Intensive Care Med (2002) 28:459465

DOI 10.1007/s00134-002-1233-6 ORIGINAL

Emily E. Wade H2 Antagonist-induced thrombocytopenia:

Jill A. Rebuck
Mark A. Healey is this a real phenomenon?
Frederick B. Rogers

Received: 7 May 2001 Abstract Critically ill patients rou- Keywords Thrombocytopenia
Accepted: 2 January 2002 tinely receive H2 antagonists for Histamine antagonist Critical care
Published online: 12 March 2002 stress ulcer prophylaxis while at risk Intensive care unit Cimetidine
Springer-Verlag 2002 for gastrointestinal bleeding. In these Ranitidine Famotidine Platelet
patients it is often difficult to assess count
No financial support was provided in any accurately the cause of adverse ef-
part for this paper fects such as thrombocytopenia. We
evaluate the literature to better de-
fine thrombocytopenia related to H2
antagonist administration and dis-
E.E. Wade cuss mechanism, potential as a risk
Department of Pharmacy, factor and case reports describing the
University of Pittsburgh Medical Center,
304 Scaife Hall, 200 Lothrop Street, severity and duration of thrombocy-
Pittsburgh, PA 15213, USA topenia.
J.A. Rebuck () M.A. Healey
F.B. Rogers
Department of Surgery,
Division of Trauma/Critical Care,
University of Vermont College of Medicine,
Fletcher Allen Health Care,
111 Colchester Avenue, Burlington,
VT 05401, USA
e-mail: jill.rebuck@vtmednet.org
Tel.: +1-802-8474711
Fax: +1-802-847-5908
Correspondence to:
J.A. Rebuck, Fletcher Allen Health Care,
Department of Pharmacotherapy,
111 Colchester Avenue, Burlington,
VT 05401, USA

Introduction care unit (ICU) patients who develop thrombocytopenia

Thrombocytopenia occurs in both inpatient and outpa-
tient settings, although the incidence is greatly increased
in critically ill patients, with reports ranging from 23 to
63% [1]. Significant increases in length of stay and mor-
tality have been reported in patients with documented
thrombocytopenia, defined as a platelet count less than
100,000/mm3 [1, 2, 3]. Medical and surgical intensive
demonstrate an increased length of stay of 417 days [1,
2, 3]. Furthermore, thrombocytopenia is a marker of dis-
ease severity and has been associated with a worsening
prognosis [1, 2, 3, 4]. The mean direct medical cost per
patient for each event is substantial, as much as $5,600
per patient [5].
In critically ill patients it is difficult to assess accu-
rately the cause of adverse effects such as thrombocyto-
460
penia. Multiple disease states such as sepsis and gastro-
intestinal bleeding experienced by ICU patients contrib-
ute to this problem. Decreased renal and hepatic function
result in drug accumulation leading to an increase in ad-
verse effects. Critically ill patients require multiple med-
ications, many of which have the potential for substantial
drug interactions. Moreover, multiple studies have asso-
ciated specific medications with the development of
thrombocytopenia [1, 2, 3, 6, 7].
Critically ill patients routinely receive H2 antagonists
for stress ulcer prophylaxis while at risk for gastrointes-
tinal bleeding [8, 9]. According to a 1999 survey of
stress ulcer prophylaxis, 67% of critical care physicians
identified an H2 antagonist as the most common agent
for stress ulcer prophylaxis [10]. This frequently pre-
scribed antisecretory class of medications is important in
the medical management of at risk patients in the ICU
[11]. Health care providers presume H2 antagonists are a
well-established cause of thrombocytopenia. Although
other medications such as phenytoin and cephalosporins
are also related to a drop in platelet count [12], the H2
antagonists are typically the first medication to be impli-
cated and substituted with an alternative antisecretory
agent. Thus, it is important to distinguish between H2 an-
tagonist-associated thrombocytopenia and H2 antagonist-
induced thrombocytopenia in order to evaluate the risk-
to-benefit ratio of the continuation of H2 antagonist ad-
ministration. Upon consulting the tertiary literature, the
reported incidence of H2 antagonist thrombocytopenia is
unknown and, thus, is documented as rare [13, 14, 15].
Better to define thrombocytopenia related to H2 antago-
nist administration, we review case reports describing
the severity and duration of thrombocytopenia caused by
all commercially available H2 antagonists. Secondly, the
association with risk factors and mechanism are dis-
cussed.
Case reports
Cimetidine has been implicated as a cause of thrombocy-
topenia, which is reversible upon discontinuation of the
medication [16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33]. Similar cases have been reported
for a small number of patients receiving ranitidine [34,
35, 36, 37, 38, 39] and famotidine [40, 41, 42, 43].
Twenty-nine case reports of patients who received H2
antagonists and developed thrombocytopenia have been
published (Table 1). The mean age of the patients was
59 years (20 males; 9 females). The average duration of
therapy was 14 days (range of 175 days) before medi-
cation discontinuation secondary to thrombocytopenia.
Patients may have developed thrombocytopenia prior to
laboratory confirmation. The platelet count dropped to a
mean nadir of 39,000/mm3 (range of 1,000100,000/mm3),
demonstrating significant episodes of thrombocytopenia
are associated with H2 antagonist administration. Platelet
count decreased an average of 82% from baseline. The
mean time to platelet recovery was 7 days after the dis-
continuation of therapy. More than 90% of patients who
developed thrombocytopenia while receiving an H2 an-
tagonist also had at least one documented independent
risk factor for thrombocytopenia.
Of the 29 case reports, four patients were rechal-
lenged with the same medication and one patient with a
different H2 antagonist. These patients had a similar
mean age to those in other case reports. All five patients
were being treated for gastrointestinal bleeding. Cirrho-
sis and severe rejection of a renal transplant were present
in two separate patients. The three patients who received
the same medication upon rechallenge and whose plate-
let counts were available for evaluation had a decrease in
platelet count of 78% to a mean nadir of 28,000/mm3.
Platelet recovery was achieved by one of the three pa-
tients. Of the other two patients, one died before platelet
recovery and the other patient refused further laboratory
evaluation. The platelet count of the patient rechallenged
with ranitidine rather than cimetidine remained within
normal limits for 3 months after rechallenge.
It is important to note the large number of patients
who had at least one independent risk factor for throm-
bocytopenia. At least 90% of the case reports include
documented risk factors associated with the development
of thrombocytopenia, such as sepsis, gastrointestinal
bleeding, older age, renal and hepatic dysfunction. Four
of the 29 patients were determined to not have dissemi-
nated intravascular coagulation (DIC). No mention of the
presence or absence of DIC was included in the other 21
reports, including the two patients with sepsis. In addi-
tion, the reports did not reveal if patients had central or
arterial lines placed and rarely were additional medica-
tions mentioned, which would also be potential causes of
thrombocytopenia. Patients who develop thrombocyto-
penia while receiving H2 antagonists experience large
decreases in their platelet count, often to levels that
would leave a patient susceptible to a spontaneous bleed.
This is especially worrisome in the majority of patients
who were receiving the medication as treatment for a
gastrointestinal bleed.
The majority of case reports involved cimetidine, with
a smaller number concerning ranitidine or famotidine. Ni-
zatidine was not reported to be associated with the devel-
opment of thrombocytopenia in published case reports.
This does not necessarily suggest nizatidine does not
have the same potential to cause thrombocytopenia as the
other agents or that cimetidine has the greatest potential.
We believe cimetidine is associated with the highest num-
ber of reports because it has been available for the longest
period of time and thus was prescribed exclusively prior
to the development of other H2 antagonists. Consequent-
ly, fewer reports of other H2 antagonists associated with
thrombocytopenia were documented due to the predomi-
 461

Table 1 Summary of H2 antagonist case reports of thrombocytopenia (TDD total daily dose, i.v. intravenous, p.o. per oral, WNL within
normal limits, NR not reported, GIB gastrointestinal bleed, TMP/SMZ trimethoprim/sulfamethoxazole)

Medication TDD Route Duration Baseline Nadir Time to Organ dysfunction Concurrent risk
(mg) (days) platelet count platelet count recovery factors
(per mm3) (per mm3) (days)

Cimetidine [18] 800 i.v. 10 150,000 30,000 NR NR Sepsis, GIB,

ampicillin,
gentamicin
Cimetidine [19] 800 i.v. 7 WNL 19,000 7 NR GIB
Cimetidine [19] 800 i.v. 2 60,000 20,000 6 NR GIB, alcohol
abuse
Cimetidine [20] 1200 p.o. 6 176,000 24,000 2 NR GIB
Cimetidine [21] 900 p.o. 60 670,000 57,000 NR Cirrhosis GIB
Cimetidine [22] 600 p.o. 35 WNL 13,000 10 NR NR
Cimetidinea [23] 1200 i.v. 7 110,000 22,000 3 Cirrhosis Alcohol abuse,
GIB
Cimetidinea [24] 600 i.v. 5 110,000 40,000 3 Renal transplant NR
(mild rejection)
Cimetidine [25] 1000 p.o. 49 184,000 6,000 8 Hepatosplenomegaly Sarcoidosis
Cimetidine [26] 1200 i.v. 5 220,000 95,000 3 NR GIB, gentamicin
Cimetidine [16] 900 p.o. 7 WNL 2,000 7 NR Quinidine,
acetomenophen
Cimetidinea [17] NR NR NR NR 1,000 Several NR Alcohol abuse,
GIB
Cimetidine [27] 1200 i.v. 5 >100,000 20,000 4 Hepatic GIB, splenomegaly-
insufficiency induced thrombo-
cytopenia
Cimetidinea [28] 1200 i.v. 4 270,000 35,000 8 NR GIB, cancer,
tobramycin,
ampicillin
Cimetidine [29] 1200 NR 75 225,000 1,000 6 NR Phenytoin
Cimetidine [30] 800 i.v. 6 192,000 28,000 No NR Phenytoin
recovery
Cimetidine [30] 800 i.v. 4 125,000 35,000 14 NR Phenytoin
Cimetidine [31] 1200 i.v. 7 60,00073,000 5,000 14 Postnecrotic GIB, furosemide
cirrhosis,
hepatosplenomegaly
Cimetidine [32] 900 i.v. 1 WNL 75,000 9 NR GIB
Cimetidineb [33] 800 p.o. NR WNL 50,000 NR NR GIB
Ranitidine [34] 300 p.o. 8 200,000 <50,000 14 NR Cyclosporine,
furosemide
Ranitidine [35] 300 p.o. 18 404,000 31,000 4 NR GIB
Ranitidine [36] 300 p.o. 7 525,000 <100,000 14 NR Blood dyscrasia,
TMP/SMZ
Ranitidine 300 p.o. 14 NR 70,000 2 Renal insufficiency Hydralazine,
[37, 38] aspirin
Ranitidine [39] 150 i.v. 3 249,000 39,000 16 Chronic liver disease NR
Famotidine [40] 40 i.v. 2 282,000 13,000 2 NR Diazepam
Famotidine [41] 20 i.v. 4 288,000 95,000 1 NR Sepsis
Famotidine [42] 40 p.o. 12 252,000 99,000 1 NR GIB, severe
hemophilia
Famotidine [43] 40 p.o. 7 NR 47,000 6 Chronic renal failure Concurrent
leukopenia
a Rechallenged with cimetidine
b Rechallenged with ranitidine
462
nance of this adverse effect already reported in the litera-
ture associated with the medication class.
Risk factor studies
Multiple studies have been conducted to identify risk
factors associated with the development of thrombocyto-
penia in the ICU environment [1, 2, 3, 6, 7]. Cawley re-
cently published a chart review of 193 surgical-trauma
intensive care patients [1]. The use of H2 antagonists was
not considered to be a risk factor in the 25 patients who
developed thrombocytopenia, as similar percentages of
patients with and without thrombocytopenia received H2
antagonists [1]. The patient population in this study ex-
perienced a low frequency of thrombocytopenia, which
may have decreased the power of the study to detect a
difference [1]. In a retrospective review of 162 medical
ICU patients, 53% of non-thrombocytopenic, versus
44% of thrombocytopenic, patients were administered
H2 antagonist therapy [2].
Bonfiglio examined medical-surgical ICU patients
and demonstrated a comparable change in mean platelet
count for patients administered sucralfate (90,000/mm3)
or H2 antagonists (89,000/mm3) [6]. Furthermore, of the
factors identified to be associated with thrombocytope-
nia, 1% were related to H2 antagonist therapy [6]. How-
ever, the authors defined thrombocytopenia as a platelet
count of less than 200,000/mm3 rather than less than
100,000/mm3 [6]. The most recent prospective study,
which involved 147 surgical ICU patients, failed to dem-
onstrate a correlation between H2 antagonist administra-
tion and development of thrombocytopenia [3]. Forty
percent of the patients with thrombocytopenia also had
documented DIC [3]. A further prospective study of 63
trauma ICU patients revealed an 18% increase in the in-
cidence of H2 antagonist administration in the group
which did not develop thrombocytopenia [7]. Patient da-
ta was collected for 14 days, which may not have cap-
tured all drug-induced thrombocytopenia events [7]. In
summary, all of the risk factor studies revealed a lack of
correlation between H2 antagonist administration and the
development of thrombocytopenia.
Although clinicians are able to assess the percentage
of patients who develop thrombocytopenia in the ICU, it
is extremely difficult to establish the incidence attribut-
able to medications. Critically ill patients have multiple
medical conditions and other non-pharmacological is-
sues, which are independent risk factors for thrombocy-
topenia (Table 2). Patients in the ICU are often receiving
more than one agent implicated in the development of
thrombocytopenia. A number of pharmacological agents
have been reported to be associated with this result, in-
cluding antineoplastics, heparin, phenytoin, milrinone,
inamrinone, quinidine, trimethoprim/sulfamethoxazole
and H2 antagonists [12].
Table 2 Non-pharmacological
risk factors for development of Central or arterial line [1, 6]
Sepsis [1, 2, 3, 6]
thrombocytopenia
Renal insufficiency [2]
Hepatic insufficiency [2, 6]
Hemodynamic instability [6]
Bleeding or transfusions [3, 7]
Older age [7]
APACHE II score > 15 [3]
Proposed mechanisms for H2 receptor
antagonist-associated thrombocytopenia
Case reports have yielded two potential mechanisms of
H2 antagonist-induced thrombocytopenia. The first of
these is bone marrow suppression secondary to inhibi-
tion of DNA synthesis [16, 44, 45, 46]. The second
mechanism, which occurs rarely, is the development of
platelet antibodies during H2 antagonist administration
[6, 17, 47].
The earliest proposed mechanism of thrombocytope-
nia was related to the thiourea side chain on metiamide,
the first H2 antagonist available in the United States [16,
44, 45]. It was demonstrated that radiolabeled metiamide
and thiourea were readily accepted by bone marrow cells
[16]. The cells did not retain radiolabeled cimetidine,
which does not contain the thiourea side chain [16].
However, with widespread use of cimetidine, case re-
ports were published documenting patients who experi-
enced thrombocytopenia and leukopenia. Byron demon-
strated that activation of H2 receptors with 4-methylhis-
tamine, a H2 receptor agonist, stimulated the bone mar-
row pluripotent stem cell to move from the G0 phase of
the cell cycle to the DNA synthetic phase [46]. When
metiamide was added with 4-methylhistamine, the shift
to the DNA synthetic phase did not occur [46]. Byron re-
vealed a possible cause of bone marrow inhibition due to
lack of stem cell differentiation leading to thrombocyto-
penia and leukopenia [46]. Other studies have found the
same bone marrow response to other H2 agonist and an-
tagonist combinations [47, 48, 49]. This mechanism
would explain why other H2 antagonists are also report-
ed to cause thrombocytopenia.
Patients have demonstrated positive antibody tests
while receiving H2 antagonists [16, 17, 50]. A positive re-
action has been found for platelet antibodies from serum
drawn at platelet nadir during cimetidine therapy and do-
nor platelets were lysed when combined with patient se-
rum [16]. Serum after platelet recovery was positive for
cimetidine antibodies [16]. Plasma combined with cimeti-
dine and donor-labeled platelets for a serotonin release
assay revealed a high amount of serotonin release as
compared to control, which demonstrated platelet anti-
body activity in the presence of cimetidine [17]. After ex-
posure to occasional ranitidine or nizatidine administra-
tion, patient serum has revealed anti-IgG antibodies
 463

bound to platelets when ranitidine was added at pharma-
cological doses [50]. These experiments were performed
in vitro; therefore, the pathogenetic significance of the
presence of antibodies is unclear. This does, however,
provide a plausible explanation for the development of
thrombocytopenia in patients receiving H2 antagonists.
Recommendations
The risk of bleeding is particularly high in critically ill pa-
tients due to a variety of contributing factors, including an
increased number of invasive procedures performed in the
ICU. It is well documented that the concern about bleeding
escalates as the platelet count declines [12, 51,52]. When
the platelet count decreases to less than 100,000/mm3, the
patient is considered to have mild thrombocytopenia [1, 2,
3]. Typically, patients are not at significant risk of bleed-
ing, but the situation should be corrected if possible and
the patient carefully monitored. At this point it is important
to weigh the risk-to-benefit ratio of each therapy that may
be contributing to thrombocytopenia.
Examining H2 antagonist therapy reveals that multiple
trials have studied this pharmacological class for its use
in stress ulcer prophylaxis and the availability of both an
oral and parenteral route of administration. Alternative
agents include sucralfate and proton pump inhibitors.
Ranitidine has demonstrated increased efficacy com-
pared to sucralfate for prevention of clinically important
gastrointestinal bleeding in critically ill patients [9]. Pro-
ton pump inhibitors, both in the oral and parenteral form,
have demonstrated efficacy in stress ulcer prophylaxis
when compared to H2 antagonists, but the literature
available is limited by small patient numbers [53, 54].
However, proton pump inhibitors are not associated with
the development of thrombocytopenia [55]. Yet, switch-
ing from a H2 antagonist to a proton pump inhibitor may
increase the cost of therapy and, thus, should be reserved
for patients requiring acute acid suppression who are at
risk for bleeding due to thrombocytopenia.
While case reports support the assumption that H2 an-
tagonist administration is associated with thrombocytope-
nia, case-control trials have not conclusively demonstrated
a correlation [1, 2, 3, 6, 7]. Thus, H2 antagonist therapy
should be continued in patients with mild thrombocytope-
nia. At a platelet count of less than 50,000/mm3, a patient
is considered to have moderate to severe thrombocytope-
nia [9]. Further decreases in platelet count increase the
risk of bleeding secondary to invasive procedures and pre-
dispose the patient to a spontaneous bleeding episode. At
this level of thrombocytopenia, the risk-to-benefit ratio for
continuation of H2 antagonist argues shifting therapy to-
ward consideration of an alternative agent.
Conclusion
Upon review of the available case reports and risk factor
studies, H2 antagonist-induced thrombocytopenia does in
fact occur, but the incidence is in all probability over-
reported. Typically prescribed dosing regimens of these
medications as well as the duration of administration do
not appear to be related to the onset of thrombocytopenia.
In patients receiving H2 antagonists who develop thrombo-
cytopenia, the platelet count may decline as much as 80%,
frequently placing the patient at a higher risk for bleeding.
The majority of patients described in the literature possess
at least one documented risk factor, such as sepsis or gas-
trointestinal bleeding, prior to H2 antagonist administra-
tion. Furthermore, recent risk factor studies have revealed
H2 antagonist therapy was not associated with a higher in-
cidence of thrombocytopenia in critically ill patients.
If presented with thrombocytopenia in the absence of
a proven risk factor, the clinician should consider H2 an-
tagonist-related platelet decrease. Risk factor studies
have not revealed a correlation between H2 antagonist
administration and thrombocytopenia; therefore, critical-
ly ill patients should not routinely be switched to an al-
ternative agent. In most cases other more frequent causes
of thrombocytopenia should be considered the source.
H2 antagonist administration has been associated with
thrombocytopenia in multiple published case reports. If
thrombocytopenia is determined to be related to H2 an-
tagonist administration, the clinician should consider an
alternative antisecretory agent, such as a proton pump in-
hibitor, when significant thrombocytopenia (<50,000/mm3)
develops due to the risk of spontaneous bleeding. In the
future, a prospective multi-center trial is needed to enroll
patients to analyze further the relationship between H2
antagonist administration and thrombocytopenia.

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