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

• Published in: Research and practice in thrombosis and haemostasis 2024-01, Vol.8 (1), p.102276-102276, Article 102276
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: atherosclerosis; hyperlipidemia; inflammation; Original; platelets; thrombin
• ISSN: 2475-0379; 2475-0379
• DOI: 10.1016/j.rpth.2023.102276

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. This study aimed to investigate the role of FXI in promoting platelet and endothelial cell activation in a model of hyperlipidemia. 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. 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. FXI activation promotes the proinflammatory phenotype of hyperlipidemia by priming platelet activation and inciting endothelial cell dysfunction. •Hyperlipidemia and obesity are associated with chronic vascular inflammation and clotting.•We studied the effect of diet-induced obesity on platelet sensitivity and inflammatory markers.•Targeting coagulation factor XI reduced platelet priming for activation and inflammation.•Our study demonstrates that factor XI activation promotes vascular dysfunction in hyperlipidemia.