Hemorrhagic infarction following cerebral vasospasm

Among 528 cases with ruptured aneurysm, 10 cases (1.9%) developed hemorrhagic infarction following vasospasm. There was no obvious relationship between the occurrence and location of aneurysm and the neurological grade on admission. Hemorrhagic infarction occurred from day 9 to 25 (mean day 16) after aneurysmal rupture, and the major neurological symptoms were aggravation of consciousness level, which appeared in 6 cases. On the CT scans of the hemorrhagic infarction following vasospasm, nine cases revealed heterogeneous hemorrhage as assembled of spotty or linear hemorrhages within the ischemic infarction, and 5 cases had massive hemorrhagic infarction in size with mass effect. Although surgical therapy for 2 cases and conservative therapy for 8 cases were performed, the results were unfavorable; ie, 2 cases were good, 5 fair or poor, and 3 died. Especially, 5 cases with massive hemorrhagic infarction obviously resulted in poor prognosis. In our series, induced hypertension therapy for vasospasm was considered as a risk factor. In conclusion, it is necessary to avoid induced hypertension therapy in the remission stage of vasospasm and serial SPECT study might be recommended as a useful prospective method estimating the vasospasm.     

Hemorrhagic transformation after fibrinolytic therapy with tissue plasminogen activator in a rat thromboembolic model of stroke

In this study, the effects of early vs. delayed tPA treatment on the development of hemorrhagic transformation was compared in a rat thromboembolic model of stroke. Fibrinolysis was performed by administering tPA intravenously at 2 or 6 h after ischemic onset. Twenty-four hours later, confluent hemorrhagic infarction was observed only in rats treated with tPA at 6 h at the rate of 50%. In this delayed treatment group, significantly increased numbers of polymorphonuclear leukocytes (PMNL) were observed to accumulate inside microvessels within the ischemic core. PMNL accumulation may be related to the induction of hemorrhagic infarction after delayed tPA treatment.     

Hemorrhagic transformation after fibrinolytic therapy with tissue plasminogen activator in a rat thromboembolic model of stroke

TNFalpha (100 U/ml, 24 h) upregulated intercellular adhesion molecule 1 (ICAM1) expression and fluid phase endocytosis (FPE) of horseradish peroxidase on brain microvascular endothelial cell (BMEC) culture. The protein kinase C (PKC) inhibitor staurosporin (0. 5-10 nM) antagonized ICAM1 expression and FPE due to TNFalpha, whereas the protein kinase A inhibitor H89 (0.5-10 nM) did not. These findings indicate that a PKC-dependent mechanism may affect TNFalpha signalling on different barrier properties of BMECs.     

Recombinant human tissue plasminogen activator protects the basal lamina in experimental focal cerebral ischemia

While recombinant tissue plasminogen activator (rt-PA) is successfully used in human ischemic stroke, it may also cause hemorrhagic complications. Animal experiments have shown that hemorrhages are related to microvascular basal lamina damage. We investigated the effects of different doses of rt-PA on the brain microvasculature. Experimental cerebral ischemia in rats was induced for 3 h and followed by 24 h reperfusion (suture model). Each group of rats (n = 6) received either treatment (0.9, 9, or 18 mg rt-PA/kg body weight) or saline (control group) at the end of ischemia. The loss of microvascular basal lamina antigen collagen type IV was measured by Western blot of the ischemic and non-ischemic basal ganglia and cortex. Compared with the contralateral non-ischemic area, collagen type IV was significantly reduced in the ischemic area: (basal ganglia/cortex) 43% +/- 9% / 64% +/- 4 %. Low/moderate doses of rt-PA had a protective effect: 0.9 mg 79% +/- 3% / 89% +/- 6%, 9 mg 72% +/- 9%/ 81% +/- 12% (p < 0.05). Higher doses of rt-PA (18 mg) had a similar effect as seen in untreated controls: 57% +/- 11% / 59% +/- 9% (p < 0.05, Anova). MMP-9 and MMP-2, measured by gelatine zymography, steadily increased over higher doses of rt-PA: MMP-9 (basal ganglia/cortex): control 115% +/- 4% / 123% +/- 3% compared with 18 mg rt-PA 146% +/- 5%/ 162% +/- 6% (p < 0.05) and MMP-2: control 109% +/- 4%/ 116% +/- 5% and 18 mg rt-PA 222% +/- 15%/ 252% +/- 2% (p < 0.05). Low to moderate doses of rt-PA protect the microvascular basal lamina, whereas high doses of rt-PA have the opposite effect, probably due to increased coactivation of MMP-2 and MMP-9.     

Recombinant tissue plasminogen activator attenuates basal lamina antigen loss after experimental focal cerebral ischemia

Abstract

Background and purpose: The use of recombinant tissue plasminogen activator (rt-PA) is a proven therapy in acute stroke. Main concerns are based on hemorrhagic complications, which are connected with microvascular integrity loss. The aim of this study was to evaluate microvascular changes after various doses of rt-PA.

Methods and results: Focal cerebral ischemia for 3 hours was induced using the suture model in rats and followed by 24 hours of reperfusion. Six rats received either saline, 0.9, 9, or 18 mg rtPA/kg body weight at the end of ischemia. By immunostaining of collagen type IV the density of microvessels and the total stained area in the basal ganglia and cortex was measured. Comparison of the ischemic with the non-ischemic hemisphere showed significantly less reduction of the number of microvessels in rats treated with low-dose rt-PA than in the other groups: controls 17 ± 3% (basal ganglia), 12 ± 7% (cortex); 0.9 mg rt-PA, 18 ± 3%, 10 ± 4%; 9 mg, 21 ± 4%, 13 ± 7%; 18 mg, 22 ± 4%, 15 ± 8%. A similar effect was observed on the total stained area: control 25 ± 4% (basal ganglia), 14 ± 7% (cortex); 0.9 mg rt-PA, 23 ± 2%, 7 ± 4%; 9 mg, 28 ± 4%, 15 ± 4%; 18 mg, 29 ± 4%, 17 ± 5%, p<0.001. The significant reduction of the area of infarction after low and moderate doses of rt-PA was visualized with an MAP2-antibody, and the volume was calculated by 3-D reconstruction: control, 165.2 mm 3 ± 21%; 0.9 mg rt-PA, 102.6 mm 3 ± 16%; 9 mg, 101.2 mm 3 ± 17%; 18 mg, 133.0 mm 3 ± 24%; p < 0.001.

Conclusions: Rats exposed to low-dose rt-PA preserved basal lamina structures, and showed smaller infarct sizes. The protective effect of low-dose rt-PA might be due to an increased microvascular patency rate.     

急性缺血性卒中重组组织型纤溶酶原激活剂静脉溶栓致出血性转化及其预后的危险因素分析

目的 探讨急性缺血性卒中重组组织型纤溶酶原激活剂(rt-PA)静脉溶栓后发生出血性转化(HT)的可能危险因素以及这些危险因素对患者预后的影响.方法 128例急性缺血性卒中患者发病6h内接受rt-PA静脉溶栓治疗,选取溶栓前临床和实验室资料,通过比较HT组与非HT组之间的差异,筛选与HT相关的可能危险因素,并进一步通过Logistic回归分析影响HT及其预后的独立危险因素.结果 128例溶栓患者有29例继发HT(22.66％),其中16例为症状性脑出血(12.50％),死亡2例,占HT的6.90％.Logistic回归分析表明房颤(OR=1.293,95％ CIl.224 ～1.589,P=0.00l)、早期CT改变(OR=2.452,95％ CI 1.132～3.309,P=0.034)、基线舒张压≥100 mm Hg(1 mm Hg=0.133 kPa,OR=9.265,95％ CI 1.435 ～ 59.836,P=0.019)、基线血糖≥11.1 mmol/L(OR=3.037,95％ CI0.252 ～ 57.593,P=0.047)、NIHSS评分＞15分(OR=8.752,95％CI 1.035 ～30.285,P=0.023)和溶栓时间窗＞3h(OR=98.74,95％CI 5.067 ～ 186.120,P=0.002)6项为HT独立危险因素,其中基线血糖≥11.1 mmol/L(OR=3.265,95％ CI 0.435 ～ 59.863,P=0.045)、NIHSS评分＞15分(OR=10.453,95％ CI 5.647～38.185,P=0.003)和溶栓时间窗＞3h(OR =2.541,95％CI 1.098 ～51.086,P=0.017)影响了HT患者的预后.结论 溶栓前的舒张压、血糖水平、神经功能缺损程度、CT低密度改变或水肿占位效应、房颤和溶栓时间窗是HT的独立危险因素,其中基线血糖水平、神经功能缺损程度和溶栓时间窗影响了溶栓后HT患者的预后.     

Recombinant tissue plasminogen activator attenuates basal lamina antigen loss after experimental focal cerebral ischemia

BACKGROUND AND PURPOSE: The use of recombinant tissue plasminogen activator (rt-PA) is a proven therapy in acute stroke. Main concerns are based on hemorrhagic complications, which are connected with microvascular integrity loss. The aim of this study was to evaluate microvascular changes after various doses of rt-PA. METHODS AND RESULTS: Focal cerebral ischemia for 3 hours was induced using the suture model in rats and followed by 24 hours of reperfusion. Six rats received either saline, 0.9, 9, or 18 mg rtPA/kg body weight at the end of ischemia. By immunostaining of collagen type IV the density of microvessels and the total stained area in the basal ganglia and cortex was measured. Comparison of the ischemic with the non-ischemic hemisphere showed significantly less reduction of the number of microvessels in rats treated with low-dose rt-PA than in the other groups: controls 17 +/- 3% (basal ganglia), 12 +/- 7% (cortex); 0.9 mg rt-PA, 18 +/- 3%, 10 +/- 4%; 9 mg, 21 +/- 4%, 13 +/- 7%; 18 mg, 22 +/- 4%, 15 +/- 8%. A similar effect was observed on the total stained area: control 25 +/- 4% (basal ganglia), 14 +/- 7% (cortex); 0.9 mg rt-PA, 23 +/- 2%, 7 +/- 4%; 9 mg, 28 +/- 4%, 15 +/- 4%; 18 mg, 29 +/- 4%, 17 +/- 5%, p<0.001. The significant reduction of the area of infarction after low and moderate doses of rt-PA was visualized with an MAP2-antibody, and the volume was calculated by 3-D reconstruction: control, 165.2 mm 3 +/- 21%; 0.9 mg rt-PA, 102.6 mm 3 +/- 16%; 9 mg, 101.2 mm 3 +/- 17%; 18 mg, 133.0 mm 3 +/- 24%; p < 0.001. CONCLUSIONS: Rats exposed to low-dose rt-PA preserved basal lamina structures, and showed smaller infarct sizes. The protective effect of low-dose rt-PA might be due to an increased microvascular patency rate.     

急性脑梗死重组组织型纤溶酶原激活物静脉溶栓后严重出血性转化研究进展

严重出血性转化是静脉溶栓治疗最危险的并发症。本文对近年来有关静脉溶栓后严重出血性转化的定义、临床表现、影像学特征以及相关危险因素的研究进展进行综述。对具有严重出血性转化高风险的急性脑梗死患者可以选择低剂量重组组织型纤溶酶原激活物(recombinant tissue plasminogen activator,rtPA)静脉溶栓治疗,以降低症状性颅内出血的发生风险。     

Association of tissue plasminogen activator and plasminogen activator inhibitor polymorphism with myocardial infarction: A meta-analysis

Introduction

To investigate whether t-PA Alu repeat insertion/deletion (I/D) and PAI-1 4 G/5 G genetic variations are associated with the risk of MI.

Methods

We conducted a meta-analysis to assess the association between the t-PA I/D and PAI-1 4 G/5 G polymorphisms and risk of MI. We also performed subgroup analyses based on ethnicity (Caucasian, Asian, and African), gender and age. Forty one eligible studies including 12,461 cases and 14,993 controls were identified to evaluate the impact of PAI-1 4 G/5 G polymorphism on MI. Seven studies investigated the relationship between t-PA I/D and MI.

Results

This meta-analysis revealed that the PAI-1 4 G allele (4 G/4 G and 4 G/5 G genotype) was associated with an increased risk of MI compared with the 5 G allele in the overall population (OR = 1.094, 95% CI = 1.021 - 1.172, p = 0.011). The relative risks of MI for 4 G/4 G genotype was increased when compared to 5 G/5 G genotype and 5 G allele, with odds ratio at 1.157 (95% CI 1.015 - 1.320, p = 0.029) and 1.126 (95% CI = 1.015 - 1.249, p = 0.025). However, the results show that the 4 G/5 G polymorphism risk for MI was not associated with ethnicity stratification as Caucasian, Asian or African population. No substantial differences in the genotype distributions were observed in the MI group and control group along the lines of gender and age. After multivariable analysis t-PA I/D polymorphism showed no consistent association with MI.

Conclusions

This study suggests that the 4 G/5 G polymorphism of PAI-1 may be a risk factor for MI in overall populations.     

Hemorrhagic transformation is related to the duration of occlusion and treatment with tissue plasminogen activator in a nonembolic stroke model

The availability of reperfusion therapy for acute ischemic stroke patients has made the causes and significance of hemorrhagic transformation an area of intense interest and controversy. Ninety-two male Wistar rats underwent transient middle cerebral artery occlusion (MCAO) of between 1 and 6 h. Forty animals received 10 mg kg-1 of recombinant tissue plasminogen activator (rtPA), infused over 20 min, starting 5 min before reperfusion. At 18-24 h, the animals were sacrificed. The presence of hemorrhagic transformation (HT) on stained sections was recorded and total ischemic lesion area was quantified using image analysis software. Seventeen animals (11 with HT) were subjected to immunohistochemical analysis for detection of endothelial barrier antigen (EBA), quantified in three sections, in eight different fields per section. Chi-squared analysis and logistic regression were used to assess the contribution of rtPA and duration of occlusion to HT development. Nested, repeated measures analyses of variance were performed to assess the changes in EBA caused by ischemia and associated with HT. Fifty-nine animals developed HT that was significantly associated with occlusion duration (p < 0.0001) and ischemic lesion size (p = 0.0007). The presence of rtPA accelerated HT development. Statistically significant side-to-side differences in the presence of EBA were found in the striatum (core of the infarct) of animals with HT (p < 0.001) and without HT (p < 0.001), but only in animals with durations of occlusion of 2 h or more. Duration of occlusion is an important predictor of HT in transient MCAO in the rat and is closely associated with EBA expression.     

Morphological changes following experimental intraventricular haemorrhage and intraventricular fibrinolytic treatment with recombinant tissue plasminogen activator

Intraventricular haemorrhage (IVH) occurs in up to 50% of patients with primary intracerebral haemorrhage and aneurysmal subarachnoid haemorrhage. It is a significant and independent contributor to mortality and morbidity in these intracranial haemorrhages. Using a model of isolated IVH, we assessed the morphological changes induced by intraventricular bleeding and investigated the effects of intraventricular fibrinolytic treatment following IVH. IVH was induced in 32 pigs by intraventricular infusion of 10 ml autologous blood along with thrombin. The treatment group received an intraventricular injection of 1.5 mg (1 mg/ml) tissue plasminogen activator (tPA) following the injection of blood. The placebo group received the same volume of normal saline. Morphological examinations of the brains were carried out 7 days and 6 weeks following IVH. The ventricles were incompletely filled with blood and significantly enlarged in the placebo group 7 days after the IVH. In contrast, no residual intraventricular clots were visible in the animals treated with tPA, and the diameters of the lateral ventricles had returned to normal within 7 days. Marked losses of the ependymal covering of the ventricular walls were found in the placebo-treated animals, while the ependymal layer was largely intact in the animals treated with tPA. No haemorrhages induced by tPA were observed. The results indicate that intraventricularly administered tPA significantly enhances the lysis of intraventricular blood clots, accelerates the resolution of acute posthaemorrhagic hydrocephalus, and preserves the integrity of the ependymal layer. Received: 6 October 1999 / Revised, accepted: 26 January 2000     

急性脑梗死患者阿替普酶静脉溶栓的疗效及出血性转化影响因素分析

目的研究阿替普酶(rt-PA)静脉溶栓治疗急性脑梗死(ACI)的疗效,并分析静脉溶栓后出血性转化(HT)的影响因素。方法选择发病在6h以内的ACI患者174例,根据治疗方法的不同分为静脉溶栓和常规治疗两组,比较两组治疗前和治疗后24h、14d美国国立卫生研究院卒中量表(NIHSS)评分,90d后改良Rankin量表(m RS)评分的变化,并记录不良反应;比较静脉溶栓组有无出血并发症患者之间的影响因素,多因素回归分析确定溶栓后HT的独立危险因素。结果 1静脉溶栓组溶栓后24h、14d NIHSS评分较溶栓前明显降低(P0.05),常规治疗组治疗后24 h、14 d NHISS评分与溶栓前比较,差异无统计学意义(P0.05),治疗后同一时间点比较静脉溶栓组的NHISS评分均低于常规治疗组(P0.05);2静脉溶栓组患者90d后预后良好率高于常规治疗组(58.4%vs42.3%,2=4.423,P0.05)。两组之间死亡率差异没有统计学意义(12.5%vs19.2%,2=1.487,P0.05;3多因素回归分析显示治疗前NHISS评分(OR:1.517,1.2142.261,P0.05)、心房颤动病史(OR:1.431,1.2792.041,P0.05)是溶栓后HT的独立危险因素。结论rt-PA静脉溶栓对发病6h内的ACI患者的疗效优于常规治疗;治疗前NHISS评分、有心房颤动病史是影响溶栓后HT的独立危险因素。     

Imbalance of plasminogen activator inhibitor-I/ tissue plasminogen activator and tissue factor/tissue factor pathway inhibitor in young Japanese men with myocardial infarction

To evaluate the association between haemostatic parameters and increased risk of myocardial infarction (MI) at a young age, we measured fibrinogen, factor VII, antithrombin III, protein C, protein S, tissue factor (TF), free form tissue factor pathway inhibitor (TFPI), plasminogen, alpha2-antiplasmin, tissue plasminogen activator (tPA), plasminogen activator inhibitor-I (PAI-I), and lipoprotein (a) in 140 young men with MI before age 45 and 150 age-matched healthy men. TF, TF/TFPI ratio, PAI-I, PAI-I/tPA ratio, plasminogen, and lipoprotein (a) in young MI patients were all significantly higher than controls, while TFPI, antithrombin II, and tPA were significantly lower (P <0.001 of each). Significant determinants of MI risk were PAI-I/tPA ratio (R2 = 0.300, P <0.001), TF/TFPI ratio (R2 = 0.049, P <0.001), antithrombin III (R2 = 0.034, P <0.001), hyperlipidaemia (R2 = 0.019, P = 0.004), diabetes (R2 = 0.014, P = 0.015), lipoprotein (a) (R2 = 0.012, P = 0.023), alpha2-antiplasmin (R2= 0.014, P = 0.012), and protein C (R2= 0.012, P = 0.018). We conclude that the imbalances of PAI-I/tPA and TF/TFPI are significantly associated with MI at a young age, perhaps mediated via impaired fibrinolytic activity.     

Hemorrhagic transformation in cerebral embolism

We studied the mechanism of hemorrhagic infarction after acute cerebral embolism in 160 patients by brain computed tomography and angiography. Hemorrhagic infarction during the month after the embolic event was evident in 65 patients (40.6%). Initial angiography a median of 1.5 (range 1-60) days after the event revealed occlusion of the cerebral arteries in 117 of 142 patients (82.4%), and reopening of the vessels was observed in 56 (94.9%) of 59 patients who had follow-up angiography a median of 20 (range 3-47) days after the event. The incidence of hemorrhagic infarction was higher in patients greater than or equal to 70 years old (31 of 61, 50.8%) than in those aged 50-69 years (27 of 72, 37.5%) or less than 50 years (seven of 27, 25.9%) (greater than or equal to 70 vs. less than 50, p less than 0.05). In patients with moderate or large infarcts, hemorrhagic infarction developed in 50.0% or 51.5%, respectively, while in those with small infarcts it developed in only 2.9% (p less than 0.05). No correlation was found between hemorrhagic infarction and history of hypertension or blood pressure during the acute stage of stroke. Thrombolytic and/or anticoagulant therapy did not affect the incidence of hemorrhagic infarction (40.0% with vs. 40.7% without therapy) but tended to cause massive hematoma. Our results indicate that hemorrhagic transformation in cerebral embolism is caused not only by reopening of the occluded vessels but also by other factors such as age and size of the infarct. Hypertension per se seems to be less important for hemorrhagic infarction.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of experimental chronic hypertension on tissue plasminogen activator activity, plasminogen activator inhibition and plasmin inhibition

Chronic hypertension was induced in rats after partial nephrectomy. The systolic blood pressure was significantly elevated from the first week after nephrectomy to the end of the experimentation (8th week). Plasminogen activator activity (PAA) and plasminogen activator inhibition (PAI) showed a tissue- and time-dependent pattern of changes in some key organs compared to controls (sham-operated rats). Two weeks after nephrectomy (one week after the induction of hypertension) the PAA was markedly increased in lungs, heart and aorta. In aorta the PAA continued to be enhanced until the end of the experimentation (the 8th week after nephrectomy), while in heart and lungs the PAA returned to the normal eight weeks after nephrectomy. In vena cava, brain and liver no change in PAA was noticed compared to controls. Tissue PAI was mostly increased or unchanged, while tissue plasmin inhibition (PI) was unchanged. The differential response of PAA and PAI was varying not only from one organ to another or in the same organ at a given time but also in the same organ throughout experimentation. In a number of nephrectomized rats, however, hypertension was not induced. In these rats similar changes in tissue PAA and PAI were noted compared to hypertensive nephrectomized rats. Therefore, all the changes in the parameters studied should be due to the partial nephrectomy itself. In conclusion, experimentally induced chronic hypertension had not any effect on tissue PAA, PAI and PI.