Acute thrombocytopenia caused by sensitivity to the glucuronide conjugate of acetaminophen

Bougie, Daniel W.; Benito, A.; Sánchez‐Abarca, Luis Ignacio; Torres, Ricardo; Birenbaum, Jessica; Aster, Richard H.

doi:10.1182/blood-2006-12-063941

Cited by 16 publications

(14 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glucuronidation is a predominant conjugation pathway for acetaminophen clearance. Antibodies to the acetaminophen-glucuronide conjugate have been detected in acetaminophen-induced thrombocytopenia [66]. Acetaminophen is a substrate and weak inhibitor of OAT1, while most other NSAIDs are strong inhibitors of OAT1 [55].…”

Section: Results: Disproportionate Molecular Targets Identified By Damentioning

confidence: 99%

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Burkhart

Abernethy

Jackson³

2015

J. Med. Toxicol.

View full text Add to dashboard Cite

Drug features that are associated with StevensJohnson syndrome (SJS) have not been fully characterized. A molecular target analysis of the drugs associated with SJS in the FDA Adverse Event Reporting System (FAERS) may contribute to mechanistic insights into SJS pathophysiology. The publicly available version of FAERS was analyzed to identify disproportionality among the molecular targets, metabolizing enzymes, and transporters for drugs associated with SJS. The FAERS in-house version was also analyzed for an internal comparison of the drugs most highly associated with SJS. Cyclooxygenases 1 and 2, carbonic anhydrase 2, and sodium channel 2 alpha were identified as disproportionately associated with SJS. Cytochrome P450 (CYPs) 3A4 and 2C9 are disproportionately represented as metabolizing enzymes of the drugs associated with SJS adverse event reports. Multidrug resistance protein 1 (MRP-1), organic anion transporter 1 (OAT1), and PEPT2 were also identified and are highly associated with the transport of these drugs. A detailed review of the molecular targets identifies important roles for these targets in immune response. The association with CYP metabolizing enzymes suggests that reactive metabolites and oxidative stress may have a contributory role. Drug transporters may enhance intracellular tissue concentrations and also have vital physiologic roles that impact keratinocyte proliferation and survival. Data mining FAERS may be used to hypothesize mechanisms for adverse drug events by identifying molecular targets that are highly associated with druginduced adverse events. The information gained may contribute to systems biology disease models.

show abstract

Section: Results: Disproportionate Molecular Targets Identified By Damentioning

confidence: 99%

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Burkhart

Abernethy

Jackson³

2015

J. Med. Toxicol.

View full text Add to dashboard Cite

show abstract

“…Using serum from these patients, we tested whether the NOD/scid mouse, when challenged with naproxen or acetaminophen, would produce a sufficient amount of the glucuronide conjugate to promote platelet clearance by the metabolite-specific antibodies. As shown in Figure 6A, injection of 50 mg/kg acetaminophen into mice previously infused with platelets and an antibody specific for acetaminophen glucuronide 28 led to clearance of approximately 80% of the transfused cells after 24 hours. In contrast, acetaminophen alone and patient serum alone had no effect.…”

Section: Sensitivity Of the In Vivo Assay Was Enhanced By Injecting Dmentioning

confidence: 99%

“…[25][26][27] In particular, conjugation of drugs to glucuronic acid by ester or ether linkage through the action of uridine 5Ј-diphosphate-glucuronyltranferases is similar in the 2 species. 26 We previously described patients with DITP whose antibodies were specific for glucuronide conjugates of the non-steroidal anti-inflammatory drug (NSAID) naproxen 24 and the anti-pyretic acetaminophen, 28 and failed to react with platelets in the presence of the unmodified primary drugs. Using serum from these patients, we tested whether the NOD/scid mouse, when challenged with naproxen or acetaminophen, would produce a sufficient amount of the glucuronide conjugate to promote platelet clearance by the metabolite-specific antibodies.…”

Section: Sensitivity Of the In Vivo Assay Was Enhanced By Injecting Dmentioning

confidence: 99%

“…Studies illustrated in Figure 6A and B provide evidence that mice injected intraperitoneally with acetaminophen and naproxen produce metabolites that accumulate in the circulation at levels sufficient to cause platelet destruction by antibodies specific for the glucuronide conjugates of these drugs. 24,28 Many drugs become linked to glucuronide in vivo, a form in which urinary excretion is facilitated, 25,26 and glucuronides appear to be especially prone to induce DDAbs specific for platelets. 24,28 Findings described here suggest that the mouse model may provide an efficient way to screen suspect patient samples for glucuronidespecific antibodies.…”

mentioning

confidence: 99%

“…24,28 Many drugs become linked to glucuronide in vivo, a form in which urinary excretion is facilitated, 25,26 and glucuronides appear to be especially prone to induce DDAbs specific for platelets. 24,28 Findings described here suggest that the mouse model may provide an efficient way to screen suspect patient samples for glucuronidespecific antibodies.Glucuronides can also induce antibodies capable of causing life-threatening immune hemolytic anemia, 30,31 and there is no apparent reason why the model cannot be used to study this condition as well. Metabolites other than glucuronides can also induce sensitization leading to immune cytopenia.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Drug-dependent clearance of human platelets in the NOD/scid mouse by antibodies from patients with drug-induced immune thrombocytopenia

Bougie

Nayak

Boylan

et al. 2010

Blood

Self Cite

View full text Add to dashboard Cite

Drug-induced immune thrombocytopenia (DITP) is a relatively common and sometimes life-threatening condition caused by antibodies that bind avidly to platelets only when drug is present. How drugdependent antibodies (DDAbs) are induced and how drugs promote their interaction with platelets are poorly understood, and methods for detecting DDAbs are suboptimal. A small animal model of DITP could provide a new tool for addressing these and other questions concerning pathogenesis and diagnosis. We examined whether the nonobese diabetic/ severe combined immunodeficient (NOD/ scid) mouse, which lacks xenoantibodies and therefore allows infused human platelets to circulate, can be used to study drug-dependent clearance of platelets by DDAbs in vivo. In this report, we show that the NOD/scid model is suitable for this purpose and describe studies to optimize its sensitivity for drug-dependent human antibody detection. We further show that the mouse can produce metabolites of acetaminophen and naproxen for which certain drug-dependent antibodies are specific in quantities sufficient to enable these antibodies to cause platelet destruction. The findings indicate that the NOD/ scid mouse can provide a unique tool for studying DITP pathogenesis and may be particularly valuable for identifying metabolite-specific antibodies capable of causing immune thrombocytopenia or hemolytic anemia. (Blood. 2010;116(16): 3033-3038) IntroductionDrug-induced immune thrombocytopenia (DITP) can be triggered by various medications through several distinct mechanisms. 1,2 In a comprehensive survey of DITP cases reported since 1998, George and coworkers identified 17 drugs that were considered to be "probable" causes of DITP and 51 thought to be "definite" causes on the basis of having met, respectively, 3 or 4 well-defined clinical criteria. 3,4 This analysis has helped greatly to define which drugs are capable of causing DITP but does not provide proof in an individual patient that a particular drug was responsible. Evidence supporting a cause-and-effect relationship between drug exposure and thrombocytopenia can be obtained by identifying a drugdependent antibody (DDAb) that reacts with platelets only when the implicated drug is present. 1,2,5 However, relatively few laboratories are experienced in DDAb detection, and it is not rare for antibody testing to be negative in a patient with a clinical history strongly suggestive of DITP. 1,2 Moreover, there is not uniform agreement as to whether detection of a DDAb provides conclusive evidence that the antibody caused platelet destruction. Partly for these reasons, identification of a DDAb is not included among the George criteria. The most stringent of these criteria calls for thrombocytopenia to recur when a patient is exposed a second time to the implicated drug. 3 While a rechallenge can provide convincing evidence that thrombocytopenia was drug-induced, it is often impractical and can be difficult to justify for reasons of patient safety.A surrogate small animal model for direct demonstration...

show abstract

Nonclinical Evaluation of Compound‐Related Cytopenias

O'Rourke¹

2022

Schalm's Veterinary Hematology

View full text Add to dashboard Cite

Acute thrombocytopenia caused by sensitivity to the glucuronide conjugate of acetaminophen

Cited by 16 publications

References 10 publications

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Data Mining FAERS to Analyze Molecular Targets of Drugs Highly Associated with Stevens-Johnson Syndrome

Drug-dependent clearance of human platelets in the NOD/scid mouse by antibodies from patients with drug-induced immune thrombocytopenia

Nonclinical Evaluation of Compound‐Related Cytopenias

Contact Info

Product

Resources

About