Effect of Azathioprine on the Anticoagulant Activity of Warfarin

Abstract

Glimepiride-induced thrombocytopenic purpuraTO THE EDITOR: Oral sulfonylurea antidiabetic drugs such as glyburide 1 and chlorpropamide 2 , 3 are known to induce thrombocytopenia. George et a l . 4 recently reviewed published reports of drug-induced thrombocytopenia and proposed criteria to evaluate the level of evidence for a causal relationship of each drug to thrombocytopenia. We report a patient who developed thrombocytopenia after glimepiride treatment. According to the criteria developed by George et al., our observations support the existence of a causal relationship between glimepiride and thrombocytopenia.Case Report. A 68-year-old white man was referred to our hospital on April 21, 1998, with a petechial rash associated with hematoma on his trunk, legs, and face. Clinical examination showed hemorrhagic bullae in the mouth and gingival bleeding. No lymphadenopathy or hepatosplenomegaly was observed. His previous medical history included chronic psychosis, which had been treated for 12 years by pipotiazine 12.5 mg every six weeks (last injection April 3, 1998) and trihexyphenidyl 4 mg/d. In February 1998, his physician prescribed glimepiride 1 mg/d, an oral sulfonylurea antidiabetic drug, for hyperglycemia. Platelet counts at the outset of treatment and during the following weeks were not available, but the patient reported no symptoms of bleeding and stopped glimepiride after several weeks of treatment. On April 19, the patient restarted glimepiride treatment and, on April 21, was referred for hemorrhagic syndrome. His platelet count confirmed thrombocytopenia (1 × 1 0 9 /L). A bone marrow aspirate was diluted with peripheral blood, but showed no malignant cells, and there was no serologic evidence of recent viral infection (HIV-1, -2; hepatitis B, C, A; cytomegalovirus; Epstein-Barr virus). The platelet count was too low to assess platelet-associated immunoglobulins, but platelet receptor antibodies were found. All medication was withdrawn; prednisone 1 mg/kg/d and human immunoglobulins 0.4 g/kg/d for 2 d were prescribed. The hemorrhagic syndrome decreased on day 7, but the platelet count was 2 × 1 0 9 /L. After two weeks, the platelet count increased to 23 × 1 0 9 /L and was completely normalized after four weeks of prednisone therapy (281 × 10 9 /L). Prednisone was progressively reduced, and platelet count was normal (346 × 1 0 9 /L) six months after glimepiride was discontinued.

A Case Report of Warfarin Resistance Due to Azathioprine and Review of the Literature

“…This 3.4-fold increase in dosage is consistent with reports of 3-to 4-fold increases. [1][2][3] Other causes of warfarin resistance were excluded, and the patient' s ulcerative colitis during this time of warfarin adjustment remained stable.…”

“…More recently, a patient with recurrent pulmonary embolism and an autoimmune disease began taking azathioprine for a steroid-sparing effect. 1 After starting azathioprine, the warfarin dosage was increased 2.5-to 4-fold in attempt to achieve a therapeutic INR of 2.0-3.0. The dosage was returned to the original maintenance dosage after azathioprine was discontinued.…”

“…One report found plasma concentrations of warfarin were reduced during concomitant therapy with azathioprine, and on withdrawal of the drug, plasma levels increased. 1 The authors concluded that the interaction was caused by a change in warfarin pharmacokinetics, either reduction in absorption or enhanced metabolism. In 1977, when rats were given warfarin intravenously and 6-MP orally, the prothrombin time was reduced.…”

Azathioprine in dermatology: The past, the present, and the future

“…[224][225][226][227][228] There have been reports of patients on warfarin who bled severely after azathioprine was discontinued. 224 Recurrent thrombosis with initiation of azathioprine therapy has also been reported.…”

“…226 The mechanism by which azathioprine induces warfarin resistance is not exactly known but may be due to pharmacodynamic or pharmacokinetic factors. 228 The warfarin dose may have to be increased 3 to 4 times to compensate for azathioprine's interaction. 226 This interaction appears to be dose-dependent, as it becomes apparent with azathioprine doses greater than 100 mg daily.…”