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Immediate hypersensitivity and delayed hypersensitivity to Clopidogrel
Abstract
Clopidogrel is a new antiplatelet prescribed for the secondary prevention of atherosclerotic events. The literature shows that the clinical manifestations of clopidogrel hypersensitivity include urticaria1, skin rash2-4, and angioedema5. The precise immunological mechanism underlying clopidogrel hypersensitivity has not been established. We describe two cases of hypersensitivity reaction due to clopidogrel. The first constituted an immediate reaction after clopidogrel intake. In this case we demonstrated type 1 hypersensitivity using cutaneous tests. The second case represented a delayed hypersensitivity reaction confirmed by oral challenge testing, in which good tolerance to other antiplatelet drugs such as ticlopidine was demonstrated.
... The switching of clopidogrel towards another thienopyridine has been rarely described even in type-H (hematologic) reactions [39,40] because they are often dangerous and severe reactions which may have a fatal outcome [41]. The best way to investigate allergic cross- reactivity among the three thienopyridines are the skin tests, followed by an oral challenge test with the alternative mole- cule [42], but that means a wash-out period of some days or weeks is required off and steroids suspension, which could give otherwise skin tests false negative responses [43]. Pa- tients with a recent drug hypersensitivity reaction have a lower threshold and they are more likely to develop an im- munologic reaction to a new drug [44], so the introduction or substitution of a new drug may induce an exacerbation of the existing symptoms related to the drug allergy (a flare-up of cutaneous rash in exanthema, after 1 or 2 days of treatment with the new medication) and often the new or -more fre- quently -enhanced ''rash'' could be misunderstood as a new allergy to the novel drug [44]. ...
... On the other hand, cardiolo- gists prefer to switch therapy from clopidogrel to prasugrel without performing any wash-out period (36) or not to stop thienopyridines either in front of a severe cutaneous reaction as Toxic Epidermo-Necrolysis (TEN), which can be as le- thal and dramatic as a stent thrombosis [45]; in that way no therapeutic discontinuation could occur. For the safety of patient and to avoid the flare-up effect, a wash-out period and an allergic workup should be done before starting a new thienopyridine in patients with a known hypersensitivity, especially when a patient should start a "de novo" therapeu- tic course with an antiplatelet drug [27,42]. The introduction of ticagrelor on the market has increased the weaponry of antiplatelet agents. ...
Background and objective:
The thienopyridine family includes ticlopidine, clopidogrel and prasugrel which are antiplatelet drugs largely used, mainly associated to aspirin, for treatment of acute coronary syndromes and after percutaneous coronary interventions, to avoid thrombosis. In some patients, thienpyridines may cause hypersensitivity reactions which jeopardize the optimal therapeutic and preventive approach to vascular diseases. The management of thienopyridine hypersensitivity seems to be best done as an interdisciplinary collaboration between the allergist and cardiologist.
Method:
The present study investigates the management of thienopyridines hypersensitivity on the basis of published case reports and studies, comparing the pro and contro of pharmacological treatments, different desensitization protocols to thienopyridines and substitution of antiplatelet agents eaches others, according to the point of view of cardiologist and allergist. For the cardiologist, the important issues are the necessity of continuing therapy, the desired duration of therapy based on the clinical indication of the individual patient and appropriateness of using one of the alternative P2Y12 inhibitors. For the allergist, the important issues are weighing the risk and benefits of the various therapeutic options: treating "through" desensitization, or switching to an alternative agent.
Results and conclusion:
All the data seem to suggest that only working together, a cardio-allergy team of specialists may evaluate and offer the best approach to clinical decision-making for the individual patient.
... Proposed mechanisms include direct mast cell activation, complement system activation, immune complex deposition, T-cell activation and IgE-mediated hypersensitivity. 12 Hypersensitivity to metabolites of clopidogrel rather than clopidogrel itself has also been suggested as a possibility. In our case, immune complex deposition could readily explain the development of drug-induced leucocytoclastic vasculitis. ...
We describe a case of leucocytoclastic vasculitis manifested as exanthematous rash in a 57-year-old woman on long-term therapy with clopidogrel. The diagnosis was confirmed by skin biopsy. The patient was managed symptomatically with oral antihistaminics and topical steroids in consultation with dermatologists. Clopidogrel therapy was discontinued on suspicion of drug-induced vasculitis. The rash resolved completely within 2 weeks of withdrawal of clopidogrel, satisfying criteria for a probable adverse drug reaction. Leucocytoclastic vasculitis is an unusual adverse effect of clopidogrel therapy and even rarer as a late complication.
... Although clopidogrel is well tolerated by most patients, rare but serious hypersensitivity reactions including urticaria, skin rashes and angioedema have been reported (3). Documented adverse effects associated with clopidogrel treatment include gastrointestinal complaint, thrombotic thrombocytopenic purpura, neutropenia, asthma, and hepatotoxicity (1,3). ...
Hämostaseologisch wirksame Medikamente gehören zu sehr unterschiedlichen Substanzgruppen. Diese umfassen z. B. die Heparine, Cumarinderivate, direkte Thrombininhibitoren, Plättchenaggregationshemmer, Dextrane und Hydroxyethylstärke. Diese Substanzen haben sehr unterschiedliche chemische Strukturen und verschiedene Wirkmechanismen. Sie können deshalb über sehr unterschiedliche pathogenetische Prozesse überempfindlichkeitsreaktionen mit sehr unterschiedlichen klinischen Manifestationen und Schweregraden hervorrufen (⊡ Tab. 46.1). Insgesamt sind Überempfindlichkeitsreaktionen auf die hämostaseologisch wirksamen Medikamente in Anbetracht der Häufigkeit der Anwendung aber selten.
Approximately 4 % of patients receiving clopidogrel develop hypersensitivity reactions, potentially limiting the use of this treatment. Managing clopidogrel hypersensitivity can be challenging and requires consideration of patient-specific factors. Management options include avoiding clopidogrel use, overcoming the clopidogrel reaction, and switching to an alternative antiplatelet agent.
Clopidogrel is a cornerstone of dual antiplatelet therapy. Hypersensitivity reactions potentially limit the use of this treatment and present a significant clinical challenge. The authors have developed recommendations for the management of clopidogrel hypersensitivity with consideration for the etiology, pathophysiology, and critical evaluation of potential management strategies. The clopidogrel hypersensitivity reaction is complex in mechanism and presents generally around day 5 of treatment. Generalized reactions are most common, but the reaction may also be localized or systemic. Screening patients for hypersensitivity is not always possible because the type IV delayed reaction is not detected reliably by conventional skin prick, intradermal challenge, or patch testing. Proposed strategies for management of clopidogrel hypersensitivity include treatment of the reaction with corticosteroids, clopidogrel desensitization, substituting an alternative P2Y12 inhibitor, or clopidogrel avoidance. The safety, efficacy, and cost of each potential strategy must be considered when managing a patient with clopidogrel hypersensitivity.
This chapter discusses the adverse effects of drugs that affect blood coagulation, fibrinolysis, and hemostasis. Calciphylaxis (vascular calcification, thrombosis, and skin necrosis) has been attributed to warfarin, a coumarin anticoagulants, in a patient with diabetes mellitus. However, in a study, patients with diabetes and hypertension, half of whom were taking warfarin, there was no effect on systolic blood pressure or pulse pressure. The teratogenic effects of warfarin (‘warfarin embryopathy’) include chondrodysplasia punctata, frontal bossing, a short neck, low birth weight, short limbs, polydactyly, and respiratory difficulty secondary to choanal atresia. The anticoagulants in modern rodenticides, so-called ‘superwarfarins', have very long durations of action. In cases of overdose with such agents, prolonged therapy may be required before coagulation returns to normal, as another case has demonstrated. Lepirudin, a direct thrombin inhibitor, has been associated with anaphylactic reaction in a patient, who had received five courses of lepirudin therapy uneventfully. Bleeding is uncommon with fondaparinux, indirect factor Xa inhibitors, but can be serious when it occurs, as has been illustrated by a case of spontaneous retroperitoneal bleeding from a ruptured lumbar artery in a 78-year-old man with only one kidney.
Ischemic heart disease is the second leading cause of death in the world. The proportion of deaths resulting from this condition has decreased in the last two decades, mainly as a result of improved primary and secondary prevention of cardiovascular events, as well as the development of patient awareness and medical and pharmacological management. The purpose of the present review is to analyze pathophysiological events leading to platelet involvement in cardiovascular thrombosis, as well as the role of pharmacogenetics in modulating the risk of cardiovascular disorders. The present work was performed using a PubMed search with combinations of key words relevant to the subject in both English and French. In addition to the pharmacokinetic and pharmacodynamic characteristics of platelet inhibitors, this work reviews the efficacy and adverse events observed during the clinical trials with these drugs. This review further summarizes possible therapeutic drug monitoring strategies for antiplatelet drugs. The novelty of this work is the description of the lymphocyte toxicity assay as a specific method of diagnosing and predicting possible idiosyncratic adverse events attributable to antiplatelet medication.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Ischemic heart disease is the second leading cause of death in developing countries. The
proportion of deaths resulting from this condition has decreased in the last two decades, mainly as a result of
improved primary and secondary prevention of cardiovascular events, as well as the development of patient
awareness and medical and pharmacological management. The purpose of the present review is to analyze
pathophysiological events leading to platelet involvement in cardiovascular thrombosis, as well as the role of
pharmacogenetics in modulating the risk of cardiovascular disorders. The present work was performed using
a PubMed search with combinations of key words relevant to the subject in both English and French. In
addition to the pharmacokinetic and pharmacodynamic characteristics of platelet inhibitors, this work
reviews the efficacy and adverse events observed during the clinical trials with these drugs. This review
further summarizes possible therapeutic drug monitoring strategies for antiplatelet drugs. The novelty of this
work is the description of the lymphocyte toxicity assay as a specific method of diagnosing and predicting
possible idiosyncratic adverse events attributable to antiplatelet medication.
Drugs with anticoagulant activity, including heparins, hirudins, coumarins, and platelet aggregation inhibitors belong to the most widely used drugs. Hypersensitivity reactions from these agents are rare. However, due to their widespread use, they may have a considerable impact on patient safety and treatment. Accurate diagnosis of potentially life-threatening adverse events and identification of alternatives is mandatory. We review hypersensitivity reactions caused by the different groups of anticoagulant agents and discuss the pathophysiological mechanisms, diagnostic possibilities and management options. According to patients histories the most common hypersensitivity reaction is intolerance to acetylsalicylic acid (ASA). Also localized erythematous plaques, occurring to subcutaneous application of heparins are rather common. Other hypersensitivity reactions are rare but may be life-threatening, e.g. skin necrosis due to heparin-induced thrombocytopenia. Rarely anaphylactoid reactions have been observed to ASA, heparin, and hirudin. Skin and provocation tests with immediate and late readings are the most reliable diagnostic tools for heparin- or hirudin-induced urticaria/anaphylaxis or heparin-induced delayed plaques. Provocation tests may be used to identify safe alternatives. In cases of necrosis from heparins or coumarins, all in vivo tests are contraindicated. Most in vitro tests are not universally available, and with the exception of platelet aggregation tests, they have a low sensitivity. In some anticoagulant-associated hypersensitivity reactions detailed allergologic investigation may help to identify safe treatment alternatives. Typically, several tests are needed, and therefore the test procedures are time consuming.
Clopidogrel, an ideal treatment for prevention of subacute stent thrombosis, may not be feasible to use in every patient. Ticlopidine (plus aspirin) is a very good alternative, although the risks of life threatening neutropenia should mandate regular monitoring of blood counts. It is proposed that patients undergoing angioplasty and stenting should carry a warning card in an effort to make the public and general practitioners aware that antiplatelet treatment after angioplasty plays an important part in ensuring successful outcome.
Clopidogrel, an ideal treatment for prevention of subacute stent thrombosis, may not be feasible to use in every patient. Ticlopidine (plus aspirin) is a very good alternative, although the risks of life threatening neutropenia should mandate regular monitoring of blood counts. It is proposed that patients undergoing angioplasty and stenting should carry a warning card in an effort to make the public and general practitioners aware that antiplatelet treatment after angioplasty plays an important part in ensuring successful outcome.
Clopidogrel (Plavix) is a thiopyridine that inhibits the ADP-dependent pathway for platelet activation and has been shown in numerous trials to be effective for a wide variety of patients with cardiovascular disease, particularly those who have undergone coronary stent implantation and who present with acute coronary syndromes. Allergic rashes are one of the common side effects of clopidogrel, which leads to its discontinuation. Type I (Gell and Combs classification) allergic reactions to drugs may be amenable to drug desensitization, allowing safe and prolonged use of the drug. This case series describes a protocol for clopidogrel desensitization over an 8-hr period using 15 doubling doses of clopidogrel given by mouth to achieve a maintenance dose of 75 mg a day. This case series suggests that patients who have had type I drug allergy to clopidogrel may be rapidly desensitized using this protocol. Further studies enrolling a larger number of patients are indicated to confirm the safety and efficacy of this regimen.
Successful desensitiza-tion with Clopidogrel after a positive skin test
- Vigo Pg
- Al Macdowell
- Wedner
- Hj
Vigo PG, MacDowell AL, Wedner HJ. Successful desensitiza-tion with Clopidogrel after a positive skin test. Ann Allergy Asth-ma Immunol 2005; 94:132. Allergol et Immunopathol 2007;35(5):213-5
Successful desensitization with Clopidogrel after a positive skin test
- Vigo