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Drug-Induced Thrombocytopenia
Introduction
Drug-induced thrombocytopenia (DIT) is a common clinical problem, and numerous drugs have been implicated in the development of thrombocytopenia. The risk of thrombocytopenia after any drug is low, and only a small number of patients taking a suspected medication will develop the problem. However, many patients who develop DIT are taking multiple medications and are critically ill, making the diagnosis difficult. Rapid recognition of thrombocytopenia in affected patients and identification and removal of the offending agent before clinically significant bleeding occurs is imperative. Available laboratory tests have limited specificity and sensitivity and lack a sufficiently rapid turn around time to make a diagnosis in the acute setting. Thus, DIT is usually a clinical diagnosis that can be supported only by resolution of thrombocytopenia after cessation of drug. Certain drugs have a well-documented association with thrombocytopenia ( Table 103.1 ). Heparin-induced thrombocytopenia is discussed in Chapter 104 .
Table 103.1
Drugs Commonly Implicated as Triggers of Drug-Induced Thrombocytopenia a
Modified from Aster, R. H., & Bougie, D. W. (2007). Drug-induced immune thrombocytopenia. N Engl J Med, 357 , 580–587.
| Drug Category | Drugs Implicated in Five or More Reports | Other Drugs |
|---|---|---|
| Heparins | Unfractionated heparin, low-molecular weight heparin | |
| Cinchona alkaloids | Quinine, quinidine | |
| Platelet inhibitors | Abciximab, eptifibatide, tirofiban | |
| Antirheumatic agents | Gold salts | d -penicillamine |
| Antimicrobial agents | β-lactam antibiotics, linezolid, rifampin, sulfonamides, vancomycin | |
| Sedatives and anticonvulsant agents | Carbamazepine, phenytoin, valproic acid | Diazepam |
| Histamine receptor antagonists | Cimetidine | Ranitidine |
| Analgesic agents | Acetaminophen, diclofenac, naproxen | Ibuprofen |
| Diuretic agents | Chlorothiazide | Hydrochlorothiazide |
| Chemotherapeutic and immunosuppressant agents | Fludarabine, oxaliplatin | Cyclosporine, rituximab, ABT-263 |
a For a more extensive list, see the University of Oklahoma website: ( http://moon.ouhsc.edu/platelets/ditp.html ).
Pathology
More than a 100 drugs have been implicated in DIT. Drugs cause thrombocytopenia by two basic mechanisms: decreased platelet production or increased platelet destruction. Decreased production is usually due to marrow suppression. It is an expected complication of chemotherapy agents but can be seen with other agents. More commonly, DIT is due to targeted immune destruction of platelets brought on by the drug.
Decreased Production
DIT resulting from decreased production is usually the result of generalized dose-dependent myelosuppression. Many chemotherapeutic agents suppress the bone marrow and cause leukopenia, anemia, and often severe thrombocytopenia. The cytopenias resolve with cessation of chemotherapy. Other nonchemotherapeutic agents, such as the antiepileptic drug valproate, can also cause myelosuppression. The dose-dependent association between valproate and neutropenia and thrombocytopenia is well documented. Selective depression of megakaryocyte production has been associated with drugs, such as thiazide diuretics, ethanol, and tolbutamide, and can lead to isolated thrombocytopenia.
Increased Destruction
Platelet destruction in DIT is usually immune-mediated, and the mechanism involves the drug-induced production of antiplatelet antibodies that bind to platelets and trigger their consumption by macrophages in the reticuloendothelial system.
Hapten-Induced Antibody
Certain small-molecule drugs may act as haptens and can become covalently linked to platelet surface antigens to form hapten–protein complexes. Antibodies directed at these cell surface protein complexes are produced and result in platelet destruction and thrombocytopenia. This phenomenon is responsible for the thrombocytopenia observed with penicillin and penicillin derivatives. Hapten-induced immune hemolytic anemia occurs much more commonly with penicillins, whereas DIT by this mechanism is less common.
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