What is Paroxysmal Nocturnal Hemoglobinuria?

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare blood disorder in children. It is an acquired disorder due to somatic mutations affecting hematogenic progenitor or multipotent stem cells in the bone marrow.

The mutation occurs in the PIG-A gene on chromosome number Xp22.2. PIG-A normally codes for an anchor protein, Glucosyl phosphatidyl anchor protein (GPI-AP), found in the plasma membrane of hematopoietic stem cells.

The anchor protein binds and maintains complement regulatory proteins on the cellular surface, such as CD55, CD59, etc. Loss of GPI-AP results in loss of protective protein, resulting in the unopposed action of the alternate complement pathway—hemolysis.

The anchor protein is attached to the plasma membrane and the GPI protein, followed by CD55 and CD 59. These CD55 and CD59 keep the alternate complement pathway under check. CD55 keeps the C3 convertase in check, whereas CD59 keeps the membrane attack complex (C5b-C9) under check. There are some mutations, and now the GPI-anchor protein is lost here because of the absence of conversion due to mutation. Due to GPI anchor protein loss, the CD55 and CD59 are also lost. This leads to the destruction or disruption of paroxysmal nocturnal hemoglobinuria RBC due to activation of membrane attack complex causing intravascular hemolysis. The image below explains PNH in a simpler way.

GPI-Anchored Protein Found Deficient in Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Complement Regulatory Proteins
  • CD 55, also called decay-accelerating protein (DAF).
  • CD 59, also called membrane inhibitor of reactive lysis (MIRL).
• Proteins With Immunologic Significance
  • It includes CD58, CD16b, and CD14 (EBP).
• Receptors
  • It includes CD83, Folate receptor, and cellular prion protein.
• Enzymes
  • Leukocyte ALP, AChE, and 5-Ectonucleotidase.
• Miscellaneous proteins
  • CD24 and CD48.

Clinical features of Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Intermittent Or Chronic Hemolytic Anemia

• Leukopenia or thrombocytopenia may also occur.
• Nocturnal or morning hemoglobinuria is seen more in adults than children.
• About 69% can develop bone marrow (BM) failure and aplastic anemia.
• Thrombosis and Thromboembolism may also occur.
  • Abnormal surface expression of proteins on platelets.
  • It can cause Budd-Chiari syndrome and splenomegaly.
  • Pain in the abdomen, neck, and head.
• Rare patients can develop acute myelogenous leukemia (AML
• The mortality in PNH is related primarily to developing aplastic anemia or thrombotic complications.

Classification of Paroxysmal Nocturnal Hemoglobinuria (PNH) 

Investigations in Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Hemoglobin is normally too low.
• If anemia is present, it will be initially normal and later become microcytic.
• Peripheral blood film - Anisocytosis, poikilocytosis.
• Due to chronic hemolysis -increased retic count, hemosiderinuria, increased serum LDH and reduced haptoglobin.
• The investigation of choice - flow cytometry - can detect the absence of CD55 and CD59.
• Fluorescence-labeled aerolysin testing can heighten the detection of sensitivity by binding selectively to GPI anchors.
• Greatly reduced levels of RBC AChE activity and DAF are also found.
• Older RBC lysis tests - Ham or Sucrose tests are no longer needed.

Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH)

• The initial Drug of Choice is Eculizumab
• Anti-C5 -Monoclonal antibody.
• It effectively reduces hemolysis with regular time usage.
• It is approved for use in adults and useful in11-17 years children.
• Eculizumab -causes severe, self-limiting headaches.
• Patients should receive a meningococcal vaccine before taking Eculizumab.
• However, it cannot prevent hematopoietic clonal expansion or bone marrow failure syndrome (BMFS).

Definitive Or Curative Therapy: Hematopoietic Stem Cell Transplantation (HSCT)

It is particularly required in children, especially if aplastic anemia develops in patients. Nonmyeloablative transplantation with reduced-intensity conditioning regimens is often used.

Other Therapies Used for Treatment

• Steroids are used for acute hemolysis episodes.
• Heparin and low molecular-weight heparin are used in thrombosis. 
• Iron supplementation.
• For managing bone marrow failure
  • Androgens such as fluoxymesterone are prescribed.
  • Anti-thymocyte globulin.
  • Cyclosporine.
  • EPO, G-CSF.

Management of Paroxysmal Nocturnal Hemoglobinuria (PNH) Based on Disease Classification

Frequently Asked Questions

Q: What is the drug of choice in Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Answer: The initial Drug of Choice for Paroxysmal Nocturnal Hemoglobinuria is Eculizumab.

Q: Wher is the mutation seen in Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Answer: The mutation occurs in the PIG-A gene on chromosome number Xp22.2.

Q: Which are the Complement Regulatory Proteins in PNH?

Answer: CD 55 which is also known as decay-accelerating protein (DAF) and CD 59, also called membrane inhibitor of reactive lysis (MIRL) are the Complement Regulatory Proteins in PNH.

Q: What is the investigation of choice in PNH?

Answer: Flow cytometry

Also Read: Marfan Syndrome : Signs, Diagnosis, Management and Prognosis

Hope you found this blog helpful for your NEET SS Pediatrics Hematology preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.