Unique Coagulation Driven by IL-6 Trans-Signaling Associated with Liver Injury in COVID-19

ALEXANDRIA, VA – Data from a new study presented this week at The Liver Meeting Digital Experience^® – held by the American Association for the Study of Liver Diseases – found that COVID-19 coagulation impairment, driven in part by endothelial Factor VIII, is associated with liver injury in infected patients. The study’s findings also show that IL-6 trans-signaling, which may play a role in COVID-19 development, results in prothrombotic liver sinusoidal endothelial cells (LSECs) that may mediate the liver injury via elevated Factor VIII and activation of coagulation in the liver microvasculature.

Hepatocellular liver injury in COVID-19 has been linked to severe illness and death, but little is known about how this liver injury unfolds. Vascular thrombosis ─ a condition where a vein is obstructed by a blood clot─ in the liver is also associated with COVID-19. For this new study, supported in part by an AASLD Foundation research award, researchers at Yale School of Medicine explored a hypothesis: Could COVID-19’s unique coagulopathy, which is primarily the result of endothelial inflammation and platelet activation, cause COVID-19-associated liver injury by activating coagulation in the liver microcirculation?

“We undertook this study because liver injury in COVID-19 is common and its long-term consequences at this point are unknown,” says the study’s co-author, Matthew McConnell, MD, a gastroenterology researcher and instructor at Yale University School of Medicine in New Haven, CT. “We hope that by gaining a better understanding of what causes liver injury in COVID-19, we can better advise patients about its potential consequences. Additionally, infections leading to critical illness often cause adverse outcomes in liver disease patients through poorly defined mechanisms. Because COVID-19 is at its core a severe critical illness, it may be broadly beneficial for patients with liver disease to better understand how the inflammatory milieu of this type of illness affects the liver.”

For their study, the researchers measured coagulation parameters and liver tests in 68 patients age 18 or older who had Polymerase Chain Reaction (PCR)confirmed COVID-19 at Yale-New Haven Hospital in Connecticut. They evaluated liver tests within five days before and five days after they assessed coagulation parameters and recorded peak values. In the absence of liver tests within this window, they recorded the closest possible liver tests available. In addition to individual parameters,  thromboelastography (TEG) was also performed and a hypercoagulable profile defined as two parameters indicating hypercoagulability.

They separated patients’ data into two groups based on alanine transaminase (ALT) results: either ALT more than three times the upper limit of normal (ULN) or ALT that is less than three times the upper limit of normal. They found that Factor VIII activity, fibrinogen, and Factor II activity were all significantly elevated in the plasma of patients with ALT more than three times ULN, and a significantly higher percentage of these patients had a hypercoagulable TEG profile.

The data suggested a role for activation of coagulation in COVID-19 liver injury. To better understand this, theycultured primary human LSECs with IL-6 and sIL-6R to simulate the IL-6 trans-signaling thought to play an important role in COVID-19. Compared to controls, IL-6/IL-6R stimulation increased Factor VIII and von Willebrand factor mRNA by qPCR. This suggested a prothrombotic LSEC phenotype in patients with COVID-19. IL-6/IL-6R complex also induced activation of STAT transcription factors, which are known to induce Factor VIII expression.

“These findings may be significant for several reasons. Defining a specific mechanism of liver injury in COVID-19 allows the identification of therapeutic targets for liver-related complications that may arise in these patients,” says Dr. McConnell. “Because the coagulopathy of COVID-19 involves elevated levels of Factor VIII and fibrinogen, both of which are primarily produced in the liver, understanding the mechanisms of hypercoagulability in the liver may be a key to the development of new therapies for the systemic hypercoagulability of COVID-19. Also, severe infections are associated with worsening liver failure in patients with cirrhosis. This study provides an enhanced understanding of the mechanism of liver injury in critical illness and may lead to better therapies for these patients.”

Dr. McConnell will present these findings at The Liver Meeting Digital Experience ™  during Parallel: COVID-19 and the Liver on November. 15 at 5:30 PM ET. The corresponding abstract “Liver Injury in COVID-19 Is Associated With Endothelial-Mediated Hypercoagulability Driven by IL-6 Trans-Signaling” can be found in the journal, HEPATOLOGY.

About the AASLD

AASLD is the leading organization of clinicians and researchers committed to preventing and curing liver disease. The work of our members has laid the foundation for the development of drugs used to treat patients with viral hepatitis. Access to care and support of liver disease research are at the center of AASLD’s advocacy efforts.

 

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