PNH has an intimate link with AAA, for several reasons. As stated above, sometimes a patient with PNH becomes 'less haemolytic' and more pancytopenic and ultimately evolves to frank AAA. In terms of pathogenesis, it is believed that AAA is essentially an organ-specific autoimmune disease that is mediated by 'activated' cytotoxic (CD8+) T lymphocytes, which are able to inhibit haemopoietic stem cells. Recently, skewing of the T-cell repertoire indicating the presence of abnormally expanded T-cell clones has been observed also in PNH. Most importantly, intensive immunosuppressive treatment is standard of care in AAA, and a beneficial response to the same treatment can be obtained also in PNH (see below).
In view of these facts, it seems that an element of BMF in PNH is the rule rather than the exception; an extreme view is that
PNH is a form of AAA in which BMF is masked by the enormous expansion of the PNH clone that populates the patient's bone marrow. In other words, it appears that two different mechanisms cooperate in producing PNH: autoimmune damage to stem cells and a somatic mutation in the PIG-A gene. This notion is supported by two further lines of evidence. Using targeted inactivation of the PIG-A gene in mouse embryonic stem cells, one can produce mice with a PNH cell population. However, this population does not grow further, as it does in PNH patients. Using refined flow cytometry technology, PNH cells harbouring PIG-A mutations can be demonstrated in normal people at a frequency of the order of 10 per million. Both of these findings indicate that some other factor is required in addition to a somatic mutation in the PIG-A gene in order to cause PNH. Most likely, the same cytotoxic damage to stem cells that would otherwise cause PNH spares the PNH stem cells, thus allowing the PNH clone to grow to the size when it gives clinical PNH. The mechanism whereby the PNH cells escape damage is not yet known.
In dealing with a patient with PNH, we must always consider that, unlike other acquired haemolytic anaemias, PNH may be lifelong. In addition, we must keep in mind the triad that defines the disease, namely haemolysis, BMF and the tendency to thrombosis. At the same time, we must consider, for each individual patient and upon discussion with the patient, whether to be content with supportive treatment or whether to aim for radical treatment.
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