Original Articles
Vol. 1 No. 3 (2022)
Crosstalk between hemostasis inhibitors and cholesterol biomarkers in multiple sclerosis
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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.
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.
Received: 31 May 2022
Accepted: 8 September 2022
Accepted: 8 September 2022
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The individual roles of cholesterol pathway biomarkers (CPB) and hemostasis inhibitors with neuroimaging outcomes were previously investigated in multiple sclerosis (MS). The purpose of this extension study was to investigate potential crosstalk between plasma CPB [total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and apolipoproteins (Apo) ApoA-I, ApoAII, ApoB, ApoC-II and ApoE] and hemostasis inhibitors [heparin cofactor-II (HCII), protein C (PC), protein S (PS), thrombomodulin, ADAMTS13 and PAI-1] in a cohort of 127 MS patients, and 40 healthy individuals (HI). The associations were assessed with regressions. In MS patients, HCII was positively associated with TC, LDL-C, HDL-C and ApoA-I (p=0.028, 0.027, 0.002 and 0.027, respectively) but negatively associated with ApoCII (p=0.018). PC was positively associated with ApoC-II (p=0.001) and ApoB (p=0.016) whereas PS was associated with TC (p=0.024) and ApoE (p=0.003) in MS. The ApoC-II associations were not observed in HI. The negative association between ApoC-II and HCll was an exception amongst other positive associations between CPB and hemostasis inhibitors in MS. CPB do not modulate the PC associations with neurodegeneration in MS.
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Kappus N, Weinstock-Guttman B, Hagemeier J, et al. Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry. 2016;87(2):181-7.
Jakimovski D, Topolski M, Genovese AV, et al. Vascular aspects of multiple sclerosis: emphasis on perfusion and cardiovascular comorbidities. Expert Review of Neurotherapeutics. 2019;19(5):445-58. DOI: https://doi.org/10.1080/14737175.2019.1610394
Zhornitsky S, McKay KA, Metz LM, et al. Cholesterol and markers of cholesterol turnover in multiple sclerosis: relationship with disease outcomes. Multiple Sclerosis and Related Disorders. 2016;5:53-65. DOI: https://doi.org/10.1016/j.msard.2015.10.005
Hussain G, Wang J, Rasul A, et al. Role of cholesterol and sphingolipids in brain development and neurological diseases. Lipids in Health and Disease. 2019;18(1):26. DOI: https://doi.org/10.1186/s12944-019-0965-z
Kontush A, Chapman MJ. Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis. Pharmacological Reviews. 2006;58(3):342-74. DOI: https://doi.org/10.1124/pr.58.3.1
Tettey P, Simpson S, Taylor B, et al. An adverse lipid profile and increased levels of adiposity significantly predict clinical course after a first demyelinating event. Journal of Neurology, Neurosurgery & Psychiatry. 2017;88(5):395-401. DOI: https://doi.org/10.1136/jnnp-2016-315037
Weinstock-Guttman B, Zivadinov R, Mahfooz N, et al. Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis. Journal of Neuroinflammation. 2011;8(1):127. DOI: https://doi.org/10.1186/1742-2094-8-127
Murali N, Browne RW, Fellows Maxwell K, et al. Cholesterol and neurodegeneration: longitudinal changes in serum cholesterol biomarkers are associated with new lesions and gray matter atrophy in multiple sclerosis over 5 years of follow-up. European Journal of Neurology. 2020;27(1):188-e4. DOI: https://doi.org/10.1111/ene.14055
Jorissen W, Wouters E, Bogie JF, et al. Relapsing-remitting multiple sclerosis patients display an altered lipoprotein profile with dysfunctional HDL. Scientific Reports. 2017;7(1):43410. DOI: https://doi.org/10.1038/srep43410
Isshiki M, Hirayama S, Ueno T, et al. Apolipoproteins C-II and C-III as nutritional markers unaffected by inflammation. Clinica Chimica Acta. 2018;481:225-30. DOI: https://doi.org/10.1016/j.cca.2018.03.004
Fellows Maxwell K, Bhattacharya S, Bodziak ML, et al. Oxysterols and apolipoproteins in multiple sclerosis: a 5 year follow-up study[S]. Journal of Lipid Research. 2019;60(7):1190-8. DOI: https://doi.org/10.1194/jlr.M089664
Mandoj C, Renna R, Plantone D, et al. Anti-annexin antibodies, cholesterol levels and disability in multiple sclerosis. Neuroscience Letters. 2015;606:156-60. DOI: https://doi.org/10.1016/j.neulet.2015.08.054
Davalos D, Mahajan KR, Trapp BD. Brain fibrinogen deposition plays a key role in MS pathophysiology - Yes. Mult Scler. 2019;25(11):1434-5. DOI: https://doi.org/10.1177/1352458519852723
Ziliotto N, Bernardi F, Jakimovski D, et al. Hemostasis biomarkers in multiple sclerosis. European Journal of Neurology. 2018;25(9):1169-76. DOI: https://doi.org/10.1111/ene.13681
Ziliotto N, Zivadinov R, Baroni M, et al. Plasma levels of protein C pathway proteins and brain magnetic resonance imaging volumes in multiple sclerosis. European Journal of Neurology. 2020;27(2):235-43. DOI: https://doi.org/10.1111/ene.14058
Aihara K-i, Azuma H, Takamori N, et al. Heparin Cofactor II Is a Novel Protective Factor Against Carotid Atherosclerosis in Elderly Individuals. Circulation. 2004;109(22):2761-5. DOI: https://doi.org/10.1161/01.CIR.0000129968.46095.F3
Rau JC, Mitchell JW, Fortenberry YM, et al. Heparin cofactor II: discovery, properties, and role in controlling vascular homeostasis. Seminars in thrombosis and hemostasis. 2011;37(4):339-48. DOI: https://doi.org/10.1055/s-0031-1276582
Aihara K-i, Azuma H, Akaike M, et al. Heparin Cofactor II as a Novel Vascular Protective Factor Against Atherosclerosis. Journal of Atherosclerosis and Thrombosis. 2009;16(5):523-31. DOI: https://doi.org/10.5551/jat.1552
Griffin JH, Zlokovic BV, Mosnier LO. Activated protein C, protease activated receptor 1, and neuroprotection. Blood. 2018;132(2):159-69. DOI: https://doi.org/10.1182/blood-2018-02-769026
Kim J-A, Kim J-E, Song SH, et al. Influence of blood lipids on global coagulation test results. Ann Lab Med. 2015;35(1):15-21. DOI: https://doi.org/10.3343/alm.2015.35.1.15
Orsi FA LW, Van der Laarse A, Ruhaak LR, Rosendaal FR, Cannegieter SC, Cobbaert C. Association of apolipoproteins C-I, C-II, C-III and E with coagulation markers and venous thromboembolism risk. Clin Epidemiol. 2019;11. DOI: https://doi.org/10.2147/CLEP.S196266
Dejan Jakimovski RZ, Michael G. Dwyer, Niels Bergsland, Deepa P. Ramasamy, Richard W. Browne, Bianca Weinstock-Guttman and Murali Ramanathan. High density lipoprotein cholesterol and apolipoprotein A-I are associated with greater cerebral perfusion in multiple sclerosis. Journal of the Neurological Sciences. 2020;418. DOI: https://doi.org/10.1016/j.jns.2020.117120
Ziliotto N, Bernardi F, Jakimovski D, et al. Coagulation Pathways in Neurological Diseases: Multiple Sclerosis. Frontiers in Neurology. 2019;10(409). DOI: https://doi.org/10.3389/fneur.2019.00409
Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis. The 2013 revisions. 2014;83(3):278-86. DOI: https://doi.org/10.1212/WNL.0000000000000560
Browne RW, Jakimovski D, Ziliotto N, et al. High-density lipoprotein cholesterol is associated with multiple sclerosis fatigue: A fatigue-metabolism nexus? J Clin Lipidol. 2019;13(4):654-63.e1. DOI: https://doi.org/10.1016/j.jacl.2019.06.003
Ziliotto N, Zivadinov R, Jakimovski D, et al. Relationships Among Circulating Levels of Hemostasis Inhibitors, Chemokines, Adhesion Molecules, and MRI Characteristics in Multiple Sclerosis. Frontiers in Neurology. 2020;11(1178). DOI: https://doi.org/10.3389/fneur.2020.553616
Maccallum, Cooper, Martin, et al. Associations of protein C and protein S with serum lipid concentrations. British Journal of Haematology. 1998;102(2):609-15. DOI: https://doi.org/10.1046/j.1365-2141.1998.00800.x
Otsuka Y, Ueda M, Nakazono E, et al. Relationship between plasma protein S levels and apolipoprotein C-II in Japanese middle-aged obese women and young nonobese women. Blood Coagulation & Fibrinolysis. 2018;29(1):39-47. DOI: https://doi.org/10.1097/MBC.0000000000000662
Griffin JH, Kojima K, Banka CL, et al. High-density lipoprotein enhancement of anticoagulant activities of plasma protein S and activated protein C. The Journal of clinical investigation. 1999;103(2):219-27. DOI: https://doi.org/10.1172/JCI5006
Onodera H, Nakashima I, Fujihara K, et al. Elevated Plasma Level of Plasminogen Activator Inhibitor-1 (PAI-1) in Patients with Relapsing-Remitting Multiple Sclerosis. The Tohoku Journal of Experimental Medicine. 1999;189(4):259-65. DOI: https://doi.org/10.1620/tjem.189.259
Iida K, Tani S, Atsumi W, et al. Association of plasminogen activator inhibitor-1 and low-density lipoprotein heterogeneity as a risk factor of atherosclerotic cardiovascular disease with triglyceride metabolic disorder: a pilot cross-sectional study. Coronary Artery Disease. 2017;28(7):577-87. DOI: https://doi.org/10.1097/MCA.0000000000000521
Li D, Mehta JL. Oxidized LDL, a critical factor in atherogenesis. Cardiovasc Res. 2005;68(3):353-4. DOI: https://doi.org/10.1016/j.cardiores.2005.09.009
Palavra F, Marado D, Mascarenhas-Melo F, et al. New Markers of Early Cardiovascular Risk in Multiple Sclerosis Patients: Oxidized-LDL Correlates with Clinical Staging. Disease Markers. 2013;34:567162. DOI: https://doi.org/10.1155/2013/567162
Wang H, Eckel RH. Lipoprotein lipase in the brain and nervous system. Annu Rev Nutr. 2012;32:147-60. DOI: https://doi.org/10.1146/annurev-nutr-071811-150703
Goulbourne CN, Gin P, Tatar A, et al. The GPIHBP1-LPL complex is responsible for the margination of triglyceride-rich lipoproteins in capillaries. Cell Metab. 2014;19(5):849-60. DOI: https://doi.org/10.1016/j.cmet.2014.01.017
Pratt CW, Whinna HC, Church FC. A comparison of three heparin-binding serine proteinase inhibitors. J Biol Chem. 1992;267(13):8795-801. DOI: https://doi.org/10.1016/S0021-9258(19)50349-0
Wosu L, McCormick S, Kalant N. Interaction of high and low density lipoproteins on glycosaminoglycan secretion by human vascular smooth muscle cells and fibroblasts. Can J Biochem Cell Biol. 1984;62(10):984-90. DOI: https://doi.org/10.1139/o84-126
Xu H, Jiang J, Chen W, et al. Vascular Macrophages in Atherosclerosis. J Immunol Res. 2019;2019:4354786. DOI: https://doi.org/10.1155/2019/4354786
Ladewig G, Jestaedt L, Misselwitz B, et al. Spatial diversity of blood-brain barrier alteration and macrophage invasion in experimental autoimmune encephalomyelitis: a comparative MRI study. Exp Neurol. 2009;220(1):207-11. DOI: https://doi.org/10.1016/j.expneurol.2009.08.027
Grajchen E, Hendriks JJA, Bogie JFJ. The physiology of foamy phagocytes in multiple sclerosis. Acta Neuropathol Commun. 2018;6(1):124. DOI: https://doi.org/10.1186/s40478-018-0628-8
Wouters E, Grajchen E, Jorissen W, et al. Altered PPARgamma Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis. Int J Mol Sci. 2020;21(23). DOI: https://doi.org/10.3390/ijms21239329
Chang HR, Josefs T, Scerbo D, et al. Role of LpL (Lipoprotein Lipase) in Macrophage Polarization In Vitro and In Vivo. Arterioscler Thromb Vasc Biol. 2019;39(10):1967-85. DOI: https://doi.org/10.1161/ATVBAHA.119.312389
Babaev VR, Fazio S, Gleaves LA, et al. Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in vivo. The Journal of Clinical Investigation. 1999;103(12):1697-705. DOI: https://doi.org/10.1172/JCI6117
Wolska A, Dunbar RL, Freeman LA, et al. Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism. Atherosclerosis. 2017;267:49-60. DOI: https://doi.org/10.1016/j.atherosclerosis.2017.10.025
Mailleux J, Vanmierlo T, Bogie JF, et al. Active liver X receptor signaling in phagocytes in multiple sclerosis lesions. Multiple Sclerosis Journal. 2018;24(3):279-89. DOI: https://doi.org/10.1177/1352458517696595
Verbout NG, Yu X, Healy LD, et al. Thrombin mutant W215A/E217A treatment improves neurological outcome and attenuates central nervous system damage in experimental autoimmune encephalomyelitis. Metabolic Brain Disease. 2015;30(1):57-65. DOI: https://doi.org/10.1007/s11011-014-9558-8
Gveric D, Hanemaaijer R, Newcombe J, et al. Plasminogen activators in multiple sclerosis lesions: Implications for the inflammatory response and axonal damage. Brain. 2001;124(10):1978-88. DOI: https://doi.org/10.1093/brain/124.10.1978
How to Cite
1.
Parambi R, Ziliotto N, Bernardi F, Baroni M, Browne RW, Jakimovski D, et al. Crosstalk between hemostasis inhibitors and cholesterol biomarkers in multiple sclerosis. Bleeding Thromb Vascul Biol [Internet]. 2022 Oct. 17 [cited 2026 Jan. 28];1(3). Available from: https://www.btvb.org/btvb/article/view/41
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