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Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution 1963

Rarely, distinct drug-dependent IgG molecules destroy RBCs or several that the patient is receiving) is most likely to explain a diag-
WBCs in addition to platelets. For example, both platelet- and nosis of D-ITP. 10,12–14 The clinician should focus on drugs that have
leukocyte-reactive quinidine-dependent IgG molecules have been been started 5–10 days before the onset of the platelet count decrease
detected in a patient with quinidine-induced bicytopenia. Sometimes (Fig. 132.5A). Also, with drugs such as quinine, in which there may
the immune process is directed against a pluripotent hematopoietic be intermittent exposure (e.g., consumption of gin and tonic), a very
stem cell, resulting in pancytopenia accompanied by BM aplasia or recent exposure (previous 1 or 2 days) usually explains the abrupt
hypoplasia (e.g., gold-, carbamazepine-, or quinidine-induced pancy- onset of symptomatic thrombocytopenia.
topenia). A BM aspirate should be performed in patients with sus- After the physician has identified one or more potential agents,
pected drug-induced bicytopenia or pancytopenia because a the next step is to determine whether these drugs have previously
hypoplastic BM may be indicative of drug-induced aplastic anemia. been implicated as causes of D-ITP. The box Search Strategies When
Investigating Patient With Possible Drug-Induced Immune Throm-
bocytopenic Purpura includes some strategies for identifying drugs
Diagnosis implicated in D-ITP.
Demonstration of drug-dependent binding of IgG to platelets in
A high index of clinical suspicion is required to make the diagnosis. vitro can be important for diagnosis (see Fig. 132.5B). Labeled
Moreover, clinicians need to evaluate which drug (often among Ig-specific probes (e.g., phase II assays) or GP capture techniques
(phase III assays) can be used (see Table 132.3). In other cases, D-ITP
test results are negative, but the diagnosis still seems likely based on
clinical features and supporting literature (see Fig. 132.6).
TABLE List of Drugs Implicated in Drug-Induced Immune There are certain caveats in diagnostic testing. First, metabolites
132.5 Thrombocytopenia must sometimes be used instead of the parent drug to detect the IgG.
Drugs Common to All Three Lists 12–14 Second, the target drug (or metabolite) must be included in the wash
Quinine, quinidine, rifampin, trimethoprim-sulfamethoxazole, buffer used in these assays. Third, despite these maneuvers, the sen-
vancomycin sitivity of in vitro assays is relatively low, and the diagnosis of D-ITP
George 12 Reese 13 Arnold 14 must often be made on clinical grounds. Sometimes the diagnosis is
Acetaminophen Abciximab a Abciximab a confirmed by inadvertent or deliberate reexposure to the suspected
Alprenolol Acetaminophen Carbamazepine drug. However, deliberate drug challenge is not often performed
Aminoglutethimide Amiodarone Ceftriaxone because of its potential risk.
Aminosalicylic acid Ampicillin Eptifibatide b A novel approach to identify drug-dependent platelet-reactive
Amiodarone Carbamazepine Ibuprofen antibodies was reported by investigators at the Milwaukee Blood
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Amphotericin B Eptifibatide b Mirtazapine Center. They used nonobese diabetic/severe combined immunode-
Amrinone Ethambutol Oxaliplatin ficient (NOD/SCID) mice (which lack xenoantibodies, thereby
Chlorothiazide Haloperidol Penicillin allowing infused human platelets to circulate) to identify drug-
Chlorpromazine Ibuprofen Suramin dependent antibodies in patient sera, including antibodies that only
Cimetidine Irinotecan Tirofiban b recognize drug metabolites (presumably, mice produce the same or
Danazol Naproxen Heparin c similar drug metabolites as humans, which are recognized by the
Diatrizoate meglumine Oxaliplatin drug-dependent antibodies).
Diazepam Phenytoin
Diazoxide Piperacillin
Diclofenac Ranitidine
Digoxin Simvastatin Search Strategies When Investigating a Patient With Possible
Ethambutol Sulfisoxazole Drug-Induced Immune Thrombocytopenic Purpura
Haloperidol Tirofiban b
Interferon-α Valproic acid Four sources of information as to whether a drug has been implicated
Iopanoic acid as a cause of D-ITP:
• PubMed search (http://www.ncbi.nlm.nih.gov/pubmed): [name of
Levamisole drug] and [thrombocytopenia]. By way of example, the author
Lithium encountered a patient who developed severe thrombocytopenia
Meclofenamate 5 days after starting treatment with mirtazapine (Fig. 132.6).
Methyldopa Searching [mirtazapine] and [thrombocytopenia] in December
Minoxidil 2014 identified two reports 17,18 of mirtazapine-induced D-ITP
Nalidixic acid syndrome.
Naphazoline • Drug-induced thrombocytopenia website (http://www.ouhsc.edu/
Nitroglycerin platelets/ditp.html): Investigators at the University of Oklahoma
Oxprenolol published a comprehensive survey of drugs implicated in
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D-ITP using clinical criteria ; a website maintained by these
Sulfasalazine investigators is updated every 2 years.
Sulfisoxazole • Database from drug-dependent platelet-reactive antibody
Tamoxifen testing at the BloodCenter of Wisconsin, 1995–2010 (http://
Thiothixene www.ouhsc.edu/platelets/InternetPostingLab2_18_11Frames.htm):
Tolmetin the BloodCenter of Wisconsin maintains a website reporting
a Subtype of D-ITP where patient’s antibodies (either naturally occurring or that its experience in detecting drug-dependent platelet-reactive
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are formed after treatment with abciximab) bind to platelet GPIIb/IIIa antibodies. 12
subsequent to binding of abciximab (chimeric human-murine Fab that • Combined approach that uses clinical criteria, laboratory
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recognizes GPIIb/IIIa) to platelets. criteria, and Adverse Event Reporting System. Table 132.5
b Subtype of D-ITP caused by fiban-dependent antibodies (either naturally- (middle column) lists two dozen drugs (including those drugs
occurring or that are formed after treatment with eptifibatide or tirofiban) that identified by two other comprehensive reviews 12,14 ) for which
recognize neoepitopes on platelet GPIIb/IIIa that form subsequent to binding of convincing clinical and laboratory evidence exists. To review
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fiban drug to GPIIb/IIIa. the comprehensive list of all drugs investigated in this study,
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c HIT is considered a distinct subtype of D-ITP disorder, given its unusual
pathogenesis centered on IgG-induced platelet activation. interested readers can consult the online supplemental
D-ITP, Drug-induced immune thrombocytopenia; HIT, heparin-induced table (http://bloodjournal.hematologylibrary.org/content/
thrombocytopenia. suppl/2010/06/08/blood-2010-03-276691.DC1/TableS1.pdf).