The human genome contains hundreds of regions whose patterns of genetic variation indicate recent positive natural selection, yet for most the underlying gene and the advantageous mutation remain unknown. We developed a method, composite of multiple signals (CMS), that combines tests for multiple signals of selection and increases resolution by up to 100-fold. By applying CMS to candidate regions from the International Haplotype Map, we localized population-specific selective signals to 55 kilobases (median), identifying known and novel causal variants. CMS can not just identify individual loci but implicates precise variants selected by evolution.
Anticoagulants are a well known cause of drug-induced liver injury (DILI). We recently encountered a 45-year-old male who developed DILI during treatment with enoxaparin, a low-molecular-weight heparin (LMWH), for dural venous thrombosis. The man received enoxaparin 80 mg subcutaneously, twice daily. After 4 days, the patient was asymptomatic but he developed liver aminotransferase elevations: AST 340 U/L and ALT 579 U/L. Investigation revealed an R ratio of 19.9 by day 5 and a Roussel Uclaf Causality Assessment Method score of 10, giving a high probable likelihood that enoxaparin was the cause of hepatic injury. Enoxaparin was discontinued on day 7, and 1 week later AST and ALT had decreased to 61 and 273 U/L, respectively. This case prompted a literature search and a review of the FDA Adverse Event Reporting System (FAERS) database for the range of hepatic adverse events (HAEs) associated with this class. A MEDLINE/PubMed search was conducted using DILI terms and cross-referenced with the anticoagulant classes. A Freedom of Information Act (FOIA) request was also made to identify adverse events (AEs) associated with enoxaparin in FAERS. Case type, severity of outcome, and demographic information were analyzed. Five publications have reported DILI with enoxaparin. Trial data found elevations in ALT >3 times the upper limit of normal (ULN) for unfractionated heparins (UFH) and LMWH in 8 and 4–13 % of subjects, respectively. However, liver injury in all cases was mild, self-limited, and asymptomatic. Our FOIA request yielded 8336 adverse events related to enoxaparin over a 14-year period (Jan 2000–Sept 2014). Specific HAEs were found in 4 % of reports, but all were described with other serious adverse events. The reported outcomes of hospitalization (75 %), death (17 %), and life-threatening medical events (5 %) were likely due to other related serious adverse events such as hemorrhage (28 %) and thrombocytopenia (11 %). We conclude that LMWH-related liver injury is uncommon and reversible. The mechanism of liver injury is not known, although an idiosyncratic effect is postulated. Although the FAERS database lists hepatic injury in 4 % of all enoxaparin-related AEs, it appears that serious outcomes are related to non-hepatic events.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.