Platelets in patients with acute ischemic stroke are exhausted and refractory to thrombin, due to cleavage of the seven-transmembrane thrombin receptor (PAR-1)

Platelet activation is involved in the pathogenesis of cerebrovascular ischemia, but the major agonist involved has yet to be identified. To investigate the role of thrombin in platelet activation in patients with acute ischemic stroke, and while thrombin is the most likely candidate for activation of the thrombin receptor PAR-1 in vivo, we assessed its cleavage and internalization using the antibodies SPAN12, binding to uncleaved PAR-1, and WEDE15, recognizing cleaved and uncleaved, but not internalized PAR-1. In contrast to healthy age-matched controls, platelets from stroke patients exhibited significant cleavage and internalization of PAR-1 (P<0.001) and failed to respond to thrombin in vitro. Enhanced surface expression of CD62P, CD63, TSP-1 and less mepacrine uptake showed platelet degranulation during stroke. Platelets from patients with acute cerebral ischemia are exhausted and desensitized to thrombin through cleavage of PAR-1, indicating that high concentrations of thrombin occur with acute cerebrovascular ischemic events in vivo.     

Pathogenesis of transient ischemic attacks within the vertebrobasilar arterial system.

Regional cerebral blood flow (rCBF) was measured by xenon 133 inhalation in 36 patients with vertebrobasilar arterial insufficiency (VBI), three patients with brain stem infarction, and 15 age-matched normal controls before and after inducing postural hypotension. Probes mounted over the suboccipital area by means of a helmet were used to measure rCBF over the brain stem and cerebellar regions. When lying flat, rCBF values measured over both cerebral hemispheres and the brain stem-cerebellar regions in patients with VBI were not significantly different from normal controls. Unlike carotid transient ischemic attacks, regional flow reduction rarely persisted for three weeks after transient ischemic symptoms in patients with VBI. When postural hypotension was induced, rCBF became significantly reduced in patients with VBI whether or not they were treated with papaverine. Dysautoregulation was restricted to vertebral, basilar, and posterior cerebral arterial distribution in patients with VBI of 1 to 12 months' duration, but was more widespread and involved both cerebral hemispheres in long-standing VBI. Hemodynamic factors and dysautoregulation appear to play a part in the pathogenesis of symptoms of VBI.     

短暂性脑缺血发作后短期内发生脑梗死的风险分析

目的分析ABCD2评分结合MRA对短暂性脑缺血发作(TIA)后7~30d脑梗死发生的评估价值。方法以2008年12月~2009年10月住院的TIA患者为研究对象,收集其临床资料和磁共振血管成像(MRA)检查结果,按Johnston提出的7分"ABCD2"评分法给予评分,随访TIA后7d和30d内脑梗死的发生率,并分析"AB-CD2"评分、MRA与TIA后短期内发生脑梗死的关系。结果 50例(42.0%)TIA患者于30d内发生脑梗死,其中29例(24.4%)发生于7d内;"ABCD2"评分与TIA后7d和30d脑梗死发生率之间呈直线相关,"ABCD2"评分越高,脑梗死的发生率越高(P0.001);TIA后7d和30d颅内动脉狭窄≥50%的患者中脑梗死发生率比50%的患者明显增高(P0.05)。结论 "ABCD2"评分法对TIA后脑梗死发生有预测价值,"ABCD2"评分结合MRA检查能进一步提高预测的准确性。     

Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke

BACKGROUND: Aspirin, or acetylsalicylic acid, is widely used to prevent ischemic vascular disease. Clinical and experimental data suggest that a rebound effect occurs 4 or fewer weeks after interruption of aspirin therapy. OBJECTIVE: To study the discontinuation of aspirin therapy as a risk factor for ischemic stroke (IS). DESIGN: Case-control study. SETTING: Stroke unit. PARTICIPANTS: Three hundred nine patients with IS or transient ischemic attack undergoing long-term aspirin treatment before their index event and 309 age-, sex-, and antiplatelet therapy-matched controls who had not had an IS in the previous 6 months. METHODS: We compared the frequency of aspirin therapy discontinuation during the 4 weeks before an ischemic cerebral event in patients and the 4 weeks before interview in controls. RESULTS: The 2 groups had a similar frequency of risk factors, except for coronary heart disease, which was more frequent in patients (36% vs 18%; P < .001). Aspirin use had been discontinued in 13 patients and 4 controls. Aspirin interruption yielded an odds ratio for IS/transient ischemic attack of 3.4 (95% confidence interval, 1.08-10.63; P < .005) after adjustment in a multivariable model. CONCLUSIONS: These results highlight the importance of aspirin therapy compliance and give an estimate of the risk associated with the discontinuation of aspirin therapy in patients at risk for IS, particularly those with coronary heart disease.     

Role of carotid stenosis in ischemic stroke

Using Doppler ultrasonography, we evaluated the frequency and severity of carotid artery stenosis in 261 patients with carotid ischemic strokes, 813 patients with carotid transient ischemic attacks, 500 patients with asymptomatic neck bruits, and 500 controls. Most patients with strokes and transient ischemic attacks had no associated carotid artery disease (55% and 64%, respectively), and such patients without neck bruits were even more likely to be without carotid artery disease (69% and 77%, respectively). Carotid stenosis was more frequent and more likely to be severe in symptomatic than in asymptomatic patients (p less than 0.0002), even after adjusting for age and sex. Carotid stenosis is present in only a minority of patients with strokes and transient ischemic attacks, especially if neck bruits are absent, and the cause of the ischemic cerebral events in most of these patients remains unexplained.     

Peripheral iron metabolism in patients with focal cerebral ischemia

To ascertain the possible role of iron as a risk factor for cerebral ischemia, we studied the serum levels of iron, transferrin and ferritin in 42 patients between the third and seventh days after a cerebral ischemic event (transient ischemic attack, reversible ischemic neurological deficit or cerebral infarction) and in 62 matched controls. The serum levels of iron did not differ significantly between cerebral ischemic patient and control groups. Serum transferrin levels were lower and ferritin higher in stroke patients than in controls. These values were not influenced by age, blood pressure, or smoking and alcohol drinking habits. These results suggest that iron stores could be related to the risk for cerebral ischemia.     

Platelet aggregation in focal cerebral ischemia – a clinical study

In a consecutive series of 35 patients with transient ischemic attacks (TIAs) 26 patients (74%) had pathological platelet aggregation 4 weeks after the latest TIA. Pathological platelet aggregation was the most frequent factor leading to a prophylactic treatment of the TIAs. Among 12 patients with reversible ischemic neurological deficit (RIND) only one had pathological platelet aggregation, and among 54 patients with completed stroke 37% had pathological platelet aggregation 4 weeks after the cerebral infarction.
It is possible by the antiaggregating agents acetylsalicylic acid and dipyridamole to normalize in vitro pathological platelet aggregation. The frequency of side effects was low. During this treatment further TIAs were stopped in 17/19 patients, and remission were seen in 14/14 stroke patients. Compared with the remissions during treatment with anticoagulants there was a tendency of more favouarble outcome in the group of stroke patients when treated with antiaggregating agents.     

Noninvasive Assessment of Intracranial Perfusion in Acute Cerebral Ischemia

Single-photon emission computed tomography (SPECT) and transcranial Doppler sonography (TCD) may help to determine a target group of patients w1th maximum therapeutiC response for tissue rescue after acute stroke. As previously described, the cerebral perfusion mdex represents a combination of these techniques, and is calculated by multiplying assigned values for TCD and SPECT perfusion patterns. The three grades of cerebral perfusion index (1–5, 6–12, 15–20) may predict short-term outcome if the index is based on SPECT and TCD performed w1thin the first 6 hours after stroke. A total of 30 consecutive patients were studied (18 with middle cerebral artery stroke and 12 with transient ischemic attack or minor stroke) Neurological deficit was scored using the Canadian Neurological Scale. SPECT and TCD were performed 4 ± 2 hours after the onset. Forty-five minutes were required to perform both tests, evaluate the results, and calculate the cerebral perfusion index. The mean score ( ± standard deviation) of the neurological deficit on admission was 84 ± 20 in patients with transient ischemic attack/minor stroke and 54 ± 33 in patients with stroke (p < 0 009) The volume of 1schemic lesion was measured on computed tomography scans performed more than 3 days after the ictus. Patients with transient ischemic attack/minor stroke had lesion volumes of 8 ± 7 cm3 compared to 72 ± 26 cm3 for those with stroke (p < 0.0001). The mean cerebral perfusion index in the transient ischemic attack group was 18 ± 4, while in the stroke group it was 4 ± 1 (p < 0.0001 ). Clinical examination on admission correctly predicted a reversible neurological deficit in 9 of 12 patients in the transient ischemic attack group and the irreversibility of brain damage in 14 of 18 patients in the stroke group. With the three-grades scale, cerebral perfusion index correctly identified 10 transient ischemic attacks and 17 strokes. Noninvasive diagnosis of intracranial perfusion abnormalities using SPECT and TCD correlates with the clinical outcome and the volume of brain damage, and therefore may improve the accuracy of prognosis in the hyperacute phase of cerebral ischemia. Cerebral perfusion index is a fast and qualitative scoring system that may be used for early differentiation of transient ischemic attacks, minor strokes, and strokes durmg the first 6 hours of cerebral ischemia.     

中风病人血浆内皮素动态变化及其与病情关系的研究

用放免法测定９８例中风病人的血浆内皮素（ＥＴ）含量在不同病情、病程时期的动态变化。结果发现ＩＴＡ与脑供血不足患者ＥＴ水平明显高于对照组（Ｐ＜０．０５）；脑梗塞患者急性期及恢复期ＥＴ水平均较对照组有显著差异（Ｐ＜０．０１），且梗塞范围越大ＥＴ水平增高越显著；ＳＡＨ病人发病后１周ＥＴ水平迅速上升高达数倍，４周后即降至原有水平。结果表明ＥＴ参与了中风的发生与发展，是引起缺血损伤和脑血管痉挛的重要因素。     

短暂性缺血发作对后续大面积脑梗死预后的影响

目的 观察同侧短暂性缺血发作(TIA)对后继大面积脑梗死的影响.方法 将51例首次发病的大面积脑梗死患者,按照是否预先发生同侧的TIA及发生间隔进行分组,采用欧洲卒中评分方法在治疗前及治疗3周时评价各组患者神经功能缺损程度.结果 发病前4周有TIA发生的脑梗死患者较无TIA发作的脑梗死患者入院时及治疗3周后欧洲脑卒中评分有差异(P<0.05),TIA发生时间小于1周者入院时及3周后评分好于病前2～4周发生TIA者,但仅入院时有统计学意义(P<0.05).结论 脑梗死前发生的同侧TIA可能产生缺血耐受现象,对后继发生的脑梗死起保护作用.     

症状性脑动脉狭窄支架成形术后近期疗效以及再狭窄观察

目的评价脑动脉狭窄血管内支架成形术后近期疗效以及观察再狭窄的情况。方法回顾性分析2003~2004年接受颅内外动脉支架术的11例症状性脑动脉狭窄患者,随访3~12月,就术后短期内临床疗效以及再狭窄情况进行分析。结果本组11例患者,5例颈内动脉系统TIA患者,术后随访6~12个月,仅1例有3次TIA,症状类似术前,余4例患者均未见发作;4例椎-基底动脉系统TIA患者,术后随访6个月,仅1例出现发作性眩晕2次,其余3例随访期内未出现TIA。11例患者于17根血管上放17枚支架,随访3~12个月,11/17出现了再狭窄(64%),超过50%的再狭窄为5/17,其中大脑中动脉M1段占2/17,颈内动脉颅外段(C1、C3段)占2/17,椎动脉起始部占1/17。6/17根血管再狭窄率介于10%~30%之间,6/17无再狭窄发生。结论血管内支架成形术有利于预防和改善临床症状,但支架后再狭窄是不可忽视的问题,采取积极的应对措施是预防再狭窄的关键。     

Evidence of hypercoagulability and inflammation in young patients long after acute cerebral ischaemia

INTRODUCTION: Young subjects with acute cerebral ischaemia - stroke or transient ischaemic attack - form an etiologically heterogeneous and often not clearly explained group of patients. The aim was to investigate possible disturbances in haemostasis and inflammation long after an acute cerebral ischaemic event. MATERIALS AND METHODS: Forty-four consecutive patients referred after having suffered from acute cerebral ischaemia before the age of 45 participated 1 to 9 years (median value 5 years) after the event. At the time of blood sampling 33 (75%) patients were receiving antithrombotic treatment. Forty-six apparently healthy subjects of the same age group served as controls. In all subjects global haemostasis parameters (overall haemostasis, coagulation and fibrinolytic potential), thrombophilia, several markers of haemostasis activation and inflammation were determined. RESULTS: Patients did not differ from controls in most of the conventional risk factors and the presence of most forms of thrombophilia, although in seven (17.5%) patients the weak presence of lupus anticoagulants was observed. Patients had significantly increased overall haemostasis and coagulation potential, increased soluble P-selectin and D-dimer, decreased overall fibrinolysis potential and increased fibrinogen and C-reactive protein compared to controls. The subgroups of patients receiving antiplatelet treatment, with thrombophilia and recurrent acute cerebral ischaemia, did not differ significantly from the other patients. CONCLUSIONS: In young patients long after acute cerebral ischaemia an imbalance in the haemostatic system and a minor, but significant degree of inflammation was detected. The mechanisms behind haemostatic imbalance seem to be enhanced thrombin generation, platelet activation and depressed fibrinolysis.     

疏血通对急性缺血性脑卒中的临床疗效研究

目的 评价疏血通在急性缺血性脑卒中的临床疗效.方法 选择急性缺血性脑卒中患者196例,按随机数字表法分为治疗组(98例)和对照组(98例),分别在入院时及治疗后2周进行神经功能缺损评分、认知功能障碍评估及临床结局评定,并用经颅多普勒监测治疗前后脑血流量变化.结果 治疗组神经功能及临床结局改善及明显改善率明显高于对照组,而恶化病例明显减少.2组治疗后认知功能障碍评分均较治疗前明显改善,差异有统计学意义(P＜0.05),其中治疗组改善更显著.治疗后2组脑血流量较治疗前明显增加,差异有统计学意义(P＜0.05),其中治疗组改善更显著.结论 疏血通治疗急性缺血性脑卒中疗效显著,值得推广应用.

Abstract：

Objective To evaluate the therapeutic effect of Shuxuetong injection on acute ischemic stroke. Methods One hundred and ninety-six patients with acute ischemic stroke were randomly divided into Shuxuetong injection treatment group (n=98) and control group (n=98). The neurological deficiency scores, scores of cognitive dysfunction and clinical outcomes were evaluated; and the cerebral blood flow were evaluated by Doppler before treatment and 2 weeks after the therapy.Results The improvement of neurological function and clinical outcomes in the Shuxuetong injection treatment group was more obvious as compared with that in the control group and the improvement rate of patients in the treatment group was higher than that in the controls; Patients in the Shuxuetong injection treatment group enjoyed less worsening than the controls. The cognitive dysfunction 2 weeks after the therapy were significantly improved as compared with those before treatment (P＜0.05); and the cerebral blood flow after the treatment was significantly increased as compared with that before the treatment (P＜0.05); these improvements in the Shuxuetong injection treatment group were much obvious as compared with those in the controls. Conclusion Shuxuetong is effective in treating cerebral ischemic patients.     

Transient global amnesia: a quantified electroencephalographic study

In 13 patients who experienced transient global amnesia (TGA), quantified electroencephalographic (qEEG) records were carried out within 1 week of the episodes, and compared with those in 13 cases with cerebral transient ischemic attacks (TIA), and 13 normal controls, matched for age and sex. A statistical comparison of the absolute power showed few differences between TGA and TIA patients, and many statistical differences between TGA patients and controls. The qEEG pattern reveales an involvement of the temporo-parietal structures in TGA patients. These findings suggest the presence of subclinical sequelae, after the TGA attack.     

Evaluation of anticoagulants in patients with cerebral infarction with slight to moderate neurological deficit

In a non-randomized controlled study carried out on 238 hospitalized patients with cerebral infarction, anticoagulant treatment (AC) was compared with the natural course in the prevention of transient ischemic attacks (TIA), cerebral infarction, stroke, stroke or death. 137 patients were allocated to AC, mean follow-up 30.5 months, and 101 patients were allocated to the controls (untreated group), mean follow-up 25.2 months. There were no statistically significant differences among the patients in the group who had suffered TIA (AC treated group 10.2%, untreated group 5.9%), cerebral infarction (AC treated group 10.2%, untreated group 11.9%), stroke (AC treated group 14.6%, untreated group 12.9%), stroke or death (AC treated group 22.6%, untreated group 19.8%). Minor bleedings occurred significantly more frequently (P less than 0.01) in the treated group. Severe bleedings occurred in 8 patients in the treated group (5.8%) compared to 1 of the controls (1%). It is concluded from the trial that AC can only seldom be recommended as prophylactic against new strokes in patients with cerebral infarction due to arterial thromboembolism.     

短暂性脑缺血发作患者短期发生脑梗死的危险因素分析

目的分析短暂性脑缺血发作(TIA)患者7d和30d内进展为脑梗死的危险因素。方法以119例住院TIA患者为研究对象,收集其临床资料和磁共振血管成像(MRA)结果,并按Johnston提出的7分"ABCD2"评分法给予评分,随访发生TIA后7d和30d内脑梗死的发生率。结果 TIA发生后50例(42.0%)患者于30d内发生脑梗死,其中29例(24.4%)发生于7d内。Logistic回归分析发现,症状持续时间≥10min、ABCD2评分≥4分是TIA后7d发生脑梗死的独立危险因素;发作次数≥3次、颅内动脉狭窄≥50%是TIA后30d发生脑梗死的独立危险因素。抗凝治疗是TIA进展为脑梗死的保护因素。结论发作持续时间长、次数多、颅内动脉狭窄重和"ABCD2"评分高的TIA患者短期内脑梗死发生危险性较高,抗凝治疗可使TIA患者有降低脑梗死发生的风险性。     

New therapeutic possibility of blocking cytokine-induced neutrophil chemoattractant on transient ischemic brain damage in rats

Earlier we indicated that neutrophilic invasion into cerebral parenchyma is an important step in rat cerebral ischemia-reperfusion injury and the production of chemotactic factors, cytokine-induced neutrophil chemoattractant (CINC) precede the neutrophilic invasion. The aim of the present study was to evaluate the role of CINC production and the therapeutic possibility of blocking CINC activity in the transient ischemic brain damage in rats. Focal transient ischemia was produced by intraluminal occlusion of the right middle cerebral artery for 60 min. An enzyme immunoassay was used to measure the brain concentration of CINC and myeloperoxidase activity in ischemic areas was measured as a marker of neutrophilic accumulation. An immunohistochemical staining technique was used to detect the immunopositive cells for anti-CINC antibody. Further, application of anti-CINC antibody or anti-neutrophil antibody to rats was used to evaluate the role of CINC production. In ischemic areas, CINC production was detected and peaked 12 h after reperfusion, which followed 60 min of ischemia. Intraperitoneal injection of anti-neutrophil antibody 24 h before and immediately after reperfusion significantly reduced the brain water content and partially reduced the CINC production in ischemic areas. Further, immunohistochemical staining showed that anti-CINC antibody was found on the endothelial surface of venules and on parts of neutrophils that had invaded the ischemic area 6 to 24 h after reperfusion. Also, treatment with anti-CINC antibody reduced ischemic edema formation 24 h after reperfusion and the size of infarction areas 7 days after reperfusion. It thus appears that CINC, mainly produced by endothelium activated by factors released from neutrophils, plays an important role in ischemic brain damage. Furthermore, the blocking of CINC activity with antibody suggests an immuno-therapeutic approach to the treatment of stroke patients.     

Early recurrent ischemic stroke. A case-control study.

BACKGROUND AND PURPOSE: Data concerning potentially treatable risk factors for early recurrent stroke are limited. Therefore, we carried out a retrospective case-control study to identify factors predisposing to early reinfarction. SUMMARY OF REVIEW: We identified all patients admitted to Duke University Hospital or the Durham Veterans Administration Medical Center during 1 year having two documented ischemic strokes within 90 days (n = 12 of 273). Twelve randomly selected patients matched for age, sex, and race but having only a single stroke served as controls. There were no significant differences between the groups with respect to a variety of factors including the presence of hypertension, diabetes, a history of transient ischemic attack, a history of stroke, cerebral site of the index stroke, and subtype of the index stroke. A potential cardioembolic source was more frequently identified in the patients with early recurrent stroke (seven of the 12 case-control pairs were discordant for a potential cardioembolic source; McNemar's chi 2 test, p less than or equal to 0.02). CONCLUSIONS: Of the variables examined, the presence of a potential cardioembolic source was the single statistically significant factor associated with reinfarction within the first 90 days after ischemic stroke. The limitations and possible therapeutic implications of these results are discussed.     

Platelet MAO activity in anorexia nervosa patients with and without a major depressive disorder

Platelet MAO activity was determined in 33 anorexia nervosa patients. A subgroup of 15 patients who met Research Diagnostic Criteria for a concomitant major depressive disorder were found to have, both initially and after 5 weeks of treatment, significantly lower mean platelet monoamine oxidase (MAO) activity than 28 matched normal control subjects. In contrast, mean platelet MAO activity in the patients who did not meet criteria for major depressive disorder was similar to values in control subjects. The authors found that significantly more depressed patients had low MAO activity compared with nondepressed patients and controls. Platelet MAO activity may be useful in discriminating among subtypes of anorexia nervosa patients.     

Platelet thromboxane release after subarachnoid hemorrhage and surgery

We studied adenosine diphosphate-induced platelet aggregation and the associated release of thromboxane B2 in platelet-rich plasma from 88 patients with subarachnoid hemorrhage and 26 healthy controls. During the first 3 days after subarachnoid hemorrhage, the patients showed significantly decreased (p less than 0.05) platelet aggregability and thromboxane release relative to the controls, but these effects disappeared in a few days. Platelet count increased for 3 weeks after subarachnoid hemorrhage. Surgery in 67 patients was followed by significant increases in platelet aggregability (p less than 0.05) and thromboxane release (p less than 0.001). Greatest thromboxane release was found in the eight patients showing delayed (postoperative) ischemic deterioration with a permanent neurologic deficit. Although platelet hyperaggregability and increased thromboxane release were particularly prominent in these eight patients, the role of these hematologic parameters in the pathogenesis of delayed ischemic deterioration remains unclear.