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Annals of Hematology Nov 2020Wider use of clozapine, one of the most effective antipshychotic drugs, is precluded by its propensity to cause agranulocytosis. Currently, clozapine is used for... (Review)
Review
Wider use of clozapine, one of the most effective antipshychotic drugs, is precluded by its propensity to cause agranulocytosis. Currently, clozapine is used for treatment-resistant schizophrenia, with mandatory blood count monitoring for the duration of treatment. Agranulocytosis occurs in up to 0.8% of patients and presents a significant medical challenge, despite decreasing mortality rates. In this paper, we review the epidemiology of clozapine-induced agranulocytosis (CLIA), advances in identifying genetic risk factors, and the preventive measures to reduce the risk of CLIA. We discuss the pathogenesis of CLIA, which, despite receiving considerable scientific attention, has not been fully elucidated. Finally, we address the clinical management and suggest the approach to clozapine re-challenge in patients with a previous episode of neutropenia. With a significant proportion of clozapine recipients in Western hemisphere being Black, we comment on the importance of recognizing benign ethnic neutropenia as a potential impediment to clozapine administration. This review aims to aid haematologists and psychiatrists to jointly manage neutropenia and agranulocytosis caused by clozapine.
Topics: Black People; Clozapine; Humans; Neutropenia; Risk Factors
PubMed: 32815018
DOI: 10.1007/s00277-020-04215-y -
Hematology. American Society of... Dec 2017Non-chemotherapy idiosyncratic drug-induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an... (Review)
Review
Non-chemotherapy idiosyncratic drug-induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an incidence of 2.4 to 15.4 cases per million population. Affected patients typically experience severe neutropenia within several weeks to several months after first exposure to a drug, and mortality is ∼5%. The drugs most frequently associated with IDIN include metamizole, clozapine, sulfasalazine, thiamazole, carbimazole, amoxicillin, cotrimoxazole, ticlopidine, and valganciclovir. The idiosyncratic nature of IDIN, the lack of mouse models and diagnostic testing, and its low overall incidence make rigorous studies to elucidate possible mechanisms exceptionally difficult. An immune mechanism for IDIN involving neutrophil destruction by hapten (drug)-specific antibodies and drug-induced autoantibodies is frequently suggested, but strong supporting evidence is lacking. Although laboratory testing for neutrophil drug-dependent antibodies is rarely performed because of the complexity and low sensitivity of tests currently in use, these assays could possibly be enhanced by using reactive drug metabolites in place of the parent drug. Patients typically experience acute, severe neutropenia, or agranulocytosis (<0.5 × 10 neutrophils/L) and symptoms of fever, chills, sore throat, and muscle and joint pain. Diagnosis can be difficult, but timely recognition is critical because if left untreated, there is an increase in mortality. Expanded studies of the production and mechanistic role of reactive drug metabolites, genetic associations, and improved animal models of IDIN are essential to further our understanding of this important disorder.
Topics: Animals; Chemotherapy-Induced Febrile Neutropenia; Humans; Incidence; Mice
PubMed: 29222255
DOI: 10.1182/asheducation-2017.1.187 -
Sao Paulo Medical Journal = Revista... Sep 2005Neutropenia and agranulocytosis may be defined as granulocyte counts of less than 1,500/mm3 and 500/mm3, respectively. Agranulocytosis is a rare and serious disease... (Review)
Review
CONTEXT
Neutropenia and agranulocytosis may be defined as granulocyte counts of less than 1,500/mm3 and 500/mm3, respectively. Agranulocytosis is a rare and serious disease often caused by drugs. Its mortality rate is around 10%. The most common manifestations are infections such as tonsillitis, pharyngitis, stomatitis or pneumonia. Although dipyrone is one of the drugs known to be associated with agranulocytosis, the strength of the association has been a matter of much debate. Moreover, alternative analgesic and antipyretic agents are not devoid of serious side effects.
CONCLUSIONS
It is therefore necessary to establish the incidence of agranulocytosis in Latin America and the role of dipyrone. The ongoing LATIN Study is a multicenter international case-control study that will provide answers for these questions.
Topics: Agranulocytosis; Anemia, Aplastic; Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Dipyrone; Humans; Incidence; Latin America; Neutropenia; Pilot Projects
PubMed: 16358101
DOI: 10.1590/s1516-31802005000500009 -
Archives of Disease in Childhood Oct 1957
Topics: Agranulocytosis; Child; Humans; Infant; Neutropenia
PubMed: 13479149
DOI: 10.1136/adc.32.165.431 -
Atencion Primaria 2021To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and...
OBJECTIVE
To analyze whether the drug safety update issued by the Spanish Agency of Medicines and Healthcare Products (AEMPS), dated October 30, 2018, on agranulocytosis and metamizole contains accurate and necessary information to protect patients from the presentation of this adverse reaction (AR) and if the official documentation of medicines containing metamizole for doctors, pharmacists and the general population conforms to the guidelines of the AEMPS to reduce this risk.
SETTING AND PARTICIPANTS
Drug safety update, bibliographic search, information at the European Medicines Agency on metamizole drugs marketed in Spain, technical datasheets, leaflets, Bot PLUS Health Information Database and Catalog of Pharmaceutical Specialties. Notification of 4cases of agranulocytosis due to metamizole after the drug safety update was issued.
MAIN INTERVENTIONS AND MEASUREMENTS
Comparison of the key points of the drug safety update and official documents on metamizole with the bibliography. Description of the 4cases of agranulocytosis due to metamizole and application of the causality and severity algorithm.
RESULTS
The drug safety update contains omissions and contradiction in respect to the bibliography and the actual use of metamizole in healthcare practice. The official documents show a lack of updating, unapproved indications and doses higher than those recommended. The drug safety update has not stopped the presentation of cases of agranulocytosis due to metamizole.
CONCLUSIONS
The AEMPS drug safety update can be improved and it is necessary to update the official information documents on metamizole for health professionals and patients in order to decrease the risk of agranulocytosis.
Topics: Agranulocytosis; Anti-Inflammatory Agents, Non-Steroidal; Databases, Factual; Dipyrone; Humans; Spain
PubMed: 33823317
DOI: 10.1016/j.aprim.2021.102047 -
Postgraduate Medical Journal Sep 2005
Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Humans; Neutropenia; Risk Factors; Schizophrenia
PubMed: 16143678
DOI: 10.1136/pgmj.2004.031161 -
Pharmacogenomics Mar 2019Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause... (Review)
Review
Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause agranulocytosis and neutropenia. In this article, we provide an overview of the current understanding of the genetics of clozapine-associated agranulocytosis and neutropenia. We now know that the genetic etiology of clozapine-associated neutropenia is complex and is likely to involve variants from several genes including HLA-DQB1, HLA-B and SLCO1B3/SLCO1B7. We describe recent findings relating to the Duffy-null genotype and its association with benign neutropenia in individuals with African ancestry. Further advances will come from sequencing studies, large, cross-population studies and in understanding the molecular mechanisms underlying these associations.
Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Genetic Association Studies; Genotype; HLA-B Antigens; HLA-DQ beta-Chains; Humans; Neutropenia; Schizophrenia; Solute Carrier Organic Anion Transporter Family Member 1B3
PubMed: 30767710
DOI: 10.2217/pgs-2018-0188 -
Archives of Disease in Childhood Oct 1951
Topics: Agranulocytosis; Child; Humans; Infant; Neutropenia
PubMed: 14886052
DOI: 10.1136/adc.26.129.438 -
BMJ Case Reports Mar 2017
Topics: Aged; Agranulocytosis; Anti-Bacterial Agents; Cephalosporins; Exanthema; Female; Fever; Humans
PubMed: 28270401
DOI: 10.1136/bcr-2017-219403 -
Medicine Dec 2016Pregnancy is a complicated physiological process. Physiological leukocytosis often takes place and it is primarily related to the increased circulation of neutrophils,...
RATIONALE
Pregnancy is a complicated physiological process. Physiological leukocytosis often takes place and it is primarily related to the increased circulation of neutrophils, especially during the last trimester of pregnancy. Noncongenital agranulocytosis during pregnancy is rare and reported only occasionally, while in most of the cases, the agranulocytosis has already occurred prior to pregnancy or induced by identified factors such as antibiotics, antithyroid agents, or cytotoxic agents. Gestation-induced agranulocytosis has not been reported, so we present a case of gestation-induced agranulocytosis in this article.
PATIENTS CONCERN
In this case, we present a Chinese woman (aged 25) in her 38th week of the first gestation who had the complication of agranulocytosis. No abnormality was detected in regular examinations before pregnancy and in the first trimester. Since the last trimester of pregnancy, the patient began to suffer from agranulocytosis and intermittent fever, the maximum being temperature 38.8°C. At admission, the neutrophil granulocytes were 0.17 × 10 L and the bone marrow biopsy showed that agranulocytosis was detected, but the levels of red blood cell and megalokaryocyte were normal. In addition, antinuclear antibodies were detected at a dilution of 1:40, but anti-dsDNA, antiphospholipid antibody, and neutrophil granulocyte antibody were negative.
DIAGNOSES
The patient was empirically treated as having pneumonia.
INTERVENTIONS
We tried to use granulocyte colony-stimulating factor, γ-globulin, glucocorticoids, antibiotics, and antifungi agents to treat the patient, but her symptoms were not alleviated until the patient had a cesarean section.
OUTCOMES
After 24 hours of cesarean section, the temperature and neutrophil granulocyte returned to normal. After a year of follow-up, we found that the patient and the baby were healthy.
LESSONS
Agranulocytosis during pregnancy seems to be associated with immunosuppression induced by immunoregulations and termination of pregnancy may be effective for refractory pregnancy complicated with agranulocytosis, but further studies are needed to confirm this.
Topics: Adult; Agranulocytosis; Anti-Bacterial Agents; Cesarean Section; Female; Fever; Humans; Pregnancy; Pregnancy Complications, Hematologic
PubMed: 28033275
DOI: 10.1097/MD.0000000000005717