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Paroxysmal Nocturnal Haemoglobinuria (PNH)
Clinical Features
Laboratory Diagnosis
Molecular Genetics
Outcome and Therapy
PNH was recognised over a 100 years ago as a distinct haemolytic anaemia. It is an acquired haemopoietic stem cell disorder in which a somatic mutation of the X-linked PIG-A gene results in a partial or complete deficiency of all proteins linked to the cell membrane by the GPI (glycosylphosphatidylinositol) anchor.
The haemolytic anaemia seen in PNH appears to be due to a deficiency of two GPI-linked complement regulatory molecules from the red-cell membrane:
- CD55 (Decay-Acceleration Factor)
- CD59 (Membrane Inhibitor of Reactive Lysis)
Association with Aplastic Anaemia
Most if not all cases of PNH have underlying bone marrow failure (aplastic anaemia, occasionally myelodysplastic syndrome). There is a pathogenic link between PNH and aplastic anaemia in that the aplastic process appears to select for PNH clones.
- Uncommon disease. Frequency may be similar to that of aplastic anaemia (2-6 per million)
- Chronic haemolysis with acute episodes (paroxysms)
- Cytopenias of varying severity
- Thrombotic tendency (Budd Chiari syndrome), venous thrombosis occurs in 40-50% of cases
- Median age: 35 years, but affects all ages
- Median survival: 10-15 years
- Spontaneous remissions seen in some cases
- Major causes of morbidity and mortality are venous thrombosis and complications from progressive pancytopenia.
- Ham Test (acidified serum lysis test): a positive result requires a PNH clone sufficiently large to facilitate the observation of serum haemoglobin.
- Gel Test: CD56 and CD59 antibodies embedded in flat-bed gel matrix fail to bind red-cells from PNH patients. A positive result should be confirmed by:
- Flow Cytometry: partial or complete deficit of cell-membrane GPI-linked markers such as CD14, CD16, CD48, CD52, CD55, CD59, CD66, affecting all haemopoietic cell-types.
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Three-colour flow cytometric analysis of peripheral blood granulocytes from a case of PNH. The cells in the lower left quadrant are from the PNH clone, and show a significant reduction in CD16 and CD59 expression, and almost complete absence of CD55 expression, compared to the residual 'normal' granulocyte population in the upper right-hand quadrant. |
Mutations occur throughout entire PIG-A coding region. Frameshifts are the most common, with small deletions and small insertions also occurring.
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Fluorescent DNA sequencing electrophoretogram showing a single base pair substitution at nucleotide 549 (from TGG to TGT), causing the amino acid residue at codon 183 to change from cysteine to tryptophan, and resulting in a PIG-A protein with no detectable function. |
- warfarin anti-coagulant as primary prophylaxis (if no contraindications)
- folic acid and iron supplements if anaemic
- blood transfusion support in cases of severe symptomatic anaemia, and platelet transfusions in cases of severe thrombocytopenia
- immunosuppressive therapy (cyclosporin A or anti-lymphocyte globulin) to counter the immune-mediated aplasia associated with PNH
- bone marrow transplant maybe appropriate in some cases
MDS/AML is seen in a relatively small proportion of PNH patients, but may be a consequence of the underlying aplasia rather than directly related to the PNH defect. The blast cells in such cases may or may not be GPI deficient.
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Document last updated:
Tuesday, 18 November 2003
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