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

作者：Tia C. L. Kohs, Helen H. Vu, Kelley R. Jordan, Iván Parra‐Izquierdo, Monica T. Hinds, Joseph J. Shatzel, Paul Kievit, Terry K. Morgan, Samuel Tassi Yunga, Thuy T. M. Ngo, Joseph E. Aslan, Michael Wallisch, Christina U. Lorentz, Erik I. Tucker, David Gailani, Jonathan R. Lindner, Cristina Puy, Owen J. T. McCarty · 发表于：Research and Practice in Thrombosis and Haemostasis · 年份：2023 · DOI：10.1016/j.rpth.2023.102276 · 被引用次数：17 · 研究领域：Blood Coagulation and Thrombosis Mechanisms、Platelet Disorders and Treatments、Coagulation, Bradykinin, Polyphosphates, and Angioedema

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: = 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 i...