PB0856 - Chronic inflammation of the liver and bile ducts contributes to platelet hypoactivity and platelet-leukocyte aggregate formation in Mdr2-/- mice

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Hanna Englert, MSc

PhD Candidate
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany

Co-Author(s)

JG

Julian C. Gerwers

MD Student
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
NW

Nina Wolska

Postdoc
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
JK

Jenny Krause

MD
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
DS

Dorothee Schwinge

Postdoc
University Medical Center Hamburg Eppendorf
Hamburg, Hamburg, Germany
CS

Christoph Schramm

MD
University Medical Centre Hamburg Eppendorf
Hamburg, Hamburg, Germany
TR

Thomas Renné

Head of Department
Institut für Klinische Chemie und Laboratoriumsmedizin, Zentrum für Diagnostik, UKE, Hamburg, Germany
Hamburg, Hamburg, Germany

Background: Platelets and leukocytes are known to be key players in inflammation. Increased thrombotic risk has been linked to liver disease due to a dynamic disequilibrium between pro- and anticoagulation. Formation of platelet-leukocyte aggregates (PLAs) is a recently observed phenomenon, associated with a wide range of cardiovascular diseases, stroke, and inflammatory diseases, but has not been described previously in liver diseases. Cholangitis is a chronic liver disease, characterized by inflammation, fibrosis, and biliary strictures, eventually resulting in cirrhosis, liver failure and cancer. Intrahepatic cholestasis and cholangitis can be mimicked using Mdr2 (Abcb4) KO mice, which fail to secrete phospholipid from the liver into the biliary system.

Aims: In this study we aimed to investigate the role of platelets and the formation of PLAs in a mouse model of cholangitis.

Methods: Anti-coagulated blood from 4-, 8-, 12-, and 20-week-old Mdr2-/- and control (wild-type, WT) mice was activated with ADP, thrombin, or collagen-related peptide (CRP-xl) and analyzed for activation markers (p-selectin expression and integrin GPIIb/IIIa activation) using flow cytometry. PLAs were measured by flow cytometry in a resting state, without the addition of any activators. Liver lysates were analyzed for inflammatory markers using a multiplex cytokine assay.

Results: Mdr2-/- platelets were slightly preactivated under resting conditions but appear to be hypoactive when stimulated. An increase in PLA formation in Mdr2-/- compared to WT animals was noted. Liver lysates from Mdr2-/- mice showed a pro-inflammatory cytokine profile in comparison to WT mice.

Conclusion(s): Taken together, our data suggest that chronic liver and biliary inflammation in Mdr2-/- mice promote platelet hypoactivity and PLA formation.