Blood, 1953, Vol. 8, No. 9, pp. 769-812.
© 1953 American Society of Hematology, Inc.
Paroxysmal Nocturnal Hemoglobinuria
Relation of the Clinical Manifestations to Underlying
Pathogenic Mechanisms
WILLIAM H. CROSBY LT. COL., MC, UNITED STATES ARMY1
1 Department of Hematology, Army Medical Service Graduate School, Walter
Reed Army Medical Center, Washington 12, D.C.
1. Paroxysmal noctural 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 hemobytic 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.
Submitted on October 22, 1952
Accepted on May 22, 1953
