolysis → dark urine, especially in the morning (haemoglobinuria)

  2. Thrombosis (major cause of mortality)

    • In unusual sites: hepatic veins (Budd–Chiari), cerebral, mesenteric

  3. Bone marrow failure

    • Aplastic anaemia, pancytopenia, or overlap with myelodysplastic syndromes (MDS)

-Others:

  • Fatigue, dyspnoea (from anaemia)

  • Jaundice, abdominal pain (from haemolysis)

Investigations

Haemolysis markers:

  • ↓ Haemoglobin

  • ↑ LDH, indirect bilirubin, reticulocytes

  • ↓ Haptoglobin

  • Haemoglobinuria ± positive urinary haemosiderin

Confirmatory test:

  • Flow cytometry: absence of CD55/CD59 on red/white cells
    (GPI-anchored surface proteins)

Management

Supportive care:

  • Blood transfusions (cautious crossmatching)

  • Folic acid supplementation

  • Thrombosis prophylaxis/treatment (low threshold for anticoagulation)

–Disease-modifying therapy:

  • Eculizumab or ravulizumab (anti-C5 monoclonal antibodies)

    • Reduce haemolysis, transfusion needs, and thrombosis risk

    • Increase risk of meningococcal infection → vaccination required

–Bone marrow transplant:

  • Considered in severe bone marrow failure or resistant disease

Prognosis

  • Variable, depending on:

    • Degree of haemolysis

    • Risk and management of thrombosis

    • Presence of bone marrow failure

 

  • With C5 inhibitors, outcomes are significantly improved

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