Hemorrhagic Transformation after Tissue Plasminogen Activator Reperfusion Therapy for Ischemic Stroke: Mechanisms, Models, and Biomarkers

Molecular Neurobiology

Volumn 52, Issue 3, 2015, Pages 1572-1579

  Wang, Wei ^a   Li, Mingchang ^a   Chen, Qianxue ^a   Wang, Jian ^b  

^a RENMIN HOSPITAL OF WUHAN UNIVERSITY   (China)

^b JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Blood brain barrier; Hemorrhagic transformation; Ischemic stroke; Tissue plasminogen activator

Indexed keywords

ADENOSINE TRIPHOSPHATASE (POTASSIUM SODIUM); BIOLOGICAL MARKER; CYTOPLASM PROTEIN; GELATINASE A; GELATINASE B; INTERLEUKIN 1; INTERLEUKIN 6; INTERLEUKIN 8; MONOCYTE CHEMOTACTIC PROTEIN 1; N METHYL DEXTRO ASPARTIC ACID; N METHYL DEXTRO ASPARTIC ACID NR1; PLASMINOGEN ACTIVATOR INHIBITOR 1; PROTEIN S100B; STROMELYSIN; THROMBIN ACTIVATABLE FIBRINOLYSIS INHIBITOR; TISSUE PLASMINOGEN ACTIVATOR; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; CPB2 PROTEIN, HUMAN; FIBRINOLYTIC AGENT; ISOPROSTANE DERIVATIVE; MATRIX METALLOPROTEINASE; NERVE PROTEIN; SERPINE1 PROTEIN, HUMAN;

APOPTOSIS; ASTROCYTE; BLOOD BRAIN BARRIER; BLOOD CLOT LYSIS; BRAIN HEMORRHAGE; BRAIN INFARCTION SIZE; BRAIN ISCHEMIA; BRAIN PERFUSION; COMPUTER ASSISTED TOMOGRAPHY; CYTOKINE RELEASE; DISEASE MODEL; DISEASE SEVERITY; DRUG ACTIVITY; ENDOTHELIAL DYSFUNCTION; ENZYME ACTIVATION; ENZYME INHIBITION; FIBRINOLYTIC THERAPY; HUMAN; INTRACEREBRAL HEMORRHAGIC TRANSFORMATION; MICROGLIA; MIDDLE CEREBRAL ARTERY OCCLUSION; NERVE CELL NECROSIS; NEUTROPHIL CHEMOTAXIS; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OXIDATIVE STRESS; PROTEIN BLOOD LEVEL; PROTEIN CLEAVAGE; PROTEIN DEGRADATION; PROTEIN EXPRESSION; REPERFUSION; REPERFUSION THERAPY; REVIEW; ADVERSE EFFECTS; ANIMAL; BIOLOGICAL MODEL; BLOOD; CEREBRAL HEMORRHAGE; CHEMICALLY INDUCED; COMPLICATION; DRUG EFFECTS; EARLY DIAGNOSIS; ENZYMOLOGY; MACROPHAGE ACTIVATION; MOUSE; NEUROIMAGING; PATHOPHYSIOLOGY; PHYSIOLOGY; VASCULAR ENDOTHELIUM;

ANIMALS; ASTROCYTES; BIOMARKERS; BLOOD-BRAIN BARRIER; BRAIN ISCHEMIA; CARBOXYPEPTIDASE B2; CEREBRAL HEMORRHAGE; CHEMOTAXIS, LEUKOCYTE; DISEASE MODELS, ANIMAL; EARLY DIAGNOSIS; ENDOTHELIUM, VASCULAR; F2-ISOPROSTANES; FIBRINOLYTIC AGENTS; HUMANS; MACROPHAGE ACTIVATION; MATRIX METALLOPROTEINASES; MICE; MICROGLIA; MODELS, NEUROLOGICAL; NERVE TISSUE PROTEINS; NEUROIMAGING; OXIDATIVE STRESS; PLASMINOGEN ACTIVATOR INHIBITOR 1; THROMBOLYTIC THERAPY; TISSUE PLASMINOGEN ACTIVATOR;

EID: 84942837592     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-014-8952-x     Document Type: Review

References (99)

1. Sumii T, Lo EH (2002) Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 33(3):831–836
2. Wang X, Lo EH (2003) Triggers and mediators of hemorrhagic transformation in cerebral ischemia. Mol Neurobiol 28(3):229–244
3. Nour M, Scalzo F, Liebeskind DS (2013) Ischemia-reperfusion injury in stroke. Interv Neurol 1(3–4):185–199
4. Hong JM, Lee JS, Song HJ et al (2014) Therapeutic hypothermia after recanalization in patients with acute ischemic stroke. Stroke 45(1):134–140
5. Jickling GC, Liu D, Stamova B et al (2014) Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab 34(2):185–199
6. Tilley BCLP, Brott TG, Lu M et al (1997) Total quality improvement method for reduction of delays between emergency department admission and treatment of acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Arch Neurol 54(12):1466–1474
7. Rosell A, Foerch C, Murata Y et al (2008) Mechanisms and markers for hemorrhagic transformation after stroke. Acta Neurochir Suppl 105:173–178
8. Lee SR, Wang X, Tsuji K et al (2004) Extracellular proteolytic pathophysiology in the neurovascular unit after stroke. Neurol Res 26(8):854–861
9. del Zoppo GJ, Mabuchi T (2003) Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab 23(8):879–894
10. Lo EH, Broderick JP, Moskowitz MA (2004) tPA and proteolysis in the neurovascular unit. Stroke 35(2):354–356
11. Zan L, Zhang X, Xi Y et al (2014) Src regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion. Neuroscience 262:118–128
12. Rosell ACE, Ortega-Aznar A, Hernández-Guillamon M et al (2008) MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 39(4):1121–1126
13. Rosenberg GA (2002) Matrix metalloproteinases in neuroinflammation. Glia 39(3):279–291
14. Rosell A, Ortega-Aznar A, Alvarez-Sabin J et al (2006) Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke 37(6):1399–1406
15. Suofu Y, Clark JF, Broderick JP et al (2012) Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience 212:180–189
16. Lu ASY, Guan F, Broderick JP et al (2013) Matrix metalloproteinase-2 deletions protect against hemorrhagic transformation after 1 h of cerebral ischemia and 23 h of reperfusion. Neuroscience 253:361–367
17. Inzitari D GB, Nencini P, Gori AM, Nesi M, Palumbo V, Piccardi B, Armillis A, Pracucci G, Bono G, Bovi P, Consoli D, Guidotti M, Nucera A, Massaro F, Micieli G, Orlandi G, Perini F, Tassi R, Tola MR, Sessa M, Toni D, Abbate R; MAGIC Study Group (2013) MMP9 variation after thrombolysis is associated with hemorrhagic transformation of lesion and death. Stroke 44(10):2901–2903
18. ElAli A, Doeppner TR, Zechariah A et al (2011) Increased blood-brain barrier permeability and brain edema after focal cerebral ischemia induced by hyperlipidemia: role of lipid peroxidation and calpain-1/2, matrix metalloproteinase-2/9, and RhoA overactivation. Stroke 42(11):3238–3244
19. Graham CA, Chan RW, Chan DY et al (2012) Matrix metalloproteinase 9 mRNA: an early prognostic marker for patients with acute stroke. Clin Biochem 45(4–5):352–355
20. Demir RUH, Özel L, Özdemir G et al (2012) Relationship between plasma metalloproteinase-9 levels and volume and severity of infarct in patients with acute ischemic stroke. Acta Neurol Belg 112(4):351–356
21. Jha R, Battey TW, Pham L et al (2014) Fluid-attenuated inversion recovery hyperintensity correlates with matrix metalloproteinase-9 level and hemorrhagic transformation in acute ischemic stroke. Stroke 45(4):1040–1045
22. Rodríguez JAST, Orbe J, Purroy A et al (2013) proMetalloproteinase-10 is associated with brain damage and clinical outcome in acute ischemic stroke. J Thromb Haemost 11(8):1464–1473
23. Liu DCT, Guo H, Fernández JA et al (2004) Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat Med 10(12):1379–1383
24. Nicole O, Docagne F, Ali C et al (2001) The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nat Med 7(1):59–64
25. Wang X, Lee SR, Arai K et al (2003) Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med 9(10):1313–1317
26. Chen F, Ohashi N, Li W et al (2009) Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure. Hepatology 50(6):1914–1923
27. Planas AM, Sole S, Justicia C (2001) Expression and activation of matrix metalloproteinase-2 and -9 in rat brain after transient focal cerebral ischemia. Neurobiol Dis 8(5):834–846
28. Kaplan RC, Smith NL, Zucker S et al (2008) Matrix metalloproteinase-3 (MMP3) and MMP9 genes and risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke. Atherosclerosis 201(1):130–137
29. Adibhatla RM, Hatcher JF (2008) Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol Disord Drug Targets 7(3):243–253
30. Tsirka SE, Rogove AD, Bugge TH et al (1997) An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J Neurosci 17(2):543–552
31. Siao CJ, Fernandez SR, Tsirka SE (2003) Cell type-specific roles for tissue plasminogen activator released by neurons or microglia after excitotoxic injury. J Neurosci 23(8):3234–3242
32. Vivien D, Gauberti M, Guedin P et al (2009) Cerebral ischemia (2), how to neutralize the neurotoxic effects of tPA. Med Sci (Paris) 25(10):855–857
33. Pang PT, Lu B (2004) Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF. Ageing Res Rev 3(4):407–430
34. Kanazawa M, Igarashi H, Kawamura K et al (2011) Inhibition of VEGF signaling pathway attenuates hemorrhage after tPA treatment. J Cereb Blood Flow Metab 31(6):1461–1474
35. Zan L, Wu H, Jiang J et al (2011) Temporal profile of Src, SSeCKS, and angiogenic factors after focal cerebral ischemia: correlations with angiogenesis and cerebral edema. Neurochem Int 58(8):872–879
36. Wang J, Tsirka SE (2005) Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 128(Pt 7):1622–1633
37. Ishiguro MKK, Suzuki Y, Ishizuka F et al (2012) A rho kinase (ROCK) inhibitor, fasudil, prevents matrix metalloproteinase-9 related hemorrhagic transformation in mice treated with tissue plasminogen activator. Neuroscience 220:302–312
38. Switzer JAHD, Ergul A, Waller JL et al (2011) Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke 42(9):2633–2635
39. Cui J, Chen S, Zhang C et al (2012) Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia. Mol Neurodegener 7:21
40. Hu Q, Chen C, Khatibi NH et al (2011) Lentivirus-mediated transfer of MMP-9 shRNA provides neuroprotection following focal ischemic brain injury in rats. Brain Res 1367:347–359
41. Souvenir R, Fathali N, Ostrowski RP et al (2011) Tissue inhibitor of matrix metalloproteinase-1 mediates erythropoietin-induced neuroprotection in hypoxia ischemia. Neurobiol Dis 44(1):28–37
42. Chaturvedi M, Figiel I, Sreedhar B et al (2012) Neuroprotection from tissue inhibitor of metalloproteinase-1 and its nanoparticles. Neurochem Int 61(7):1065–1071
43. Hu Q, Chen C, Yan J et al (2009) Therapeutic application of gene silencing MMP-9 in a middle cerebral artery occlusion-induced focal ischemia rat model. Exp Neurol 216(1):35–46
44. Asahi M, Asahi K, Wang X et al (2000) Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab 20(3):452–457
45. Gursoy-Ozdemir Y, Can A, Dalkara T (2004) Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke 35(6):1449–1453
46. Krizanac-Bengez L, Hossain M, Fazio V et al (2006) Loss of flow induces leukocyte-mediated MMP/TIMP imbalance in dynamic in vitro blood-brain barrier model: role of pro-inflammatory cytokines. Am J Physiol Cell Physiol 291(4):C740–C749
47. Hartz AM, Bauer B, Soldner EL et al (2012) Amyloid-beta contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy. Stroke 43(2):514–523
48. Enciu AMGM, Popescu BO (2013) Triggers and effectors of oxidative stress at blood-brain barrier level: relevance for brain ageing and neurodegeneration. Oxid Med Cell Longev 2013:297512
49. Lochhead JJ, McCaffrey G, Quigley CE et al (2010) Oxidative stress increases blood-brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenation. J Cereb Blood Flow Metab 30(9):1625–1636
50. Welsh P, Lowe GD, Chalmers J et al (2008) Associations of proinflammatory cytokines with the risk of recurrent stroke. Stroke 39(8):2226–2230
51. Dimitrijevic OB, Stamatovic SM, Keep RF et al (2006) Effects of the chemokine CCL2 on blood-brain barrier permeability during ischemia-reperfusion injury. J Cereb Blood Flow Metab 26(6):797–810
52. Vinters HV (1987) Cerebral amyloid angiopathy. A critical review. Stroke 18(2):311–324
53. Bevilacqua MP (1993) Endothelial-leukocyte adhesion molecules. Annu Rev Immunol 11:767–804
54. Wang J (2010) Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol 92(4):463–477
55. Murata Y, Rosell A, Scannevin RH et al (2008) Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 39(12):3372–3377
56. Harris AKEA, Kozak A, Machado LS et al (2005) Effect of neutrophil depletion on gelatinase expression, edema formation and hemorrhagic transformation after focal ischemic stroke. BMC Neurosci 3(6):49
57. Xing Y, Guo ZN, Yan S et al (2014) Increased globulin and its association with hemorrhagic transformation in patients receiving intra-arterial thrombolysis therapy. Neurosci Bull 30(3):469–476
58. Wang J, Dore S (2007) Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 27(5):894–908
59. Li YN, Pan R, Qin XJ et al (2014) Ischemic neurons activate astrocytes to disrupt endothelial barrier via increasing VEGF expression. J Neurochem 129(1):120–129
60. Milner RC SJ, Hung S (2007) Fibronectin- and vitronectin-induced microglial activation and matrix metalloproteinase-9 expression is mediated by integrins alpha5beta1 and alphavbeta5. J Immunol 178(12):8158–8167
61. Del ZGF H, Gu YH (2012) Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab 32(5):919–932
62. Durukan A, Tatlisumak T (2009) Animal models of ischemic stroke. Handb Clin Neurol 92:43–66
63. Hs HA (2008) Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review. J Cereb Blood Flow Metab 28(12):1877–1891
64. Wells AJ, Vink R, Blumbergs PC et al (2012) A surgical model of permanent and transient middle cerebral artery stroke in the sheep. PLoS One 7(7):e42157
65. Namura S, Zhu J, Fink K et al (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18(10):3659–3668
66. Hermann DMKE, Hata R, Hossmann KA et al (2001) Relationship between metabolic dysfunctions, gene responses and delayed cell death after mild focal cerebral ischemia in mice. Neuroscience 104(4):947–955
67. Hata R, Maeda K, Hermann D et al (2000) Evolution of brain infarction after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 20(6):937–946
68. Rosito M, Lauro C, Chece G et al (2014) Transmembrane chemokines CX3CL1 and CXCL16 drive interplay between neurons, microglia and astrocytes to counteract pMCAO and excitotoxic neuronal death. Front Cell Neurosci 8:193
69. Liu Z, He D, Zhang X et al (2012) Neuroprotective effect of early and short-time applying sophoridine in pMCAO rat brain: down-regulated TRAF6 and up-regulated p-ERK1/2 expression, ameliorated brain infarction and edema. Brain Res Bull 88(4):379–384
70. Campos F, Qin T, Castillo J et al (2013) Fingolimod reduces hemorrhagic transformation associated with delayed tissue plasminogen activator treatment in a mouse thromboembolic model. Stroke 44(2):505–511
71. Pfeilschifter W, Spitzer D, Czech-Zechmeister B et al (2011) Increased risk of hemorrhagic transformation in ischemic stroke occurring during warfarin anticoagulation: an experimental study in mice. Stroke 42(4):1116–1121
72. Pfeilschifter W, Spitzer D, Pfeilschifter J et al (2011) Warfarin anticoagulation exacerbates the risk of hemorrhagic transformation after rt-PA treatment in experimental stroke: therapeutic potential of PCC. PLoS One 6(10):e26087
73. Ito A, Niizuma K, Shimizu H et al (2014) SMTP-7, a new thrombolytic agent, decreases hemorrhagic transformation after transient middle cerebral artery occlusion under warfarin anticoagulation in mice. Brain Res 1578:38–48
74. Kitashoji A, Egashira Y, Mishiro K et al (2013) Cilostazol ameliorates warfarin-induced hemorrhagic transformation after cerebral ischemia in mice. Stroke 44(10):2862–2868
75. England TJ, Bath PM, Sare GM et al (2010) Asymptomatic hemorrhagic transformation of infarction and its relationship with functional outcome and stroke subtype: assessment from the tinzaparin in acute ischaemic stroke trial. Stroke 41(12):2834–2839
76. Zhao R, Feng XY, Zhang M et al (2014) Progressive hemorrhagic transformation following dual antiplatelet therapy. CNS Neurosci Ther 20(1):92–94
77. Garcia-Yebenes I, Sobrado M, Zarruk JG et al (2011) A mouse model of hemorrhagic transformation by delayed tissue plasminogen activator administration after in situ thromboembolic stroke. Stroke 42(1):196–203
78. Dijkhuizen RM, Asahi M, Wu O et al (2002) Rapid breakdown of microvascular barriers and subsequent hemorrhagic transformation after delayed recombinant tissue plasminogen activator treatment in a rat embolic stroke model. Stroke 33(8):2100–2104
79. Tissue plasminogen activator for acute ischemic stroke (1995) The national institute of neurological disorders and stroke rt-pa stroke study group. N Engl J Med 333(24):1581–1587
80. Wahlgren N, Ahmed N, Davalos A et al (2007) Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 369(9558):275–282
81. Hacke W, Kaste M, Bluhmki E et al (2008) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359(13):1317–1329
82. Furlan A, Higashida R, Wechsler L et al (1999) Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial prolyse in acute cerebral thromboembolism. Jama 282(21):2003–2011
83. Lewandowski CA, Frankel M, Tomsick TA et al (1999) Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke 30(12):2598–2605
84. Broderick JP, Palesch YY, Demchuk AM et al (2013) Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 368(10):893–903
85. Nezu T, Koga M, Nakagawara J et al (2011) Early ischemic change on CT versus diffusion-weighted imaging for patients with stroke receiving intravenous recombinant tissue-type plasminogen activator therapy: stroke acute management with urgent risk-factor assessment and improvement (SAMURAI) rt-PA registry. Stroke 42(8):2196–2200
86. Jaillard A, Cornu C, Durieux A et al (1999) Hemorrhagic transformation in acute ischemic stroke. The MAST-E study MAST-E group. Stroke 30(7):1326–1332
87. Lin KKK, Law M, Babb J et al (2007) Measuring elevated microvascular permeability and predicting hemorrhagic transformation in acute ischemic stroke using first-pass dynamic perfusion CT imaging. AJNR Am J Neuroradiol 28(7):1292–1298
88. Neeb L, Villringer K, Galinovic I et al (2013) Adapting the computed tomography criteria of hemorrhagic transformation to stroke magnetic resonance imaging. Cerebrovasc Dis Extra 3(1):103–110
89. Bokura H, Saika R, Yamaguchi T et al (2011) Microbleeds are associated with subsequent hemorrhagic and ischemic stroke in healthy elderly individuals. Stroke 42(7):1867–1871
90. Fiehler J AG, Boulanger JM, Derex L, Gass A, Hjort N, Kim JS, Liebeskind DS, Neumann-Haefelin T, Pedraza S, Rother J, Rothwell P, Rovira A, Schellinger PD, Trenkler J; MR STROKE Group (2007) Bleeding risk analysis in stroke imaging before thromboLysis (BRASIL): pooled analysis of T2*-weighted magnetic resonance imaging data from 570 patients. Stroke 38(10):2738–2744
91. Fan YHZL, Lam WW, Mok VC et al (2003) Cerebral microbleeds as a risk factor for subsequent intracerebral hemorrhages among patients with acute ischemic stroke. Stroke 34(10):2459–2462
92. Moriya Y, Takahashi W, Kijima C et al (2013) Predictors for hemorrhagic transformation with intravenous tissue plasminogen activator in acute ischemic stroke. Tokai J Exp Clin Med 38(1):24–27
93. Kimura K, Aoki J, Shibazaki K et al (2013) New appearance of extraischemic microbleeds on T2*-weighted magnetic resonance imaging 24 hours after tissue-type plasminogen activator administration. Stroke 44(10):2776–2781
94. Scalzo FAJ, Hu X, Saver JL et al (2013) Multi-center prediction of hemorrhagic transformation in acute ischemic stroke using permeability imaging features. Magn Reson Imaging 31(6):961–969
95. Lakhan SE, Kirchgessner A, Tepper D et al (2013) Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke. Front Neurol 4:32
96. Foerch C, Wunderlich MT, Dvorak F et al (2007) Elevated serum S100B levels indicate a higher risk of hemorrhagic transformation after thrombolytic therapy in acute stroke. Stroke 38(9):2491–2495
97. Ribo MMJ, Molina CA, Arenillas JF et al (2004) Admission fibrinolytic profile is associated with symptomatic hemorrhagic transformation in stroke patients treated with tissue plasminogen activator. Stroke 35(9):2123–2127
98. Cocho D, Borrell M, Marti-Fabregas J et al (2006) Pretreatment hemostatic markers of symptomatic intracerebral hemorrhage in patients treated with tissue plasminogen activator. Stroke 37(4):996–999
99. Kelly PJ, Morrow JD, Ning M et al (2008) Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study. Stroke 39(1):100–104