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PubMed · 10492853

Future directions in thrombolysis.

J T Willerson·P Zoldhelyi
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Abstract

An extensive body of research conducted in the past 25 years has helped foster understanding of the mechanisms and pathogenesis of the acute coronary syndromes and occlusive disease. Thus, it is well established that thrombosis is caused by vascular injury and that immediate lysis of the arterial thrombus and subsequent prevention of thrombotic reocclusion are critical to the treatment of these disorders. Remarkable progress in the understanding of the biological and molecular mechanisms involved in vascular-wall-platelet interactions, platelet-platelet interactions, and coagulation has led to the identification of multiple targets for drug discovery and the development of numerous antithrombotic drugs. The purpose of this article is to review emerging antithrombotic therapies, introduce potential future molecular targets for drug discovery efforts, and discuss novel strategies for managing patients with coronary disease.

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ClopidogrelCoronary DiseaseCoronary ThrombosisCyclooxygenase 2Enzyme InhibitorsFibrinolytic AgentsForecastingHumansIsoenzymesMembrane ProteinsP-SelectinPlatelet ActivationPlatelet Aggregation InhibitorsPlatelet Glycoprotein GPIIb-IIIa ComplexProstaglandin-Endoperoxide SynthasesThrombolytic TherapyTiclopidineJournal ArticleReview

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J T Willerson, P Zoldhelyi. 1999. Future directions in thrombolysis.. https://doi.org/10.1002/clc.4960221608

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Clopidogrel-precipitated rhabdomyolysis in a stable heart transplant patient.

OBJECTIVE: To report the case of an orthotopic heart transplant recipient who developed rhabdomyolysis precipitated by the addition of clopidogrel to the existing regimen of cyclosporine and atorvastatin, which had been tolerated for more than 3 years without adverse effects or laboratory evidence of myositis. CASE SUMMARY: Fourteen years after cardiac transplantation, a 58-year-old woman began a planned 4 week course of clopidogrel 75 mg/day following coronary angioplasty and placement of a stent in the left circumflex coronary artery. Almost 4 weeks later, she presented with severe muscle pain and weakness and laboratory evidence of rhabdomyolysis, with marked elevations of plasma creatine kinase (96,000 U/L) and urine myoglobin (332,872 microg/L) as well as early acute renal failure (serum creatinine 2.9 mg/dL). Symptoms and laboratory abnormalities resolved with cessation of cyclosporine, atorvastatin, and clopidogrel. Clopidogrel was not restarted, while atorvastatin and cyclosporine were; the patient had no recurrence of symptoms up to 15 months later. DISCUSSION: Both atorvastatin and cyclosporine, as well as clopidogrel's active thiol derivative, are metabolized by the cytochrome P450 3A4 isoenzyme. Cyclosporine is also a moderate inhibitor of this isoenzyme. We postulate that competition between atorvastatin and clopidogrel for CYP3A4 receptors, already partially inhibited by cyclosporine, led to increased atorvastatin concentrations, resulting in the acute onset of rhabdomyolysis. This theory is further supported by the patient's continued ability to tolerate the combination of atorvastatin and cyclosporine, without clopidogrel, on rechallenge. Use of the Naranjo probability scale revealed that rhabdomyolysis was probably precipitated by the addition of clopidogrel to the stable baseline regimen of cyclosporine and atorvastatin. CONCLUSIONS: Practitioners must be conscious of the potential for adverse effects when prescribing clopidogrel to heart transplant patients who are concomitantly receiving cyclosporine and a statin. If concomitant administration is required, careful clinical and laboratory monitoring of the patient is necessary.

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