Acta haemat.

67: 136-138 (1982)

Aplastic Anemia after Prolonged Ingestion of Indomethacin

A. Kornberg, E. A. Rachmilewitz
Hematology Service, Hadassah Mount Scopus-University Hospital, Jerusalem, Israel

Key Words. Aplastic anemia • Indomethacin

Abstract. Two rare cases of aplastic anemia after prolonged ingestion of indomethacin
are described. One patient recovered spontaneously within several weeks following dis­
continuation of the drug while the second one died. The aplastic anemia may be related
to the inhibitory effect of indomethacin on prostaglandins and cyclic nucleotides which
have a regulatory role in erythropoiesis and myelopoiesis.

Indomethacin is commonly used as an salicylic acid intermittently for osteoarthrosis in

anti-inflammatory drug. The common ad­
verse effects of the drug include peptic ul­
ceration and headaches [12]. The develop­
ment of aplastic anemia following indome­
thacin ingestion is rare and has been de­
scribed only in three cases [1, 3, 8]. We
wish to report two cases of severe aplastic
anemia which developed after prolonged
ingestion of the drug. One patient recovered
spontaneously within a few weeks after ces­
sation of the drug, while the second one
died.
Case Report
Case 1
A 65-year-old Arab male was admitted in
November 1980 following 2 months of progressive
weakness and generalized purpura. During the last
his knees. 3 months before admission it was quite
clear that he was treated only with indomethacin,
50-75 mg/day. Physical examination revealed gen­
eralized pallor and purpura without hepatospleno-
rnegaly or lymphadenopathy. The hemoglobin
was 5 g/dl, hematocrit 17°/o, leukocyte count
1X 1OVliter with 5°/o neutrophils and 95°/o lym­
phocytes, platelet count 5 X t0 9/liter, and reticulo­
cytes 0.4°/o. Bone marrow biopsy showed increased
fatty tissue and complete absence of nucleated ele­
ments except for a relative increase in lympho­
cytes and plasma cells. He was treated with oxy-
methalone, pyridoxine, folic acid and prednisone
for 2 months without any improvement. The pa­
tient was readmitted in January 1981 because of
septicemia with Escherichia coli. The blood counts
were the same. Despite treatment with blood and
platelet transfusions, antibiotics and corticoster­
oids, he died 1 month after admission.
Case 2
A 60-year-old woman was admitted in April
1980 with progressive weakness, fatigability and
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2 years he had been taking indomethacin and acetyl- weight loss of 5 kg during a period of 4 months.
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Aplastic Anemia after Prolonged Ingestion of Indomelhacin
During the last 4 years she had been treated peri­
odically with indomethacin, 50-100 mg/day, for
osteoarthrosis. She denied taking any other medi­
cation during the last year except for chlorprop­
amide, 250 mg/day, to control her diabetes melli-
tus. On admission, the physical examination was
unremarkable. The hemoglobin level was 6 g/dl,
hematocrit 18%, leukocyte count 3X lOVliter with
30% neutrophils and 70% lymphocytes, platelet
count 18 X lOVliter and reticulocytes 1.1%. Fer-
rokinetic studies revealed plasma 59Fe T i 2,
140 min, plasma iron turnover, 0.6 mg/dl blood/
24/h and red blood cell utilization after 14 days,
40%. Ham test was negative. Bone biopsy showed
hypoplastic marrow with increased fatty tissue, few
megakaryocytes, scattered islands of myeloid and
erythroid precursors and relative increase in plas­
ma cells and lymphocytes. 1 month after discon­
tinuation of indomethacin, the hemoglobin rose
spontaneously to 9 g/dl and the platelet count to
80XlOVliter. 6 months later, the hemoglobin was
11 g/dl, leukocyte count 6X lOVliter and platelet
count 120X lOVliter.
Discussion
A cause and effect relationship between
indomethacin and aplastic anemia in the
two patients is highly suggested by the de­
velopment of severe aplastic anemia after
prolonged ingestion of indomethacin in the
first case and the spontaneous recovery fol­
lowing discontinuation of the drug in the
second case. The first patient received also
acetylsalicylic acid but denied taking any
other medication except indomethacin in
the last 3 months prior to admission. The
second patient received chlorpropamide
which was associated with the development
of pure red blood cell aplasia [9], although
the rare possibility of chlorpropami­
de-induced aplastic anemia cannot be en­
tirely excluded.
Three rare cases of fatal aplastic anemia
related to indomethacin usage have been re­
137
ported [1. 3, 8], However, the patient de­
scribed by Menkes and Kutas [8] was also
treated with gold salts which have been re­
ported to be one of the agents most fre­
quently associated with drug-induced aplas­
tic anemia [11). The findings of the case de­
scribed by Canada and Burka [1] have been
questioned [4].
Indomethacin may induce aplastic ane­
mia by affecting the metabolism of prostag­
landins and cyclic nucleotides. Prostaglan­
dins, cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophos­
phate (cGMP) are involved in the matura­
tion and differentiation of the progenitor
cells of the bone marrow. Schooley and
Mahhnan [10] and Dukes [2] have shown
that prostaglandins of the E, F and A series
and cyclic nucleotides stimulate erythro-
poiesis. Kurland et al. [6, 7] have demon­
strated that the granulocyte-macrophage
progenitor cells are inhibited by the E-series
prostaglandins, whereas their proliferative
ability can be augmented by prostaglandins
F»« through different receptors. The regula­
tory role of prostaglandins on myelopoiesis
may be mediated by the cyclic nucleotides.
It has been shown that cGMP augments the
stimulatory action of colony-stimulating fac­
tor on myelopoiesis, whereas increased con­
centrations of cAMP inhibit it [6], Under
normal conditions there seems to be a bal­
ance between prostaglandins of the E serie
and F2« and also between cAMP and
cGMP. Indomethacin inhibits the synthesis
of prostaglandins and indirectly the produc­
tion of cyclic nucleotides [5]. It is possible
that any alteration in the concentration of
one of these substances by prolonged inges­
tion of indomethacin may alter myelopoiesis
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and erythropoiesis and result in aplastic
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anemia.
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138
References
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Received: April 13, 1981
Accepted: May 4, 1981
A. Kornberg, MD, Hematology Service,
Hadassah Mount Scopus University Hospital,
Jerusalem (Israel)
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