Leucocytoclastic vasculitis associated with clopidogrel

Cutaneous and Ocular Toxicology, 2012; 31(2): 171–173 © 2012 Informa Healthcare USA, Inc. ISSN 1556-9527 print/ISSN 1556-9535 online DOI: 10.3109/15569527.2011.627578

letter to the editor

Leucocytoclastic vasculitis associated with clopidogrel Seval Erpolat1, Yunus Nazli2, Necmettin Colak2, and Sibel Yenidunya3 Department of Dermatology, 2Department of Cardiovascular surgery, and 3Department of Pathology, Faculty of Medicine, University of Fatih, Ankara, Turkey

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Keywords: Clopidogrel, leucocytoclastic vasculitis, coronary artery disease

Editor, Clopidogrel, a thienopyridine derivative, is an antiplatelet agent that inhibits platelet aggregation by blocking the adenosine diphosphate receptor that is responsible for initiating platelet adhesion and aggregation. Currently, clopidogrel is mainly used for prevention of coronary artery disease and for the early and long- term prevention of atherothrombotic events (1,2). We report a case of leucocytoclastic vasculitis (LCV) associated with clopidogrel treatment. To the best of our knowledge, there is no other report of LCV related to clopidogrel treatment in English literature. Treatment with clopidogrel was initiated in a 45 yearold-man after insertion of a stent following acute inferior myocardial infarction. High-dose clopidogrel was given as a total first day dose of 600 mg followed by a dose of 75 mg daily. Four days after starting the clopidogrel therapy, painful cutaneous eruptions appeared on the lower legs including palpable purpura and ecchymosis (Figure 1A, 1B, and 1C). He had undergone a previous coronary artery bypass grafting (CABG) surgery using the left internal mammary artery to the left anterior descending (LAD) coronary artery 7 years ago. Because of the critical coronary lesions and the clinical status, it was decided to perform an elective CABG re-operation. The patient was under treatment of oral acetylsalicylic acid (100 mg), metoprolol (50 mg), atorvastatin (20 mg) and ramipril (2.5 mg) once daily for 7 years. He denied the use of any other medication. He had no previous history of adverse effect to any drug. He had no complaints of arthralgia or abdominal pain. Physical examination showed palpable purpura and ecchymosis on the lower legs. Blood cell count, serum biochemistry, urine analysis,

coagulation profile, whole autoantibodies (antinuclear antibody, extractable nuclear antigen, antineutrophil cytoplasmic antibody, anticardiolipin antibody IgM, and antiphospholipid antibodies), complement (C3, C4), and cryoglobulins were all normal. Microscopic examination of hematoxylin-eosin stained sections of the skin biopsy specimen showed degenerated epidermis, perivascular lymphocytic infiltrate and some eosinophils in the superficial and deep dermis, fibrinoid necrosis and leucocytoclasia (Figure 2). Cutaneous vasculitis was diagnosed with clinical and histopathological findings. Then clopidogrel was discontinued. Because he had critical coronary artery disease, his other medications were continued even after the development of the vasculitis. His skin lesions resolved within 7 days after discontinuation of the clopidogrel and disappeared completely in 2 weeks without the need of specific therapy. Two weeks after, we successfully performed triple on-pump redo-CABG operation with saphenous vein grafts (to the LAD, the circumflex artery, right coronary posterior descending artery) in the patient. After an uneventful postoperative course, the patient was discharged on the seventh postoperative day. The antiplatelet drug clopidogrel is an oral thienopyridine derivate that has been extensively used for treatment and secondary prevention of variety of cardiovascular disease. 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).

Address for Correspondence: Seval Erpolat, M.D, Department of Dermatology, Faculty of Medicine, University of Fatih, Alparslan Turkes Caddesi No: 57, 06510, Ankara, Turkey. Tel: +90 312 203 52 04. Fax: +90 312 221 36 20. E-mail: [email protected]. (Received 20 July 2011; revised 23 September 2011; accepted 24 September 2011)

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Figure 1. Ecchymosis, palpable purpura on the anterior aspect (A), posterior aspect (B) of the right leg, and both (C) legs.

Figure 2. (A) Histopathological examination of the patient showing perivascular lymphocytes and nuclear debris in the dermis (Hematoxylin and eosin stain, original magnification ×200). (B) Vascular injury, including alterations of the vessel walls, with extravasation of red cells and eosinophils (arrowhead) (Hematoxylin and eosin stain, original magnification ×400).

Mucocutaneous reactions associated with clopidogrel include lichenoid reaction, fixed drug eruption, hemorrhagic herpes zoster, and acute generalized exanthematous pustulosis (4–7). To the best of our knowledge, the current case is the first report of leucocytoclastic vasculitis associated with clopidogrel therapy. LCV also known as hypersensitivity vasculitis is a vasculitic process that involves the small blood vessels and primarily postcapillary venules. Numerous internal conditions including adverse effect of medications, infections, malignancies, allergic reactions, connective tissue, and autoimmune disorders have been associated with LCV (8,9). The American College of Rheumatology has developed criteria for the classification of hypersensitivity vasculitis. Hypersensitivity vasculitis due to drugs can be identified on the basis of the following five defining

characteristic: (1) Age >16 (2) Use of possible offending drug in temporal relation to the symptoms (3) Palpable purpura (4) Maculopapular rash and (5) Biopsy of the skin showing neutrophils around an arteriole or venule (10). In our patient, cutaneous eruptions developed 4 days after starting clopidogrel treatment and resolved 7 days after the drug discontinuation. In fact, a resolution after drug discontinuation, that strongly supports a cause-effect, was clear in this patient. Other drugs were ruled out as a cause due to their medication for a long time. Moreover in the cutaneous biopsy, several eosinophils were observed which are valuable indicators of drug-induced vasculitis (11). As clopidogrel is widely used in clinical practice, skin side effects, secondary to use of clopidogrel, are important problems. As far as drug-induced cutaneous vasculitis is Cutaneous and Ocular Toxicology

Leucocytoclastic vasculitis 173 concerned, the quick withdrawal of the offending drug usually leads to resolution, while some patients progress to serious, life threatening disease if the offending drug is not stopped.

Declaration of interest The authors declare no conflicts of interest.


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