Paroxysmal Nocturnal Hemoglobinuria: Relation of the Clinical Manifestations to Underlying Pathogenic Mechanisms

Abstract

1. Paroxysmal nocturnal hemoglobinuria is believed to be an acquired disease of the hematopoietic system in which abnormal red cells, white cells, and platelets are produced. The lesion of the cells probably involves the stromal proteins in such a fashion that they are susceptible to the proteolytic effect of a sytem of normal plasma enzymes. The severity of the disease depends upon the degree of sensitivity of a given patient’s blood cells to the plasma hemolytic system.2. The plasma enzyme system that mediates the destruction of PNH cells consists of hemolytic factors and their inhibitors. The most important inhibitor is easily destroyed by thrombin, allowing increased hemolysis. As a consequence of this, any reaction in the patient that involves the blood coagulation system is apt to cause a hemolytic crisis.3. PNH red cells are destroyed intravascularly causing hemoglobinemia. Hemoglobinuria, hemosiderinuria, and abnormalities of iron metabolism are sequels of this reaction.4. Anemia in PNH is a result of hemolytic disease (short red cell life span) together with a relative bone marrow deficiency.5. Hemolytic crises in PNH occur when plasma hemolytic activity increases. The intensity of activity depends upon a balance that exists between the hemolytic enzymes in the patient’s plasma and two inhibitory factors. Hemolytic crises take place when the balance is disturbed in favor of the hemolytic factors. Increased hemolysis at night may be due to changes in the balance of the inhibitor-hemolysin system in addition to the effect on pH that may be produced by retention of CO2 during sleep. Hemolytic crises have sometimes been due to the temporary appearance of an autoimmune reaction.6. Aregenerative crises occur when the bone marrow temporarily suspends production of blood cells. This may result in severe anemia, agranulocytic angina, or both. Purpura is rare in PNH.7. Chronic leukopenia in PNH is believed to be due to a leukocytic abnormality. The susceptibility to infection of patients with PNH may be related to the defective white cells.8. Thrombocytopenia is believed to be due to a platelet abnormality. The platelets are prone to agglutinate, and their abnormality may be the basis of the susceptibility to thrombosis that these patients exhibit.9. The sensitivity of the platelets to the PNH hemolytic enzymes and the sensitivity of the PNH inhibitor to the action of thrombin suggests that a vicious cycle of activity exists between the PNH hemolytic system and the coagulation system of the blood.10. Dicumarol is able to impede this cycle. Its use has sometimes relieved the anemia. Dicumarol is of special value in protecting patients with PNH against thrombotic accidents. Heparin, on the other hand, by acting against the PNH inhibitor system actually causes increased hemolysis.11. Etiologic factors are discussed, but the etiology of PNH is unknown.12. As of July 1953, there had been published at least one hundred and sixty-two case reports of PNH.