{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T16:34:31Z","timestamp":1788885271534,"version":"build-2803163510"},"reference-count":80,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T00:00:00Z","timestamp":1603065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO-2016\/21\/B\/NZ4\/00543"],"award-info":[{"award-number":["UMO-2016\/21\/B\/NZ4\/00543"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Epidemiological studies confirm the high risk of ischemic events in multiple sclerosis (MS) that are associated with increased pro-thrombotic activity of blood platelets. The most potent physiological platelet agonist is thrombin, which activates platelets via cleavage of specific protease-activated receptors (PARs). Our current study is aimed to determine the potential genetics and proteomic abnormalities of PAR1 in both platelets and megakaryocytes, which may have thromboembolic consequences in the course of MS. The obtained results were correlated with the expression level of platelet and megakaryocyte transcripts for APOA1 and A2M genes encoding atherosclerosis biomarkers: apolipoprotein A1 (ApoA1) and \u03b1-2-macroglobulin (\u03b12M), respectively. Moreover, PAR1 functionality in MS platelets was assessed by flow cytometry, determining the level of platelet\u2013platelet and platelet\u2013leukocyte aggregates, platelet microparticles and surface expression of P-selectin. As a PAR1 agonist, the synthetic TRAP-6 peptide was used, which made it possible to achieve platelet activation in whole blood without triggering clotting. Comparative analyses showed an elevated level of platelet activation markers in the blood of MS patients compared to controls. The mRNA expression of gene coding \u03b12M was upregulated, whilst ApoA1 was down-regulated, both in platelets and megakaryocytes from MS patients. Furthermore, we observed an increase in both mRNA expression and surface density of PAR1 in platelets and megakaryocytes in MS compared to controls. Both the level of platelet activation markers and PAR1 expression showed a high correlation with the expression of transcripts for APOA1 and A2M genes.<\/jats:p>","DOI":"10.3390\/ijms21207722","type":"journal-article","created":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T09:36:28Z","timestamp":1603100188000},"page":"7722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Increased Pro-Thrombotic Platelet Activity Associated with Thrombin\/PAR1-Dependent Pathway Disorder in Patients with Secondary Progressive Multiple Sclerosis"],"prefix":"10.3390","volume":"21","author":[{"given":"Angela","family":"Dziedzic","sequence":"first","affiliation":[{"name":"Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7029-1857","authenticated-orcid":false,"given":"Elzbieta","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Neurological Rehabilitation, Medical University of Lodz, Milionowa 14, 93-113 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7838-4097","authenticated-orcid":false,"given":"Michal","family":"Bijak","sequence":"additional","affiliation":[{"name":"Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0209-4103","authenticated-orcid":false,"given":"Lukasz","family":"Przyslo","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurology and Epileptology, Research Institute of Polish Mother\u2019s Memorial Hospital, Rzgowska 281\/289, 93-338 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1197-1713","authenticated-orcid":false,"given":"Joanna","family":"Saluk-Bijak","sequence":"additional","affiliation":[{"name":"Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141\/143, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3715","DOI":"10.1016\/j.febslet.2011.08.004","article-title":"The Molecular Basis of Neurodegeneration in Multiple Sclerosis","volume":"585","author":"Lassmann","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S1474-4422(11)70105-3","article-title":"Vascular aspects of multiple sclerosis","volume":"10","author":"Cambron","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000367614","article-title":"New multiple sclerosis phenotypic classification","volume":"72","author":"Lublin","year":"2014","journal-title":"Eur. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1159\/000320245","article-title":"Risk of arterial cardiovascular diseases in patients with multiple sclerosis: A population-based cohort study","volume":"35","author":"Christiansen","year":"2010","journal-title":"Neuroepidemiology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1177\/1352458513475833","article-title":"High risk of cardiovascular diseases after diagnosis of multiple sclerosis","volume":"19","author":"Jadidi","year":"2013","journal-title":"Mult. Scler. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1093\/brain\/awh104","article-title":"Trends in survival and cause of death in Danish patients with multiple sclerosis","volume":"127","author":"Stenager","year":"2004","journal-title":"Brain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1159\/000335496","article-title":"Multiple sclerosis and risk of venous thromboembolism: A population-based cohort study","volume":"38","author":"Christensen","year":"2012","journal-title":"Neuroepidemiology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1111\/jth.12523","article-title":"The risk of venous thromboembolism in patients with multiple sclerosis: The Clinical Practice Research Datalink","volume":"12","author":"Peeters","year":"2014","journal-title":"J. Thromb. Haemost."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1111\/ene.12598","article-title":"Increased risk of ischaemic stroke among patients with multiple sclerosis","volume":"22","author":"Tseng","year":"2015","journal-title":"Eur. J. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"101423","DOI":"10.1016\/j.msard.2019.101423","article-title":"Incident cardiovascular disease in patients diagnosed with multiple sclerosis: A multi-database study","volume":"37","author":"Persson","year":"2019","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hong, Y., Tang, H.R., Ma, M., Chen, N., Xie, X., and He, L. (2019). Multiple sclerosis and stroke: A systematic review and meta-analysis. BMC Neurol., 19.","DOI":"10.1186\/s12883-019-1366-7"},{"key":"ref_12","first-page":"1756285617741056","article-title":"Decreased platelet number in multiple sclerosis during alemtuzumab infusion: A common, transient and clinically silent phenomenon","volume":"11","author":"Puthenparampil","year":"2017","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/S0165-5728(98)00246-X","article-title":"Platelet activating factor is elevated in cerebral spinal fluid and plasma of patients with relapsing-remitting multiple sclerosis","volume":"94","author":"Callea","year":"1999","journal-title":"J. Neuroimmunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.jneuroim.2005.06.019","article-title":"Plasma levels of soluble adhesion molecules sPECAM-1, sP-selectin and sE-selectin are associated with relapsing-remitting disease course of multiple sclerosis","volume":"167","author":"Kuenz","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2020\/2868014","article-title":"Oxidative Damage of Blood Platelets Correlates with the Degree of Psychophysical Disability in Secondary Progressive Multiple Sclerosis","volume":"2020","author":"Dziedzic","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s11010-017-2955-7","article-title":"Flow cytometric analysis reveals the high levels of platelet activation parameters in circulation of multiple sclerosis patients","volume":"430","author":"Morel","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"240918","DOI":"10.1155\/2015\/240918","article-title":"Relationship between the Increased Haemostatic Properties of Blood Platelets and Oxidative Stress Level in Multiple Sclerosis Patients with the Secondary Progressive Stage","volume":"2015","author":"Morel","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3476","DOI":"10.1111\/jcmm.14244","article-title":"Increased level of fibrinogen chains in the proteome of blood platelets in secondary progressive multiple sclerosis patients","volume":"23","author":"Bijak","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1124\/mol.112.083477","article-title":"Protease-activated receptor (PAR) 1 and PAR4 differentially regulate factor V expression from human platelets","volume":"83","author":"Duvernay","year":"2013","journal-title":"Mol. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12959-019-0194-8","article-title":"Protease-activated receptors (PARs): Mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases","volume":"17","author":"Heuberger","year":"2019","journal-title":"Thromb. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1172\/JCI6042","article-title":"Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin","volume":"103","author":"Kahn","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1097\/00001721-199312000-00014","article-title":"Post-receptor events associated with thrombin-induced platelet activation","volume":"4","author":"McNicol","year":"1993","journal-title":"Blood Coagul. Fibrinolysis"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"De Luca, C., Vurtuoso, A., Maggio, N., and Papa, M. (2017). Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102128"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1055\/s-0038-1655767","article-title":"Inhibition of Protease-Activated Receptor (PAR1) Reduces Activation of the Endothelium, Coagulation, Fibrinolysis and Inflammation during Human Endotoxemia","volume":"118","author":"Schoergenhofer","year":"2018","journal-title":"Thromb. Haemost."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e553","DOI":"10.1016\/S2352-3018(18)30214-5","article-title":"Vorapaxar for HIV-associated inflammation and coagulopathy (ADVICE): A randomised, double-blind, placebo-controlled trial","volume":"5","author":"Kent","year":"2018","journal-title":"Lancet HIV"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/s11239-012-0750-6","article-title":"Atopaxar and its effects on markers of platelet activation and inflammation: Results from the LANCELOT CAD program","volume":"34","author":"Bhatt","year":"2012","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_27","first-page":"81","article-title":"The impact of athrosclerosis on cognition and disability in multiple sclerosis patients: The ATHUS score","volume":"23","author":"Valavanis","year":"2019","journal-title":"Hippokratia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1093\/gerona\/61.12.1262","article-title":"Apolipoprotein A1 Is a Stronger Prognostic Marker Than Are HDL and LDL Cholesterol for Cardiovascular Disease and Mortality in Elderly Men","volume":"61","author":"Florvall","year":"2006","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"350","DOI":"10.5551\/jat.41335","article-title":"Alpha-2-macroglobulin as a Promising Biological Marker of Endothelial Function","volume":"25","author":"Shimomura","year":"2017","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_30","first-page":"65","article-title":"Platelets: Essential components of the immune system","volume":"16","author":"Ali","year":"2015","journal-title":"Curr. Trends Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9060143","DOI":"10.1155\/2016\/9060143","article-title":"Platelet Activation: The Mechanisms and Potential Biomarkers","volume":"2016","author":"Yun","year":"2016","journal-title":"BioMed Res. Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1111\/j.1582-4934.2010.01114.x","article-title":"Microparticles\u2014Messengers of biological information","volume":"14","author":"Hoyer","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nm1620","article-title":"Type II monocytes modulate T cell-mediated central nervous system autoimmune disease","volume":"13","author":"Weber","year":"2007","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/nm1177","article-title":"Experimental autoimmune encephalomyelitis repressed by microglial paralysis","volume":"11","author":"Heppner","year":"2005","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/1742-2094-5-27","article-title":"Evidence of platelet activation in multiple sclerosis","volume":"5","author":"Sheremata","year":"2008","journal-title":"J. Neuroinflammation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1038\/nature06559","article-title":"Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets","volume":"451","author":"Han","year":"2008","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1161\/CIRCRESAHA.111.256370","article-title":"Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis","volume":"110","author":"Langer","year":"2012","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1053\/j.tcam.2012.07.005","article-title":"New models of hemostasis","volume":"27","author":"McMichael","year":"2012","journal-title":"Top. Companion Anim. Med."},{"key":"ref_39","first-page":"71","article-title":"Hemostatic and cellular functions of factor XIII","volume":"34","author":"Bijak","year":"2013","journal-title":"Pol. Merkur. Lek."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.hoc.2006.11.004","article-title":"Coagulation 2006: A modern view of hemostasis","volume":"21","author":"Hoffman","year":"2007","journal-title":"Hematol.\/Oncol. Clin. North Am."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11189","DOI":"10.1073\/pnas.96.20.11189","article-title":"Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity","volume":"96","author":"Andersen","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1160\/TH06-05-0278","article-title":"Review: Laboratory markers quantifying prothrombin activation and actions of thrombin in venous and arterial thrombosis do not accurately assess disease severity or the effectiveness of treatment","volume":"96","author":"Ofosu","year":"2006","journal-title":"Thromb. Haemost."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1001\/jamaneurol.2020.0664","article-title":"Evaluating the Risk of Macrovascular Events and Mortality among People with Multiple Sclerosis in England","volume":"77","author":"Palladino","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1353-e88","DOI":"10.1111\/ene.12518","article-title":"Multiple sclerosis clinical course and cardiovascular disease risk\u2014Swedish cohort study","volume":"21","author":"Roshanisefat","year":"2014","journal-title":"Eur. J. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"764","DOI":"10.7326\/0003-4819-141-10-200411160-00007","article-title":"Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease","volume":"141","author":"Wei","year":"2004","journal-title":"Ann. Intern. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1378\/chest.99.3.557","article-title":"Cardiotoxicity of interferon. A review of 44 cases","volume":"99","author":"Sonnenblick","year":"1991","journal-title":"Chest"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.2337\/dc06-0811","article-title":"Prevalence of diabetes in patients with multiple sclerosis","volume":"29","author":"Hussein","year":"2006","journal-title":"Diabetes Care"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.cjca.2017.12.005","article-title":"Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms","volume":"34","author":"Petrie","year":"2018","journal-title":"Can. J. Cardiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"329","DOI":"10.4103\/2045-8932.114760","article-title":"On the origin of microparticles: From \u201cplatelet dust\u201d to mediators of intercellular communication","volume":"3","author":"Hargett","year":"2013","journal-title":"Pulm. Circ."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/sji.12068","article-title":"The role of microparticles in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus","volume":"78","author":"Dye","year":"2013","journal-title":"Scand. J. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"R156","DOI":"10.1186\/ar2833","article-title":"Increased levels of circulating microparticles in primary Sj\u00f6gren\u2019s syndrome, systemic lupus erythematosus and rheumatoid arthritis and relation with disease activity","volume":"11","author":"Sellam","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Gowert, N.S., Donner, L., Chattarjee, M., Eisele, Y.S., Towhid, S.t., Munzer, P., Walker, B., Ogorek, I., Borst, O., and Grandoch, M. (2014). Blood platelets in the progression of Alzheimer\u2019s disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090523"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2170","DOI":"10.1016\/j.molimm.2010.05.009","article-title":"Complement activation on platelets: Implications for vascular inflammation and thrombosis","volume":"47","author":"Peerschke","year":"2010","journal-title":"Mol. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1155\/2006\/709869","article-title":"Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis","volume":"22","author":"Waubant","year":"2006","journal-title":"Dis. Markers"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1055\/s-0030-1267042","article-title":"Platelet- and megakaryocyte-derived microparticles","volume":"36","author":"Flaumenhaft","year":"2010","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1084\/jem.191.8.1413","article-title":"P-Selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo","volume":"191","author":"Frenette","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.4049\/jimmunol.172.4.2011","article-title":"Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: A novel pathway for immune response amplification","volume":"172","author":"Danese","year":"2004","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"409","DOI":"10.3389\/fneur.2019.00409","article-title":"Coagulation Pathways in Neurological Diseases: Multiple Sclerosis","volume":"10","author":"Ziliotto","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"672","DOI":"10.5604\/17322693.1059587","article-title":"The synthesis of proteins in unnucleated blood platelets","volume":"67","author":"Bijak","year":"2013","journal-title":"Postepy Hig. Med. Dosw. (Online)"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/j.1423-0410.2010.01333.x","article-title":"De novo protein synthesis in mature platelets: A consideration for transfusion medicine","volume":"99","author":"Schubert","year":"2010","journal-title":"Vox Sang."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1365-2141.1990.tb02554.x","article-title":"The origin and physiological relevance of alpha-granule adhesive proteins","volume":"74","author":"Harrison","year":"1990","journal-title":"Br. J. Haematol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1538-7836.2008.03211.x","article-title":"Protein synthesis by platelets: Historical and new perspectives","volume":"7","author":"Weyrich","year":"2009","journal-title":"J. Thromb. Haemost."},{"key":"ref_63","unstructured":"Yuksel, B., Koc, P., Goksu, E.O., Karacay, E., Kurtulus, F., Cekin, Y., and Gamceli, Y.B. Is multiple sclerosis a risk factor for atherosclerosis?. J. Neuroradiol., 2019."},{"key":"ref_64","first-page":"364","article-title":"Cardiovascular Dysfunction in Multiple Sclerosis","volume":"10","author":"Mincu","year":"2015","journal-title":"Maedica"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1590\/S0066-782X1999000600001","article-title":"Are apolipoproteins A and B better than lipoproteins for assessing risk of obstructive coronary heart disease?","volume":"72","author":"Manfroi","year":"1999","journal-title":"Arq. Bras. Cardiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1161\/01.ATV.15.2.228","article-title":"The Role of Lipoprotein A-I and Lipoprotein A-I\/A-II in Predicting Coronary Artery Disease","volume":"15","author":"Nguyen","year":"1995","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1309\/PJE6-X9E5-LX6K-NELY","article-title":"Apolipoprotein A-I-derived amyloid in atherosclerosis. Its association with plasma levels of apolipoprotein A-I and cholesterol","volume":"115","author":"Mucchiano","year":"2001","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"188-e4","DOI":"10.1111\/ene.14055","article-title":"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","volume":"27","author":"Murali","year":"2020","journal-title":"Eur. J. Neurol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"87-e8","DOI":"10.1111\/ene.13769","article-title":"Hypertension and heart disease are associated with development of brain atrophy in multiple sclerosis: A 5-year longitudinal study","volume":"26","author":"Jakimovski","year":"2019","journal-title":"Eur. J. Neurol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"102389","DOI":"10.1016\/j.msard.2020.102389","article-title":"Apolipoproteins AI and E are associated with neuroaxonal injury to gray matter in multiple sclerosis","volume":"45","author":"McComb","year":"2020","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"McComb, M., Kirkheli, M., Uher, T., Browne, R.W., Srpova, B., Oechtering, J., Maleska Maceski, A., Tyblova, M., Jakimovski, D., and Ramasamy, D.P. (2020). Neuroprotective associations of apolipoproteins A-I and A-II with neurofilament levels in early multiple sclerosis. J. Clin. Lipidol.","DOI":"10.1016\/j.jacl.2020.07.001"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0145-305X(99)00018-X","article-title":"Alpha2-macroglobulin: An evolutionarily conserved arm of the innate immune system","volume":"23","author":"Armstrong","year":"1999","journal-title":"Dev. Comp. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"12927","DOI":"10.1038\/s41598-019-49144-7","article-title":"Molecular form and concentration of serum \u03b1(2)-macroglobulin in diabetes","volume":"9","author":"Yoshino","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s00401-006-0134-0","article-title":"Expression of alpha2-macroglobulin, neutrophil elastase, and interleukin-1alpha differs in early-stage and late-stage atherosclerotic lesions in the arteries of the circle of Willis","volume":"113","author":"Larionov","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/0002-8703(95)90003-9","article-title":"Serum glycoproteins and severity of coronary atherosclerosis","volume":"129","author":"Mori","year":"1995","journal-title":"Am. Heart J."},{"key":"ref_76","first-page":"433","article-title":"Evaluation of factors predisposing to arterial thrombosis in coronary artery disease","volume":"42","author":"Saxena","year":"1990","journal-title":"Indian Heart J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1212\/WNL.46.4.907","article-title":"Defining the clinical course of multiple sclerosis: Results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis","volume":"46","author":"Lublin","year":"1996","journal-title":"Neurology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1097\/NT.0000000000000092","article-title":"Body Mass Index: Obesity, BMI, and Health: A Critical Review","volume":"50","author":"Nuttall","year":"2015","journal-title":"Nutr. Today"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1212\/WNL.33.11.1444","article-title":"Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)","volume":"33","author":"Kurtzke","year":"1983","journal-title":"Neurology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1207\/s15327752jpa6703_13","article-title":"Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients","volume":"67","author":"Beck","year":"1996","journal-title":"J. Personal. 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