Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH), sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced hemolytic anemia (anemia due to destruction of red blood cells in the bloodstream), red urine (due to the appearance of hemoglobin in the urine) and thrombosis. PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol leading to absence of protective proteins on the membrane). It may develop on its own ("primary PNH") or in the context of other bone marrow disorders such as aplastic anemia ("secondary PNH"). Only a minority have the telltale red urine in the morning.
Treatment is usually supportive (blood transfusion for anemia, anticoagulation for thrombosis), although the monoclonal antibody eculizumab (Soliris) is being used to treat some cases.
Signs and symptoms
Most people with "primary PNH" have red urine at some point in their disease course. Many of them continue to have low-grade breakdown of red blood cells, leading to anemia. Typical symptoms of anemia are tiredness, shortness of breath and palpitations. On laboratory examination of the urine, breakdown products of red blood cells (hemoglobin and hemosiderin) may be identified. A small proportion of patients report abdominal pain, dysphagia (difficulty swallowing) and odynophagia (pain during swallowing), as well as erectile dysfunction in men – this occurs mainly when the breakdown of red blood cells is rapid.
Forty percent of patients develop thrombosis (a blood clot) at some point in their illness. This is the main cause of severe complications and death in PNH. These may develop in common sites (deep vein thrombosis of the leg veins and resultant pulmonary embolism when these clots break off and enter the lungs), but in PNH blood clots may also form in more unusual sites: the hepatic vein (causing Budd-Chiari syndrome), the portal vein of the liver (causing portal vein thrombosis), the superior or inferior mesenteric vein (causing mesenteric ischemia) and veins of the skin. Cerebral venous thrombosis, an uncommon form of stroke, is more common in PNH.
Blood tests in PNH show changes consistent with hemolytic anemia: low hemoglobin, raised lactate dehydrogenase, raised reticulocytes (immature red cells released by the bone marrow to replace the destroyed cells), raised bilirubin (a breakdown product of hemoglobin) and decreased levels of haptoglobin. The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies.
A sugar or sucrose lysis test, in which a patient's red blood cells are placed in low ionic strength solution and observed for hemolysis, is used for screening. A more specific test for PNH, called Ham's acid hemolysis (after Dr Thomas Ham, who described the test in 1937) test, is performed if the sugar test is positive for hemolysis. More sensitive modern methods include flow cytometry for CD55 and CD59 on white and red blood cells. Dependent on the presence of these molecules on the cell surface, they are classified as type I, II or III PNH cells. Type I cells have normal levels of CD55 and CD59, type II have reduced levels and type III have absent levels. The higher the number of type III cells, the higher the risk of hemolysis and thrombosis.
PNH is classified by the context under which it is diagnosed:
- Classic PNH. Evidence of PNH in the absence of another bone marrow disorder.
- PNH in the setting of another specified bone marrow disorder.
- Subclinical PNH. PNH abnormalities on flow cytometry without signs of hemolysis.
All cells have proteins attached to their membranes and they are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. PNH occurs as a result of a defect in one of these mechanisms.
The enzyme phosphatidylinositol glycan A (PIGA) is needed to make glycosylphosphatidylinositol (GPI), a molecule that anchors proteins to the cell membrane. The gene that codes for PIGA is located on the X chromosome, which means that only one active copy of the gene for PIGA is present in each cell. If a mutation occurs in this gene then PIGA may be defective, which leads to a defect in the GPI anchor. When this mutation occurs in a bone marrow stem cell (which are used to make red blood cells as well as white blood cells and platelets), all of the cells it produces will also have the defect. Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the complement system, and without these anchors the cells are more easily targeted by the complement proteins. The complement system is part of the immune system and helps to destroy invading microorganisms. Without the proteins that protect them from complement, red blood cells are destroyed. The main proteins which carry out this function are the decay-accelerating factor (DAF) (CD55) which disrupts formation of C3 convertase, and protectin (CD59) which binds the membrane attack complex and prevents C9 from binding to the cell.
The increased destruction of red blood cells results in anemia. The increased rate of thrombosis is due to dysfunction of platelets due to binding by complement, or possibly due to low nitric oxide levels.
The symptoms of esophageal spasm, erectile dysfunction and abdominal pain are attributed to the fact that hemoglobin released during hemolysis binds with circulating nitric oxide, a substance that is needed to relax smooth muscle. This theory is supported by the fact that these symptoms improve on administration of nitrates or sildenafil (Viagra), which improves the effect of nitric oxide on muscle cells. There is a suspicion that chronic hemolysis causing chronically depleted nitric oxide may lead to the development of pulmonary hypertension (increased pressure in the blood vessels supplying the lung), which in turn puts strain on the heart and causes heart failure.
PNH is a chronic condition. In patients who have only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventative treatment with warfarin decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).
Episodes of thrombosis are treated as they would in other patients, but given that PNH is a persisting underlying cause it is likely that treatment with warfarin or similar drugs needs to be continued long-term after an episode of thrombosis.
There is disagreement as to whether steroids (such as prednisolone) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significant anemia this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced.
A new monoclonal antibody, eculizumab, protects blood cells against immune destruction by inhibiting the complement system. It has been shown to reduce the need for blood transfusion in patients with significant hemolysis.
Screening for PNH is performed every year in people with previous aplastic anemia, and may be performed in people with myelodysplastic syndrome of the "refractory anemia" type.
PNH is rare, with an annual rate of 1-2 cases per million. Many cases develop in people who have previously been diagnosed with aplastic anemia or myelodysplastic syndrome. The fact that PNH develops in MDS also explains why there appears to be a higher rate of leukemia in PNH, as MDS can sometimes transform into leukemia.
25% of female cases of PNH are discovered during pregnancy. This group has a high rate of thrombosis, and the risk of death of both mother and child are significantly increased (20% and 8% respectively).