Drug-induced immune
hemolytic anemia (DIIHA) is rare, and a specialized laboratory is often required to provide the optimal serological tests to confirm the diagnosis. The most common drugs associated with DIIHA and the hypotheses for the mechanisms thought to be involved have changed during the last few decades. The drugs most frequently associated with DIIHA at this time are
cefotetan,
ceftriaxone, and
piperacillin. DIIHA is attributed most commonly to
drug-dependent
antibodies that can only be detected in the presence of
drug (eg,
cephalosporin antibodies). DIIHA can also be associated with
drug-independent
antibodies; such
antibodies do not need
drug to be present to obtain in vitro reactions (eg,
fludarabine). In these latter cases, the
drug affects the immune system, causing production of red cell (RBC)
autoantibodies; the clinical and laboratory findings are identical to
autoimmune hemolytic anemia (AIHA), other than the remission associated with discontinuing the
drug. Some of the mechanisms involved in DIIHA are controversial. The most acceptable one involves drugs, like
penicillin, that covalently bind to
proteins (eg, RBC
membrane proteins); RBCs become coated with
drug in vivo and, a
drug antibody (usually
IgG) attaches to the
drug-coated RBCs that are subsequently cleared by macrophages. The most controversial is the so-called
immune complex mechanism, which has been revised to suggest that most drugs are capable of binding to RBC
membrane proteins, but not covalently like
penicillins. The combined membrane plus
drug can create an immunogen; the
antibodies formed can be
IgM or
IgG and often activate
complement, leading to acute intravascular lysis and sometimes
renal failure; fatalities are more common in this group. It is still unknown why and how some drugs induce RBC
autoantibodies, sometimes causing AIHA.