Risk Factors for Hemorrhagic Stroke

  • Alessandro BiffiEmail author
Part of the Stroke Revisited book series (STROREV)


Hemorrhagic stroke accounts for approximately 5–15% of all acute stroke events worldwide, with its two most common subtypes being intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). Each of these hemorrhagic stroke subtypes accounts for 5–10% of all strokes, with noticeable variations in incidence across geographic regions and racial/ethnic groups. Despite significant advancements in neurocritical care and preventative strategies, morbidity and mortality related to ICH and SAH continue to represent a substantial public health problem worldwide. Indeed, despite accounting for a minority of stroke cases, hemorrhagic stroke accounts for almost half of all stroke-related morbidity and mortality. An in-depth understanding of the genetic, personal, and environmental risk factors influencing hemorrhagic stroke risk will be crucial to implementing novel, effective primary and secondary prevention strategies aimed at preserving lives and preventing disability among at-risk individuals. This chapter will focus on presenting existing evidence on risk factors for ICH and SAH, aiming at providing a critical review of published studies and highlighting current unresolved epidemiological questions pertaining to hemorrhagic stroke.


  1. 1.
    Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450–60.CrossRefPubMedGoogle Scholar
  2. 2.
    Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701.CrossRefPubMedGoogle Scholar
  3. 3.
    Biffi A, Greenberg SM. Cerebral amyloid angiopathy: a systematic review. J Clin Neurol. 2011;7:1–9.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Biffi A, Anderson C, Battey TW, et al. Association between blood pressure control and risk of recurrent intracerebral hemorrhage. JAMA. 2015;314(9):904–12.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Rost NS, Greenberg SM, Rosand J. The genetic architecture of intracerebral hemorrhage. Stroke. 2008;39:2166–73.CrossRefPubMedGoogle Scholar
  6. 6.
    Woo D, Sekar P, Chakraborty R, et al. Genetic epidemiology of intracerebral hemorrhage. J Stroke Cerebrovasc. 2005;14:239–43.CrossRefGoogle Scholar
  7. 7.
    Devan WJ, Falcone GJ, Anderson CD, et al. Heritability estimates identify a substantial genetic contribution to risk and outcome of intracerebral hemorrhage. Stroke. 2013;44:1578–83.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Biffi A, Sonni A, Anderson CD, et al. Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Ann Neurol. 2010;68:934–43.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Biffi A, Shulman JM, Jagiella JM, et al. Genetic variation at CR1 increases risk of cerebral amyloid angiopathy. Neurology. 2012;78:334–41.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Valant V, Keenan B, Anderson C, et al. TOMM40 in cerebral amyloid angiopathy related intracerebral hemorrhage: comparative genetic analysis with Alzheimer’s disease. Transl Stroke Res. 2012;3(Suppl 1):S102–12.CrossRefGoogle Scholar
  11. 11.
    Hamaguchi T, Okino S, Sodeyama N, et al. Association of a polymorphism of the transforming growth factor-{beta}1 gene with cerebral amyloid angiopathy. J Neurol Neurosur Ps. 2005;76:696–9.CrossRefGoogle Scholar
  12. 12.
    Peila R, Yucesoy B, White LR, et al. A TGF-beta1 polymorphism association with dementia and neuropathologies: the HAAS. Neurobiol Aging. 2007;28:1367–73.CrossRefPubMedGoogle Scholar
  13. 13.
    Woo D, Broderick JP. Spontaneous intracerebral hemorrhage: epidemiology and clinical presentation. Neurosurg Clin N Am. 2002;13:265–79.CrossRefPubMedGoogle Scholar
  14. 14.
    Woo D, Falcone GJ, Devan WJ, et al. Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. Am J Hum Genet. 2014;94:511–21.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Fornage M, Debette S, Bis JC, et al. Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. Ann Neurol. 2011;69:928–39.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Verhaaren BF, Debette S, Bis JC, et al. Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. Circ Cardiovasc Genet. 2015;8:398–409.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Raffeld MR, Biffi A, Battey TW, et al. APOE epsilon4 and lipid levels affect risk of recurrent nonlobar intracerebral hemorrhage. Neurology. 2015;85:349–56.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Volonghi I, Pezzini A, Del Zotto E, et al. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. The COL4A1 stroke syndrome. Curr Med Chem. 2010;17:1317–24.CrossRefPubMedGoogle Scholar
  19. 19.
    Gould DB, Phalan FC, Van Mil SE, et al. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N Engl J Med. 2006;354:1489–96.CrossRefPubMedGoogle Scholar
  20. 20.
    Weng YC, Sonni A, Labelle-Dumais C, et al. COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage. Ann Neurol. 2012;71:470–7.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Jeanne M, Labelle-Dumais C, Jorgensen J, et al. COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke. Am J Hum Genet. 2012;90:91–101.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Rannikmae K, Davies G, Thomson PA, et al. Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology. 2015;84:918–26.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Poon MT, Bell SM, Al-Shahi Salman R. Epidemiology of intracerebral haemorrhage. Front Neurol Neurosci. 2015;37:1–12.CrossRefPubMedGoogle Scholar
  24. 24.
    Flaherty ML, Woo D, Haverbusch M, et al. Racial variations in location and risk of intracerebral hemorrhage. Stroke. 2005;36:934–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Labovitz DL, Halim A, Boden-Albala B, et al. The incidence of deep and lobar intracerebral hemorrhage in whites, blacks, and Hispanics. Neurology. 2005;65:518–22.CrossRefPubMedGoogle Scholar
  26. 26.
    Woo D, Rosand J, Kidwell C, et al. The ethnic/racial variations of intracerebral hemorrhage (ERICH) study protocol. Stroke. 2013;44:e120–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Walsh KB, Woo D, Sekar P, et al. Untreated hypertension: a powerful risk factor for lobar and nonlobar intracerebral hemorrhage in whites, blacks, and hispanics. Circulation. 2016;134:1444–52.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hong KS, Bang OY, Kang DW, et al. Stroke statistics in Korea: part I. Epidemiology and risk factors: a report from the Korean stroke society and clinical research center for stroke. J Stroke. 2013;15:2–20.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Toyoda K. Epidemiology and registry studies of stroke in Japan. J Stroke. 2013;15:21–6.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Benjamin EJ, Blaha MJ, Chiuve SE et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017; 135:00–00.Google Scholar
  31. 31.
    Ariesen MJ, Claus SP, Rinkel GJE, et al. Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke. 2003;34:2060–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Van Asch CJ, Luitse MJ, Rinkel GJ, et al. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9:167–76.CrossRefPubMedGoogle Scholar
  33. 33.
    Zia E, Pessah-Rasmussen H, Khan FA, et al. Risk factors for primary intracerebral hemorrhage: a population-based nested case-control study. Cerebrovasc Dis. 2006;21:18–25.CrossRefPubMedGoogle Scholar
  34. 34.
    Martini SR, Flaherty ML, Brown WM, et al. Risk factors for intracerebral hemorrhage differ according to hemorrhage location. Neurology. 2012;79:2275–82.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Jackson CA, Sudlow CLM. Is hypertension a more frequent risk factor for deep than for lobar supratentorial intracerebral haemorrhage? J Neurol Neurosurg. 2006;77:1244–52.CrossRefGoogle Scholar
  36. 36.
    Rothwell PM, Howard SC, Dolan E, et al. Effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol. 2010;9:469–80.CrossRefPubMedGoogle Scholar
  37. 37.
    Jolink WM, Klijn CJ, Brouwers PJ, et al. Time trends in incidence, case fatality, and mortality of intracerebral hemorrhage. Neurology. 2015;85:1318–24.CrossRefPubMedGoogle Scholar
  38. 38.
    Lionakis N, Mendrinos D, Sanidas E, et al. Hypertension in the elderly. World J Cardiol. 2012;4:135–47.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Larsson SC, Wallin A, Wolk A, et al. Differing association of alcohol consumption with different stroke types: a systematic review and meta-analysis. BMC Med. 2016;14:178.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Xin X, He J, Frontini MG, et al. Effects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2001;38:1112–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Gorelick PB, Kelly MA. Alcohol as a risk factor for stroke. Heart Dis Stroke. 1992;1:255–8.PubMedGoogle Scholar
  42. 42.
    Thrift AG, Mcneil JJ, Forbes A, et al. Risk factors for cerebral hemorrhage in the era of well-controlled hypertension. Melbourne risk factor study (MERFS) group. Stroke. 1996;27:2020–5.CrossRefPubMedGoogle Scholar
  43. 43.
    Giroud M, Creisson E, Fayolle H, et al. Risk factors for primary cerebral hemorrhage: a population-based study—the stroke registry of Dijon. Neuroepidemiology. 1995;14:20–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Iribarren C, Jacobs DR, Sadler M, et al. Low total serum cholesterol and intracerebral hemorrhagic stroke: is the association confined to elderly men? Stroke. 1996;27:1993–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Segal AZ, Chiu RI, Eggleston-Sexton PM, et al. Low cholesterol as a risk factor for primary intracerebral hemorrhage: a case-control study. Neuroepidemiology. 1999;18:185–93.CrossRefPubMedGoogle Scholar
  46. 46.
    Yano K, Reed DM, Maclean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu heart program. Stroke. 1989;20:1460–5.CrossRefPubMedGoogle Scholar
  47. 47.
    Wang X, Dong Y, Qi X, et al. Cholesterol levels and risk of hemorrhagic stroke: a systematic review and meta-analysis. Stroke. 2013;44:1833–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Xie L, Wu W, Chen J, et al. Cholesterol levels and hemorrhagic stroke risk in east Asian versus non-east Asian populations: a systematic review and meta-analysis. Neurologist. 2017;22:107–15.CrossRefPubMedGoogle Scholar
  49. 49.
    Mckinney JS, Kostis WJ. Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials. Stroke. 2012;43:2149–56.CrossRefPubMedGoogle Scholar
  50. 50.
    Pandit AK, Kumar P, Kumar A, et al. High-dose statin therapy and risk of intracerebral hemorrhage: a meta-analysis. Acta Neurol Scand. 2016;134:22–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Bos MJ, Koudstaal PJ, Hofman A, et al. Decreased glomerular filtration rate is a risk factor for hemorrhagic but not for ischemic stroke: the Rotterdam study. Stroke. 2007;38:3127–32.CrossRefPubMedGoogle Scholar
  52. 52.
    Ovbiagele B, Wing JJ, Menon RS, et al. Association of chronic kidney disease with cerebral microbleeds in patients with primary intracerebral hemorrhage. Stroke. 2013;44:2409–13.CrossRefPubMedGoogle Scholar
  53. 53.
    Kim SH, Shin DW, Yun JM, et al. Kidney dysfunction and cerebral microbleeds in neurologically healthy adults. PLoS One. 2017;12:e0172210.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hoirisch-Clapauch S, Nardi AE, Gris JC, et al. Are the antiplatelet and profibrinolytic properties of selective serotonin-reuptake inhibitors relevant to their brain effects? Thromb Res. 2014;134:11–6.CrossRefPubMedGoogle Scholar
  55. 55.
    Pozzi M, Roccatagliata D, Sterzi R. Drug abuse and intracranial hemorrhage. Neurol Sci. 2008;29(Suppl 2):S269–70.CrossRefPubMedGoogle Scholar
  56. 56.
    Treadwell SD, Robinson TG. Cocaine use and stroke. Postgrad Med J. 2007;83:389–94.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Mcevoy AW, Kitchen ND, Thomas DG. Intracerebral haemorrhage and drug abuse in young adults. Brit J Neurosurg. 2000;14:449–54.CrossRefGoogle Scholar
  58. 58.
    Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004;164:880–4.CrossRefPubMedGoogle Scholar
  59. 59.
    Flaherty ML, Haverbusch M, Sekar P, et al. The increasing burden of anticoagulant-associated intracerebral hemorrhage. Stroke. 2006;37:623.Google Scholar
  60. 60.
    Shireman TI, Howard PA, Kresowik TF, et al. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke. 2004;35:2362–7.CrossRefPubMedGoogle Scholar
  61. 61.
    An SJ, Kim TJ, Yoon BW. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: an update. J Stroke. 2017;19:3–10.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Charidimou A, Shoamanesh A, Al-Shahi Salman R, et al. Cerebral amyloid angiopathy, cerebral microbleeds and implications for anticoagulation decisions: the need for a balanced approach. Int J Stroke. 2018;13:117–20.CrossRefPubMedGoogle Scholar
  63. 63.
    Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857–67.CrossRefPubMedGoogle Scholar
  64. 64.
    Gorelick PB. Combining aspirin with oral anticoagulant therapy: is this a safe and effective practice in patients with atrial fibrillation? Stroke. 2007;38:1652–4.CrossRefPubMedGoogle Scholar
  65. 65.
    Investigators A, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:2066–78.CrossRefGoogle Scholar
  66. 66.
    Covassin N, Somers VK. Sleep apnea, hypertension, and hemorrhagic stroke-deja vu all over again. J Am Soc Hypertens. 2016;10:197–200.CrossRefPubMedGoogle Scholar
  67. 67.
    Floras JS. Hypertension and sleep apnea. Can J Cardiol. 2015;31:889–97.CrossRefPubMedGoogle Scholar
  68. 68.
    Koo DL, Kim JY, Lim JS, et al. Cerebral microbleeds on MRI in patients with obstructive sleep apnea. J Clin Sleep Med. 2017;13:65–72.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Sacco S, Ricci S, Carolei A. Migraine and vascular diseases: a review of the evidence and potential implications for management. Cephalalgia. 2012;32:785–95.CrossRefPubMedGoogle Scholar
  70. 70.
    Sacco S, Ornello R, Ripa P, et al. Migraine and hemorrhagic stroke: a meta-analysis. Stroke. 2013;44:3032–8.CrossRefPubMedGoogle Scholar
  71. 71.
    Gaist D, Gonzalez-Perez A, Ashina M, et al. Migraine and risk of hemorrhagic stroke: a study based on data from general practice. J Headache Pain. 2014;15:74.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017;389:655–66.CrossRefPubMedGoogle Scholar
  73. 73.
    Broderick JP, Brown RD Jr, Sauerbeck L, et al. Greater rupture risk for familial as compared to sporadic unruptured intracranial aneurysms. Stroke. 2009;40:1952–7.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Broderick JP, Sauerbeck LR, Foroud T, et al. Familial intracranial aneurysm (FIA) study protocol. BMC Med Genet. 2005;6(17)Google Scholar
  75. 75.
    Ruigrok YM, Buskens E, Rinkel GJ. Attributable risk of common and rare determinants of subarachnoid hemorrhage. Stroke. 2001;32:1173–5.CrossRefPubMedGoogle Scholar
  76. 76.
    Alg VS, Sofat R, Houlden H, et al. Genetic risk factors for intracranial aneurysms: a meta-analysis in more than 116,000 individuals. Neurology. 2013;80:2154–65.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Yasuno K, Bilguvar K, Bijlenga P, et al. Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat Genet. 2010;42:420–5.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    De Rooij NK, Linn FH, Van Der Plas JA, et al. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg. 2007;78:1365–72.CrossRefGoogle Scholar
  79. 79.
    Eden SV, Meurer WJ, Sanchez BN, et al. Gender and ethnic differences in subarachnoid hemorrhage. Neurology. 2008;71:731–5.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Algra AM, Klijn CJ, Helmerhorst FM, et al. Female risk factors for subarachnoid hemorrhage: a systematic review. Neurology. 2012;79:1230–6.CrossRefPubMedGoogle Scholar
  81. 81.
    Kim CK, Kim BJ, Ryu WS, et al. Impact of smoking cessation on the risk of subarachnoid haemorrhage: a nationwide multicentre case control study. J Neurol Neurosurg. 2012;83:1100–3.CrossRefGoogle Scholar
  82. 82.
    Lindekleiv H, Sandvei MS, Njolstad I, et al. Sex differences in risk factors for aneurysmal subarachnoid hemorrhage: a cohort study. Neurology. 2011;76:637–43.CrossRefPubMedGoogle Scholar
  83. 83.
    Lindekleiv H, Sandvei MS, Romundstad PR, et al. Joint effect of modifiable risk factors on the risk of aneurysmal subarachnoid hemorrhage: a cohort study. Stroke. 2012;43:1885–9.CrossRefPubMedGoogle Scholar
  84. 84.
    Andreasen TH, Bartek J Jr, Andresen M, et al. Modifiable risk factors for aneurysmal subarachnoid hemorrhage. Stroke. 2013;44:3607–12.CrossRefPubMedGoogle Scholar
  85. 85.
    Yoon BW, Bae HJ, Hong KS, et al. Phenylpropanolamine contained in cold remedies and risk of hemorrhagic stroke. Neurology. 2007;68:146–9.CrossRefPubMedGoogle Scholar
  86. 86.
    Lee SM, Choi NK, Lee BC, et al. Caffeine-containing medicines increase the risk of hemorrhagic stroke. Stroke. 2013;44:2139–43.CrossRefPubMedGoogle Scholar
  87. 87.
    Feigin VL, Rinkel GJ, Lawes CM, et al. Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies. Stroke. 2005;36:2773–80.CrossRefPubMedGoogle Scholar
  88. 88.
    Kawate N, Kayaba K, Hara M, et al. Body mass index and incidence of subarachnoid hemorrhage in Japanese community residents: the Jichi medical school cohort study. J Stroke Cerebrovasc. 2017;26:1683–8.CrossRefGoogle Scholar
  89. 89.
    Phan K, Moore JM, Griessenauer CJ, et al. Aspirin and risk of subarachnoid hemorrhage: systematic review and meta-analysis. Stroke. 2017;48:1210–7.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media Singapore 2018

Authors and Affiliations

  1. 1.Divisions of Stroke, Memory Disorders and Behavioral Neurology, Department of NeurologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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