Current understanding of the mechanisms of idiosyncratic drug-induced agranulocytosis

Johnston, Alexander; Uetrecht, Jack

doi:10.1517/17425255.2015.985649

Cited by 78 publications

(95 citation statements)

References 93 publications

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“…Idiosyncratic drug reactions are generally inconsistent with direct cytotoxicity, and there is growing evidence that most are mediated by the adaptive immune system 32. The manifestations of an “allergic” reaction, such as rash, that occur in some cases have not been recorded in deferiprone‐induced agranulocytosis 32.…”

Section: Discussionmentioning

confidence: 99%

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Deferiprone‐induced agranulocytosis: 20 years of clinical observations

Tricta¹,

Uetrecht

Galanello

et al. 2016

American J Hematol

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Use of the iron chelator deferiprone for treatment of iron overload in thalassemia patients is associated with concerns over agranulocytosis, which requires weekly absolute neutrophil counts (ANC). Here, we analyze all episodes of agranulocytosis (n = 161) and neutropenia (n = 250) during deferiprone use in clinical trials (CT) and postmarketing surveillance programs (PMSP). Rates of agranulocytosis and neutropenia in CT were 1.5% and 5.5%, respectively. Of the agranulocytosis cases, 61% occurred during the first 6 months of therapy and 78% during the first year. These events appeared to be independent of dose, and occurred three times more often in females than males. Their duration was not significantly shortened by use of G‐CSF. No patient with baseline neutropenia (n = 12) developed agranulocytosis during treatment, which raises questions about the validity of prior neutropenia as a contraindication to use. Only 1/7 novel neutropenia cases in CT progressed to agranulocytosis with continued treatment, indicating that neutropenia does not necessarily lead to agranulocytosis. The agranulocytosis fatality rate was 0% in CT and 15/143 (11%) in PMSP. Rechallenge with deferiprone produced agranulocytosis in 75% of patients in whom the event had already occurred, and in 10% with previous neutropenia. Weekly ANC monitoring allows early detection and interruption of therapy, but does not prevent agranulocytosis from occurring. Its relevance appears to decrease after the first year of therapy, when agranulocytosis occurs less often. Based upon analysis of data collected over the past 20 years, it appears that patient education may be the key to minimizing agranulocytosis‐associated risks during deferiprone therapy. Am. J. Hematol. 91:1026–1031, 2016. © 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

“…The manifestations of an “allergic” reaction, such as rash, that occur in some cases have not been recorded in deferiprone‐induced agranulocytosis 32.…”

Section: Discussionmentioning

confidence: 99%

Deferiprone‐induced agranulocytosis: 20 years of clinical observations

Tricta¹,

Uetrecht

Galanello

et al. 2016

American J Hematol

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“…The characteristics of drug-induced agranulocytosis are most consistent with an immune mechanism [4]. The antineutrophil cytoplasm antibody antigens have been identified in parents [5].…”

Section: Novel Association Betweenmentioning

confidence: 99%

Novel Association between <b><i>Flavin-Containing Monooxygenase 3</i></b> Gene Polymorphism and Antithyroid Drug-Induced Agranulocytosis in the Han Population

Hasan

Zhang

et al. 2019

Ann Nutr Metab

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Some effective antithyroid drugs (ATDs) have been widely used for patients with Graves’ disease (GD) but are associated with ATD-induced agranulocytosis. We selected 29 ATD-induced agranulocytosis patients, 44 ATD-induced neutropenia patients, and 140 GD controls among the Chinese Han population who were recruited at the First Affiliated Hospital of Xi’an Jiao Tong University. We assessed their response to ATDs treatment by performing genotyping for a candidate gene association study of samples from patients receiving treatment. Human flavin-containing monooxygenase 3 (FMO3), which is the major hepatic enzyme involved in the production of N-oxide of trimethylamine, catalyzes the oxygenation of a variety of drug compounds. Six single SNP, genotype, haplotype (HAP), and association analyses of the FMO3 gene with ATD-induced agranulocytosis/neutropenia under different models (i.e., additive, dominant, and recessive models) were performed. Rs1736557, which caused an amino acid variation V257M, showed a strong association between ATD-induced agranulocytosis and GD controls after Bonferroni correction (p = 0.011, OR 2.301, 95% CI 1.201–4.409). The presence of HAP 3 (HAP3) in the FMO3 gene HAP was statistically associated with ATD-induced agranulocytosis (p = 0.038, permutation p value). Our findings indicate that genetic variations in the FMO3 gene are associated with the response to ATDs maintenance treatment in ATD-induced agranulocytosis patients of Chinese Han population.

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“…The clinical manifestations of drug-induced agranulocytosis (DIA) include fever, septic shock, pneumonia, sore throat, cutaneous infection, and other infections [29]. The mechanism of DIA has not been fully elucidated; however, two main hypotheses have been proposed [30]. The immune mechanism is based on the presence of antibodies to circulating neutrophils found in the DIA patients, suggesting that an immunological reaction is occurring.…”

Section: Discussionmentioning

confidence: 99%

“…The immune mechanism is based on the presence of antibodies to circulating neutrophils found in the DIA patients, suggesting that an immunological reaction is occurring. Whereas the toxic mechanism proposes that the involvement of reactive metabolites produced by drug metabolism can stimulate a cascade of T cell-mediated reactions primarily against the myeloid cells [30,31]. All classes of medicines have been implicated in agranulocytosis.…”

Section: Discussionmentioning

confidence: 99%

Iatrogenic AKI and Agranulocytosis: a Cautious Tale of Medication Use in Elderly Patients

Qin¹,

Cang²,

Liu³

et al. 2017

J Clin Exp Nephrol

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A 83-year-old female patient suffered from acute kidney injury a month after percutaneous coronary intervention. Two weeks before hospitalization, she experienced nausea and intermittent watery diarrhea. Laboratory test showed high levels of serum creatine kinase and lactate dehydrogenase, which were remarkably decreased after ceasing rosuvastatin and valsartan treatment. Despite the recovery of renal function, unfortunately one week later, she was diagnosed with agranulocytosis because of antibiotic therapy. When we stopped meropenem and switched to granulocyto-colony stimulating factor treatment, her white blood cell count returned to a normal range. In our case, both rhabdomyolysis and agranulocytosis were induced by drugs. We provided a literature review of the causes of acute kidney injury and the pathogenesis of rhabdomyolysis and agranulocytosis. We discussed how drugs might lead to these complications. This case highlights the need to be aware of the potential side effects of drugs, especially those given to elderly patients who are likely to be receiving several medications concurrently for managing chronic diseases.

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Current understanding of the mechanisms of idiosyncratic drug-induced agranulocytosis

Cited by 78 publications

References 93 publications

Deferiprone‐induced agranulocytosis: 20 years of clinical observations

Deferiprone‐induced agranulocytosis: 20 years of clinical observations

Novel Association between <b><i>Flavin-Containing Monooxygenase 3</i></b> Gene Polymorphism and Antithyroid Drug-Induced Agranulocytosis in the Han Population

Iatrogenic AKI and Agranulocytosis: a Cautious Tale of Medication Use in Elderly Patients

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