Neutropenia due to Clopidogrel in a Patient with End-Stage Renal Disease

Case Report

A 33-year-old male hemodialysis patient started treatment with clopidogrel 75 mg/day after undergoing coronary artery bypass graft surgery. His baseline hematologic values were normal at the time of discharge. Concomitant drugs at the start of treatment were amlodipine, simvastatin, calcium acetate, and erythropoietin for at least 2 years, with no adverse hematologic consequences. Three weeks after starting clopidogrel, the man was admitted to the emergency department because of a temperature >39 °C with chill.

On admission, the patient was severely ill. There was no splenomegaly or lymphadenopathy. Laboratory studies revealed hemoglobin 10.6 g/dL, platelets 150 × 10³/mm³, leukocytes 1.5 × 10³/mm³, with neutrophils 35%, lymphocytes 65%, and no atypical cells in the blood smear. C-reactive protein was 22 mg/dL (normal 0–6), aspartate aminotransferase 32 U/L (0–40), alanine aminotransferase 27 U/L (0–40), γ-glutamyltransferase 54 U/L (8–61), creatinine 7.89 mg/dL (0.5–1.4), and blood urea nitrogen 75 mg/dL (0–20). Blood cultures and cerebral fluid were sterile. Liver and renal function test results, serologic test results for viral infection (HIV, Epstein—Barr virus, cytomegalovirus, hepatitis B and C, parvovirus B19), and serum levels of vitamin B₁₂ and folic acid were normal. There was no evidence of autoimmune disorders.

All drugs were discontinued and a bone marrow biopsy was performed, which showed hypocellular marrow. The diagnosis of neutropenic fever was made. Thus, the patient was treated with vancomycin, meropenem, and granulocyte colony-stimulating factor. In the following days, his condition improved dramatically and the temperature returned to normal. All hematologic abnormalities resolved on day 5 after clopidogrel cessation. Excluding other causes, clopidogrel-associated neutropenia was considered since the neutropenia resolved promptly after withdrawal of the drug.

Discussion

Clopidogrel is accepted as a well-tolerated drug. ¹ Only a few cases of adverse effects have been reported, including aplastic anemia, ² thrombotic thrombocytopenic purpura, ³ and systemic inflammatory response syndrome and acute arthritis. ⁴ Although clopidogrel-induced neutropenic fever was previously reported in only 5 cases with normal renal function, ⁴ to our knowledge, neutropenic effect of this drug has not yet been established in patients with end-stage renal disease or moderate renal impairment. The mechanism of neutropenia is not well understood, but our case suggested toxicity with a time of installation of 20 days and a time of recovery of 5 days. Use of the Naranjo probability scale indicated a probable relationship between neutropenia and clopidogrel in this patient. ⁵ The adverse reaction appeared after clopidogrel was initiated, resolved promptly on withdrawal of the drug, and no other medications were likely to be the cause.

It is important for physicians to remember that clopidogrel can be associated with leukopenia and even neutropenic fever. Thus, careful clinical and hematologic monitoring should be performed, especially during the first months in patients who have renal disease treated with clopidogrel. Because the frequency of this adverse effect is still unknown in patients with end-stage renal failure, additional similar reports may shed light on its incidence, clinical importance, and mechanism.