Aetiology
The aetiology of paroxysmal nocturnal haemoglobinuria (PNH) stems from two factors: a somatic mutation in a haematopoietic stem cell and a background of bone marrow hypoplasia.[4][5] The somatic mutation is always in the phosphatidylinositol glycan anchor (PIG-A) gene, which codes for an enzyme needed to synthesise the glycosylphosphatidylinositol anchor. Because the anchor cannot be synthesised in the affected cells, the proteins attached to the membrane by these means are missing (PNH III cells) or greatly reduced (PNH II cells), particularly the complement defence proteins CD55 and CD59.[6] No cause for the somatic mutation is known other than the natural rate of mutation due to unrepaired transcriptional mistakes occurring during replication. [Figure caption and citation for the preceding image starts]: The glycosylphosphatidylinositol anchor in PNHFrom the collection of Dr Wendell F. Rosse [Citation ends].
In order for the defective clone to increase sufficiently in size, and consequently cause clinical symptoms, suppression of haematopoiesis, such as in aplastic anaemia, seems to be needed.[7] This is presumed in most cases to be autoimmune in origin (i.e., a T-cell-mediated attack on the bone marrow), although drug- and chemical-induced hypoplasias have also been noted. No cause for 'idiopathic' marrow hypoplasia can usually be assigned. Upon marrow recovery, the glycosylphosphatidylinositol-deficient clone may become dominant. In approximately 25% of patients, the PNH clone will disappear with immunosuppressive therapy.[8] Remaining patients will maintain a clone. In 30% of patients, the clone will expand and patients may develop clinical symptoms.[8]
Pathophysiology
Most of the pathophysiology of classic PNH arises from the effects of the activation of complement on blood cells lacking the complement defence proteins CD55 and, especially, CD59.[1] Thus, even minor activation that normally occurs all the time (causing continuous low-grade haemolysis) and is exaggerated at night (causing nocturnal exacerbations) results in more of the lytic terminal complexes being deposited on the abnormal blood cells. For red blood cells (RBCs), this results in the penetration of the membrane and lysis of the cell intravascularly, resulting in the release of haemoglobin into the plasma, which, if sufficient, results in haemoglobinuria. Complement may be further activated by infection, surgery, and trauma, resulting in paroxysms of haemolysis; although paroxysms may also occur without apparent cause. The amount of haemolysis depends on the number of abnormal RBCs (the clone size), their abnormality, and the degree of activation of complement.
The resultant haemoglobinaemia readily binds nitric oxide in the tissues, resulting in smooth muscle contraction which manifests as oesophageal spasm and abdominal pain.[9] This deprivation of nitric oxide may cause vascular spasm, resulting in erectile dysfunction, pulmonary hypertension, and renal dysfunction. Most patients have unusual 'fatigue', which is exacerbated during haemoglobinuric episodes. Haemoglobinuria may affect kidney function, either acutely when massive or chronically, leading to potential kidney failure.[10]
The activation of complement on the abnormal platelets results in their activation and this, along with other causes, results primarily in venous thromboses, but arterial events may also occur.[1][11] These are often in unusual sites such as the hepatic veins, abdominal veins, or cerebral sinuses, but are also common in deep veins and occasionally in arteries.
Classification
Proposed classification[3]
Classic haemolytic PNH: clone size large enough to result in clinical evidence of haemolysis with no evidence of another bone marrow disorder
PNH in the setting of another specific bone marrow disorder, such as aplastic anaemia-PNH (evidence of PNH in the setting of aplastic anaemia) and low-risk myelodysplastic syndrome-PNH (evidence of PNH in the setting of myelodysplasia)
Subclinical PNH: clone size too small to result in evidence of haemolysis
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