Predictive value of liver function and free triiodothyronine levels for hemorrhagic transformation after intravenous thrombolysis in patients with acute ischemic stroke_West China Medical Journal

Authors：

ZHANG Li ,  YANG Weimin , LI Mengjie , ZHANG Zhuo

Department of Neurology, the First Affiliate Hospital of Zhengzhou University, Zhengzhou, Henan 45000, P. R. China;

Corresponding author：

YANG Weimin, Email: weiminyanghn@163.com

Keywords：

Acute stroke; ischemia; thrombolysis; hemorrhagic transformation; influencing factors

DOI：

10.7507/1002-0179.202104258

Video：

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Objective To analyze the influencing factors of hemorrhagic transformation (HT) after intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke (AIS). Methods AIS patients hospitalized in the Department of Neurology of the First Affiliated Hospital of Zhengzhou University between June 2017 and June 2020 and receiving rt-PA intravenous thrombolysis were selected. Patients were divided into two groups according to whether they had HT, HT group and non-HT group. General data such as patient’s age, sex, past history, score of National Institute of Health Stroke Scale (NIHSS) before thrombolysis, and related biochemical examination indicators were collected, to analyze the difference between the patients with HT or not, and analyze the related factors affecting the HT of AIS patients after intravenous thrombolysis. Results A total of patients 323 were included. Among them, 46 cases (14.2%) had HT, and 277 cases (85.8%) had no-HT. Except for serum free triiodothyronine (FT3), atrial fibrillation, hypertension, cerebral infarction area, NIHSS score before thrombolysis, uric acid, blood glucose before thrombolysis, white blood cell count, albumin level, alanine aminotransferase, aspartate aminotransferase / alanine aminotransferase and C-reactive protein (P<0.05), there was no significant difference in other indexes between the two groups (P>0.05). Logistic regression analysis showed that NIHSS score≥13 before thrombolysis, aspartate aminotransferase / alanine aminotransferase, blood glucose before thrombolysis≥12.74 mmol/L, low FT3 level, massive cerebral infarction, and atrial fibrillation were independent risk factors for HT after thrombolysis in AIS. Conclusions FT3 and aspartate aminotransferase / alanine aminotransferase levels may be good biomarkers for predicting HT after intravenous thrombolysis. For patients with reduced albumin and uric acid levels, supplementation of exogenous uric acid and albumin may help reduce the risk of HT after AIS thrombolysis.

Citation： ZHANG Li, YANG Weimin, LI Mengjie, ZHANG Zhuo. Predictive value of liver function and free triiodothyronine levels for hemorrhagic transformation after intravenous thrombolysis in patients with acute ischemic stroke. West China Medical Journal, 2022, 37(12): 1798-1804. doi: 10.7507/1002-0179.202104258 Copy

1.	中华医学会神经病学分会, 中华医学会神经病学分会脑血管病学组, 中国医学科学院北京协和医院神经科, 等. 中国急性缺血性脑卒中诊治指南 2018. 中华神经科杂志, 2018, 51(9): 666-682.
2.	刘雯, 陈国芳, 王琛, 等. 脑白质病变对急性脑梗死 rt-PA 静脉溶栓患者临床预后及出血转化的影响. 神经损伤与功能重建, 2020, 15(5): 281-284.
3.	Xu X, Li C, Wan T, et al. Risk factors for hemorrhagic transformation after intravenous thrombolysis in acute cerebral infarction: a retrospective single-center study. World Neurosurg, 2017, 101: 155-160.
4.	张迎春, 杨谦. 胆红素在缺血性脑梗死中的意义及研究进展. 中国实用神经疾病杂志, 2019, 22(10): 1152-1156.
5.	王红梅, 张婷, 陈静炯, 等. 低 T3 水平与大动脉粥样硬化型脑梗死患者短期预后的关系. 临床荟萃, 2020, 35(6): 517-520.
6.	Yokoyama M, Watanabe T, Otaki Y, et al. Association of the aspartate aminotransferase to alanine aminotransferase ratio with BNP level and cardiovascular mortality in the general population: the Yamagata study 10-year follow-up. Dis Markers, 2016, 2016: 4857917.
7.	吴月, 殷梅. 炎症反应与急性缺血性脑卒中静脉溶栓后出血转化的研究进展. 神经疾病与精神卫生, 2020, 20(12): 890-894.
8.	毛中臣, 孙永, 赵燕, 等. 61 例大面积脑梗死患者的临床资料分析. 深圳中西医结合杂志, 2019, 29(4): 129-130.
9.	Yoo J, Baek JH, Park H, et al. Thrombus volume as a predictor of nonrecanalization after intravenous thrombolysis in acute stroke. Stroke, 2018, 49(9): 2108-2115.
10.	Chen SL, Li JP, Li LF, et al. Elevated preoperative serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio is associated with better prognosis in patients undergoing curative treatment for gastric adenocarcinoma. Int J Mol Sci, 2016, 17(6): 911.
11.	Xing Y, Guo ZN, Yan S, et al. Increased globulin and its association with hemorrhagic transformation in patients receiving intra-arterial thrombolysis therapy. Neurosci Bull, 2014, 30(3): 469-476.
12.	Tan G, Lei C, Hao Z, et al. Liver function may play an uneven role in haemorrhagic transformation for stroke subtypes after acute ischaemic stroke. Eur J Neurol, 2016, 23(3): 597-604.
13.	Wang YY, Lin SY, Chuang YH, et al. Activation of hepatic inflammatory pathways by catecholamines is associated with hepatic insulin resistance in male ischemic stroke rats. Endocrinology, 2014, 155(4): 1235-1246.
14.	Sayre NL, Sifuentes M, Holstein D, et al. Stimulation of astrocyte fatty acid oxidation by thyroid hormone is protective against ischemic stroke-induced damage. J Cereb Blood Flow Metab, 2016, 37(2): 514-527.
15.	da Conceição RR, Laureano-Melo R, Oliveira KC, et al. Antidepressant behavior in thyroidectomized Wistar rats is induced by hippocampal hypothyroidism. Physiol Behav, 2016, 157: 158-164.
16.	Sabbaghziarani F, Mortezaee K, Akbari M, et al. Stimulation of neurotrophic factors and inhibition of proinflammatory cytokines by exogenous application of triiodothyronine in the rat model of ischemic stroke. Cell Biochem Funct, 2017, 35(1): 50-55.
17.	Mokhtari T, Akbari M, Malek F, et al. Improvement of memory and learning by intracerebroventricular microinjection of T3 in rat model of ischemic brain stroke mediated by upregulation of BDNF and GDNF in CA1 hippocampal region. Daru, 2017, 25(1): 4.
18.	Jeong HS, Choi EK, Song IU, et al. Differences in brain glucose metabolism during preparation for ¹³¹I ablation in thyroid cancer patients: thyroid hormone withdrawal versus recombinant human thyrotropin. Thyroid, 2017, 27(1): 23-28.
19.	Bing Y, Zhu S, Jiang K, et al. Reduction of thyroid hormones triggers down-regulation of hepatic CYP2B through nuclear receptors CAR and TR in a rat model of acute stroke. Biochem Pharmacol, 2014, 87(4): 636-649.
20.	Docter R, Krenning EP, de Jong M, et al. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf), 2010, 39(5): 499-518.
21.	Suda S, Muraga K, Kanamaru T, et al. Low free triiodothyronine predicts poor functional outcome after acute ischemic stroke. J Neurol Sci, 2016, 368: 89-93.
22.	Bunevicius A, Iervasi G, Bunevicius R. Neuroprotective actions of thyroid hormones and low-T3 syndrome as a biomarker in acute cerebrovascular disorders. Expert Rev Neurother, 2015, 15(3): 315-326.
23.	Wang Y, Zhou S, Bao J, et al. Low T₃ levels as a predictor marker predict the prognosis of patients with acute ischemic stroke. Int J Neurosci, 2017, 127(7): 559-566.
24.	Wang X, Lo EH. Triggers and mediators of hemorrhagic transformation in cerebral ischemia. Mol Neurobiol, 2003, 28(3): 229-244.
25.	Yang N, Lin M, Wang BG, et al. Low level of low-density lipoprotein cholesterol is related with increased hemorrhagic transformation after acute ischemic cerebral infarction. Eur Rev Med Pharmacol, 2016, 20(4): 673-678.
26.	Yao M, Ni J, Zhou L, et al. Elevated fasting blood glucose is predictive of poor outcome in non-diabetic stroke patients: a sub-group analysis of SMART. PLoS One, 2016, 11(8): e0160674.
27.	张海华, 王素文, 管丽娜. 急诊绿色通道开通对急性缺血性脑卒中患者静脉溶栓效果的影响. 山东医药, 2018, 58(21): 77-79.
28.	Ke X, Wu X, Guo H, et al. Association of ALOX5AP rs10507391/SG13S114 A>T polymorphism with cerebral infarction in the Chinese population: a meta-analysis study. Int J Neurosci, 2015, 125(10): 726-732.
29.	李丽. 脑梗死静脉溶栓治疗后出血性转化及其预后的危险因素分析. 中西医结合心脑血管病杂志, 2015, 13(6): 837-839.
30.	郑伟, 郭莘, 邢效如, 等. 急性脑梗死静脉溶栓后出血性转化发生现状及影响因素研究. 解放军预防医学杂志, 2020, 38(9): 28-30.
31.	陈子龙, 苏宇. 急性缺血性脑卒中患者介入取栓后出血转化的相关危险因素. 卒中与神经疾病, 2020, 27(6): 734-737.
32.	Calleja AI, García-Bermejo P, Cortijo E, et al. Insulin resistance is associated with a poor response to intravenous thrombolysis in acute ischemic stroke. Diabetes Care, 2011, 34(11): 2413-2417.
33.	Johnston KC, Bruno A, Pauls Q, et al. Intensive vs standard treatment of hyperglycemia and functional outcome in patients with acute ischemic stroke: the SHINE randomized clinical trial. JAMA, 2019, 322(4): 326-335.
34.	Squadrito GL, Cueto R, Splenser AE, et al. Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys, 2000, 376(2): 333-337.
35.	Mizuma A, Yenari MA. Anti-inflammatory targets for the treatment of reperfusion injury in stroke. Front Neurol, 2017, 8: 467.
36.	Spitsin SV, Scott GS, Mikheeva T, et al. Comparison of uric acid and ascorbic acid in protection against EAE. Free Radic Biol Med, 2002, 33(10): 1363-1371.
37.	Ruan Y, Yuan C, Liu Y, et al. High fibrinogen-to-albumin ratio is associated with hemorrhagic transformation in acute ischemic stroke patients. Brain Behav, 2021, 11(1): e01855.
38.	Prajapati KD, Sharma SS, Roy N. Current perspectives on potential role of albumin in neuroprotection. Rev Neurosci, 2011, 22(3): 355-363.
39.	Chamorro A, Amaro S, Castellanos M, et al. Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. Lancet Neurol, 2014, 13(5): 453-460.
40.	邹荣成, 王静, 张力. 急性缺血性脑卒中病人静脉溶栓后血清白蛋白水平与出血性转化的关系探讨. 中西医结合心脑血管病杂志, 2019, 17(20): 3108-3111.

1. 中华医学会神经病学分会, 中华医学会神经病学分会脑血管病学组, 中国医学科学院北京协和医院神经科, 等. 中国急性缺血性脑卒中诊治指南 2018. 中华神经科杂志, 2018, 51(9): 666-682.
2. 刘雯, 陈国芳, 王琛, 等. 脑白质病变对急性脑梗死 rt-PA 静脉溶栓患者临床预后及出血转化的影响. 神经损伤与功能重建, 2020, 15(5): 281-284.
3. Xu X, Li C, Wan T, et al. Risk factors for hemorrhagic transformation after intravenous thrombolysis in acute cerebral infarction: a retrospective single-center study. World Neurosurg, 2017, 101: 155-160.
4. 张迎春, 杨谦. 胆红素在缺血性脑梗死中的意义及研究进展. 中国实用神经疾病杂志, 2019, 22(10): 1152-1156.
5. 王红梅, 张婷, 陈静炯, 等. 低 T3 水平与大动脉粥样硬化型脑梗死患者短期预后的关系. 临床荟萃, 2020, 35(6): 517-520.
6. Yokoyama M, Watanabe T, Otaki Y, et al. Association of the aspartate aminotransferase to alanine aminotransferase ratio with BNP level and cardiovascular mortality in the general population: the Yamagata study 10-year follow-up. Dis Markers, 2016, 2016: 4857917.
7. 吴月, 殷梅. 炎症反应与急性缺血性脑卒中静脉溶栓后出血转化的研究进展. 神经疾病与精神卫生, 2020, 20(12): 890-894.
8. 毛中臣, 孙永, 赵燕, 等. 61 例大面积脑梗死患者的临床资料分析. 深圳中西医结合杂志, 2019, 29(4): 129-130.
9. Yoo J, Baek JH, Park H, et al. Thrombus volume as a predictor of nonrecanalization after intravenous thrombolysis in acute stroke. Stroke, 2018, 49(9): 2108-2115.
10. Chen SL, Li JP, Li LF, et al. Elevated preoperative serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio is associated with better prognosis in patients undergoing curative treatment for gastric adenocarcinoma. Int J Mol Sci, 2016, 17(6): 911.
11. Xing Y, Guo ZN, Yan S, et al. Increased globulin and its association with hemorrhagic transformation in patients receiving intra-arterial thrombolysis therapy. Neurosci Bull, 2014, 30(3): 469-476.
12. Tan G, Lei C, Hao Z, et al. Liver function may play an uneven role in haemorrhagic transformation for stroke subtypes after acute ischaemic stroke. Eur J Neurol, 2016, 23(3): 597-604.
13. Wang YY, Lin SY, Chuang YH, et al. Activation of hepatic inflammatory pathways by catecholamines is associated with hepatic insulin resistance in male ischemic stroke rats. Endocrinology, 2014, 155(4): 1235-1246.
14. Sayre NL, Sifuentes M, Holstein D, et al. Stimulation of astrocyte fatty acid oxidation by thyroid hormone is protective against ischemic stroke-induced damage. J Cereb Blood Flow Metab, 2016, 37(2): 514-527.
15. da Conceição RR, Laureano-Melo R, Oliveira KC, et al. Antidepressant behavior in thyroidectomized Wistar rats is induced by hippocampal hypothyroidism. Physiol Behav, 2016, 157: 158-164.
16. Sabbaghziarani F, Mortezaee K, Akbari M, et al. Stimulation of neurotrophic factors and inhibition of proinflammatory cytokines by exogenous application of triiodothyronine in the rat model of ischemic stroke. Cell Biochem Funct, 2017, 35(1): 50-55.
17. Mokhtari T, Akbari M, Malek F, et al. Improvement of memory and learning by intracerebroventricular microinjection of T3 in rat model of ischemic brain stroke mediated by upregulation of BDNF and GDNF in CA1 hippocampal region. Daru, 2017, 25(1): 4.
18. Jeong HS, Choi EK, Song IU, et al. Differences in brain glucose metabolism during preparation for ¹³¹I ablation in thyroid cancer patients: thyroid hormone withdrawal versus recombinant human thyrotropin. Thyroid, 2017, 27(1): 23-28.
19. Bing Y, Zhu S, Jiang K, et al. Reduction of thyroid hormones triggers down-regulation of hepatic CYP2B through nuclear receptors CAR and TR in a rat model of acute stroke. Biochem Pharmacol, 2014, 87(4): 636-649.
20. Docter R, Krenning EP, de Jong M, et al. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf), 2010, 39(5): 499-518.
21. Suda S, Muraga K, Kanamaru T, et al. Low free triiodothyronine predicts poor functional outcome after acute ischemic stroke. J Neurol Sci, 2016, 368: 89-93.
22. Bunevicius A, Iervasi G, Bunevicius R. Neuroprotective actions of thyroid hormones and low-T3 syndrome as a biomarker in acute cerebrovascular disorders. Expert Rev Neurother, 2015, 15(3): 315-326.
23. Wang Y, Zhou S, Bao J, et al. Low T₃ levels as a predictor marker predict the prognosis of patients with acute ischemic stroke. Int J Neurosci, 2017, 127(7): 559-566.
24. Wang X, Lo EH. Triggers and mediators of hemorrhagic transformation in cerebral ischemia. Mol Neurobiol, 2003, 28(3): 229-244.
25. Yang N, Lin M, Wang BG, et al. Low level of low-density lipoprotein cholesterol is related with increased hemorrhagic transformation after acute ischemic cerebral infarction. Eur Rev Med Pharmacol, 2016, 20(4): 673-678.
26. Yao M, Ni J, Zhou L, et al. Elevated fasting blood glucose is predictive of poor outcome in non-diabetic stroke patients: a sub-group analysis of SMART. PLoS One, 2016, 11(8): e0160674.
27. 张海华, 王素文, 管丽娜. 急诊绿色通道开通对急性缺血性脑卒中患者静脉溶栓效果的影响. 山东医药, 2018, 58(21): 77-79.
28. Ke X, Wu X, Guo H, et al. Association of ALOX5AP rs10507391/SG13S114 A>T polymorphism with cerebral infarction in the Chinese population: a meta-analysis study. Int J Neurosci, 2015, 125(10): 726-732.
29. 李丽. 脑梗死静脉溶栓治疗后出血性转化及其预后的危险因素分析. 中西医结合心脑血管病杂志, 2015, 13(6): 837-839.
30. 郑伟, 郭莘, 邢效如, 等. 急性脑梗死静脉溶栓后出血性转化发生现状及影响因素研究. 解放军预防医学杂志, 2020, 38(9): 28-30.
31. 陈子龙, 苏宇. 急性缺血性脑卒中患者介入取栓后出血转化的相关危险因素. 卒中与神经疾病, 2020, 27(6): 734-737.
32. Calleja AI, García-Bermejo P, Cortijo E, et al. Insulin resistance is associated with a poor response to intravenous thrombolysis in acute ischemic stroke. Diabetes Care, 2011, 34(11): 2413-2417.
33. Johnston KC, Bruno A, Pauls Q, et al. Intensive vs standard treatment of hyperglycemia and functional outcome in patients with acute ischemic stroke: the SHINE randomized clinical trial. JAMA, 2019, 322(4): 326-335.
34. Squadrito GL, Cueto R, Splenser AE, et al. Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys, 2000, 376(2): 333-337.
35. Mizuma A, Yenari MA. Anti-inflammatory targets for the treatment of reperfusion injury in stroke. Front Neurol, 2017, 8: 467.
36. Spitsin SV, Scott GS, Mikheeva T, et al. Comparison of uric acid and ascorbic acid in protection against EAE. Free Radic Biol Med, 2002, 33(10): 1363-1371.
37. Ruan Y, Yuan C, Liu Y, et al. High fibrinogen-to-albumin ratio is associated with hemorrhagic transformation in acute ischemic stroke patients. Brain Behav, 2021, 11(1): e01855.
38. Prajapati KD, Sharma SS, Roy N. Current perspectives on potential role of albumin in neuroprotection. Rev Neurosci, 2011, 22(3): 355-363.
39. Chamorro A, Amaro S, Castellanos M, et al. Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. Lancet Neurol, 2014, 13(5): 453-460.
40. 邹荣成, 王静, 张力. 急性缺血性脑卒中病人静脉溶栓后血清白蛋白水平与出血性转化的关系探讨. 中西医结合心脑血管病杂志, 2019, 17(20): 3108-3111.

West China Medical Journal

Predictive value of liver function and free triiodothyronine levels for hemorrhagic transformation after intravenous thrombolysis in patients with acute ischemic stroke

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