CONNFERENCE UPDATE: AASLD 2020
Endothelial-mediated hypercoagulability is associated with liver injury in COVID-19
Hepatocellular liver injury has been associated with severe illness and death among COVID-19 patients, but the mechanisms leading to these undesirable outcomes have remained unknown. While liver enzyme derangement appears to be mild in COVID-19 patients, hepatic dysfunction may still have significant impact on the systemic disease pathophysiology of COVID-19 due to the liver’s central role in drug metabolism, coagulation, and the production of albumin and acute-phase reactants.1 According to Dr. Matthew McConnell, Yale School of Medicine, United States, liver injury has been observed in 40-60% of COVID-19 patients hospitalized in the Yale health system. Multivariate analysis revealed an association between abnormal liver tests and severe COVID-19 implications including ICU admission, mechanical ventilation and death.2
In particular, vascular thrombosis, a condition where a vein is obstructed by a blood clot, is commonly observed in the livers of COVID-19 patients. Dr. McConnell and his team hypothesized that COVID-19’s unique coagulopathy, which is primarily the result of endothelial inflammation and platelet activation, could cause liver injury by inducing microvascular thrombosis in the liver. From the Yale-New Haven Hospital Connecticut, 68 patients who had COVID-19 confirmed by polymerase chain reaction (PCR) were recruited into a study to have their coagulation parameters measured and liver status tested. For consistency purposes, the liver tests were performed 5 days before and after coagulation parameters assessments, and their peak values were recorded. In the absence of liver tests within this window, the closest possible liver test result was recorded. In addition to individual parameters, thromboelastography (TEG) was also performed and was defined as having 2 parameters of hypercoagulability.
Depending on their alanine transaminase (ALT) levels, the patients were categorized into groups of having ALT >3 times the upper limit of normal (ULN) or <3 times the ULN. In patients with ALT >3 times ULN, factor VIII, fibrinogen and factor II were found to be significantly elevated in the plasma (p<0.05). A significantly higher proportion of these patients also had a hypercoagulable TEG profile (p<0.05), suggesting that thrombosis may play an important role in the commonly observed hepatocellular liver injury among COVID-19 patients.
To better understand this interaction, the researchers have further cultured primary human liver sinusoidal endothelial cells (LSECs) with interleukin 6 (IL6) and soluble IL6 receptor (IL6R) to simulate the activation of the IL6 trans-signalling pathway that is implicated in the pathogenesis of COVID-19. In previous studies, an increased level of factor VIII and other coagulation markers was found to be a well-established risk factor for deep venous thrombosis, and an elevated IL6 was found to be an independent factor associated with factor VIII levels.3
In the simulated environment, Dr. McConnell and his team similarly found that an IL6/IL6R stimulation has significantly increased the level of factor VIII and von Willebrand factor mRNA expression among LSECs (p<0.01 and p<0.05, respectively). The IL6/IL6R complex also induced the activation of signal transducer and activator of transcription (STAT) 1 and 3 transcription factors (p<0.01), which are known to induce factor VIII expression. Together, these data suggested that a majority of COVID-19 patients are of a prothrombotic LSEC phenotype, and that the commonly observed liver injury may be caused by an elevated level of factor VIII which is mediated by the IL6 trans-signalling pathway implicated in COVID-19 pathogenesis.
By defining a specific mechanism of liver injury among COVID-19 patients, a therapeutic target towards the liver-related COVID-19 complications may be identified in the future. Based on the results of the studies, Dr. McConnell concluded that, “Procoagulant endotheliopathy occurs in COVID-19 patients and is associated with liver injury, and that IL6 trans-signaling is a driver of endotheliopathy via the activation of STAT3.”
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