Brain regulation of thrombosis and hemostasis from theory to practice

Stroke

Volumn 44, Issue 11, 2013, Pages 3275-3285

  Fisher, Mark J ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Blood brain barrier; Hemorrhage; Hemostasis; Thrombosis

Indexed keywords

ACETYLSALICYLIC ACID; ANTITHROMBIN III; BLOOD CLOTTING FACTOR; BLOOD CLOTTING FACTOR 7; BLOOD CLOTTING FACTOR 8; BLOOD CLOTTING FACTOR 9; BLOOD CLOTTING INHIBITOR; CILOSTAZOL; CLOPIDOGREL; DABIGATRAN; DIPYRIDAMOLE; ENDOTHELIAL NITRIC OXIDE SYNTHASE; FIBRIN; PLACEBO; PLASMINOGEN ACTIVATOR INHIBITOR 1; PROSTACYCLIN; PROSTACYCLIN SYNTHASE; PROTEASE NEXIN I; PROTEOHEPARAN SULFATE; RIVAROXABAN; THROMBOMODULIN; THROMBOPLASTIN; TISSUE FACTOR PATHWAY INHIBITOR; TISSUE PLASMINOGEN ACTIVATOR; UROKINASE; WARFARIN;

ANTICOAGULANT THERAPY; ANTIOXIDANT ACTIVITY; ARTERY THROMBOSIS; ARTICLE; BLEEDING TENDENCY; BLOOD BRAIN BARRIER; BLOOD COMPONENT; BLOOD FLOW; BRAIN BLOOD VESSEL; BRAIN FUNCTION; BRAIN HEMORRHAGE; CEREBROVASCULAR ACCIDENT; DRUG EFFICACY; FIBRIN DEPOSITION; FIBRINOLYSIS; HEMOSTASIS; HUMAN; HYPERTENSION; NONHUMAN; OCCLUSIVE CEREBROVASCULAR DISEASE; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REGULATORY MECHANISM; RISK FACTOR; RISK REDUCTION; THROMBOCYTE ACTIVATION; THROMBOCYTE AGGREGATION; THROMBOCYTOPENIA; VASCULAR AMYLOIDOSIS; VASCULAR ENDOTHELIUM; VEIN THROMBOSIS;

BLOOD-BRAIN BARRIER; HEMORRHAGE; HEMOSTASIS; THROMBOSIS;

ANIMALS; ANTITHROMBIN III; BLOOD COAGULATION; BRAIN; CEREBRAL HEMORRHAGE; DISEASE MODELS, ANIMAL; EPOPROSTENOL; HEMOSTASIS; HUMANS; MICROCIRCULATION; NITRIC OXIDE; PLASMINOGEN ACTIVATOR INHIBITOR 1; PROTEASE NEXINS; STROKE; THROMBOMODULIN; THROMBOPLASTIN; THROMBOSIS; TISSUE PLASMINOGEN ACTIVATOR;

EID: 84888292079     PISSN: 00392499     EISSN: 15244628     Source Type: Journal    
DOI: 10.1161/STROKEAHA.113.000736     Document Type: Article

References (124)

1. Aird WC. Coagulation. Crit Care Med. 2005;33(12 suppl):S485-S487.
2. del Zoppo GJ. Virchow's triad: the vascular basis of cerebral injury. Rev Neurol Dis. 2008;5(suppl 1):S12-S21.
3. Wolberg AS, Aleman MM, Leiderman K, Machlus KR. Procoagulant activity in hemostasis and thrombosis: Virchow's triad revisited. Anesth Analg. 2012;114:275-285.
4. Mackman N. Tissue-specific hemostasis in mice. Arterioscler Thromb Vasc Biol. 2005;25:2273-2281.
5. Rosenberg RD, Aird WC. Vascular-bed-specific hemostasis and hypercoagulable states. N Engl J Med. 1999;340:1555-1564.
6. Aird WC. Vascular bed-specific thrombosis. J Thromb Haemost. 2007;5(suppl 1):283-291.
7. Osterud B, Bajaj MS, Bajaj S P. Sites of tissue factor pathway inhibitor (TFPI) and tissue factor expression under physiologic and pathologic conditions. On behalf of the Subcommittee on Tissue factor Pathway Inhibitor (TFPI) of the Scientific and Standardization Committee of the ISTH. Thromb Haemost. 1995;73:873-875.
8. Yamamoto K, de Waard V, Fearns C, Loskutoff DJ. Tissue distribution and regulation of murine von Willebrand factor gene expression in vivo. Blood. 1998;92:2791-2801.
9. Lurie F, Kistner RL, Eklof B, Kessler D. Mechanism of venous valve closure and role of the valve in circulation: a new concept. J Vasc Surg. 2003;38:955-961.
10. Primignani M, Martinelli I, Bucciarelli P, Battaglioli T, Reati R, Fabris F, et al. Risk factors for thrombophilia in extrahepatic portal vein obstruction. Hepatology. 2005;41:603-608.
11. Michiels JJ, Berneman ZN, Schroyens W, Van Vliet HH. Pathophysiology and treatment of platelet-mediated disturbances, major thrombosis and bleeding complications in essential thrombocythaemia and poycythaemia vera. Platelets. 2004;15:67-84.
12. Comp PC, Elrod JP, Karzenski S. Warfarin-induced skin necrosis. Semin Thromb Hemost. 1990;16:293-298.
13. Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature. 1994;368:419-424.
14. Weiler-Guettler H, Christie PD, Beeler DL, Healy AM, Hancock WW, Rayburn H, et al. A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state. J Clin Invest. 1998;101:1983-1991.
15. Healy AM, Hancock WW, Christie PD, Rayburn HB, Rosenberg RD. Intravascular coagulation activation in a murine model of thrombomodulin deficiency: effects of lesion size, age, and hypoxia on fibrin deposition. Blood. 1998;92:4188-4197.
16. Weiler H, Lindner V, Kerlin B, Isermann BH, Hendrickson SB, Cooley BC, et al. Characterization of a mouse model for thrombomodulin deficiency. Arterioscler Thromb Vasc Biol. 2001;21:1531-1537.
17. Christie PD, Edelberg JM, Picard MH, Foulkes AS, Mamuya W, Weiler-Guettler H, et al. A murine model of myocardial microvascular thrombosis. J Clin Invest. 1999;104:533-539.
18. Maroney SA, Cooley BC, Sood R, Weiler H, Mast AE. Combined tissue factor pathway inhibitor and thrombomodulin deficiency produces an augmented hypercoagulable state with tissue-specific fbrin deposition. J Thromb Haemost. 2008;6:111-117.
19. Kim JH, Kim JH, Park JA, Lee SW, Kim WJ, Yu YS, et al. Bloodneural barrier: intercellular communication at glio-vascular interface. J Biochem Mol Biol. 2006;39:339-345.
20. Nachman RL, Rafi S. Platelets, petechiae, and preservation of the vascular wall. N Engl J Med. 2008;359:1261-1270.
21. Butros LJ, Bussel JB. Intracranial hemorrhage in immune thrombocytopenic purpura: a retrospective analysis. J Pediatr Hematol Oncol. 2003;25:660-664.
22. Liu S, Agalliu D, Yu C, Fisher M. The role of pericytes in blood-brain barrier function and stroke. Curr Pharm Des. 2012;18:3653-3662.
23. Maxwell K, Berliner JA, Cancilla PA. Induction of gamma-glutamyl transpeptidase in cultured cerebral endothelial cells by a product released by astrocytes. Brain Res. 1987;410:309-314.
24. Al Ahmad A, Taboada CB, Gassmann M, Ogunshola OO. Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult. J Cereb Blood Flow Metab. 2011;31:693-705.
25. Bonerandi JJ, Bourdet D, Privat Y, Temime P. Kaposi's disease: ultrastructural study of 4 cases. Ann Dermatol Syphilligr (Paris). 1975;102:499-506.
26. Schenk P. Erythrophagocytosis in Kaposi's sarcoma in acquired immune deficiency syndrome. ORL. 1986;48:167-173.
27. Fisher M, French S, Ji P, Kim RC. Cerebral microbleeds in the elderly: a pathological analysis. Stroke. 2010;41:2782-2785.
28. Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010;68:409-427.
29. Ishii H, Salem HH, Bell CE, Laposata EA, Majerus PW. Thrombomodulin, an endothelial anticoagulant protein, is absent from the human brain. Blood. 1986;67:362-365.
30. Wong VL, Hofman FM, Ishii H, Fisher M. Regional distribution of thrombomodulin in human brain. Brain Res. 1991;556:1-5.
31. Tran N, Wong VLY, Schreiber SS, Bready J, Fisher M. Regulation of brain capillary endothelial thrombomodulin mRNA expression. Stroke. 1996;27:2304-2311.
32. Tran ND, Correale J, Schreiber SS, Fisher M. Transforming growth factor-beta mediates astrocyte-specific regulation of brain endothelial anticoagulant factors. Stroke. 1999;30:1671-1678.
33. Giwa MO, Williams J, Elderfield K, Jiwa NS, Bridges LR, Kalaria RN, et al. Neuropathologic evidence of endothelial changes in cerebral small vessel disease. Neurology. 2012;78:167-174.
34. Montes R, Puy C, Molina E, Hermida J. Is EPCR a multi-ligand receptor? Pros and cons. Thromb Haemost. 2012;107:815-826.
35. Laszik Z, Mitro A, Taylor FB Jr, Ferrell G, Esmon CT. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation. 1997;96:3633-3640.
36. Levin EG, del Zoppo GJ. Localization of tissue plasminogen activator in the endothelium of a limited number of vessels. Am J Pathol. 1994;144:855-861.
37. Shatos MA, Orfeo T, Doherty JM, Penar PL, Collen D, Mann KG. Alpha-thrombin stimulates urokinase production and DNA synthesis in cultured human cerebral microvascular endothelial cells. Arterioscler Thromb Vasc Biol. 1995;15:903-911.
38. Grau GE, de Moerloose P, Bulla O, Lou J, Lei Z, Reber G, et al. Haemostatic properties of human pulmonary and cerebral microvascular endothelial cells. Thromb Haemost. 1997;77:585-590.
39. Tran ND, Schreiber SS, Fisher M. Astrocyte regulation of endothelial tissue plasminogen activator in a blood-brain barrier model. J Cereb Blood Flow Metab. 1998;18:1316-1324.
40. Kim JA, Wang SJ, Fisher MJ. Astrocyte regulation of human brain capillary endothelial fibrinolysis. Thromb Res. 2003;112:159-165.
41. Yang F, Liu S, Wang SJ, Yu C, Paganini-Hill A, Fisher MJ. Tissue plasminogen activator expression and barrier properties of human brain microvascular endothelial cells. Cell Physiol Biochem. 2011;28:631-638.
42. Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. J Clin Invest. 1991;88:1346-1353.
43. Hultman K, Björklund U, Hansson E, Jern C. Potentiating effect of endothelial cells on astrocytic plasminogen activator inhibitor type-1 gene expression in an in vitro model of the blood-brain barrier. Neuroscience. 2010;166:408-415.
44. Drake TA, Morrissey JH, Edgington TS. Selective cellular expression of tissue factor in human tissues: Implications for disorders of hemostasis and thrombosis. Am J Pathol. 1989;134:1087-1097.
45. Fleck RA, Rao LJM, Rapaport SI, Varki N. Localization of human tissue factor antigen by immunostaining with monspecific, polyclonal antihuman tissue factor antibody. Thromb Res. 1990;57:765-782.
46. Eddleston M, de la Torre JC, Oldstone MB, Loskutoff DJ, Edgington TS, Mackman N. Astrocytes are the primary source of tissue factor in the murine central nervous system. A role for astrocytes in cerebral hemostasis. J Clin Invest. 1993;92:349-358.
47. Bouchard BA, Shatos MA, Tracy PB. Human brain pericytes differentially regulate expression of procoagulant enzyme complexes comprising the extrinsic pathway of blood coagulation. Arterioscler Thromb Vasc Biol. 1997;17:1-9.
48. Bajaj MS, Kuppuswamy MN, Manepalli AN, Bajaj SP. Transcriptional expression of tissue factor pathway inhibitor, thrombomodulin and von Willebrand factor in normal human tissues. Thromb Haemost. 1999;82:1047-1052.
49. Xu Y, Slayter HS. Immunocytochemical localization of endogenous antithrombin III in the vasculature of rat tissues reveals locations of anticoagulantly active heparan sulfate proteoglycans. J Histochem Cytochem. 1994;42:1365-1376.
50. Richard B, Arocas V, Guillin MC, Michel JB, Jandrot-Perrus M, Bouton MC. Protease nexin-1: a cellular serpin down-regulated by thrombin in rat aortic smooth muscle cells. J Cell Physiol. 2004;201:138-145.
51. Kim JA, Tran ND, Li Z, Yang F, Zhou W, Fisher MJ. Brain endothelial hemostasis regulation by pericytes. J Cereb Blood Flow Metab. 2006;26:209-217.
52. Choi BH, Suzuki M, Kim T, Wagner SL, Cunningham DD. Protease nexin-1. Localization in the human brain suggests a protective role against extravasated serine proteases. Am J Pathol. 1990;137:741-747.
53. Broos K, Feys HB, De Meyer SF, Vanhoorelbeke K, Deckmyn H. Platelets at work in primary hemostasis. Blood Rev. 2011;25:155-167.
54. Siegle I, Klein T, Zou MH, Fritz P, Kömhoff M. Distribution and cellular localization of prostacyclin synthase in human brain. J Histochem Cytochem. 2000;48:631-641.
55. Tone Y, Inoue H, Hara S, Yokoyama C, Hatae T, Oida H, et al. The regional distribution and cellular localization of mRNA encoding rat prostacyclin synthase. Eur J Cell Biol. 1997;72:268-277.
56. Moore C, Sanz-Rosa D, Emerson M. Distinct role and location of the endothelial isoform of nitric oxide synthase in regulating platelet aggregation in males and females in vivo. Eur J Pharmacol. 2011;651:152-158.
57. Kimura C, Oike M, Ohnaka K, Nose Y, Ito Y. Constitutive nitric oxide production in bovine aortic and brain microvascular endothelial cells: a comparative study. J Physiol. 2004;554(pt 3):721-730.
58. Guillot PV, Guan J, Liu L, Kuivenhoven JA, Rosenberg RD, Sessa WC, et al. A vascular bed-specific pathway regulates cardiac expression of endothelial nitric oxide synthase. J Clin Invest. 1999;103:799-805.
59. Nandigam RN, Viswanathan A, Delgado P, Skehan ME, Smith EE, Rosand J, et al. MR imaging detection of cerebral microbleeds: effect of susceptibility- weighted imaging, section thickness, and field strength. AJNR Am J Neuroradiol. 2009;30:338-343.
60. Poels MM, Vernooij MW, Ikram MA, Hofman A, Krestin GP, van der Lugt A, et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke. 2010;41(10 suppl):S103-S106.
61. Greenberg SM. Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment. Neurology. 1998;51:690-694.
62. *-weighted MRI: correlation with stroke subtype, stroke recurrence, and leukoaraiosis. Stroke. 2002;33:1536-1540.
63. Lee SH, Bae HJ, Ko SB, Kim H, Yoon BW, Roh JK. Comparative analysis of the spatial distribution and severity of cerebral microbleeds and old lacunes. J Neurol Neurosurg Psychiatry. 2004;75:423-427.
64. *-weighted MR images of patients with recurrent stroke: association with combination of stroke subtypes and leukoaraiosis. AJNR Am J Neuroradiol. 2004;25:714-719.
65. Maia LF, Vasconcelos C, Seixas S, Magalhães R, Correia M. Lobar brain hemorrhages and white matter changes: clinical, radiological and laboratorial profiles. Cerebrovasc Dis. 2006;22:155-161.
66. Görner A, Lemmens R, Schrooten M, Thijs V. Is leukoaraiosis on CT an accurate surrogate marker for the presence of microbleeds in acute stroke patients? J Neurol. 2007;254:284-289.
67. Gao T, Wang Y, Zhang Z. Silent cerebral microbleeds on susceptibilityweighted imaging of patients with ischemic stroke and leukoaraiosis. Neurol Res. 2008;30:272-276.
68. Yamada S, Saiki M, Satow T, Fukuda A, Ito M, Minami S, et al. Periventricular and deep white matter leukoaraiosis have a closer association with cerebral microbleeds than age. Eur J Neurol. 2012;19:98-104.
69. Lee SH, Heo JH, Yoon BW. Effects of microbleeds on hemorrhage development in leukoaraiosis patients. Hypertens Res. 2005;28:895-899.
70. Pettersen JA, Sathiyamoorthy G, Gao FQ, Szilagyi G, Nadkarni NK, St George-Hyslop P, et al. Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. Arch Neurol. 2008;65:790-795.
71. Jeon SB, Kwon SU, Cho AH, Yun SC, Kim JS, Kang DW. Rapid appearance of new cerebral microbleeds after acute ischemic stroke. Neurology. 2009;73:1638-1644.
72. *-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol. 1999;20:637-642.
73. Schrag M, McAuley G, Pomakian J, Jiffry A, Tung S, Mueller C, et al. Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study. Acta Neuropathol. 2010;119:291-302.
74. Fan YH, Zhang L, Lam WW, Mok VC, Wong KS. Cerebral microbleeds as a risk factor for subsequent intracerebral hemorrhages among patients with acute ischemic stroke. Stroke. 2003;34:2459-2462.
75. Greenberg SM, Nandigam RN, Delgado P, Betensky RA, Rosand J, Viswanathan A, et al. Microbleeds versus macrobleeds: evidence for distinct entities. Stroke. 2009;40:2382-2386.
76. Young VG, Halliday GM, Kril JJ. Neuropathologic correlates of white matter hyperintensities. Neurology. 2008;71:804-811.
77. Back SA, Kroenke CD, Sherman LS, Lawrence G, Gong X, Taber EN, et al. White matter lesions defined by diffusion tensor imaging in older adults. Ann Neurol. 2011;70:465-476.
78. Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease-systematic review and meta-analysis. Neurobiol Aging. 2009;30:337-352.
79. Popescu BO, Toescu EC, Popescu LM, Bajenaru O, Muresanu DF, Schultzberg M, et al. Blood-brain barrier alterations in ageing and dementia. J Neurol Sci. 2009;283:99-106.
80. Pires PW, Dams Ramos CM, Matin N, Dorrance AM. The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol. 2013;304:H1598-H1614.
81. Carrano A, Hoozemans JJ, van der Vies SM, van Horssen J, de Vries HE, Rozemuller AJ. Neuroinflammation and blood-brain barrier changes in capillary amyloid angiopathy. Neurodegener Dis. 2012;10:329-331.
82. Kallenberg K, Dehnert C, Dörfler A, Schellinger PD, Bailey DM, Knauth M, et al. Microhemorrhages in nonfatal high-altitude cerebral edema. J Cereb Blood Flow Metab. 2008;28:1635-1642.
83. Cullen KM, Kócsi Z, Stone J. Pericapillary haem-rich deposits: evidence for microhaemorrhages in aging human cerebral cortex. J Cereb Blood Flow Metab. 2005;25:1656-1667.
84. Cullen KM, Kócsi Z, Stone J. Microvascular pathology in the aging human brain: evidence that senile plaques are sites of microhaemorrhages. Neurobiol Aging. 2006;27:1786-1796.
85. De Reuck J, Deramecourt V, Cordonnier C, Leys D, Pasquier F, Maurage CA. Prevalence of small cerebral bleeds in patients with a neurodegenerative dementia: a neuropathological study. J Neurol Sci. 2011;300:63-66.
86. Tanskanen M, Mäkelä M, Myllykangas L, Rastas S, Sulkava R, Paetau A. Intracerebral hemorrhage in the oldest old: a population-based study (vantaa 85+). Front Neurol. 2012;3:103.
87. Kumar P, Shen Q, Pivetti CD, Lee ES, Wu MH, Yuan SY. Molecular mechanisms of endothelial hyperpermeability: implications in inflammation. Expert Rev Mol Med. 2009;11:e19.
88. Fisher M, Vasilevko V, Passos GF, Ventura C, Quiring D, Cribbs DH. Therapeutic modulation of cerebral microhemorrhage in a mouse model of cerebral amyloid angiopathy. Stroke. 2011;42:3300-3303.
89. Fisher M. The challenge of mixed cerebrovascular disease. Ann N Y Acad Sci. 2010;1207:18-22.
90. Fisher M, Vasilevko V, Cribbs DH. Mixed cerebrovascular disease and the future of stroke prevention. Transl. Stroke Res. 2012;3(suppl 1):S39-S51.
91. Vermeer SE, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM. Prevalence and risk factors of silent brain infarcts in the populationbased Rotterdam Scan Study. Stroke. 2002;33:21-25.
92. Longstreth WT Jr, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. Stroke. 1996;27:1274-1282.
93. Biffi A, Halpin A, Towfighi A, Gilson A, Busl K, Rost N, et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy. Neurology. 2010;75:693-698.
94. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA. 1998;280:1930-1935.
95. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al; MATCH Investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337.
96. Wong KS, Chan YL, Liu JY, Gao S, Lam WW. Asymptomatic microbleeds as a risk factor for aspirin-associated intracerebral hemorrhages. Neurology. 2003;60:511-513.
97. Flaherty ML. Anticoagulant-associated intracerebral hemorrhage. Semin Neurol. 2010;30:565-572.
98. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
99. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.
100. *-weighted MR images and recurrent hemorrhagic stroke in patients treated with warfarin following ischemic stroke. AJNR Am J Neuroradiol. 2008;29:1483-1486.
101. Lee SH, Ryu WS, Roh JK. Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage. Neurology. 2009;72:171-176.
102. Lovelock CE, Cordonnier C, Naka H, Al-Shahi Salman R, Sudlow CL, Sorimachi T, et al; Edinburgh Stroke Study Group. Antithrombotic drug use, cerebral microbleeds, and intracerebral hemorrhage: a systematic review of published and unpublished studies. Stroke. 2010;41:1222-1228.
103. Smith EE, Rosand J, Knudsen KA, Hylek EM, Greenberg SM. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology. 2002;59:193-197.
104. Qiu C, Cotch MF, Sigurdsson S, Jonsson PV, Jonsdottir MK, Sveinbjrnsdottir S, et al. Cerebral microbleeds, retinopathy, and dementia: the AGES-Reykjavik Study. Neurology. 2010;75:2221-2228.
105. Takashima Y, Mori T, Hashimoto M, Kinukawa N, Uchino A, Yuzuriha T, et al. Clinical correlating factors and cognitive function in community-dwelling healthy subjects with cerebral microbleeds. J Stroke Cerebrovasc Dis. 2011;20:105-110.
106. van Es AC, van der Grond J, de Craen AJ, Westendorp RG, Bollen EL, Blauw GJ, et al; PROSPER Study Group. Cerebral microbleeds and cognitive functioning in the PROSPER study. Neurology. 2011;77:1446-1452.
107. Poels MM, Ikram MA, van der Lugt A, Hofman A, Niessen WJ, Krestin G P, et al. Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study. Neurology. 2012;78:326-333.
108. Lin S, Yin Q, Zhong Q, Lv FL, Zhou Y, Li JQ, et al. Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage. J Neuroinflammation. 2012;9:46.
109. Vernooij MW, Haag MD, van der Lugt A, Hofman A, Krestin GP, Stricker BH, et al. Use of antithrombotic drugs and the presence of cerebral microbleeds: the Rotterdam Scan Study. Arch Neurol. 2009;66:714-720.
110. Ge L, Niu G, Han X, Gao Y, Wu Q, Wu H, et al. Aspirin treatment increases the risk of cerebral microbleeds. Can J Neurol Sci. 2011;38:863-868.
111. Gresele P, Momi S, Falcinelli E. Anti-platelet therapy: phosphodiesterase inhibitors. Br J Clin Pharmacol. 2011;72:634-646.
112. Rubin LL, Hall DE, Porter S, Barbu K, Cannon C, Horner HC, et al. A cell culture model of the blood-brain barrier. J Cell Biol. 1991;115:1725-1735.
113. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1-13.
114. Gotoh F, Tohgi H, Hirai S, Terashi A, Fukuuchi Y, Otomo E, et al. Cilostazol stroke prevention study: A placebo controlled double-blind trial for secondary prevention of cerebral infarction. J Stroke Cerebrovasc Dis. 2000;9:147-157.
115. Huang Y, Cheng Y, Wu J, Li Y, Xu E, Hong Z, et al; Cilostazol versus Aspirin for Secondary Ischaemic Stroke Prevention Cooperation Investigators. Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol. 2008;7:494-499.
116. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, et al; CSPS 2 Group. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised noninferiority trial. Lancet Neurol. 2010;9:959-968.
117. Kim HH, Liao JK. Translational therapeutics of dipyridamole. Arterioscler Thromb Vasc Biol. 2008;28:s39-s42.
118. García-Bonilla L, Sosti V, Campos M, Penalba A, Boada C, Sumalla M, et al. Effects of acute post-treatment with dipyridamole in a rat model of focal cerebral ischemia. Brain Res. 2011;1373:211-220.
119. Liu S, Yu C, Yang F, Paganini-Hill A, Fisher MJ. Phosphodiesterase inhibitor modulation of brain microvascular endothelial cell barrier properties. J Neurol Sci. 2012;320:45-51.
120. Hase Y, Okamoto Y, Fujita Y, Kitamura A, Nakabayashi H, Ito H, et al. Cilostazol, a phosphodiesterase inhibitor, prevents no-reflow and hemorrhage in mice with focal cerebral ischemia. Exp Neurol. 2012;233:523-533.
121. Kasahara Y, Nakagomi T, Matsuyama T, Stern D, Taguchi A. Cilostazol reduces the risk of hemorrhagic infarction after administration of tissue-type plasminogen activator in a murine stroke model. Stroke. 2012;43:499-506.
122. Liu S, Vasilevko V, Cribbs DH, Fisher M. A mouse model of cerebral microbleeds. Stroke. 2013;44:AWP297.
123. Westover MB, Bianchi MT, Yang C, Schneider JA, Greenberg SM. Estimating cerebral microinfarct burden from autopsy samples. Neurology. 2013;80:1365-1369.
124. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. Stroke. 2009;40:2276-2293.