DRUG-INDUCED "IN VIVO" RED BLOOD CELL SENSITIZATION
a. Background. The list of drugs capable of causing hematologic abnormalities
continues to grow. Some of these abnormalities involve RBCs and some may be
caused by Immune mechanisms. Many drugs seem to lead to formation of antibodies,
either against the drug itself, or against intrinsic RBC antigens. Substances that act as
immunogenes usually have to be of a molecular weight greater than 5,000 daltons.
Drugs usually fall into the category termed by immunologists as "simple chemicals, for
example, well-defined organic compounds of molecular weight under 1,000 daltons (for
example, penicillin has a molecular weight of 300 daltons). It is widely accepted, that
for a simple chemical to induce an immune response, it must first bind irreversibly to
some tissue macromolecules (for example, protein). The conjugated proteins formed
are termed hapten-protein conjugates can induce the formation of antibodies specific for
the simple chemical whereas the un-conjugated simple chemical itself is incapable of
inducing antibody synthesis. Although it has not been proved, it is thought that most
antibodies to drugs are formed in this way. The antibodies, once formed, may cause
positive direct antiglobulin tests and sometimes hemolytic anemia (see Table 2-1) by
four possible mechanisms, one of which is not understood at present.
b. Mechanisms of Erythrocyte Sensitization.
lmmune-complex adsorption to RBCs.
(a) Some drugs will not bind firmly to RBCs. Even if they do combine
loosely, they can easily be removed with simple washing in saline. It has been shown
that drugs, such as phenacetin, and quinidine, have a high affinity for their specific
antibodies, forming antigen-antibody complexes, readily in plasma. These immune
complexes are capable of activating the complement cascade. This may lead to
intravascular hemolysis. The RBC has a positive direct antiglobulin test (see Table 2-1,
because of bound immuno-globulin-drug-complex and complement. Often, only
complement is demonstrated on the RBCs. This may be explained by the fact that the
immune-complex does not bind very firmly to the red cells and may dissociate from
them, being then free to react with other cells. This, in turn, may explain why such a
small amount of drug complex can cause so much RBC destruction.
(b) The following drugs are thought to cause a positive direct
antiglobulin test and, hence, immune hemolytic anemia through this mechanism:
stibophen (Fuadin), quinidine, para-aminosalicylic acid (PAS), quinine, phenacetin,
insecticides (chlorinated hydrocarbons), antihistamine (Antistine), sulfonamides,
isonicotinic acid hydrazide (isoniazid), chlorpromazine, amlnopyrine (Pyramidon),
Dipyrone, 1-phenylalanine mustard (melphalan), Sulfonylurea (Chlorparopamide),
insulin, rlfampin, and, possibly, tetracycline.