Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, potentially life-threatening disease of the blood characterised by hemolytic anemia, thrombosis and red urine due to breakdown of red blood cells. PNH is the only hemolytic anemia caused by an acquired intrinsic defect in the cell membrane.

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Signs and symptoms

Quite paradoxically, the destruction of red blood cells (hemolysis) is neither paroxysmal nor nocturnal the majority of the time (this constellation of symptoms is seen in only 25% of patients). On-going hemolysis is a more common characteristic.

A common finding in PNH is the presence of breakdown products of RBCs (hemoglobin and hemosiderin) in the urine.

An inconsistent, but potentially life-threatening, complication of PNH is the development of clot in the veins (venous thrombosis). These clots (thrombi) are often found in the hepatic (causing Budd-Chiari syndrome), portal (causing portal vein thrombosis), and cerebral veins (causing cerebral venous thrombosis).

Many patients with bone marrow failure (aplastic anemia) develop PNH (10-33%). Aplastic anemia can be caused by an attack by the immune system against the bone marrow. For this reason, drugs that suppress the immune system are being researched as a therapy for PNH.

Diagnosis

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 test, is performed if the sugar test is positive for hemolysis.^[1]

Modern methods include flow cytometry for CD55, CD16 and CD59 on white and red blood cells. ^[2]Dependent on the presence of these molecules on the cell surface, they are classified as type I, II or III PNH cells.

Classification

PNH is classified:

• 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.

Pathophysiology

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.

A molecule called PIGA (phosphatidylinositol glycan A) is needed to make a cell membrane anchor for proteins called GPI (glycosylphosphatidylinositol).^[3] The gene that codes for PIGA is inherited in an X-linked fashion, which means that only one active copy of the gene for PIGA may exist. 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. 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 CD16, CD55 and CD59 (CD is an acronym for cluster of differentiation).

The increased destruction of red blood cells results in anemia. The increased rate of thrombosis is due to dysfunction of platelets. They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells. The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state.

Treatment

Steroids (such as prednisolone) can decrease the severity of hemolytic crises at moderate dosage (1 mg/kg/day). 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 defficiency 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, and hence should be given under steroid cover.^{[citation needed]} Androgens like danazol are sometimes effective in steroid refractory disease but side effects can be a problem.^{[citation needed]}

A new monoclonal antibody, eculizumab, protects blood cells against immune destruction by inhibiting the complement system. ^[4]

Animal studies suggest that infusing membrane-targeted CD59 might restore protection against complement-mediated lysis, and is being developed further for use in patients.^[5]

Prophylactic use of anticoagulants (warfarin) is used to fight thrombosis.

In severe aplasia, bone marrow transplants are occasionally undertaken.

History

The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (1852).^[6][7] A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911,^[8] with further elaborations by Marchiafava in 1928^[9] and Dr Ferdinando Micheli in 1931.^[10]

References

• Sacher, Ronald A. and Richard A. McPherson. "Wildman's Clinical Interpretation of Laboratory Tests, 11th edition."
• Kumar, Vinay, Abu Abbas, and Nelson Fausto. "Robbins and Cotran Pathologic Basis of Disease, 7th edition."