Paroxysmal nocturnal hemoglobinuria (PNH)
What is it?
Paroxysmal nocturnal hemoglobinuria is a hematological condition characterized by an acquired genetic defect (PIG-A gene) of hematopoietic stem cells, which includes a defect in the enzyme phosphatidylinositol-glycan-A, which is required for the synthesis of a cell membrane protein: glycosylphosphatidylinositol (GPI). This protein is critical for the anchoring of other proteins (CD55 and CD59) to the cell membrane, which are necessary to protect the cell from the lytic action of complement. Clinical manifestations of PNH are mainly associated with the hematopoietic system and, in particular, include hemolytic anemia with negative Coombs test, but also include white and platelet counts, which can lead to aplastic anemia and a greater risk of developing leukemia. Another clinical feature of PNH is a thrombophilic condition responsible for thrombotic events.
Which are the symptoms?
The forms of PNH onset can be very diverse, therefore it is important to maintain a high index of suspicion, especially in the presence of one of the following clinical manifestations:
- hemolytic anemia has acquired a negative Coombs test.
- signs of intravascular hemolysis (hemoglobinemia, hemoglobinuria, increased LDH, decreased plasma haptoglobin)
- granulocytopenia and / or thrombocytopenia associated with reticulocytosis or signs of intravascular hemolysis
- venous thrombosis, especially in the abdominal cavity (portal vein, hepatic or mesenteric), brain or skin, in combination with signs of hemolysis or suspected PNH, especially in young people.
- aplastic anemia
- episodes of dysphagia or abdominal pain with concomitant signs of intravascular hemolysis
How is it diagnosed?
To confirm the diagnosis, we currently have peripheral blood flow cytometry tests that can identify red blood cells that are unable to attach certain proteins to the membrane (CD 55 and 59 are negative). It should be remembered that these defects can also be identified on neutrophilic granulocytes and platelets, and that they can also relate to other proteins that are unable to bind to the membrane as a result of an acquired genetic defect.
How is it treated?
Treatment depends on the severity of clinical manifestations, therefore, in mild forms (moderate hemolysis), only clinical observation with hematological checks every 6-10 months is indicated. As the clinical picture becomes clearer, possible treatments can be distinguished from purely supportive treatments such as iron preparations, folic acid and erythrocyte blood transfusion, as well as those that have some effect on the pathogenetic mechanism of the disease, such as corticosteroids, cyclosporine, anti-lymphocytic serum. If the clinical picture is dominated by cytopenia or uncontrolled hemolysis, the option of allogeneic bone marrow transplantation can be considered. Finally, thrombotic manifestations should be treated with anticoagulant therapy. None of the treatments mentioned so far have a significant effect on the pathogenetic mechanism underlying the disease. Recently, treatments capable of blocking the activity of the complementary C5 fraction have become available for the most severe forms (hemolysis not otherwise controlled, thrombosis, organ damage, abdominal pain). In particular, these are humanized monoclonal antibodies (eculizumab). Treatment is well tolerated by addressing the increased risk of bacterial coating agents (Neisseria Meningitis) and extravascular hemolysis. Although it is an effective drug, the spread of this therapy is slowing down due to the high cost of the treatment, which must be continued throughout life.
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