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Blood biomarkers for stroke

Koto Ishida, MD
Brett L Cucchiara, MD
Section Editor
Scott E Kasner, MD
Deputy Editor
John F Dashe, MD, PhD


This topic will discuss candidate blood biomarkers that may have a role in the evaluation and care of patients with stroke, as well as some of the more promising markers under investigation (table 1). Details about the clinical evaluation of stroke are reviewed elsewhere. (See "Overview of the evaluation of stroke".)

Specific blood biomarkers of autoimmune and hypercoagulable conditions relating to stroke are discussed separately. (See "Secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Blood disorders'.)


While measurement of blood markers of cardiac myocyte injury such as troponin has revolutionized the evaluation and management of patients with myocardial infarction, the role of blood biomarkers in stroke remains limited. An ideal blood biomarker for stroke would be reliable, rapidly measured, and readily available, and might assist with diagnosis, determination of stroke subtype or mechanism, or prediction of outcome or response to therapy (table 2) [1].

The development of diagnostic blood biomarkers for stroke, which might help distinguish stroke from mimics, faces tremendous challenges given the heterogeneity of stroke, the presence of the blood-brain-barrier, and the complexity of brain injury. To date, individual markers have lacked sufficient sensitivity and specificity for stroke diagnosis [2,3]. Panels of biomarkers may hold greater promise and are under active study, though they too have yet to demonstrate sufficient accuracy to be of clinical use [4-10].

In addition to diagnosis, biomarkers might assist with identification of stroke mechanism, such as markers of cardioembolism (see 'Brain natriuretic peptide (BNP)' below), carotid atherosclerosis (see 'C-reactive protein (CRP)' below), cancer hypercoagulability (see 'D-dimer' below), and large artery atherosclerosis (see 'Lipoprotein-associated phospholipase A2 (Lp-PLA2)' below). Once validated, such biomarkers could be useful for choosing specific primary and secondary prevention strategies.

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Literature review current through: Nov 2017. | This topic last updated: Sep 12, 2017.
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  1. Hlatky MA, Greenland P, Arnett DK, et al. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation 2009; 119:2408.
  2. Whiteley W, Tseng MC, Sandercock P. Blood biomarkers in the diagnosis of ischemic stroke: a systematic review. Stroke 2008; 39:2902.
  3. Bustamante A, López-Cancio E, Pich S, et al. Blood Biomarkers for the Early Diagnosis of Stroke: The Stroke-Chip Study. Stroke 2017; 48:2419.
  4. Reynolds MA, Kirchick HJ, Dahlen JR, et al. Early biomarkers of stroke. Clin Chem 2003; 49:1733.
  5. Laskowitz DT, Blessing R, Floyd J, et al. Panel of biomarkers predicts stroke. Ann N Y Acad Sci 2005; 1053:30.
  6. Laskowitz DT, Kasner SE, Saver J, et al. Clinical usefulness of a biomarker-based diagnostic test for acute stroke: the Biomarker Rapid Assessment in Ischemic Injury (BRAIN) study. Stroke 2009; 40:77.
  7. Lynch JR, Blessing R, White WD, et al. Novel diagnostic test for acute stroke. Stroke 2004; 35:57.
  8. Dambinova SA, Khounteev GA, Skoromets AA. Multiple panel of biomarkers for TIA/stroke evaluation. Stroke 2002; 33:1181.
  9. An SA, Kim J, Kim OJ, et al. Limited clinical value of multiple blood markers in the diagnosis of ischemic stroke. Clin Biochem 2013; 46:710.
  10. Knauer C, Knauer K, Müller S, et al. A biochemical marker panel in MRI-proven hyperacute ischemic stroke-a prospective study. BMC Neurol 2012; 12:14.
  11. Patton KK, Ellinor PT, Heckbert SR, et al. N-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study. Circulation 2009; 120:1768.
  12. Nakagawa K, Yamaguchi T, Seida M, et al. Plasma concentrations of brain natriuretic peptide in patients with acute ischemic stroke. Cerebrovasc Dis 2005; 19:157.
  13. Shimizu H, Murakami Y, Inoue S, et al. High plasma brain natriuretic polypeptide level as a marker of risk for thromboembolism in patients with nonvalvular atrial fibrillation. Stroke 2002; 33:1005.
  14. Llombart V, Antolin-Fontes A, Bustamante A, et al. B-type natriuretic peptides help in cardioembolic stroke diagnosis: pooled data meta-analysis. Stroke 2015; 46:1187.
  15. Montaner J, Perea-Gainza M, Delgado P, et al. Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke 2008; 39:2280.
  16. Sakai K, Shibazaki K, Kimura K, et al. Brain natriuretic peptide as a predictor of cardioembolism in acute ischemic stroke patients: brain natriuretic peptide stroke prospective study. Eur Neurol 2013; 69:246.
  17. Hajsadeghi S, Kashani Amin L, Bakhshandeh H, et al. The diagnostic value of N-terminal pro-brain natriuretic peptide in differentiating cardioembolic ischemic stroke. J Stroke Cerebrovasc Dis 2013; 22:554.
  18. Okada Y, Shibazaki K, Kimura K, et al. Brain natriuretic peptide as a predictor of delayed atrial fibrillation after ischaemic stroke and transient ischaemic attack. Eur J Neurol 2010; 17:326.
  19. Fonseca AC, Brito D, Pinho e Melo T, et al. N-terminal pro-brain natriuretic peptide shows diagnostic accuracy for detecting atrial fibrillation in cryptogenic stroke patients. Int J Stroke 2014; 9:419.
  20. Longstreth WT Jr, Kronmal RA, Thompson JL, et al. Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke 2013; 44:714.
  21. Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004; 350:655.
  22. Cushman M, Judd SE, Howard VJ, et al. N-terminal pro-B-type natriuretic peptide and stroke risk: the reasons for geographic and racial differences in stroke cohort. Stroke 2014; 45:1646.
  23. Kistorp C, Raymond I, Pedersen F, et al. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA 2005; 293:1609.
  24. Takahashi T, Nakamura M, Onoda T, et al. Predictive value of plasma B-type natriuretic peptide for ischemic stroke: a community-based longitudinal study. Atherosclerosis 2009; 207:298.
  25. Kurl S, Ala-Kopsala M, Ruskoaho H, et al. Plasma N-terminal fragments of natriuretic peptides predict the risk of stroke and atrial fibrillation in men. Heart 2009; 95:1067.
  26. Hijazi Z, Oldgren J, Andersson U, et al. Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy. Circulation 2012; 125:1605.
  27. Hijazi Z, Wallentin L, Siegbahn A, et al. N-terminal pro-B-type natriuretic peptide for risk assessment in patients with atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation). J Am Coll Cardiol 2013; 61:2274.
  28. García-Berrocoso T, Giralt D, Bustamante A, et al. B-type natriuretic peptides and mortality after stroke: a systematic review and meta-analysis. Neurology 2013; 81:1976.
  29. Rost NS, Biffi A, Cloonan L, et al. Brain natriuretic peptide predicts functional outcome in ischemic stroke. Stroke 2012; 43:441.
  30. Whiteley W, Wardlaw J, Dennis M, et al. The use of blood biomarkers to predict poor outcome after acute transient ischemic attack or ischemic stroke. Stroke 2012; 43:86.
  31. Hashimoto H, Kitagawa K, Hougaku H, et al. C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis. Circulation 2001; 104:63.
  32. Tracy RP, Psaty BM, Macy E, et al. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol 1997; 17:2167.
  33. Cucchiara BL, Messe SR, Sansing L, et al. Lipoprotein-associated phospholipase A2 and C-reactive protein for risk-stratification of patients with TIA. Stroke 2009; 40:2332.
  34. Ford ES, Giles WH. Serum C-reactive protein and self-reported stroke: findings from the Third National Health and Nutrition Examination Survey. Arterioscler Thromb Vasc Biol 2000; 20:1052.
  35. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836.
  36. Rost NS, Wolf PA, Kase CS, et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke 2001; 32:2575.
  37. Cao JJ, Thach C, Manolio TA, et al. C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. Circulation 2003; 108:166.
  38. Curb JD, Abbott RD, Rodriguez BL, et al. C-reactive protein and the future risk of thromboembolic stroke in healthy men. Circulation 2003; 107:2016.
  39. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347:1557.
  40. Bos MJ, Schipper CM, Koudstaal PJ, et al. High serum C-reactive protein level is not an independent predictor for stroke: the Rotterdam Study. Circulation 2006; 114:1591.
  41. Elkind MS, Tai W, Coates K, et al. High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke. Arch Intern Med 2006; 166:2073.
  42. Elkind MS, Luna JM, Moon YP, et al. High-sensitivity C-reactive protein predicts mortality but not stroke: the Northern Manhattan Study. Neurology 2009; 73:1300.
  43. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010; 375:132.
  44. Elkind MS, Leon V, Moon YP, et al. High-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 stability before and after stroke and myocardial infarction. Stroke 2009; 40:3233.
  45. Woodward M, Lowe GD, Campbell DJ, et al. Associations of inflammatory and hemostatic variables with the risk of recurrent stroke. Stroke 2005; 36:2143.
  46. Elkind MS, Luna JM, McClure LA, et al. C-reactive protein as a prognostic marker after lacunar stroke: levels of inflammatory markers in the treatment of stroke study. Stroke 2014; 45:707.
  47. Di Napoli M, Schwaninger M, Cappelli R, et al. Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: a statement for health care professionals from the CRP Pooling Project members. Stroke 2005; 36:1316.
  48. Arenillas JF, Alvarez-Sabín J, Molina CA, et al. C-reactive protein predicts further ischemic events in first-ever transient ischemic attack or stroke patients with intracranial large-artery occlusive disease. Stroke 2003; 34:2463.
  49. Purroy F, Montaner J, Molina CA, et al. C-reactive protein predicts further ischemic events in transient ischemic attack patients. Acta Neurol Scand 2007; 115:60.
  50. Muir KW, Weir CJ, Alwan W, et al. C-reactive protein and outcome after ischemic stroke. Stroke 1999; 30:981.
  51. Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke 2001; 32:133.
  52. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 2001; 32:917.
  53. Winbeck K, Poppert H, Etgen T, et al. Prognostic relevance of early serial C-reactive protein measurements after first ischemic stroke. Stroke 2002; 33:2459.
  54. Smith CJ, Emsley HC, Gavin CM, et al. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 2004; 4:2.
  55. Schwarzbach CJ, Schaefer A, Ebert A, et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke 2012; 43:3029.
  56. Lee EJ, Nah HW, Kwon JY, et al. Ischemic stroke in patients with cancer: is it different from usual strokes? Int J Stroke 2014; 9:406.
  57. Kim SJ, Park JH, Lee MJ, et al. Clues to occult cancer in patients with ischemic stroke. PLoS One 2012; 7:e44959.
  58. Seok JM, Kim SG, Kim JW, et al. Coagulopathy and embolic signal in cancer patients with ischemic stroke. Ann Neurol 2010; 68:213.
  59. Isenegger J, Meier N, Lämmle B, et al. D-dimers predict stroke subtype when assessed early. Cerebrovasc Dis 2010; 29:82.
  60. Alvarez-Perez FJ, Castelo-Branco M, Alvarez-Sabin J. Usefulness of measurement of fibrinogen, D-dimer, D-dimer/fibrinogen ratio, C reactive protein and erythrocyte sedimentation rate to assess the pathophysiology and mechanism of ischaemic stroke. J Neurol Neurosurg Psychiatry 2011; 82:986.
  61. Ageno W, Finazzi S, Steidl L, et al. Plasma measurement of D-dimer levels for the early diagnosis of ischemic stroke subtypes. Arch Intern Med 2002; 162:2589.
  62. Wiseman S, Marlborough F, Doubal F, et al. Blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and non-stroke: systematic review and meta-analysis. Cerebrovasc Dis 2014; 37:64.
  63. Barber M, Langhorne P, Rumley A, et al. Hemostatic function and progressing ischemic stroke: D-dimer predicts early clinical progression. Stroke 2004; 35:1421.
  64. Kang DW, Yoo SH, Chun S, et al. Inflammatory and hemostatic biomarkers associated with early recurrent ischemic lesions in acute ischemic stroke. Stroke 2009; 40:1653.
  65. Welsh P, Barber M, Langhorne P, et al. Associations of inflammatory and haemostatic biomarkers with poor outcome in acute ischaemic stroke. Cerebrovasc Dis 2009; 27:247.
  66. Krarup LH, Sandset EC, Sandset PM, Berge E. D-dimer levels and stroke progression in patients with acute ischemic stroke and atrial fibrillation. Acta Neurol Scand 2011; 124:40.
  67. Rallidis LS, Vikelis M, Panagiotakos DB, et al. Usefulness of inflammatory and haemostatic markers to predict short-term risk for death in middle-aged ischaemic stroke patients. Acta Neurol Scand 2008; 117:415.
  68. Fibrinogen Studies Collaboration, Danesh J, Lewington S, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 2005; 294:1799.
  69. Whiteley W, Jackson C, Lewis S, et al. Association of circulating inflammatory markers with recurrent vascular events after stroke: a prospective cohort study. Stroke 2011; 42:10.
  70. Turaj W, Słowik A, Dziedzic T, et al. Increased plasma fibrinogen predicts one-year mortality in patients with acute ischemic stroke. J Neurol Sci 2006; 246:13.
  71. Tanne D, Macko RF, Lin Y, et al. Hemostatic activation and outcome after recombinant tissue plasminogen activator therapy for acute ischemic stroke. Stroke 2006; 37:1798.
  72. del Zoppo GJ, Levy DE, Wasiewski WW, et al. Hyperfibrinogenemia and functional outcome from acute ischemic stroke. Stroke 2009; 40:1687.
  73. Trouillas P, Derex L, Philippeau F, et al. Early fibrinogen degradation coagulopathy is predictive of parenchymal hematomas in cerebral rt-PA thrombolysis: a study of 157 cases. Stroke 2004; 35:1323.
  74. Cocho D, Borrell M, Martí-Fàbregas J, et al. Pretreatment hemostatic markers of symptomatic intracerebral hemorrhage in patients treated with tissue plasminogen activator. Stroke 2006; 37:996.
  75. Matosevic B, Knoflach M, Werner P, et al. Fibrinogen degradation coagulopathy and bleeding complications after stroke thrombolysis. Neurology 2013; 80:1216.
  76. Mallat Z, Lambeau G, Tedgui A. Lipoprotein-associated and secreted phospholipases A₂ in cardiovascular disease: roles as biological effectors and biomarkers. Circulation 2010; 122:2183.
  77. Delgado P, Chacón P, Penalba A, et al. Lipoprotein-associated phospholipase A(2) activity is associated with large-artery atherosclerotic etiology and recurrent stroke in TIA patients. Cerebrovasc Dis 2012; 33:150.
  78. Lp-PLA(2) Studies Collaboration, Thompson A, Gao P, et al. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet 2010; 375:1536.
  79. Oei HH, van der Meer IM, Hofman A, et al. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation 2005; 111:570.
  80. Katan M, Moon YP, Paik MC, et al. Lipoprotein-associated phospholipase A2 is associated with atherosclerotic stroke risk: the Northern Manhattan Study. PLoS One 2014; 9:e83393.
  81. Lanman RB, Wolfert RL, Fleming JK, et al. Lipoprotein-associated phospholipase A2: review and recommendation of a clinical cut point for adults. Prev Cardiol 2006; 9:138.
  82. Elkind MS, Tai W, Coates K, et al. Lipoprotein-associated phospholipase A2 activity and risk of recurrent stroke. Cerebrovasc Dis 2009; 27:42.
  83. Lin J, Zheng H, Cucchiara BL, et al. Association of Lp-PLA2-A and early recurrence of vascular events after TIA and minor stroke. Neurology 2015; 85:1585.
  84. Anand N, Stead LG. Neuron-specific enolase as a marker for acute ischemic stroke: a systematic review. Cerebrovasc Dis 2005; 20:213.
  85. González-García S, González-Quevedo A, Peña-Sánchez M, et al. Serum neuron-specific enolase and S100 calcium binding protein B biomarker levels do not improve diagnosis of acute stroke. J R Coll Physicians Edinb 2012; 42:199.
  86. Castellanos M, Leira R, Serena J, et al. Plasma cellular-fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke. Stroke 2004; 35:1671.
  87. Castellanos M, Sobrino T, Millán M, et al. Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke: a multicenter confirmatory study. Stroke 2007; 38:1855.
  88. Katan M, Nigro N, Fluri F, et al. Stress hormones predict cerebrovascular re-events after transient ischemic attacks. Neurology 2011; 76:563.
  89. Greisenegger S, Segal HC, Burgess AI, et al. Copeptin and Long-Term Risk of Recurrent Vascular Events After Transient Ischemic Attack and Ischemic Stroke: Population-Based Study. Stroke 2015; 46:3117.
  90. Katan M, Fluri F, Morgenthaler NG, et al. Copeptin: a novel, independent prognostic marker in patients with ischemic stroke. Ann Neurol 2009; 66:799.
  91. Urwyler SA, Schuetz P, Fluri F, et al. Prognostic value of copeptin: one-year outcome in patients with acute stroke. Stroke 2010; 41:1564.
  92. De Marchis GM, Katan M, Weck A, et al. Copeptin adds prognostic information after ischemic stroke: results from the CoRisk study. Neurology 2013; 80:1278.
  93. Fluri F, Morgenthaler NG, Mueller B, et al. Copeptin, procalcitonin and routine inflammatory markers-predictors of infection after stroke. PLoS One 2012; 7:e48309.
  94. Meisel A, Meisel C, Harms H, et al. Predicting post-stroke infections and outcome with blood-based immune and stress markers. Cerebrovasc Dis 2012; 33:580.
  95. Wunderlich MT, Wallesch CW, Goertler M. Release of glial fibrillary acidic protein is related to the neurovascular status in acute ischemic stroke. Eur J Neurol 2006; 13:1118.
  96. Foerch C, Curdt I, Yan B, et al. Serum glial fibrillary acidic protein as a biomarker for intracerebral haemorrhage in patients with acute stroke. J Neurol Neurosurg Psychiatry 2006; 77:181.
  97. Dvorak F, Haberer I, Sitzer M, Foerch C. Characterisation of the diagnostic window of serum glial fibrillary acidic protein for the differentiation of intracerebral haemorrhage and ischaemic stroke. Cerebrovasc Dis 2009; 27:37.
  98. Undén J, Strandberg K, Malm J, et al. Explorative investigation of biomarkers of brain damage and coagulation system activation in clinical stroke differentiation. J Neurol 2009; 256:72.
  99. Foerch C, Niessner M, Back T, et al. Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke. Clin Chem 2012; 58:237.
  100. Katsanos AH, Makris K, Stefani D, et al. Plasma Glial Fibrillary Acidic Protein in the Differential Diagnosis of Intracerebral Hemorrhage. Stroke 2017; 48:2586.
  101. Ramos-Fernandez M, Bellolio MF, Stead LG. Matrix metalloproteinase-9 as a marker for acute ischemic stroke: a systematic review. J Stroke Cerebrovasc Dis 2011; 20:47.
  102. Montaner J, Molina CA, Monasterio J, et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 2003; 107:598.
  103. Castellanos M, Leira R, Serena J, et al. Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke 2003; 34:40.
  104. Montaner J, Alvarez-Sabín J, Molina C, et al. Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke 2001; 32:1759.
  105. Foerch C, Otto B, Singer OC, et al. Serum S100B predicts a malignant course of infarction in patients with acute middle cerebral artery occlusion. Stroke 2004; 35:2160.
  106. Foerch C, Singer OC, Neumann-Haefelin T, et al. Evaluation of serum S100B as a surrogate marker for long-term outcome and infarct volume in acute middle cerebral artery infarction. Arch Neurol 2005; 62:1130.
  107. Foerch C, Wunderlich MT, Dvorak F, et al. Elevated serum S100B levels indicate a higher risk of hemorrhagic transformation after thrombolytic therapy in acute stroke. Stroke 2007; 38:2491.