Warfarin-Induced Leukocytoclastic Vasculitis
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CONTINUING MEDICAL EDUCATION Warfarin-Induced Leukocytoclastic Vasculitis Bahareh Yaghoubian, PharmD; Binh Ngo, MD; May Mak, PharmD; Enrique Ostrzega, MD; Jane Tesoro, PharmD; Gladys H. Moriguchi Mitani, PharmD GOAL To understand leukocytoclastic vasculitis (LV) to better manage patients with the condition OBJECTIVES Upon completion of this activity, dermatologists and general practitioners should be able to: 1. Recognize the presentation of LV. 2. Explain the factors contributing to drug-induced LV. 3. Discuss treatments and preventive strategies for LV. CME Test on page 348. This article has been peer reviewed and is accredited by the ACCME to provide continuing approved by Michael Fisher, MD, Professor of medical education for physicians. Medicine, Albert Einstein College of Medicine. Albert Einstein College of Medicine designates Review date: May 2005. this educational activity for a maximum of 1 This activity has been planned and implemented category 1 credit toward the AMA Physician’s in accordance with the Essential Areas and Policies Recognition Award. Each physician should of the Accreditation Council for Continuing Medical claim only that credit that he/she actually spent Education through the joint sponsorship of Albert in the activity. Einstein College of Medicine and Quadrant This activity has been planned and produced in HealthCom, Inc. Albert Einstein College of Medicine accordance with ACCME Essentials. Drs. Yaghoubian, Ngo, Mak, Ostrzega, and Tesoro report no conflict of interest. Dr. Mitani is in the speakers program for Aventis Pharmaceuticals Inc and GlaxoSmithKline. The authors discuss off-label use for enoxaparin. Dr. Fisher reports no conflict of interest. Skin reactions associated with oral coumarin- Accepted for publication February 25, 2005. derived anticoagulants are an uncommon Dr. Yaghoubian is a resident in Ambulatory Care Pharmacy, Dr. Mak occurrence. Leukocytoclastic vasculitis (LV) is is an Assistant Professor of Clinical Pharmacy, Dr. Tesoro is primarily a cutaneous small vessel vasculitis, Adjunct Professor of Clinical Pharmacy, and Dr. Mitani is Associate though systemic involvement may be encoun- Professor of Clinical Pharmacy, all at the University of Southern California School of Pharmacy, Los Angeles. Dr. Ngo is a medical tered. We report 4 patients with late-onset LV resident in the Department of Medicine, Dr. Ostrzega is Director probably due to warfarin. All 4 patients pre- of the Cardiac Clinics and Fellowship Program, Dr. Tesoro is Staff sented with skin eruptions that developed after Pharmacist, and Dr. Mitani is Manager of the Cardiac/Anticoagulation receiving warfarin for several years. The results Clinic, LAC+USC Medical Center, Los Angeles. of skin lesion biopsies were available in Reprints: Gladys H. Moriguchi Mitani, PharmD, USC School of Pharmacy, 1985 Zonal Ave, Suite 604, Los Angeles, CA 90033 3 patients, confirming LV. Cutaneous lesions (e-mail: [email protected]). resolved in all patients after warfarin was VOLUME 75, JUNE 2005 329 Warfarin-Induced LV discontinued. In 2 of the 4 patients, rechallenge results of blood cultures and workups for hemato- with warfarin led to recurrence of the lesions. LV logic and collagen vascular diseases (CVDs) were may be a late-onset adverse reaction associ- negative. White blood count, platelet count, liver ated with warfarin therapy. function, antinuclear antibody, hepatitis B and Cutis. 2005;75:329-338. C viruses (HBV and HCV), complement, and rheumatoid arthritis latex function test results were either negative or within reference range. The pproximately 10% to 24% of leukocytoclas- results of a urinalysis revealed proteinuria and tic vasculitis (LV) cases are drug-induced.1 hematuria, and the renal ultrasound demonstrated A Cutaneous reactions from coumarin deriva- no abnormalities. The results of a skin lesion tives are not frequently encountered; however, sev- biopsy were interpreted as LV. eral types of skin lesions associated with the During this time, all of the patient's medications coumarin anticoagulants have been reported, except warfarin and digoxin were discontinued; war- including hemorrhage related to prolongation of farin was not considered to be a culprit. However, prothrombin time, skin necrosis,2 gangrene, purple the skin lesions persisted, and warfarin was discon- toe syndrome, and dermatitis.3 Warfarin-induced tinued 6 days later. Anticoagulation was begun necrosis was first reported in 19434; since then, with subcutaneous unfractionated heparin, and approximately 100 cases have been reported in the improvement was noted in the patient's skin lesions English literature.5 Skin necrosis occurred in during the course of her hospitalization. In mid 0.01% to 0.1% of patients taking coumarin con- October, she was discharged and restarted on all her geners.6 There also have been several case reports previous medications, including warfarin. Five days of an LV resulting from coumarin derivatives, but later, the patient presented to the anticoagulation the onset of these reactions have occurred within a clinic with an increasing number of petechial lesions relatively short time after initiation of coumarin on her arms, legs, abdomen, and back. All medica- therapy (Table 1).7-15 This report describes 4 cases tions except warfarin and digoxin were again dis- of LV that developed in patients on long-term war- continued. Subsequently, the patient continued to farin therapy. have flare-ups of her skin eruptions and hematuria, despite a series of medication changes including sub- Case Reports stituting furosemide with ethacrynic acid, changing Patient 1—The first patient was a 57-year-old white to a dye-free warfarin tablet, and switching to a trial woman with rheumatic heart disease and atrial of dicumarol in place of warfarin. fibrillation who had received warfarin therapy On December 11, the patient was readmitted to continuously for approximately 10 years following the hospital for evaluation of persistent skin a mitral valve replacement with a Kay-Shiley pros- lesions. The results of a repeat skin lesion biopsy thesis in May 1968. Additional medical history confirmed LV, and workup results for other sys- included an embolic cerebrovascular event in temic diseases, including endocarditis, were again January 1976, frequent urinary tract infections, negative. Dicumarol was discontinued, and unfrac- alcohol use, and allergy to penicillin. Her medica- tionated heparin was initiated. Within 7 days, the tions included aspirin, ferrous sulfate, skin lesions improved. By December 19, the skin acetaminophen, potassium chloride, diazepam, lesions were almost completely resolved, and yet digoxin, furosemide, and warfarin. another trial with warfarin was attempted. Eleven In September 1978, the patient was admitted to days after restarting warfarin therapy, a new set of our hospital for exacerbation of a nonpruritic mac- nonpruritic petechial maculopapules reappeared on ulopapular rash that had appeared intermittently the extremities. Warfarin was again discontinued, since January 1978 with no apparent changes in and the patient was maintained on unfractionated her medications. She was afebrile and denied heparin therapy while efforts were made to obtain chills. The results of a skin examination revealed anisindione, an oral anticoagulant belonging to the multiple discrete petechial lesions on her hands, indanedione class. On January 11, 1979, anisindione upper thighs, lower legs, and feet bilaterally and in therapy was initiated. No new cutaneous eruptions the suprapubic region. The results of a cardiac occurred during the subsequent 17 months of examination revealed that the patient was hemo- follow-up. Approximately 2 years after initiating dynamically stable. Laboratory tests on admission anisindione, the patient developed pruritis but no included an excessive prothrombin-proconvertin skin lesions. test value of 6% (reference range, 10%–20%) and Patient 2—The second patient was a 49-year-old an elevated erythrocyte sedimentation rate. The Hispanic man who began long-term warfarin therapy 330 CUTIS® Warfarin-Induced LV in September 1982 following a peripheral vascular Laboratory evaluation included a urinalysis and embolus. At that time, rheumatic mitral valve dis- 24-hour urine collection, results of which showed ease was diagnosed and a Starr-Edwards caged-ball proteinuria and gross hematuria. The prothrombin- prosthesis was implanted in October 1982. In 1983, proconvertin test value was 24%. Laboratory test he also was diagnosed with type 2 diabetes mellitus results for a complete blood count, erythrocyte sed- and was started on insulin treatment. imentation rate, C3, C4, antistreptolysin O titer, Two years after initiation of warfarin therapy, rheumatoid factor, HBV, and HCV were negative the patient was admitted to the hospital with a or within reference range. However, the patient’s 10-day history of a pruritic rash that had developed cryoglobulin level was elevated (7%), and the over both lower extremities. He was afebrile and results of a skin lesion biopsy during this admission denied chills. His medications included warfarin, was interpreted as LV. digoxin, and insulin. The patient denied any On September 18, one day after the patient's known drug allergies or any changes to his medica- admission, warfarin was discontinued, and anti- tion regimen. The skin showed multiple areas of coagulation was begun with subcutaneous unfrac- coalescing violaceous maculopapular lesions with tionated heparin. By September 29, the skin