Activation of coagulation FXI promotes endothelial inflammation and amplifies platelet activation in a nonhuman primate model of hyperlipidemia.

Kohs, Tia C L; Vu, Helen H; Jordan, Kelley R; Parra-Izquierdo, Iván; Hinds, Monica T; Shatzel, Joseph J; Kievit, Paul; Morgan, Terry K; Yunga, Samuel Tassi; Ngo, Thuy T M; Aslan, Joseph E; Wallisch, Michael; Lorentz, Christina U; Tucker, Erik I; Gailani, David; Lindner, Jonathan R; Puy, Cristina; McCarty, Owen J T

Kohs, Tia C L; Vu, Helen H; Jordan, Kelley R; Parra-Izquierdo, Iván; Hinds, Monica T; Shatzel, Joseph J; Kievit, Paul; Morgan, Terry K; Yunga, Samuel Tassi; Ngo, Thuy T M; Aslan, Joseph E; Wallisch, Michael; Lorentz, Christina U; Tucker, Erik I; Gailani, David; Lindner, Jonathan R; Puy, Cristina; McCarty, Owen J T.

Afiliação

Kohs TCL; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Vu HH; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Jordan KR; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Parra-Izquierdo I; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Hinds MT; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Shatzel JJ; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Kievit P; Division of Hematology and Oncology, Oregon Health & Science University, Portland, Oregon, USA.
Morgan TK; Division of Cardiometabolic Health, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA.
Yunga ST; Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, Oregon, USA.
Ngo TTM; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Aslan JE; Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
Wallisch M; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Lorentz CU; Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
Tucker EI; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA.
Gailani D; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.
Lindner JR; Knight Cardiovascular Institute, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA.
Puy C; Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, Oregon, USA.
McCarty OJT; Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, USA.

Res Pract Thromb Haemost ; 8(1): 102276, 2024 Jan.

Article em En | MEDLINE | ID: mdl-38226339

ABSTRACT

ABSTRACT

Background:

Hyperlipidemia is associated with chronic inflammation and thromboinflammation. This is an underlying cause of several cardiovascular diseases, including atherosclerosis. In diseased blood vessels, rampant thrombin generation results in the initiation of the coagulation cascade, activation of platelets, and endothelial cell dysfunction. Coagulation factor (F) XI represents a promising therapeutic target to reduce thromboinflammation, as it is uniquely positioned at an intersection between inflammation and thrombin generation.

Objectives:

This study aimed to investigate the role of FXI in promoting platelet and endothelial cell activation in a model of hyperlipidemia.

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 hyperlipidemia. Obese NHPs were intravenously administered a FXI blocking antibody (2 mg/kg) and studied at baseline and at 1, 7, 14, 21, and 28 days after drug administration. Platelet activation and inflammatory markers were measured using fluorescence-activated cell sorting or enzyme-linked immunosorbent assay. Molecular imaging was used to quantify vascular cell adhesion molecule 1 (VCAM-1) expression at the carotid bifurcation.

Results:

Obese NHPs demonstrated increased sensitivity for platelet P-selectin expression and phosphatidylserine exposure in response to platelet GPVI or PAR agonists compared with lean NHPs. Obese NHPs exhibited elevated levels of C-reactive protein, cathepsin D, and myeloperoxidase compared with lean NHPs. Following pharmacological inhibition of FIX activation by FXIa, platelet priming for activation by GPVI or PAR agonists, C-reactive protein levels, and endothelial VCAM-1 levels were reduced in obese NHPs.