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Synonyms: PNH, Marchiafava-Micheli anaemia
There are three features of the disease that are most uncommon together and the finding of them all is pathognomonic:
- There is an acquired haemolytic anaemia due to the susceptibility of the erythrocyte membrane to the haemolytic action of complement.
- There are thromboses in large vessels, such as hepatic, abdominal, cerebral, and subdermal veins.
- There is deficient haematopoiesis that may be mild or severe and cause a pancytopenia with aplastic anaemia.
Haemoglobin is normally contained within the erythrocytes. It is only in haemolysis that it is free in the circulation, filtered by the glomeruli and present in the urine. It was originally thought that respiratory drive diminished in sleep, causing acidosis, activation of complement and haemolysis in this condition. However, 'paroxysmal' is an incorrect description. Haemolysis actually occurs all day, but the more concentrated urine at night makes it appear darker and the haemoglobinuria is more obvious.
This is a haematopoietic stem cell mutation defect of the PIGA gene in the X chromosome.
- It is not familial and sex distribution is equal.
- It is rare, but may be slightly less rare in Southeast Asian communities.
The affected stem cell clone passes the gene to all its descendants (red cells, white cells and platelets) producing a haematological mosaic. The proportion of erythrocytes derived from this stem cell determines the severity of the disease.
The disease can present anywhere from early childhood to very late in life. In childhood and adolescence the features are more orientated towards the aplastic anaemia. PNH often presents with haemoglobinuria, abdominal pain, smooth muscle dystonias, fatigue and thrombosis.
Presentation is usually along the lines of one of the three aspects of the disease:
- Haemolytic anaemia. This is the most common form of presentation. There is haemoglobinuria that is often mistaken for haematuria. The urine is dark brown in colour, especially the first of the morning.
- Thrombosis. This is usually in veins rather than arteries and tends to affect hepatic, abdominal, cerebral and subdermal veins. The exact presentation will depend upon the veins involved - eg, Budd-Chiari syndrome, abdominal, or cerebral vein thrombosis. Thrombosis of dermal veins can cause raised, painful and red nodules in the skin over large areas, like the entire back. It subsides within a few weeks but occasionally necrosis requires skin grafts.
- Deficient haematopoiesis. This will produce symptoms of anaemia-like shortness of breath on exertion. Neutropenia and thrombocytopenia may allow infection and purpura.
Other symptoms include oesophageal spasms that occur in the morning and resolve in the day. Males often have erectile dysfunction.
Physical signs will depend upon the systems involved:
- Anaemia will cause pallor.
- Infections may produce fever and purpura may be apparent.
- The Budd-Chiari syndrome will produce hepatomegaly and ascites. There may be splenomegaly too.
- Ischaemia of the gut produces absent bowel sounds.
- Cerebral vein thrombosis produces papilloedema.
- Red, painful nodules may occur in the skin.
- Dipstick urine tests for blood will be positive, but microscopy will not show red blood cells. This is the difference between haematuria and haemoglobinuria.
- FBC will show varying degrees of anaemia, usually of a normochromic, normocytic picture, although high cell turnover can produce folate deficiency and a picture of macrocytosis. White cells and platelets may be reduced. The reticulocyte response may be high or low depending upon whether the picture is predominantly one of haemolytic anaemia or aplastic anaemia.
- LDH is elevated with haemolysis and haptoglobin low or absent.
- Bone marrow examination will differentiate an erythroid and hyperplastic marrow during the haemolytic phase or a hypoplastic marrow in the aplastic phase.
- Leukocytes have a low alkaline phosphatase score as in chronic myeloid leukaemia.
- Flow cytometry: blood test to detect CD59 (MIRL), a glycoprotein, and CD55 (DAF) in regulation of complement action. Absence or reduced expression of both CD59 and CD55 on PNH red blood cells is diagnostic. This is the latest diagnostic test which may replace the Ham and sugar-water tests as the 'gold standard' for diagnosis.
- The Ham test shows that erythrocytes are lysed by complement if the blood is acidified.
- The sugar-water test involves lysis of erythrocytes by an isotonic solution of sucrose. It is more sensitive but less specific than the Ham test.
- The complement lysis sensitivity test enables patients to be classified into one of three groups with prognostic implications.
- Group I has normal sensitivity to complement.
- Group II is moderately more sensitive than normal.
- Group III shows marked sensitivity at dilutions of 15- to 20-fold. This indicates severe disease and mean lifespan of 10 to 15 days.
- MRI with contrast can demonstrate saggital vein thrombosis.
- Venography can show thrombosis of major veins.
- MRI, ultrasound or technetium 99mTc colloid scan of the liver and spleen may demonstrate hypoperfusion.
The combination of haemolytic anaemia, aplastic anaemia and thrombosis is diagnostic but not all three features may be immediately apparent.
Blood transfusion may be required but leukocyte depletion is necessary to reduce antibody formation aggravating haemolysis. There is a risk of meningococcal infection and so meningococcal vaccination is essential.
- The 10-year risk of thrombosis in patients with large PNH clones, ie PNH granulocytes >50%, has been shown to be 44%, compared with 5.8% in those with <50% PNH granulocytes.
- Warfarin prophylaxis with a target INR of 2.5 is recommended in patients with large PNH clones who have a platelet count greater than 100 x 109/L.
- Anticoagulation can also be considered for patients with smaller clones and platelet counts less than 100 x 109/L after considering additional risk factors for thrombosis and bleeding.
- This successfully reduces haemolysis in about 70% of cases.
- The dose for adults is 20 to 40 mg daily during periods of haemolysis, reduced to that dose on alternate days at other times.
- Folate and folic acid:
- 1 mg daily is usually given to offset the high turnover of cells in haemolysis.
- Iron supplements:
- Normally haemolysis does not require iron supplements (as iron is not lost from the body), but in this condition haemoglobinuria results in loss of iron that may need replacement.
- However, this can stimulate reticulocytosis, which may trigger haemolysis. This can be prevented by adding prednisolone to replacement therapy.
- Stimulation of erythropoiesis using recombinant erythropoietin therapy.
- This is a humanised monoclonal antibody that binds and prevents activation of complement C5 and the subsequent formation of the cytolytic membrane attack complex of complement.
- It reduces intravascular haemolysis and haemoglobinuria, stabilises haemoglobin concentration and reduces the need for transfusion.
- Long-term safety and efficacy of eculizumab have been shown in studies. Survival for those treated with eculizumab was not different from that of a sex-matched and age-matched control group from the general population.
- It has been shown to improve quality of life in patients with PNH.
Although chronic treatment with eculizumab increases the risk of infections with Neisseria meningitides, the drug is generally safe and well tolerated. However, as is the case with other drugs developed for treatment of ultra-orphan diseases, eculizumab is expensive and treatment must continue indefinitely because C5 inhibition does not affect the process that underlies PNH. Moreover, due to the heterogeneous nature of the disease, treatment with eculizumab is not appropriate for all patients with PNH.
Bone marrow transplantation
Allogeneic bone marrow transplantation can cure classic PNH, but treatment-related toxicity is a major problem. Also, the problems associated with getting a compatible donor mean that it is usually reserved for the most severe cases, where there is aplastic anaemia or transformation to leukaemia.
This depends upon severity of symptoms and complications. The abnormal clone responsible for the disease may die out, but this usually takes at least five years and may be 15 to 20 years. Acute infection can reactivate the clone.
An aplastic phase leading to pancytopenia and thrombosis of hepatic, abdominal, and cerebral veins can lead to severe morbidity and mortality.
Further reading & references
- Besa EC; Paroxysmal Nocturnal Hemoglobinuria, Medscape, Aug 2011
- Phosphatidylinositol Glycan, Class A, PIGA (Paroxysmal Nocturnal Hemoglobinuria); Online Mendelian Inheritance in Man (OMIM)
- Hall C, Richards S, Hillmen P; Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2003 Nov 15;102(10):3587
- Guidelines on oral anticoagulation with warfarin, British Committee for Standards in Haematology (2011)
- Parker C; Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet. 2009 Feb 28;373(9665):759-67. Epub 2009 Jan 12.
- Parker CJ; Paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol. 2012 May;19(3):141-8. doi: 10.1097/MOH.0b013e328351c348.
- Hillmen P, Young NS, Schubert J, et al; The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep 21;355(12):1233
- Hillmen P, Hall C, Marsh JC, et al; Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004 Feb 5;350(6):552
- Parker CJ; Management of paroxysmal nocturnal hemoglobinuria in the era of complement inhibitory therapy. Hematology Am Soc Hematol Educ Program. 2011;2011:21-9. doi: 10.1182/asheducation-2011.1.21.
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Dr Hayley Willacy
Dr Colin Tidy
Dr Hannah Gronow