Enoxaparin-Induced Liver Injury: Case Report and Review of the Literature and FDA Adverse Event Reporting System (FAERS)

Abstract

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.

Comprehensive assessment of side effects in COVID-19 drug pipeline from a network perspective

“…Indeed, recent literatures have reported that these drugs do cause liver injury, such as sirolimus ( Neff et al, 2004 ; Umemura et al, 2014 ). Surprisingly, we found some drug-tissue associations which had not been labeled by FDA drug instructions were of statistical difference, such as the potential hepatotoxicity of enoxaparin ( Hahn et al, 2015 ; Pivarnik et al, 2016 ). According to the pharmacovigilance analysis of adverse drug event data, enoxaparin seems to possess significant association with hepatotoxicity (ROR=1.312, 95% CI:1.098-1.566).…”

Risk factors profile for liver damage in cardiac inpatients

“…Enoxaparin and atorvastatin had also positive and significant association with hepatotoxicity in our study in comparison with the use in control subjects. Enoxaparin could increase liver transaminase levels and, in some cases, may cause toxic hepatitis due to temporary necrosis of hepatocytes, usually around one week after the treatment initiation and in a dose-dependent manner [30][31][32][33] . Atorvastatin had well-known hepatotoxic potential, which could manifest with a wide range of clinical features, from asymptomatic increase of liver enzymes to drug-induced hepatitis in different periods from the time of treatment initiation 4 .…”

“…Other drugs, commonly prescribed to these patients are sometimes associated with hepatic damage. For example, among all reports of adverse events associated with the use of enoxaparin in a pharmacovigilance database about 4% cases involve hepatic events 5 .…”

Enoxaparin-induced hepatotoxicity: an under-recognised complication of enoxaparin therapy

“…The patient presenting with enoxaparin-induced liver injury (EILI) is likely to be asymptomatic, but symptoms may include abdominal pain or nausea 1 3 5. Hepatic laboratory analyses reveal elevations in transaminases to three times the upper limit of normal or greater and usually occur within a week of starting enoxaparin 3.…”

“…Several theories exist as to the pathophysiology of liver injury, and the near universal ALT elevation in EILI suggests a direct toxic effect on hepatocytes 11. Harril et al 11 suggested there may be a specific hepatic intracellular biomarker, miR-122, which causes hepatocyte necrosis 5…”