Historia Clinica

Blood Reviews 24 (2010) 143–150

Contents lists available at ScienceDirect

Blood Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b l r e

REVIEW

Immune hemolytic anemia associated with drug therapy
George Garratty ⁎
American Red Cross Blood Services, Southern California Region, 100 Red Cross Circle, Pomona, CA 91768, United States

articleinfo

Keywords:
Hemolytic anemia
Drugs and hemolytic anemia
Cephalosporins and hemolytic anemia
Piperacillin and hemolytic anemia
Fludarabine and hemolytic anemia
Drug antibodies

abstract
Drug-induced immune hemolytic anemia (DIIHA) is rare; it can be mild or associated with acute severe
hemolytic anemia (HA) and death. About 125 drugs have been implicated as the cause. The HA can becaused
by drug-independent antibodies that are indistinguishable, in vitro and in vivo, from autoantibodies causing
idiopathic warm type autoimmune hemolytic anemia (AIHA). More commonly, the antibodies are drugdependent (i.e., will only react in vitro in the presence of the drug). The most common drugs to cause DIIHA
are anti-microbials (e.g., cefotetan, ceftriaxone and piperacillin), whichare associated with drug-dependent
antibodies. The most common drug to cause AIHA is fludarabine. Finding out which drug is causing the
problem and stopping that drug is the first approach to therapy. It is not easy to identify the drug interactions
accurately in vitro; laboratories specializing in this area can be of great help.
© 2010 Elsevier Ltd. All rights reserved.

1. IntroductionDrugs were first suspected as a cause of immune hemolytic anemia
(IHA) in 19531 when Snapper described a patient who developed
pancytopenia with hemolytic anemia (HA), associated with a positive
direct antiglobulin test (DAT), following ingestion of mephenytoin
(Mesantoin). Harris2 was the first to document carefully the history
and serology of a case of immune hemolytic anemia due to a drug. Thedrug, stibophen, was used to treat schistosomiasis. The patient had
received a course of stibophen 10 years previously with no problems.
During the second course, the patient developed acute intravascular
hemolysis. The DAT was positive, and the patient's serum was shown
to react with allogeneic RBCs only when the drug was present. The
stibophen was stopped and the patient's hemoglobinreturned to
normal in 20 days; the serology became negative after about 60 days.
In 1967, Dausset and Contu3 reviewed the literature on druginduced immune hemolytic anemia (DIIHA) and found only 34
published cases due to 15 drugs. In 1969, Worlledge added six more
cases but no other drugs to the list.4 By 1980, we had found reports of
approximately 33 drugs as causes of DIIHA.5 In 1989, the listhad
grown to over 50 drugs that were reasonably well-documented as
causes of IHA.6 In 2007, we reported that we now found 125 drugs
that had reasonable evidence to suggest DIIHA.7 There are many more
reports in the literature, but most of these do not contain criteria, that
we demand, to be included in our list of drugs causing DIIHA. Many of
these are case reports of patients developing aHA following therapy
with a particular drug and the HA resolving once the drug is
discontinued. This is not sufficient to support that the HA is due to

⁎ Tel.: +1 909 859 7405.
E-mail address: garratty@usa.redcross.org.
0268-960X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.blre.2010.06.004

the drug or that the etiology is immune. The diagnosis must besupported with serological data showing that an antibody is involved
(see later).
Although 30% of fatal blood dyscrasias are said to be due to drugs,8
and 5% (8 of 171) of drug-related dyscrasias have been reported to be
IHA,9 DIIHA is quite rare; drug-induced immune thrombocytopenia is
more common. There are good data for the incidence of drug-induced
thrombocytopenia (10–18 cases per...