PB0705 - Pharmacological inhibition of coagulation factor XI reduces thromboinflammation in a nonhuman primate model of early atherosclerosis

Monday, June 26, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Tia C.L Kohs, PhD (she/her/hers)

Researcher
Oregon Health & Science University
Portland, Oregon, United States

Co-Author(s)

IP

Ivan Parra-Izquierdo

Senior Scientist
Oregon Health & Science University
Portland, Oregon, United States
HV

Helen H. Vu

Research Assistant I
Oregon Health & Science University
Portland, Oregon, United States
KJ

Kelley R. Jordan

Lead Research Associate
Providence Portland Medical Center
Portland, Oregon, United States
MH

Monica T. Hinds

Assistant Dean of Student Affairs and Professor of Biomedical Engineering
Oregon Health & Science University
Portland, Oregon, United States
JS

Joseph J. Shatzel

Assistant Professor
Oregon Health & Science University
Portland, Oregon, United States
PK

Paul Kievit

Assistant Professor
Oregon Health & Science University
Portland, Oregon, United States
TM

Terry K. Morgan

Professor
Oregon Health & Science University
Portland, Oregon, United States
ST

Samuel Tassi Yunga

Associate Scientist
Oregon Health & Science University
Portland, Oregon, United States
TN

Thuy T.M. Ngo

Assistant Professor
Oregon Health & Science University
Portland, Oregon, United States
Joseph E. Aslan, PhD

Associate Professor
Oregon Health & Science University
Portland, Oregon, United States
Michael Wallisch, PhD (he/him/his)

Principal Scientist
Aronora, Inc.
Portland, Oregon, United States
CL

Christina U. Lorentz

Director of Clinical Operations
Aronora, Inc
Portland, Oregon, United States
ET

Erik I. Tucker

Chief Executive Officer
Aronora, Inc.
Portland, Oregon, United States
Cristina Puy, PhD

Research Assistant Professor
Oregon Health & Science University
Portland, Oregon, United States
David Gailani, MD

Professor
Vanderbilt University Medical Center
Nashville, Tennessee, United States
JL

Jonathan R. Lindner

Professor
University of Virginia
Charlottesville, Virginia, United States
Owen J.T McCarty, PhD, FAHA

Professor and Chair of Biomedical Engineering
Oregon Health & Science University
Portland, Oregon, United States

Background: Obesity is associated with chronic inflammation and the development of atherosclerosis, which promotes a thromboinflammatory environment. This environment is characterized by a procoagulant and activated endothelium that can lead to the initiation of the coagulation cascade. Coagulation factor (F) XI represents a promising therapeutic target as it is uniquely positioned at an intersection between inflammation and thrombin generation.

Aims: Investigate the role of FXI in mediating endothelial activity and systemic platelet activation and inflammation in early atherosclerosis.

Methods: Nonhuman primates (NHPs) were fed a standard chow diet (lean, n=6) or a high-fat diet (obese, n=8) to establish a model of early atherosclerosis. Obese NHPs (n=5) were administered a FXI blocking antibody intravenously at 2 mg/kg. Blood was collected at baseline, 1, 7, 14, 21, and 28 days after treatment to assess platelet activation by flow cytometry and markers of inflammation by ELISAs. Contrast-enhanced ultrasound molecular imaging was used to quantify the expression of vascular cell adhesion molecule 1 (VCAM-1) at the carotid bifurcation in obese NHPs at baseline and 28 days after treatment.

Results: Animals in the obese cohort demonstrated increased platelet P-selectin expression and phosphatidylserine (PS) exposure in response to platelet agonists targeting glycoprotein VI (GPVI) and protease-activated receptors (PAR-1) compared to their lean counterparts. Obese NHPs also had elevated levels of C-reactive protein, cathepsin D, and myeloperoxidase compared to lean NHPs. Following administration of the FXI blocking antibody, obese NHPs demonstrated reduced P-selectin expression relative to baseline as early as one day following the initial dose. We also observed a decrease in systemic C-reactive protein and decreased endothelial VCAM-1 compared to baseline.

Conclusion(s): These data suggest that FXI, by virtue of its position at an intersection of inflammation and thrombin generation, may be a viable therapeutic target for the treatment of thromboinflammatory diseases, including atherosclerosis.