Research progress on the mechanism and predictors of hemorrhagic transformation in acute ischemic stroke_West China Medical Journal

Authors：

YANG Simin , LI Mengjie , FANG He ,  YANG Weimin

Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P. R. China;

Corresponding author：

YANG Weimin, Email: weiminyanghn@163.com

Keywords：

Acute ischemic stroke; hemorrhagic transformation; mechanism; predictor

DOI：

10.7507/1002-0179.202204136

Video：

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Abstract Full text Figures/Tables Video References Cited by

Acute ischemic stroke is the most common type of stroke. Hemorrhagic transformation is one of its serious complications, which may lead to severe neurological deterioration and poor prognosis. The occurrence of hemorrhagic transformation is mainly related to the inflammatory mechanism after infarction, blood-brain barrier injury, ischemia-reperfusion injury and abnormal coagulation function. Identification of early predictors of hemorrhagic transformation can help reduce its incidence and severity. However, the mechanism of hemorrhagic transformation is complex, and there is currently no unified standard for its prediction. This article aims to review the related mechanisms and early predictors of hemorrhagic transformation after stroke, in order to provide a reference for early identification and prevention.

Citation： YANG Simin, LI Mengjie, FANG He, YANG Weimin. Research progress on the mechanism and predictors of hemorrhagic transformation in acute ischemic stroke. West China Medical Journal, 2022, 37(6): 932-936. doi: 10.7507/1002-0179.202204136 Copy

1.	Chen Z, Hu Q, Huo Y, et al. Serum interleukin-33 is a novel predictive biomarker of hemorrhage transformation and outcome in acute ischemic stroke. J Stroke Cerebrovasc Dis, 2021, 30(2): 105506.
2.	Yaghi S, Willey JZ, Cucchiara B, et al. Treatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2017, 48(12): e343-e361.
3.	Petrovic-Djergovic D, Goonewardena SN, Pinsky DJ. Inflammatory disequilibrium in stroke. Circ Res, 2016, 119(1): 142-158.
4.	Zhu Z, Fu Y, Tian D, et al. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation, 2015, 132(12): 1104-1112.
5.	Álvarez-Sabín J, Maisterra O, Santamarina E, et al. Factors influencing haemorrhagic transformation in ischaemic stroke. Lancet Neurol, 2013, 12(7): 689-705.
6.	Chen G, Wang A, Zhao X, et al. Frequency and risk factors of spontaneous hemorrhagic transformation following ischemic stroke on the initial brain CT or MRI: data from the China National Stroke Registry (CNSR). Neurol Res, 2016, 38(6): 538-544.
7.	Guenego A, Lecler A, Raymond J, et al. Hemorrhagic transformation after stroke: inter- and intrarater agreement. Eur J Neurol, 2019, 26(3): 476-482.
8.	Neuberger U, Möhlenbruch MA, Herweh C, et al. Classification of bleeding events: comparison of ECASS Ⅲ (European Cooperative Acute Stroke Study) and the New Heidelberg Bleeding Classification. Stroke, 2017, 48(7): 1983-1985.
9.	Shah K, Clark A, Desai SM, et al. Causes, predictors, and timing of early neurological deterioration and symptomatic intracranial hemorrhage after administration of Ⅳ tPA. Neurocrit Care, 2022, 36(1): 123-129.
10.	Bracard S, Ducrocq X, Mas JL, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol, 2016, 15(11): 1138-1147.
11.	Aljundi ZE, Miyajan EO, Alharbi HA, et al. Incidence, risk factors, clinical presentation, and outcomes of hemorrhagic transformation in patients with ischemic stroke admitted to a tertiary hospital in Kingdom of Saudi Arabia. Neurosciences (Riyadh), 2020, 25(5): 345-349.
12.	Spronk E, Sykes G, Falcione S, et al. Hemorrhagic transformation in ischemic stroke and the role of inflammation. Front Neurol, 2021, 12: 661955.
13.	唐世容, 罗忠, 杨瀚杰, 等. 老年急性脑梗死后非溶栓患者出血转化的相关因素研究. 癫痫与神经电生理学杂志, 2021, 30(6): 359-362.
14.	王莹. 阿替普酶静脉溶栓治疗急性脑梗死及出血转化的相关因素分析. 中国医药指南, 2022(7): 95-97.
15.	Lei YS, Li H, Lei JY, et al. Effect of intravenous thrombolysis in acute ischemic stroke patients with cerebral microbleeds and analysis of risk factors for hemorrhagic transformation. Eur Rev Med Pharmacol Sci, 2022, 26(3): 779-786.
16.	Tu HT, Campbell BC, Christensen S, et al. Worse stroke outcome in atrial fibrillation is explained by more severe hypoperfusion, infarct growth, and hemorrhagic transformation. Int J Stroke, 2015, 10(4): 534-540.
17.	Nagaraja N, Tasneem N, Shaban A, et al. Cerebral microbleeds are an independent predictor of hemorrhagic transformation following intravenous alteplase administration in acute ischemic stroke. J Stroke Cerebrovasc Dis, 2018, 27(5): 1403-1411.
18.	Rodrigues SF, Granger DN. Blood cells and endothelial barrier function. Tissue Barriers, 2015, 3(1/2): e978720.
19.	Chu HX, Kim HA, Lee S, et al. Immune cell infiltration in malignant middle cerebral artery infarction: comparison with transient cerebral ischemia. J Cereb Blood Flow Metab, 2014, 34(3): 450-459.
20.	Jickling GC, Liu D, Ander BP, et al. Targeting neutrophils in ischemic stroke: translational insights from experimental studies. J Cereb Blood Flow Metab, 2015, 35(6): 888-901.
21.	Guruswamy R, ElAli A. Complex roles of microglial cells in ischemic stroke pathobiology: new insights and future directions. Int J Mol Sci, 2017, 18(3): 496.
22.	Lu D, Liu Y, Mai H, et al. Rosuvastatin reduces neuroinflammation in the hemorrhagic transformation after rt-PA treatment in a mouse model of experimental stroke. Front Cell Neurosci, 2018, 12: 225.
23.	del Zoppo GJ, Frankowski H, Gu YH, et al. Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab, 2012, 32(5): 919-932.
24.	Zhang W, Tian T, Gong SX, et al. Microglia-associated neuroinflammation is a potential therapeutic target for ischemic stroke. Neural Regen Res, 2021, 16(1): 6-11.
25.	Arba F, Piccardi B, Palumbo V, et al. Blood-brain barrier leakage and hemorrhagic transformation: the reperfusion injury in ischemic stroke (RISK) study. Eur J Neurol, 2021, 28(9): 3147-3154.
26.	Sadeghian N, Shadman J, Moradi A, et al. Calcitriol protects the blood-brain barrier integrity against ischemic stroke and reduces vasogenic brain edema via antioxidant and antiapoptotic actions in rats. Brain Res Bull, 2019, 150: 281-289.
27.	Jickling GC, Liu D, Stamova B, et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab, 2014, 34(2): 185-199.
28.	Kulik T, Kusano Y, Aronhime S, et al. Regulation of cerebral vasculature in normal and ischemic brain. Neuropharmacology, 2008, 55(3): 281-288.
29.	Song K, Li Y, Zhang H, et al. Oxidative stress-mediated blood-brain barrier (BBB) disruption in neurological diseases. Oxid Med Cell Longev, 2020, 2020(6): 1-27.
30.	Vandelli L, Marietta M, Gambini M, et al. Fibrinogen decrease after intravenous thrombolysis in ischemic stroke patients is a risk factor for intracerebral hemorrhage. J Stroke Cerebrovasc Dis, 2015, 24(2): 394-400.
31.	Yaghi S, Eisenberger A, Willey JZ. Symptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator: a review of natural history and treatment. JAMA Neurol, 2014, 71(9): 1181-1185.
32.	Van Doren SR. Matrix metalloproteinase interactions with collagen and elastin. Matrix Biol, 2015(44/45/46): 224-231.
33.	Vafadari B, Salamian A, Kaczmarek L. MMP-9 in translation: from molecule to brain physiology, pathology, and therapy. J Neurochem, 2016, 139(Suppl 2): 91-114.
34.	Turner RJ, Sharp FR. Implications of MMP9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke. Front Cell Neurosci, 2016, 10: 56.
35.	Zhang R, Wu X, Hu W, et al. Neutrophil-to-lymphocyte ratio predicts hemorrhagic transformation in ischemic stroke: a meta-analysis. Brain Behav, 2019, 9(9): e01382.
36.	杨毅, 张拥波. 外周血粒淋比(NLR)和衍生粒淋比(dNLR)对大动脉粥样硬化型脑梗死出血转化的预测价值研究. 昆明医科大学学报, 2021, 42(11): 33-37.
37.	Wang C, Zhang Q, Ji M, et al. Prognostic value of the neutrophil-to-lymphocyte ratio in acute ischemic stroke patients treated with intravenous thrombolysis: a systematic review and meta-analysis. BMC Neurol, 2021, 21(1): 191.
38.	Shantsila E, Lip GY. Stroke in atrial fibrillation and improving the identification of ‘high-risk’ patients: the crossroads of immunity and thrombosis. J Thromb Haemost, 2015, 13(11): 1968-1970.
39.	Zhu W, Guo Z, Yu S. Higher neutrophil counts before thrombolysis for cerebral ischemia predict worse outcomes. Neurology, 2016, 86(11): 1077.
40.	Krishnamoorthy S, Singh G, Jose K J, et al. Biomarkers in the prediction of hemorrhagic transformation in acute stroke: a systematic review and meta-analysis. Cerebrovasc Dis, 2022, 51(2): 235-247.
41.	Mehrpour M, Mehrpour M. Is the serum ferritin level a considerable predictor for hemorrhagic transformation of ischemic stroke?. Med J Islam Repub Iran, 2016, 30: 363.
42.	García-Yébenes I, García-Culebras A, Peña-Martínez C, et al. Iron overload exacerbates the risk of hemorrhagic transformation after tPA (tissue-type plasminogen activator) administration in thromboembolic stroke mice. Stroke, 2018, 49(9): 2163-2172.
43.	Wang L, Deng L, Yuan R, et al. Association of matrix metalloproteinase 9 and cellular fibronectin and outcome in acute ischemic stroke: a systematic review and meta-analysis. Front Neurol, 2020, 11: 523506.
44.	Purroy F, Farré-Rodriguez J, Mauri-Capdevila G, et al. Basal IL-6 and S100b levels are associated with infarct volume. Acta Neurol Scand, 2021, 144(5): 517-523.
45.	于永华. 急性脑梗死患者静脉溶栓后出现出血转化的危险因素探讨. 吉林医学, 2019, 40(10): 2218-2219.
46.	Gori AM, Giusti B, Piccardi B, et al. Inflammatory and metalloproteinases profiles predict three-month poor outcomes in ischemic stroke treated with thrombolysis. J Cereb Blood Flow Metab, 2017, 37(9): 3253-3261.
47.	Song Q, Wang Y, Cheng Y, et al. Serum uric acid and risk of hemorrhagic transformation in patients with acute ischemic stroke. J Mol Neurosci, 2020, 70(1): 94-101.

1. Chen Z, Hu Q, Huo Y, et al. Serum interleukin-33 is a novel predictive biomarker of hemorrhage transformation and outcome in acute ischemic stroke. J Stroke Cerebrovasc Dis, 2021, 30(2): 105506.
2. Yaghi S, Willey JZ, Cucchiara B, et al. Treatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2017, 48(12): e343-e361.
3. Petrovic-Djergovic D, Goonewardena SN, Pinsky DJ. Inflammatory disequilibrium in stroke. Circ Res, 2016, 119(1): 142-158.
4. Zhu Z, Fu Y, Tian D, et al. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation, 2015, 132(12): 1104-1112.
5. Álvarez-Sabín J, Maisterra O, Santamarina E, et al. Factors influencing haemorrhagic transformation in ischaemic stroke. Lancet Neurol, 2013, 12(7): 689-705.
6. Chen G, Wang A, Zhao X, et al. Frequency and risk factors of spontaneous hemorrhagic transformation following ischemic stroke on the initial brain CT or MRI: data from the China National Stroke Registry (CNSR). Neurol Res, 2016, 38(6): 538-544.
7. Guenego A, Lecler A, Raymond J, et al. Hemorrhagic transformation after stroke: inter- and intrarater agreement. Eur J Neurol, 2019, 26(3): 476-482.
8. Neuberger U, Möhlenbruch MA, Herweh C, et al. Classification of bleeding events: comparison of ECASS Ⅲ (European Cooperative Acute Stroke Study) and the New Heidelberg Bleeding Classification. Stroke, 2017, 48(7): 1983-1985.
9. Shah K, Clark A, Desai SM, et al. Causes, predictors, and timing of early neurological deterioration and symptomatic intracranial hemorrhage after administration of Ⅳ tPA. Neurocrit Care, 2022, 36(1): 123-129.
10. Bracard S, Ducrocq X, Mas JL, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol, 2016, 15(11): 1138-1147.
11. Aljundi ZE, Miyajan EO, Alharbi HA, et al. Incidence, risk factors, clinical presentation, and outcomes of hemorrhagic transformation in patients with ischemic stroke admitted to a tertiary hospital in Kingdom of Saudi Arabia. Neurosciences (Riyadh), 2020, 25(5): 345-349.
12. Spronk E, Sykes G, Falcione S, et al. Hemorrhagic transformation in ischemic stroke and the role of inflammation. Front Neurol, 2021, 12: 661955.
13. 唐世容, 罗忠, 杨瀚杰, 等. 老年急性脑梗死后非溶栓患者出血转化的相关因素研究. 癫痫与神经电生理学杂志, 2021, 30(6): 359-362.
14. 王莹. 阿替普酶静脉溶栓治疗急性脑梗死及出血转化的相关因素分析. 中国医药指南, 2022(7): 95-97.
15. Lei YS, Li H, Lei JY, et al. Effect of intravenous thrombolysis in acute ischemic stroke patients with cerebral microbleeds and analysis of risk factors for hemorrhagic transformation. Eur Rev Med Pharmacol Sci, 2022, 26(3): 779-786.
16. Tu HT, Campbell BC, Christensen S, et al. Worse stroke outcome in atrial fibrillation is explained by more severe hypoperfusion, infarct growth, and hemorrhagic transformation. Int J Stroke, 2015, 10(4): 534-540.
17. Nagaraja N, Tasneem N, Shaban A, et al. Cerebral microbleeds are an independent predictor of hemorrhagic transformation following intravenous alteplase administration in acute ischemic stroke. J Stroke Cerebrovasc Dis, 2018, 27(5): 1403-1411.
18. Rodrigues SF, Granger DN. Blood cells and endothelial barrier function. Tissue Barriers, 2015, 3(1/2): e978720.
19. Chu HX, Kim HA, Lee S, et al. Immune cell infiltration in malignant middle cerebral artery infarction: comparison with transient cerebral ischemia. J Cereb Blood Flow Metab, 2014, 34(3): 450-459.
20. Jickling GC, Liu D, Ander BP, et al. Targeting neutrophils in ischemic stroke: translational insights from experimental studies. J Cereb Blood Flow Metab, 2015, 35(6): 888-901.
21. Guruswamy R, ElAli A. Complex roles of microglial cells in ischemic stroke pathobiology: new insights and future directions. Int J Mol Sci, 2017, 18(3): 496.
22. Lu D, Liu Y, Mai H, et al. Rosuvastatin reduces neuroinflammation in the hemorrhagic transformation after rt-PA treatment in a mouse model of experimental stroke. Front Cell Neurosci, 2018, 12: 225.
23. del Zoppo GJ, Frankowski H, Gu YH, et al. Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab, 2012, 32(5): 919-932.
24. Zhang W, Tian T, Gong SX, et al. Microglia-associated neuroinflammation is a potential therapeutic target for ischemic stroke. Neural Regen Res, 2021, 16(1): 6-11.
25. Arba F, Piccardi B, Palumbo V, et al. Blood-brain barrier leakage and hemorrhagic transformation: the reperfusion injury in ischemic stroke (RISK) study. Eur J Neurol, 2021, 28(9): 3147-3154.
26. Sadeghian N, Shadman J, Moradi A, et al. Calcitriol protects the blood-brain barrier integrity against ischemic stroke and reduces vasogenic brain edema via antioxidant and antiapoptotic actions in rats. Brain Res Bull, 2019, 150: 281-289.
27. Jickling GC, Liu D, Stamova B, et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab, 2014, 34(2): 185-199.
28. Kulik T, Kusano Y, Aronhime S, et al. Regulation of cerebral vasculature in normal and ischemic brain. Neuropharmacology, 2008, 55(3): 281-288.
29. Song K, Li Y, Zhang H, et al. Oxidative stress-mediated blood-brain barrier (BBB) disruption in neurological diseases. Oxid Med Cell Longev, 2020, 2020(6): 1-27.
30. Vandelli L, Marietta M, Gambini M, et al. Fibrinogen decrease after intravenous thrombolysis in ischemic stroke patients is a risk factor for intracerebral hemorrhage. J Stroke Cerebrovasc Dis, 2015, 24(2): 394-400.
31. Yaghi S, Eisenberger A, Willey JZ. Symptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator: a review of natural history and treatment. JAMA Neurol, 2014, 71(9): 1181-1185.
32. Van Doren SR. Matrix metalloproteinase interactions with collagen and elastin. Matrix Biol, 2015(44/45/46): 224-231.
33. Vafadari B, Salamian A, Kaczmarek L. MMP-9 in translation: from molecule to brain physiology, pathology, and therapy. J Neurochem, 2016, 139(Suppl 2): 91-114.
34. Turner RJ, Sharp FR. Implications of MMP9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke. Front Cell Neurosci, 2016, 10: 56.
35. Zhang R, Wu X, Hu W, et al. Neutrophil-to-lymphocyte ratio predicts hemorrhagic transformation in ischemic stroke: a meta-analysis. Brain Behav, 2019, 9(9): e01382.
36. 杨毅, 张拥波. 外周血粒淋比(NLR)和衍生粒淋比(dNLR)对大动脉粥样硬化型脑梗死出血转化的预测价值研究. 昆明医科大学学报, 2021, 42(11): 33-37.
37. Wang C, Zhang Q, Ji M, et al. Prognostic value of the neutrophil-to-lymphocyte ratio in acute ischemic stroke patients treated with intravenous thrombolysis: a systematic review and meta-analysis. BMC Neurol, 2021, 21(1): 191.
38. Shantsila E, Lip GY. Stroke in atrial fibrillation and improving the identification of ‘high-risk’ patients: the crossroads of immunity and thrombosis. J Thromb Haemost, 2015, 13(11): 1968-1970.
39. Zhu W, Guo Z, Yu S. Higher neutrophil counts before thrombolysis for cerebral ischemia predict worse outcomes. Neurology, 2016, 86(11): 1077.
40. Krishnamoorthy S, Singh G, Jose K J, et al. Biomarkers in the prediction of hemorrhagic transformation in acute stroke: a systematic review and meta-analysis. Cerebrovasc Dis, 2022, 51(2): 235-247.
41. Mehrpour M, Mehrpour M. Is the serum ferritin level a considerable predictor for hemorrhagic transformation of ischemic stroke?. Med J Islam Repub Iran, 2016, 30: 363.
42. García-Yébenes I, García-Culebras A, Peña-Martínez C, et al. Iron overload exacerbates the risk of hemorrhagic transformation after tPA (tissue-type plasminogen activator) administration in thromboembolic stroke mice. Stroke, 2018, 49(9): 2163-2172.
43. Wang L, Deng L, Yuan R, et al. Association of matrix metalloproteinase 9 and cellular fibronectin and outcome in acute ischemic stroke: a systematic review and meta-analysis. Front Neurol, 2020, 11: 523506.
44. Purroy F, Farré-Rodriguez J, Mauri-Capdevila G, et al. Basal IL-6 and S100b levels are associated with infarct volume. Acta Neurol Scand, 2021, 144(5): 517-523.
45. 于永华. 急性脑梗死患者静脉溶栓后出现出血转化的危险因素探讨. 吉林医学, 2019, 40(10): 2218-2219.
46. Gori AM, Giusti B, Piccardi B, et al. Inflammatory and metalloproteinases profiles predict three-month poor outcomes in ischemic stroke treated with thrombolysis. J Cereb Blood Flow Metab, 2017, 37(9): 3253-3261.
47. Song Q, Wang Y, Cheng Y, et al. Serum uric acid and risk of hemorrhagic transformation in patients with acute ischemic stroke. J Mol Neurosci, 2020, 70(1): 94-101.

West China Medical Journal

Research progress on the mechanism and predictors of hemorrhagic transformation in acute ischemic stroke

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