Drug-Induced Thrombocytopenia: A Systematic Review of Published Case Reports
Annals of Internal Medicine, 1 December 1998.
129:886-890.
James N. George, MD; Gary E. Raskob, MSc; Shehla Rizvi Shah, MD;
Mujahid A. Rizvi, MD; Stephen A. Hamilton, MD; Scott Osborne, BA; and
Thomas Vondracek, PharmD
Purpose: To determine the strength of clinical evidence for
individual drugs as a cause of thrombocytopenia.
Data Sources: All English-language reports on drug-induced
thrombocytopenia.
Study Selection: Articles describing thrombocytopenia caused by
heparin were excluded from review. Of the 581 articles reviewed, 20 were
excluded because they contained no patient case reports. The remaining 561
articles reported on 774 patients.
Data Extraction: Two of the authors used a priori criteria to
independently review each patient case report. Two hundred fifty-nine
patient case reports were excluded from further review because of lack of
evaluable data, platelet count of 100 000 cells/mL or more, use of cytotoxic or nontherapeutic agents,
occurrence of drug-induced systemic disease, or occurrence of disease in
children. For the remaining 515 patient case reports, a level of evidence
for the drug as the cause of thrombocytopenia was assigned. Data on
bleeding complications and clinical course were recorded.
Data Synthesis: The evidence supported a definite or probable
causal role for the drug in 247 patient case reports (48%). Among the 98
drugs described in these reports, quinidine was mentioned in 38 case
reports, gold in 11, and trimethoprim-sulfamethoxazole in 10. Of the 247
patients described in the case reports, 23 (9%) had major bleeding and 2
(0.8%) died of bleeding.
Conclusions: Many reports of drug-induced thrombocytopenia do
not provide evidence supporting a definite or probable causal relation
between the disease and the drug. Future patient case reports should
incorporate standard criteria to clearly establish the etiologic role of
the drug.
Ann Intern Med. 1998;129:886-890. Annals of Internal
Medicine is published twice monthly and copyrighted © 1998 by the
American College of Physicians-American Society of Internal Medicine.
The discovery of isolated thrombocytopenia in a patient who is taking
several medications presents a challenging clinical problem. The important
diagnostic issue is to distinguish between drug-induced thrombocytopenia
and idiopathic thrombocytopenic purpura because the latter diagnosis
requires the exclusion of other causes of thrombocytopenia (1).
Therefore, the clinician must determine whether one of the patient’s
medications may be the cause of the thrombocytopenia. Laboratory
confirmation of drug-induced thrombocytopenia at the time of initial
presentation is not possible because tests for drug-dependent antiplatelet
antibodies are not available in most clinical laboratories. Furthermore,
the safety of continuing treatment with a suspected drug if results of
drug-dependent antibody tests are negative has not been established.
The diagnosis of drug-induced thrombocytopenia can be supported only by
the resolution of thrombocytopenia after discontinuation of therapy with
the suspected drug. To avoid unnecessarily interrupting required therapy,
the clinician must often decide whether to discontinue therapy with one or
more of the patient’s medications by assessing the probability that an
agent is causing the thrombocytopenia. Reviews of drug-induced
thrombocytopenia have resulted in extensive lists of drugs that have been
reported to cause thrombocytopenia (2-5).
However, these lists include so many commonly used drugs that they do not
help clinicians to decide which therapy to interrupt first.
To help clinicians better understand the likelihood that a drug will
cause thrombocytopenia, we analyzed all published reports of drug-induced
thrombocytopenia by using explicit, a priori criteria for establishing
levels of evidence of a causal relation (6).
Our systematic review has two objectives: 1) to help clinicians determine
which drugs are more likely to cause thrombocytopenia by distinguishing
drugs for which evidence shows a definite or probable causal relation from
those for which evidence is weaker and 2) to provide standardized criteria
for use in reporting occurrences of drug-induced thrombocytopenia.
Methods
The MEDLINE database was searched for literature published from 1966
through 31 December 1997. Articles were sought by using the MeSH term
thrombocytopenia with the attached subheading
chemically-induced. Limits were set for human only and
English language only. This reference list was supplemented by
publications from 1989 to 1997 retrieved by using alternate search
software (Reference Update, Research Information Systems, Inc., Carlsbad,
California) and by cross-checking against the bibliographies of retrieved
articles to identify additional reports, especially those published before
1966 (and therefore not included in the MEDLINE database). Articles
reporting thrombocytopenia associated with heparin and heparin analogues
were not retrieved because the etiologic relation of heparin to
thrombocytopenia is well established (7).
Criteria for excluding articles from further review were 1)
insufficient clinical data with which to evaluate the relation between
drug administration and thrombocytopenia; 2) platelet count of 100 000
cells/mL or more; 3) use of a known cytotoxic
agent that causes marrow suppression; 4) cases in which the patient was
exposed to a nontherapeutic agent or used an agent in a nontherapeutic
manner (for example, environmental toxins, illicit drugs, drug overdose,
and drugs not currently in use); 5) drug-induced disease that included
thrombocytopenia but predominantly involved other abnormalities, such as
aplastic anemia or the thrombotic thrombocytopenic purpura-hemolytic
uremic syndrome; and 6) patient age of 16 years or younger. The age
criterion was established because idiopathic thrombocytopenic purpura in
children is typically an acute, spontaneously resolving illness that may
not be distinguishable from drug-induced thrombocytopenia (1).
Current use of drugs in the United States was determined by listing in the
American Hospital Formulary Service (8)
and in other countries by listing in the Martindale Pharmacopoeia (9).
By using the criteria listed in Table
1, two of the authors independently reviewed each patient case report
to establish the level of evidence for a causal role of the drug in
thrombocytopenia. These criteria were established a priori for this study.
Disagreement between the two reviewers was resolved by adjudication by a
third independent reviewer. When a causal role for the drug was supported
by level I or level II evidence, the clinical importance of the
drug-induced thrombocytopenia was assessed by using standard criteria to
define three levels of severity of bleeding (10):
1) major bleeding (defined as intracranial or retroperitoneal bleeding) or
overt bleeding (defined as visible or symptomatic bleeding) with a
decrease of hemoglobin concentration by more than 2 g/dL (20 g/L) or the
requirement for transfusion of two or more units of erythrocytes; 2) minor
bleeding, defined as overt bleeding that did not meet the criteria for
major bleeding (melena, gross hematuria, epistaxis or gingival bleeding
that is prolonged for more than 30 minutes or requires medical
intervention; excessive menstrual bleeding or vaginal bleeding other than
menses); and 3) trivial bleeding, which included petechiae, purpura, brief
epistaxis or gingival bleeding, guaiac-positive stool, or microscopic
hematuria.
Selected articles are cited in this review. The full list of articles
reviewed and the database established by this review are available at
http://moon.ouhsc.edu/jgeorge. The authors intend to update this database
annually.
Results
The literature search retrieved 581 articles after exclusion of
articles reporting on heparin and heparin analogues. Twenty articles that
were reviews and descriptions of laboratory studies were excluded because
they contained no patient case reports. The remaining 561 articles
contained 774 patient case reports, of which 259 were excluded: One
hundred thirty contained insufficient clinical data with which to evaluate
the criteria cited in Table
1, 19 had platelet counts of 100 000 cells/mL or more, 14 reported on
known cytotoxic drugs, 89 reported on nontherapeutic agents or use, 10
reported on multisystem disorders that included thrombocytopenia, and 48
reported on patients who were 16 years of age or younger. Some articles
were excluded for more than one criterion.
The remaining 515 patient case reports involved 152 drugs. For these
reports, the levels of evidence (Table
1) were I, definite (87 patient case reports); II, probable (160
reports); III, possible (172 reports); and IV, unlikely (96 reports). The
initial two reviewers agreed on 452 (88%) of the 515 case reports.
Adjudication was required for 63 (12%) of the patient case reports; in all
cases, the third reviewer agreed with one of the two primary reviewers.
Forty-eight drugs had level I evidence, and 50 other drugs had level II
evidence. Table
2 lists the drugs that had level I evidence (which includes recurrent
thrombocytopenia with rechallenge in the same patient) and drugs for which
the causal relation to thrombocytopenia was validated by at least two
reports with level II evidence.
Review of clinical outcomes found that in the 247 patient case reports
with level I or level II evidence, 23 patients (9% [95% CI, 6% to 14%])
had major bleeding, including 2 patients (0.8% [CI, 0% to 3%]) who died of
bleeding; 68 patients (28% [CI, 22% to 34%]) had minor bleeding; and 96
patients (39% [CI, 33% to 45%]) had trivial bleeding. Sixty patients (24%
[CI, 19% to 30%]) had no bleeding symptoms. Both patients who died had
quinine-induced thrombocytopenia (11).
When the sex (74% women) and mean age (54 years) of the 23 patients who
experienced major bleeding were compared with the sex (57% women) and mean
age (53 years) of patients without major bleeding, the difference was not
significant (P > 0.1).
Analysis of the course of thrombocytopenia in the 87 patient case
reports that met the criteria for level I evidence showed that the time of
drug ingestion before the initial occurrence of thrombocytopenia was less
than 1 day to 3 years (median, 14 days) and that the time to recovery of a
normal platelet count was 1 to 30 days (median, 7 days). With rechallenge,
the time to the nadir of thrombocytopenia was less than 1 to 60 days
(median, 3 days) and the time to recovery was similar to the time to
recovery after the initial occurrence of thrombocytopenia (<1 to 60
days [median, 5 days]).
Discussion
Reports of drug-induced thrombocytopenia are common, but our review
found that most do not present evidence for the drug as a definite or
probable cause of the thrombocytopenia. Because many patients are taking
several drugs when thrombocytopenia is first discovered, clinicians need
to know the probability of a causal role for each drug. Our systematic
review provides the best available data with which to make a clinical
decision about which drugs may more likely be implicated as a cause of
thrombocytopenia and therefore should be discontinued. It also identifies
which drugs require stronger evidence to support a causal relation and
provides a structure for reporting future occurrences of drug-induced
thrombocytopenia.
The drugs listed in Table
2 are similar to those found in a case-control study of drugs
associated with acute thrombocytopenia (12);
in both analyses, quinidine and sulfonamides were among the most common
drugs. One difference is that dipyridamole was identified in the
case-control study as being associated with acute thrombocytopenia (12);
however, our systematic review identified no published case reports of
dipyridamole-induced thrombocytopenia. Abciximab is not listed in Table
2 because all of the reported patients with abciximab-induced
thrombocytopenia also received heparin (13)
and therefore level II evidence could not be established (Table
1). However, a recent clinical trial established the causal relation
of abciximab to thrombocytopenia with the observation that 35 of 630
patients (5.6%) who received abciximab developed thrombocytopenia with
platelet counts less than 100 000 cells/mL
compared with 8 of 635 (1.3%) patients who received placebo (P <
0.001) (14).
Reports with level I (definite) evidence for a causal relation help to
define the temporal relation between drug exposure and thrombocytopenia,
because each of these patients had recurrent thrombocytopenia after
rechallenge with the drug. Although the time from initiation of therapy
with the drug to the initial episode of thrombocytopenia varied, the onset
of thrombocytopenia after rechallenge was prompt (typically within 3
days). The time to recovery of a normal platelet count was prompt in both
episodes, with medians of 7 and 5 days. This observation may have
diagnostic value because prolonged thrombocytopenia after discontinuation
of therapy with the suspected drug would be evidence against a causal role
for that drug. An exception may be gold-induced thrombocytopenia. Many
patients with presumed gold-induced thrombocytopenia had persistently low
platelet counts, for many months, a condition attributed to the prolonged
retention of gold salts; many had recurrent thrombocytopenia when
prednisone therapy was discontinued; and some required splenectomy (15,
16). This clinical course is indistinguishable from idiopathic
thrombocytopenic purpura, and it was therefore not possible to establish a
causal role for gold in some reports.
In most patients, thrombocytopenia was discovered after the occurrence
of minor purpura. Major bleeding occurred in 23 of 247 (9% [CI, 6% to
14%]) patients with level I or II evidence of drug-induced
thrombocytopenia. Two deaths were attributable to thrombocytopenic
bleeding (fatal bleeding rate, 0.8% [CI, 0% to 3%]). Both were reported in
a letter to the editor describing quinine-induced thrombocytopenia (11).
Patients with major bleeding may be more likely to be recognized and
reported; therefore, the occurrence of major bleeding due to drug-induced
thrombocytopenia may be less than the estimate from these data.
Nevertheless, the rate of 9% derived from this systematic review suggests
that major bleeding associated with drug-induced thrombocytopenia is not
rare and is clinically important.
In some reviews of drug-induced thrombocytopenia, demonstration of
drug-dependent antiplatelet antibodies was included as evidence confirming
a causal role of a drug (2,
3, 17). However, there are no standard assays for drug-dependent
antiplatelet antibodies, no standardized criteria for distinguishing
positive from negative results, and no data on the sensitivity and
specificity of these assays based on clinical criteria for a causal
relation. Drug-dependent antiplatelet antibodies can be detected in
patients who do not develop thrombocytopenia (7,
18). Prospective studies are needed to validate the role of assays for
drug-dependent antibodies, in which results are available at the time of
the clinical diagnosis and patients with negative laboratory test results
continue therapy with the suspected drug with no adverse effects.
The limitations of our review are its restriction to English-language
publications and the difficulty in assessing some patient case reports
because they lacked detail. For example, whether other drugs were used or
continued was sometimes not explicitly stated in the patient case reports
(Table
1). In addition, the data provided on exclusion of other causes of
thrombocytopenia varied (Table
1). These limitations, however, do not alter our major conclusion-that
most reports do not present evidence for the drug as a definite or
probable cause of thrombocytopenia. Future accurate assessment of a causal
relation of drugs associated with thrombocytopenia will require inclusion
of these explicit details.
Note: A complete list of drugs implicated in patient case
reports can also be found in the electronic version of this paper at http://www.acponline.org/journals/annals/01dec98/drugdata.htm.
Requests for Reprints: James N. George, MD, Hematology-Oncology
Section, Department of Medicine, University of Oklahoma Health Sciences
Center, Box 26901, Oklahoma City, OK 73190.
Current Author Addresses: Dr. George:
Hematology-Oncology Section, Department of Medicine, University of
Oklahoma Health Sciences Center, Box 26901, Oklahoma City, OK 73190.
Mr. Raskob, Drs. Shah and Rizvi, and Mr. Osborne: Department of
Medicine, University of Oklahoma Health Sciences Center, Box 26901,
Oklahoma City, OK 73190.
Dr. Hamilton: Cancer Treatment Center, 230
North Midwest Boulevard, Suite 200, Midwest City, OK 73110.
Dr.
Vondracek: College of Pharmacy, 1110 North Stonewall, Oklahoma City, OK
73104.
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