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Review article: Biomedical intelligence

Vol. 145 No. 2122 (2015)

Aetiological blood biomarkers of ischaemic stroke

  • Julian Bruno Sonderer
  • Mira Katan Kahles
DOI
https://doi.org/10.4414/smw.2015.14138
Cite this as:
Swiss Med Wkly. 2015;145:w14138
Published
17.05.2015

Summary

Each year, over 5 million people die worldwide from stroke, and at least every sixth patient who survives will experience another stroke within five years [1]. We are therefore eager to advance early and rapid diagnosis, prognosis and optimal risk stratification, as well as secondary prevention. In this context, blood biomarkers may improve patient care, as they have already done in other fields in the past, for example, troponin T/I in patients with heart attacks, natriuretic peptides in patients with heart failure or PCT (procalcitonin) [2] in patients with pneumonia. In the setting of acute stroke, a blood biomarker can be any quantifiable entity that reflects the manifestation of a stroke-related process. The most fruitful implementation of stroke biomarkers is in areas where information from traditional clinical sources is limited. There may be markers, for example, to guide risk stratification, reveal stroke aetiology, identify patients who may benefit most from interventions, monitor treatment efficacy, and recognise the risk of short-term complications or unfavourable long-term outcomes.

For this review we focus on blood biomarkers that could help distinguish the underlying aetiology of an ischaemic stroke. Stroke tends to be a much more heterogeneous condition than ischaemic heart disease, which is caused by atherosclerosis in the vast majority of cases. Causes of stroke include small and large vessel disease, cardioembolism, dissections, and rare vasculo- and coagulopathies, among others. Because of this heterogeneity among stroke patients, it is clear that a monolithic approach to stroke prevention or secondary prevention is not warranted.

Aetiological classification is important specifically because prognosis, risk of recurrence and management options differ greatly between aetiological subtypes. Considering that today up to 30% of stroke patients still cannot be classified into a specific subtype [3], the ability to improve aetiological classification to direct prevention methods at the underlying mechanism would be of greatest interest.

For this review we collected data from studies, on aetiological blood biomarkers in ischaemic stroke patients, listed in PubMed up to October 2014. We describe the potential role of 22 selected blood biomarkers in the context of stroke aetiology. Finally we provide the readers with an outlook in this research field.

References

  1. Hankey GJ, Warlow CP. Treatment and secondary prevention of stroke: evidence, costs, and effects on individuals and populations. Lancet. 1999;354(9188):1457–63. doi: 10.1016/S0140–6736(99)04407–4. PubMed PMID: 10543686.
  2. Fluri F, Morgenthaler NG, Mueller B, Christ-Crain M, Katan M. Copeptin, procalcitonin and routine inflammatory markers-predictors of infection after stroke. PLoS One. 2012;7(10):e48309. doi: 10.1371/journal.pone.0048309. PubMed PMID: 23118979; PubMed Central PMCID: PMC3485149.
  3. Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. Classification of stroke subtypes. Cerebrovasc Dis. 2009;27(5):493–501. doi: 10.1159/000210432. PubMed PMID: 19342825.
  4. Schweizerische Aerztezeitung. 2000;81:835–40
  5. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28–e292. doi: 10.1161/01.cir.0000441139.02102.80. PubMed PMID: 24352519.
  6. Grysiewicz RA, Thomas K, Pandey DK. Epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence, mortality, and risk factors. Neurol Clin. 2008;26(4):871–95, vii. doi: 10.1016/j.ncl.2008.07.003. PubMed PMID: 19026895.
  7. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke. 2001;32(12):2735–40. PubMed PMID: 11739965.
  8. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. New Engl J Med. 1990;323(22):1505–11. doi: 10.1056/NEJM199011293232201. PubMed PMID: 2233931.
  9. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet. 1994;343(8899):687–91. PubMed PMID: 7907677.
  10. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51. doi: 10.1056/NEJMoa0905561. PubMed PMID: 19717844.
  11. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. doi: 10.1056/NEJMoa1009638. PubMed PMID: 21830957.
  12. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92. doi: 10.1056/NEJMoa1107039. PubMed PMID: 21870978.
  13. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–17. doi: 10.1056/NEJMoa1007432. PubMed PMID: 21309657.
  14. Rerkasem K, Rothwell PM. Carotid endarterectomy for symptomatic carotid stenosis. The Cochrane database of systematic reviews. 2011(4):CD001081. doi: 10.1002/14651858.CD001081.pub2. PubMed PMID: 21491381.
  15. Brott TG, Hobson RW, 2nd, Howard G, Roubin GS, Clark WM, Brooks W, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010;363(1):11–23. doi: 10.1056/NEJMoa0912321. PubMed PMID: 20505173; PubMed Central PMCID: PMC2932446.
  16. Adams HP, Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):35–41. PubMed PMID: 7678184.
  17. Ay H, Benner T, Arsava EM, Furie KL, Singhal AB, Jensen MB, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke. 2007;38(11):2979–84. doi: 10.1161/STROKEAHA.107.490896. PubMed PMID: 17901381.
  18. Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. New approach to stroke subtyping: the A-S-C-O (phenotypic) classification of stroke. Cerebrovasc Dis. 2009;27(5):502–8. doi: 10.1159/000210433. PubMed PMID: 19342826.
  19. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014;13(4):429–38. doi: 10.1016/S1474–4422(13)70310–7. PubMed PMID: 24646875.
  20. Böcker W, Heitz PU, Moch H. Pathologie. 5., vollst. überarb. Aufl. ed. München: Elsevier; 2012. Online-Ressource p.
  21. Weir NU. An update on cardioembolic stroke. Postgrad Med J. 2008;84(989):133–42; quiz 9–40. doi: 10.1136/pgmj.2007.066563. PubMed PMID: 18372484.
  22. English J, Smith W. Chapter 36 Cardio-embolic stroke. In: Marc F, editor. Handbook of Clinical Neurology. Volume 93: Elsevier; 2008. p. 719–49.
  23. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9(7):689–701. doi: 10.1016/S1474–4422(10)70104–6. PubMed PMID: 20610345.
  24. Donnan GA, Norrving B. Chapter 27 Lacunes and lacunar syndromes. In: Marc F, editor. Handbook of Clinical Neurology. Volume 93: Elsevier; 2008. p. 559–75.
  25. Deb P, Sharma S, Hassan KM. Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology. 2010;17(3):197–218. doi: 10.1016/j.pathophys.2009.12.001. PubMed PMID: 20074922.
  26. Llombart V, Garcia-Berrocoso T, Bustamante A, Fernandez-Cadenas I, Montaner J. Cardioembolic stroke diagnosis using blood biomarkers. Curr Cardiol Rev. 2013;9(4):340–52. PubMed PMID: 24527683; PubMed Central PMCID: PMC3941099.
  27. Al Haj Zen A, Caligiuri G, Sainz J, Lemitre M, Demerens C, Lafont A. Decorin overexpression reduces atherosclerosis development in apolipoprotein E-deficient mice. Atherosclerosis. 2006;187(1):31–9. doi: 10.1016/j.atherosclerosis.2005.08.023. PubMed PMID: 16183063.
  28. Xu YZ, Yang ZG, Zhang YH, Zhang YW, Hong B, Liu JM. Dynamic reduction of plasma decorin following ischemic stroke: a pilot study. Neurochem Res. 2012;37(9):1843–8. Epub 2012/06/09. doi: 10.1007/s11064–012–0787–0. PubMed PMID: 22678721.
  29. Tsai NW, Chang WN, Shaw CF, Jan CR, Chang HW, Huang CR, et al. Levels and value of platelet activation markers in different subtypes of acute non-cardio-embolic ischemic stroke. Thrombo Res. 2009;124(2):213–8. Epub 2009/02/24. doi: 10.1016/j.thromres.2009.01.012. PubMed PMID: 19233449.
  30. Duerschmied D, Bode C, Ahrens I. Immune functions of platelets. Thromb Haemost. 2014;112(4):678–91. doi: 10.1160/TH14–02–0146. PubMed PMID: 25209670.
  31. Wang JH, Zhang YW, Zhang P, Deng BQ, Ding S, Wang ZK, et al. CD40 ligand as a potential biomarker for atherosclerotic instability. Neurological Res. 2013;35(7):693–700. doi: 10.1179/1743132813Y.0000000190. PubMed PMID: 23561892; PubMed Central PMCID: PMC3770830.
  32. Oberheiden T, Nguyen XD, Fatar M, Elmas E, Blahak C, Morper N, et al. Platelet and monocyte activation in acute ischemic stroke – is there a correlation with stroke etiology? Clin Appl Thromb Hemost. 2012;18(1):87–91. Epub 2011/07/08. doi: 10.1177/1076029611412359. PubMed PMID: 21733938.
  33. Shimaoka T, Kume N, Minami M, Hayashida K, Kataoka H, Kita T, et al. Molecular cloning of a novel scavenger receptor for oxidized low density lipoprotein, SR-PSOX, on macrophages. J Biol Chem. 2000;275(52):40663–6. doi: 10.1074/jbc.C000761200. PubMed PMID: 11060282.
  34. Matloubian M, David A, Engel S, Ryan JE, Cyster JG. A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo. Nat Immunol. 2000;1(4):298–304. doi: 10.1038/79738. PubMed PMID: 11017100.
  35. Minami M, Kume N, Shimaoka T, Kataoka H, Hayashida K, Yonehara S, et al. Expression of scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX) in human atheroma. Ann N Y Acad Sci. 2001;947:373–6. PubMed PMID: 11795294.
  36. Aslanian AM, Charo IF. Targeted disruption of the scavenger receptor and chemokine CXCL16 accelerates atherosclerosis. Circulation. 2006;114(6):583–90. doi: 10.1161/CIRCULATIONAHA.105.540583. PubMed PMID: 16880330.
  37. Ma A, Pan X, Xing Y, Wu M, Wang Y, Ma C. Elevation of serum CXCL16 level correlates well with atherosclerotic ischemic stroke. Arch Med Sci. 2014;10(1):47–52. doi: 10.5114/aoms.2013.39200. PubMed PMID: 24701213; PubMed Central PMCID: PMC3953970.
  38. Carlquist JF, Muhlestein JB, Anderson JL. Lipoprotein-associated phospholipase A2: a new biomarker for cardiovascular risk assessment and potential therapeutic target. Expert Rev Mol Diagn. 2007;7(5):511–7. doi: 10.1586/14737159.7.5.511. PubMed PMID: 17892360.
  39. Tsai TH, Chen YL, Lin HS, Liu CF, Chang HW, Lu CH, et al. Link between lipoprotein-associated phospholipase A2 gene expression of peripheral-blood mononuclear cells and prognostic outcome after acute ischemic stroke. J Atheroscler Thromb. 2012;19(6):523–31. PubMed PMID: 22447189.
  40. Katan M, Moon YP, Paik MC, Wolfert RL, Sacco RL, Elkind MS. Lipoprotein-associated phospholipase A2 is associated with atherosclerotic stroke risk: the Northern Manhattan Study. PloS one. 2014;9(1):e83393. Epub 2014/01/15. doi: 10.1371/journal.pone.0083393. PubMed PMID: 24416164; PubMed Central PMCID: PMCPmc3886969.
  41. Delgado P, Chacon P, Penalba A, Pelegri D, Garcia-Berrocoso T, Giralt D, et al. Lipoprotein-associated phospholipase A(2) activity is associated with large-artery atherosclerotic etiology and recurrent stroke in TIA patients. Cerebrovas Dis. 2012;33(2):150–8. Epub 2011/12/20. doi: 10.1159/000334193. PubMed PMID: 22178747.
  42. Scholz H, Sandberg W, Damas JK, Smith C, Andreassen AK, Gullestad L, et al. Enhanced plasma levels of LIGHT in unstable angina: possible pathogenic role in foam cell formation and thrombosis. Circulation. 2005;112(14):2121–9. doi: 10.1161/CIRCULATIONAHA.105.544676. PubMed PMID: 16186421.
  43. Liu GZ, Fang LB, Hjelmstrom P, Gao XG. Enhanced plasma levels of LIGHT in patients with acute atherothrombotic stroke. Acta Neurol Scand. 2008;118(4):256–9. Epub 2008/04/04. doi: 10.1111/j.1600–0404.2008.01013.x. PubMed PMID: 18384455.
  44. Cui R, Iso H, Yamagishi K, Saito I, Kokubo Y, Inoue M, et al. High serum total cholesterol levels is a risk factor of ischemic stroke for general Japanese population: the JPHC study. Atherosclerosis. 2012;221(2):565–9. Epub 2012/02/22. doi: 10.1016/j.atherosclerosis.2012.01.013. PubMed PMID: 22341595.
  45. Kim BS, Jung HS, Bang OY, Chung CS, Lee KH, Kim GM. Elevated serum lipoprotein(a) as a potential predictor for combined intracranial and extracranial artery stenosis in patients with ischemic stroke. Atherosclerosis. 2010;212(2):682–8. doi: 10.1016/j.atherosclerosis.2010.07.007. PubMed PMID: 20691971.
  46. Zeng L, He X, Liu J, Wang L, Weng S, Wang Y, et al. Differences of circulating inflammatory markers between large- and small vessel disease in patients with acute ischemic stroke. Int J Med Sci. 2013;10(10):1399–405. doi: 10.7150/ijms.6652. PubMed PMID: 23983602; PubMed Central PMCID: PMC3753418.
  47. Ladenvall C, Jood K, Blomstrand C, Nilsson S, Jern C, Ladenvall P. Serum C-reactive protein concentration and genotype in relation to ischemic stroke subtype. Stroke. 2006;37(8):2018–23. doi: 10.1161/01.STR.0000231872.86071.68. PubMed PMID: 16809555.
  48. Rabe K, Lehrke M, Parhofer KG, Broedl UC. Adipokines and insulin resistance. Mol Med. 2008;14(11–12):741–51. doi: 10.2119/2008–00058.Rabe. PubMed PMID: 19009016; PubMed Central PMCID: PMC2582855.
  49. Kuwashiro T, Ago T, Kamouchi M, Matsuo R, Hata J, Kuroda J, et al. Significance of plasma adiponectin for diagnosis, neurological severity and functional outcome in ischemic stroke – Research for Biomarkers in Ischemic Stroke (REBIOS). Metabolism. 2014;63(9):1093–103. doi: 10.1016/j.metabol.2014.04.012. PubMed PMID: 24929894.
  50. Davis M, Espiner E, Richards G, Billings J, Town I, Neill A, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343(8895):440–4. PubMed PMID: 7905953.
  51. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347(3):161–7. doi: 10.1056/NEJMoa020233. PubMed PMID: 12124404.
  52. Lainchbury JG, Campbell E, Frampton CM, Yandle TG, Nicholls MG, Richards AM. Brain natriuretic peptide and n-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath. J Am Coll Cardiol. 2003;42(4):728–35. PubMed PMID: 12932611.
  53. Wright SP, Doughty RN, Pearl A, Gamble GD, Whalley GA, Walsh HJ, et al. Plasma amino-terminal pro-brain natriuretic peptide and accuracy of heart-failure diagnosis in primary care: a randomized, controlled trial. J Am Coll Cardiol. 2003;42(10):1793–800. PubMed PMID: 14642690.
  54. Tamura H, Watanabe T, Nishiyama S, Sasaki S, Wanezaki M, Arimoto T, et al. Elevated plasma brain natriuretic peptide levels predict left atrial appendage dysfunction in patients with acute ischemic stroke. J Cardiol. 2012;60(2):126–32. Epub 2012/04/25. doi: 10.1016/j.jjcc.2012.02.010. PubMed PMID: 22525966.
  55. Montaner J, Perea-Gainza M, Delgado P, Ribo M, Chacon P, Rosell A, et al. Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke. 2008;39(8):2280–7. Epub 2008/06/07. doi: 10.1161/strokeaha.107.505354. PubMed PMID: 18535284.
  56. Nigro N, Wildi K, Mueller C, Schuetz P, Mueller B, Fluri F, et al. BNP but Not s-cTnln is associated with cardioembolic aetiology and predicts short and long term prognosis after cerebrovascular events. PLoS One. 2014;9(7):e102704. doi: 10.1371/journal.pone.0102704. PubMed PMID: 25072816; PubMed Central PMCID: PMC4114527.
  57. Shibazaki K, Kimura K, Iguchi Y, Okada Y, Inoue T. Plasma brain natriuretic peptide can be a biological marker to distinguish cardioembolic stroke from other stroke types in acute ischemic stroke. Intern Med. 2009;48(5):259–64. PubMed PMID: 19252345.
  58. Zhixin W, Lianhong Y, Wei H, Lianda L, Longyuan J, Yingjian Z, et al. The value of the use of plasma B-type natriuretic peptide among acute ischemic stroke patients in a Chinese emergency department. Clin Neurol Neurosurg. 2013;115(9):1671–6. doi: 10.1016/j.clineuro.2013.02.021. PubMed PMID: 23518421.
  59. Yukiiri K, Hosomi N, Naya T, Takahashi T, Ohkita H, Mukai M, et al. Plasma brain natriuretic peptide as a surrogate marker for cardioembolic stroke. BMC Neurol. 2008;8:45. Epub 2008/12/17. doi: 10.1186/1471–2377–8–45. PubMed PMID: 19077217; PubMed Central PMCID: PMCPmc2621245.
  60. Cojocaru IM, Cojocaru M, Sapira V, Ionescu A, Barlan S, Tacu N. Could pro-BNP, uric acid, bilirubin, albumin and transferrin be used in making the distinction between stroke subtypes? Rom J Intern Med. 2013;51(3–4):188–95. PubMed PMID: 24620632.
  61. Fonseca AC, Matias JS, Pinho e Melo T, Falcao F, Canhao P, Ferro JM. N-terminal probrain natriuretic peptide as a biomarker of cardioembolic stroke. Int J Stroke. 2011;6(5):398–403. Epub 2011/06/08. doi: 10.1111/j.1747–4949.2011.00606.x. PubMed PMID: 21645267.
  62. Hajsadeghi S, Kashani Amin L, Bakhshandeh H, Rohani M, Azizian AR, Jafarian Kerman SR. The diagnostic value of N-terminal pro-brain natriuretic peptide in differentiating cardioembolic ischemic stroke. J Stroke Cerebrovasc Dis. 2013;22(4):554–60. Epub 2013/02/21. doi: 10.1016/j.jstrokecerebrovasdis.2013.01.012. PubMed PMID: 23422348.
  63. Rodriguez-Yanez M, Sobrino T, Blanco M, de la Ossa NP, Brea D, Rodriguez-Gonzalez R, et al. High serum levels of pro-brain natriuretic peptide (pro BNP) identify cardioembolic origin in undetermined stroke. Dis Markers. 2009;26(4):189–95. Epub 2009/09/05. doi: 10.3233/dma-2009–0630. PubMed PMID: 19729800; PubMed Central PMCID: PMCPmc3833699.
  64. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004;350(7):655–63. doi: 10.1056/NEJMoa031994. PubMed PMID: 14960742.
  65. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006;355(25):2631–9. doi: 10.1056/NEJMoa055373. PubMed PMID: 17182988.
  66. Morgenthaler NG, Struck J, Thomas B, Bergmann A. Immunoluminometric assay for the midregion of pro-atrial natriuretic peptide in human plasma. Clin Chem. 2004;50(1):234–6. doi: 10.1373/clinchem.2003.021204. PubMed PMID: 14709661.
  67. Katan M, Fluri F, Schuetz P, Morgenthaler NG, Zweifel C, Bingisser R, et al. Midregional pro-atrial natriuretic peptide and outcome in patients with acute ischemic stroke. J Am Coll Cardiol. 2010;56(13):1045–53. Epub 2010/09/18. doi: 10.1016/j.jacc.2010.02.071. PubMed PMID: 20846604.
  68. Isenegger J, Meier N, Lammle B, Alberio L, Fischer U, Nedeltchev K, et al. D-dimers predict stroke subtype when assessed early. Cerebrovasc Dis. 2010;29(1):82–6. Epub 2009/11/13. doi: 10.1159/000256652. PubMed PMID: 19907168.
  69. Tombul T, Atbas C, Anlar O. Hemostatic markers and platelet aggregation factors as predictive markers for type of stroke and neurological disability following cerebral infarction. J Clin Neurosci. 2005;12(4):429–34. Epub 2005/06/01. doi: 10.1016/j.jocn.2004.06.013. PubMed PMID: 15925775.
  70. Esmon CT. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J. 1995;9(10):946–55. PubMed PMID: 7615164.
  71. Dharmasaroja P, Dharmasaroja PA, Sobhon P. Increased plasma soluble thrombomodulin levels in cardioembolic stroke. Clin Appl Thromb Hemost. 2012;18(3):289–93. Epub 2012/01/26. doi: 10.1177/1076029611432744. PubMed PMID: 22275395.
  72. Licata G, Tuttolomondo A, Di Raimondo D, Corrao S, Di Sciacca R, Pinto A. Immuno-inflammatory activation in acute cardio-embolic strokes in comparison with other subtypes of ischaemic stroke. Thromb Haemost. 2009;101(5):929–37. Epub 2009/05/01. PubMed PMID: 19404547.
  73. Schalinske KL, Smazal AL. Homocysteine imbalance: a pathological metabolic marker. Adv Nutr. 2012;3(6):755–62. doi: 10.3945/an.112.002758. PubMed PMID: 23153729; PubMed Central PMCID: PMC3648699.
  74. Wall RT, Harlan JM, Harker LA, Striker GE. Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res. 1980;18(1–2):113–21. PubMed PMID: 7404495.
  75. Hassan A, Hunt BJ, O’Sullivan M, Bell R, D'Souza R, Jeffery S, et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain. 2004;127(Pt 1):212–9. Epub 2003/11/11. doi: 10.1093/brain/awh023. PubMed PMID: 14607791.
  76. Schonbeck U, Libby P. CD40 signaling and plaque instability. Circ Res. 2001;89(12):1092–103. PubMed PMID: 11739273.
  77. Rothlein R, Dustin ML, Marlin SD, Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol. 1986;137(4):1270–4. PubMed PMID: 3525675.
  78. Markus HS, Hunt B, Palmer K, Enzinger C, Schmidt H, Schmidt R. Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study. Stroke. 2005;36(7):1410–4. doi: 10.1161/01.STR.0000169924.60783.d4. PubMed PMID: 15905468.