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Drug-Induced Thrombosis—Experimental, Clinical, and Mechanistic Considerations
1 Hadassah Medical Center, Hebrew University, Jerusalem, 91120, Israel and Correspondence: Address correspondence to: Abraham Nyska, D. V. M., Dipl. ECVP, Toxicological Pathologist, Haharuv 18, P.O. Box 184, Timrat, 23840, Israel; e-mail:anyska{at}bezeqint.net Awareness of the dangers of drug-induced thrombosis has recently been heightened and led to demand for improved testing methodology. For example, reports indicating that some selective inhibitors of cyclooxygenase-2 (COX-2) increase the risk of myocardial infarction and atherothrombotic events caused the withdrawal of rofecoxib from global markets and the issuance of warnings concerning the usage of other COX-2 inhibitors. Drugs may exert a prothrombotic state by a variety of mechanisms–those affecting the vessel wall, the blood flow, and/or different blood constituents. Our review serves as an update to that of Gerhard Zbinden published in 1976 by presenting recently acquired data that more fully elucidate the different mechanisms by which drugs are believed to induce thrombogenic effects and discussing new methods used to detect these without losing sight of the classical pathology of thrombosis. We offer correlations between experimental findings and clinical data and conclude that, because drugs may induce a prothrombotic state by a variety of mechanisms, they should be tested for these using appropriate experimental methods and animal models.
Key Words: Thrombosis • drug-induced • animal model • COX-2 inhibitors Abbreviations: BM, basal membrane • COC, combined oral contraceptives • COX-2, cyclooxygenase-2 • DES, drug-eluting stents • EC, endothelial cell • 5-FU, 5-fluorouracil • GPIIb-IIIa, glycoprotein IIb-IIIa • HIT/T, heparin-induced thrombocytopenia/thrombosis • HRT, hormone replacement therapy • IEL, internal elastic lamina • IL-1, interleukin-1 • N, cell nucleus • PF4, platelet factor 4 • PGI2, prostacyclin • rFXIII, recombinant human factor XIII A2 dimer • SEM, scanning electron microscopy • SSRI, selective serotonin reuptake inhibitor • TEM, transmission electron microscopy • TF, tissue factor • TNF, tumor necrosis factor • t-PA, tissue-type plasminogen activator • TxA2, thromboxane • US FDA, United States Food and Drug Administration • VL, vessel lumen • VTE, venous thromboembolism
Toxicologic Pathology, Vol. 35, No. 2,
208-225 (2007) |
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