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.
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.
An enzyme called (phosphatidylinositol glycan A) is needed to make a cell membrane anchor for proteins called GPI (glycosylphosphatidylinositol). 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 (clone)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 CD55 and CD59.
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.
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.
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.
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).
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