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

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

doi:10.1016/j.rpth.2023.102276

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

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

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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. Conclusion: FXI activation promotes the proinflammatory phenotype of hyperlipidemia by priming platelet activation and inciting endothelial cell dysfunction.

Original language	English (US)
Article number	102276
Journal	Research and Practice in Thrombosis and Haemostasis
Volume	8
Issue number	1
DOIs	https://doi.org/10.1016/j.rpth.2023.102276
State	Published - Jan 2024

Keywords

atherosclerosis
hyperlipidemia
inflammation
platelets
thrombin

ASJC Scopus subject areas

Hematology

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10.1016/j.rpth.2023.102276

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Kohs, T. C. L., Vu, H. H., Jordan, K. R., Parra-Izquierdo, I., Hinds, M. T., Shatzel, J. J., Kievit, P., Morgan, T. K., Yunga, S. T., Ngo, T. T. M., Aslan, J. E., Wallisch, M., Lorentz, C. U., Tucker, E. I., Gailani, D., Lindner, J. R., Puy, C., & McCarty, O. J. T. (2024). Activation of coagulation FXI promotes endothelial inflammation and amplifies platelet activation in a nonhuman primate model of hyperlipidemia. Research and Practice in Thrombosis and Haemostasis, 8(1), Article 102276. https://doi.org/10.1016/j.rpth.2023.102276

Kohs, TCL, Vu, HH, Jordan, KR, Parra-Izquierdo, I, Hinds, MT , Shatzel, JJ , Kievit, P , Morgan, TK, Yunga, ST, Ngo, TTM , Aslan, JE, Wallisch, M, Lorentz, CU, Tucker, EI, Gailani, D, Lindner, JR, Puy, C & McCarty, OJT 2024, 'Activation of coagulation FXI promotes endothelial inflammation and amplifies platelet activation in a nonhuman primate model of hyperlipidemia', Research and Practice in Thrombosis and Haemostasis, vol. 8, no. 1, 102276. https://doi.org/10.1016/j.rpth.2023.102276

@article{8639f5991c7b4cda9ac7f923c2a9d199,

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

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. Conclusion: FXI activation promotes the proinflammatory phenotype of hyperlipidemia by priming platelet activation and inciting endothelial cell dysfunction.",

keywords = "atherosclerosis, hyperlipidemia, inflammation, platelets, thrombin",

author = "Kohs, {Tia C.L.} and Vu, {Helen H.} and Jordan, {Kelley R.} and Iv{\'a}n Parra-Izquierdo and Hinds, {Monica T.} and Shatzel, {Joseph J.} and Paul Kievit and Morgan, {Terry K.} and Yunga, {Samuel Tassi} and Ngo, {Thuy T.M.} and Aslan, {Joseph E.} and Michael Wallisch and Lorentz, {Christina U.} and Tucker, {Erik I.} and David Gailani and Lindner, {Jonathan R.} and Cristina Puy and McCarty, {Owen J.T.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2024",

month = jan,

doi = "10.1016/j.rpth.2023.102276",

language = "English (US)",

volume = "8",

journal = "Research and Practice in Thrombosis and Haemostasis",

issn = "2475-0379",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "1",

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TY - JOUR

T1 - Activation of coagulation FXI promotes endothelial inflammation and amplifies platelet activation in a nonhuman primate model of hyperlipidemia

AU - Kohs, Tia C.L.

AU - Vu, Helen H.

AU - Jordan, Kelley R.

AU - Parra-Izquierdo, Iván

AU - Hinds, Monica T.

AU - Shatzel, Joseph J.

AU - Kievit, Paul

AU - Morgan, Terry K.

AU - Yunga, Samuel Tassi

AU - Ngo, Thuy T.M.

AU - Aslan, Joseph E.

AU - Wallisch, Michael

AU - Lorentz, Christina U.

AU - Tucker, Erik I.

AU - Gailani, David

AU - Lindner, Jonathan R.

AU - Puy, Cristina

AU - McCarty, Owen J.T.

PY - 2024/1

Y1 - 2024/1

N2 - 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. Conclusion: FXI activation promotes the proinflammatory phenotype of hyperlipidemia by priming platelet activation and inciting endothelial cell dysfunction.

AB - 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. Conclusion: FXI activation promotes the proinflammatory phenotype of hyperlipidemia by priming platelet activation and inciting endothelial cell dysfunction.

KW - atherosclerosis

KW - hyperlipidemia

KW - inflammation

KW - platelets

KW - thrombin

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U2 - 10.1016/j.rpth.2023.102276

DO - 10.1016/j.rpth.2023.102276

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AN - SCOPUS:85181230877

SN - 2475-0379

VL - 8

JO - Research and Practice in Thrombosis and Haemostasis

JF - Research and Practice in Thrombosis and Haemostasis

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ER -

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

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