Protein S on the surface of plasma lipoproteins: a potential mechanism for protein S delivery to the atherosclerotic plaques?

Published: 17 October 2022
Abstract Views: 1698
PDF: 64
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.


The anticoagulant protein S (PS) binds phospholipids with very high affinity, but PS interaction with lipoproteins and lipidrich atherosclerotic plaques remains still poorly defined. We investigated PS in plasma lipoproteins and in atherosclerotic plaques from ten patients undergoing endarterectomy. PS was detected by Western blotting after exposure of the necrotic core to liposomes and was found to maintain its ability to bind phosphatidylserine micelles. The amounts of PS bound to low/very low-density lipoproteins in patient’ plasmas were higher and more variable than those detected in healthy subjects. A direct correlation between bound PS and low-density lipoproteins (LDL), plasma levels was found only in patients (r=0.921, p<0.001), thereby leading to hypothesize that the PS-phospholipids binding may increase by oxidative processes of LDL in atherosclerotic patients. The presence of the PS into the necrotic core of atherosclerotic plaques and on the surface of lipoproteins, particularly the atherogenic LDL, suggests a LDL-based delivery of PS to the atherosclerotic plaques and emphasizes the deep link between plasma lipids and coagulation in cardiovascular diseases.

Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114:1852-66. DOI:

Webb NR. High-Density Lipoproteins and Serum Amyloid A (SAA). Curr Atheroscler Rep. 2021;23:7. DOI:

Getz GS, Krishack PA, Reardon CA. Serum amyloid A and atherosclerosis Curr Opin Lipidol. 2016;27:531-5. DOI:

Hartley A, Haskard D, Khamis R. Oxidized LDL and anti-oxidized LDL antibodies in atherosclerosis - Novel insights and future directions in diagnosis and therapy. Trends Cardiovasc Med. 2019;29:22-6. DOI:

Di Scipio RG, Hermodson MA, Yates SG, Davie EW. A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S. Biochemistry. 1977;16:698-706. DOI:

Gierula M, Ahnström J. Anticoagulant protein S-New insights on interactions and functions. J Thromb Haemost. 2020;18:2801-11. DOI:

van der Meer JH, van der Poll T, van 't Veer C. TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis. Blood. 2014;123:2460-9. DOI:

Liao D, Wang X, Li M, et al. Human protein S inhibits the uptake of AcLDL and expression of SR-A through Mer receptor tyrosine kinase in human macrophages. Blood. 2009;113:165-74. DOI:

Hurtado B, Muñoz X, Recarte-Pelz P, et al. Expression of the vitamin K-dependent proteins GAS6 and protein S and the TAM receptor tyrosine kinases in human atherosclerotic carotid plaques. Thromb Haemost. 2011;105:873-82. DOI:

Anderson HA, Maylock CA, Williams JA, et al. Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells Nat Immunol. 2003;4:87-91. DOI:

Gasic GP, Arenas CP, Gasic TB, Gasic GJ. Coagulation factors X, Xa, and protein S as potent mitogens of cultured aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1992;89:2317-20. DOI:

Baroni M, Pavani G, Marescotti D, et al. Membrane binding and anticoagulant properties of protein S natural variants. Thromb Res. 2010;125:e33-9. DOI:

Marchetti G, Girelli D, Zerbinati C, et al. An integrated genomic-transcriptomic approach supports a role for the proto-oncogene BCL3 in atherosclerosis. Thromb Haemost. 2015;113:655-63. DOI:

Ziliotto N, Meneghetti S, Menegatti E, et al. Expression profiles of the internal jugular and saphenous veins: Focus on hemostasis genes. Thromb Res. 2020;191:113-24. DOI:

Wang Y, Qiao M, Mieyal JJ, et al. Molecular mechanism of glutathione-mediated protection from oxidized low-density lipoprotein-induced cell injury in human macrophages: role of glutathione reductase and glutaredoxin. Free Radic Biol Med. 2006;41:775-85. DOI:

Baroni M, Mazzola G, Kaabache T, et al. Molecular bases of type II protein S deficiency: the I203-D204 deletion in the EGF4 domain alters GLA domain function. J Thromb Haemost. 2006;4:186-91. DOI:

Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol 2010;30:2311-6. DOI:

Pryma CS, Ortega C, Dubland JA, Francis GA. Pathways of smooth muscle foam cell formation in atherosclerosis. Curr Opin Lipidol. 2019;30:117-24. DOI:

Benzakour O, Kanthou C. The anticoagulant factor, protein S, is produced by cultured human vascular smooth muscle cells and its expression is up-regulated by thrombin. Blood. 2000;95:2008-14. DOI:

Martinelli N, Baroni M, Castagna A, et al. Apolipoprotein C-III Strongly Correlates with Activated Factor VII-Anti-Thrombin Complex: An Additional Link between Plasma Lipids and Coagulation. Thromb Haemost. 2019;119:192-202. DOI:

Supporting Agencies

The study has been carried out at the Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy. The study was financially supported by Grant from Italian Ministry of University and Research, University of Ferrara, Italy (FAR 2020, FAR 2021), 5X1000 University of Ferrara grant (2021_NAZ.A_B) and by “Bando FIRD 2022 – BARONI” University of Ferrara grant.

Baroni, M., Ferraresi, P., Ziliotto, N., Bortolotti, D., Acciarri, P., Martinelli, N., Marchetti, G., Coen, M., & Bernardi, F. (2022). Protein S on the surface of plasma lipoproteins: a potential mechanism for protein S delivery to the atherosclerotic plaques?. Bleeding, Thrombosis, and Vascular Biology, 1(3).


Download data is not yet available.