Click here to view next page of this article


Paroxysmal nocturnal hemoglobinuria

Strictly speaking, paroxysmal nocturnal hemoglobinuria is not an autoimmune disease in the usual sense, but a discussion of its treatment is appropriate in this context as many of its manifestations are due to aberrant immunological reactions. Paroxysmal nocturnal hemoglobinuria can be thought of in two aspects, each of

1. The characteristic lesion in paroxysmal nocturnal hemoglobinuria is a defect in the pig-A gene, the product of which is necessary for the attachment of glycosylphosphatidylinositol-linked proteins to the membrane, in a clone or clones of hematopoietic cells. More than 20 proteins are partially or completely deficient on the abnormal cells, and it is the deficiency of two or three of these proteins that cause many of the symptoms in paroxysmal nocturnal hemoglobinuria. The loss of two complement control proteins (decay-accelerating factor [DAF, CD55].

The result is that (a) red cells are hemolyzed when even very small amounts of complement are activated, resulting in intravascular hemolysis and (b) platelets exovesiculate. The resulting vesicles are very thrombogenic and contribute to a great degree of excessive thrombosis seen in this disease.

2. Hematopoietic suppression characteristic of aplastic anemia is present to a greater or lesser degree in all patients with paroxysmal nocturnal hemoglobinuria. This disorder is presumably autoimmune in origin due to the suppression of the marrow by immune reactions.

Hemolysis in autoimmune hemolytic anemia (AIHA) is affected by IgG or IgM (rarely IgA) antibodies. In general, IgG antibodies react with their antigen at body temperature and IgM antibodies react best at lower temperatures; the exceptions to this rule are the cold-reacting IgG antibodies of paroxysmal cold hemoglobinuria and the rare warm-reacting IgM antibodies. The pathophysiology, clinical syndrome, and treatment depend upon the isotype of the antibody.

Therapy in AIHA centers around three objectives: (1) reduction in the production of antibody; (2) reduction in the amount of available antibody; or (3) diminution in the means of destruction due to antibody or complement.

IgG antibody is produced by clones of cells that have undergone isotype rearrangement and are potentially under the control of the T cell helper-suppressor system. Autoimmune antibodies presumably emerge when that control is faulty and self-recognizing antibodies are either insufficiently suppressed or are stimulated.

Drug-related antibodies can be divided into two categories: those in which the drug forms part of the antigen and those in which it does not. When the drug is a major component of the antigen, stopping the drug is usually enough to assure the cessation of the hemolysis. When the drug is not a major part of the antigen, the antibody may react either with the underlying glycoprotein.

Cold-reacting IgG (Donath-Landsteiner) antibody

Paroxysmal cold hemoglobinuria (PCH) is caused by a cold-reacting IgG antibody and is difficult both to diagnose and to treat. The traditional bithermic Donath-Landsteiner reaction is insensitive, but its sensitivity can be markedly increased by the use of the cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) as the target of lysis.

Measures to reduce the production of this IgG antibody are the same as those for the more common warm-reacting antibody; both prednisone and chemotherapy may be effective. The P antigen, with which most of these antibodies reacts, is a receptor for the parvovirus; a relationship has been suggested between infection with that organism.