替罗非班辅助血管内治疗急性缺血性脑卒中的疗效评估研究进展

急性缺血性脑卒中（AIS）是脑组织缺血缺氧而引起神经功能损伤的临床综合征。抗血小板治疗是缺血性脑卒中预防及治疗的基础。目前,AIS血管内治疗主要方法有机械取栓、血栓抽吸、动脉溶栓、支架植入等,可有效改善血运及临床症状。但血管内治疗可能会损伤血管内皮细胞,导致血小板聚集及血栓形成。血管内治疗的围手术期使用抗血小板药物是降低手术期间和术后发生血栓形成、栓塞和缺血等并发症风险的常用治疗方法。近年来,有关AIS血管内治疗中抗血小板药物的应用,特别是血小板糖蛋白Ⅱb/Ⅲa（GPⅡb/Ⅲa）受体拮抗剂,使AIS血管内治疗的发展前景充满希望。目前,美国食品药品监督管理局发布的GPⅡb/Ⅲa受体拮抗剂有3种,分别为替罗非班、阿昔单抗和依替巴肽。替罗非班是国内临床中主要应用的GPⅡb/Ⅲa受体拮抗剂,GPⅡb/Ⅲa受体作为血小板聚集、血栓形成的最终通路,其拮抗剂通过直接与GPⅡb/Ⅲa受体结合,从而快速发挥抗血小板聚集的作用。替罗非班作为的新型抗血小板药物,在心血管疾病中的应用已经基本成熟,但是在脑血管疾病中的应用仍处于探索阶段,具体用法、用量及安全性仍有较多争议,且属于超说明书用药。该文就替罗非班在急性缺血性脑卒中血管内治疗中的应用及研究进展进行综述。     

一个任重道远的话题：基层医院对急性缺血性卒中诊治指南的实践

急性缺血性卒中（acute ischemic stroke，AIS）诊治是一个系统工程。AIS诊疗指南可规范和指导临床实践，但指南在临床实践中应用时，各基层医院可能面临不同的问题。本文对临床中的常见问题包括AIS的急诊评估和转运、影像评估、溶栓和抗栓治疗及血管内治疗等进行了总结和评价。     

阿司匹林对缺血性脑血管病患者抗血小板聚集作用的临床观察

阿司匹林是抗血小板聚集药物，广泛应用在心脑血管疾病的治疗和预防。本研究对日服阿刮匹林75mg的68例缺血性脑血管病（ICVD）患者通过测定其血小板聚集率观察阿司匹林的抗血小板聚集作用。     

血小板糖蛋白Ⅱb／Ⅲa受体拮抗剂在缺血性脑卒中应用的现状

血小板糖蛋白（GP）Ⅱh／Ⅲa受体拮抗剂是一类新型抗血小板聚集药物,它通过抑制纤维蛋白原（Fg）与GPⅡb／Ⅲa特异性结合,有效地阻止各种途径诱导的血小板聚集,从而达到最大程度的抗血小板作用。在心血管领域已有大量的临床循证医学证据表明,GPⅡb／Ⅲa受体拈抗剂在急性冠脉综合征（ACS）和经皮冠状动脉介入治疗（PCI）抗栓中的疗效和安全性。近年来,国外开始陆续有GPⅡb／Ⅲa受体拮抗剂应用于缺血性脑卒中的报道,而国内的研究几乎是空白。藉此,本文就这一方面的相关研究综述如下。     

抗血小板药物治疗反应多样性与对氧磷酶1/血小板内皮聚集受体1基因相关性研究进展

抗血小板聚集药物是脑梗死患者的标准化治疗方案主要药物之一，在二级预防中占重要地位。但是，抗血小板药物疗效有很大个人差异，即抗血小板药物治疗反应多样性（VPR），其可能导致缺血性脑血管病的复发。影响VPR的因素有很多，其中遗传因素发挥重要作用。近年来有两个基因位点研究较多，对氧磷酶1（PON1）基因Q192R位点和血小板内皮聚集受体1（PEAR1）基因rs12041331位点，基因多态性和甲基化共同控制PON1酶和PEAR1受体的浓度或数量水平，从而影响药物代谢。该文拟对以上两个基因位点的基因多态性及其甲基化分别与VPR和缺血性不良事件的相关性进行综述，旨在为抗血小板药物治疗相关研究提供新的依据。     

抗血小板药物对造影阴性蛛网膜下腔出血病人颅内出血的影响

目的 探讨抗血小板药物与造影阴性蛛网膜下腔出血（NaSAH）病人出血量及出血进展的关系。方法 回顾性分析2009年5至2022年3月收治的62例NaSAH的临床资料。结果24例入院前有抗血小板药物治疗史（观察组），36例无抗血小板药物治疗史（对照组）。观察组16例服用阿司匹林，10例服用氯吡格雷，2例服用双抗治疗，抗血小板药物使用时间平均（11.4±3.8）个月。观察组出血量[（13.8±6.3）ml]明显高于对照组[（8.7±4.6）ml；P<0.05]。观察组出血扩展率（45.8%）高于对照组（23.7%；P=0.069）。结论 抗血小板药物使用与NaSAH颅内出血量增加、出血扩展有关。     

急性缺血性卒中的抗血小板治疗

急性缺血性卒中患者血小板被激活，抗血小板治疗可减少早期脑梗死的复发，减轻脑损伤的体积，降低早期死亡和改善存活者的长期预后。但抗血小板治疗增加非致死性或症状性颅内出血的发生率。阿司匹林是证据最充分且得到各国指南推荐的治疗急性缺血性卒中的抗血小板药物，对未溶栓治疗的急性缺血性卒中患者应尽早开始阿司匹林治疗。氯吡格雷、血小板糖蛋白Ⅱb/IIIa受体抑制剂、双嘧达莫、西洛他唑等单药用于治疗急性缺血性卒中的安全性和疗效目前尚无足够的证据。抗血小板药物联合应用的疗效和可能的风险尚需进一步研究。     

抗血小板药物治疗的实验室检测

基于一级和二级预防实验结果,当前国内外的缺血性心脑血管疾病防治指南均推荐应用抗血小板药物（Ⅰ级证据）。但值得注意的是约一半患者对抗血小板药物存在＂抵抗＂或＂无效＂的认识,针对上述患者的临床发现存在滞后性。本文重点讨论一些当前国内外用于抗血小板药物（阿司匹林和氯吡格雷）疗效评价实验室方法的优缺点。一些方法已应用于基础和临床研究且有证据支持可预测抗血小板药物的疗效。但至今尚无任何一项研究是通过上述实验室方法检测抗血小板药物来说明改变治疗的临床转归。因此未来的发展应是寻找更加有药物特异性和非特异性的实验室方法,并探讨这些实验室指标与药物临床效果的量化联系。     

替罗非班在动脉粥样硬化性脑血管疾病中的临床应用专家共识

<正>抗血小板治疗是血栓栓塞性疾病如急性冠脉综合征(acute coronary syndrome,ACS)和缺血性卒中的基本治疗策略。现有的抗血小板药物中(表1),阿司匹林通过抑制环氧合酶和血栓素A_2的合成发挥抗血小板聚集的作用,噻吩吡啶类(氯吡格雷、替格瑞洛)通     

急性缺血性卒中血管内治疗围手术期抗凝治疗研究进展

目前急性缺血性卒中（acuteischemicstroke,AIS）患者在血管内治疗（endovascular treatment,EVT）围手术期进行抗凝治疗的安全性和有效性尚未明确。现有研究表明,在EVT术前使用抗凝药物并不会增加患者出血或不良预后的风险。而EVT术中抗凝虽然无法显著提高血管再通率,但对于改善患者的长期预后可能有积极作用。此外,EVT术后抗凝可以预防颅内动脉再闭塞的发生,并可能有改善脑部微循环的作用。因此,对于抗凝指征更加明确的、伴有心房颤动的AIS患者是否可以尽早开始抗凝值得进一步探索,今后仍需开展更多临床研究来评估AIS患者EVT围手术期抗凝治疗的安全性和有效性。     

Ongoing and planned trials of antiplatelet therapy in the acute and long-term management of patients with ischaemic brain syndromes: setting a new standard of care

Among high vascular risk patients, acetylsalicylic acid (ASA) reduces the relative risk of serious vascular events by about one fifth. However, because ASA fails to prevent four fifths of serious vascular events, more effective, yet equally safe and affordable, antiplatelet regimens are desired. Compared with ASA, clopidogrel alone reduces the odds of serious vascular events by about 10%, and the combination of dipyridamole and ASA reduces the odds of serious vascular events by about 6%. Combining ASA with an orally administered platelet glycoprotein (GP) IIb/IIIa blocker is not effective, and indeed more hazardous than ASA alone. Among patients with non-ST-segment acute coronary syndromes (ACS), the addition of an intravenously administered GP IIb/IIIa receptor antagonist to ASA reduces the risk of vascular events by about 10% compared with ASA, and the addition of clopidogrel to ASA reduces the risk of vascular events by 20% compared with ASA alone. Among patients undergoing percutaneous coronary intervention (PCI), both the addition of an intravenously administered GP IIb/IIIa receptor antagonist to ASA, and the addition of clopidogrel to ASA reduce the risk of vascular events by 30% compared with ASA alone. The greater efficacy of the combinations of ASA with clopidogrel, and ASA with an intravenously administered GP IIb/IIIa receptor antagonist, in patients with ACS and those undergoing PCI has fostered several ongoing and planned trials of these regimens in the acute and long-term management of patients with ischaemic brain syndromes. The combination of ASA and clopidogrel is being compared with ASA alone within 12 h of onset of symptoms of TIA in two trials (FASTER, ATARI), and the use of an intravenously administered GP IIb/IIIa receptor antagonist is being compared with placebo within 6 h of onset of acute ischaemic stroke in two trials (AbESST, AbESST-2). Six trials are assessing the combination of clopidogrel and ASA in the long-term management of patients with ischaemic brain syndromes due to atherothrombosis (MATCH, CHARISMA, ARCH, CARESS, SPS3) or atrial fibrillation (ACTIVE). The MATCH trial of clopidogrel and ASA versus clopidogrel alone in patients with recent TIA or ischaemic stroke is the first which is likely to report its results - in mid 2004. The combination of dipyridamole and ASA is being compared with ASA in the ESPRIT trial and with the combination of clopidogrel and ASA in the planned PRoFESS trial. These ongoing and planned clinical trials of antiplatelet therapy promise to further define the role of combination antiplatelet therapy in the acute and long-term management of patients with ischaemic brain syndromes.     

Ischemic brain tissue salvaged from infarction by the GP IIb/IIIa platelet antagonist tirofiban

In an open pilot study, the authors tested whether the nonpeptide glycoprotein (GP) IIb/IIIa antagonist tirofiban, a highly effective and selective blocker of platelet aggregation, prevents the transition of ischemic brain tissue into the infarct proper as defined by MRI (perfusion-weighted/T2-weighted) in patients with acute ischemic stroke. The infarct volume (T2 lesion after 1 week) was smaller in treated patients (n = 10) compared with matched control subjects (n = 10; p = 0.029) with similar initial perfusion deficit (TTP-maps). The authors conclude that GP IIb/IIIa antagonists have therapeutic potential in acute stroke therapy.     

Regulation of clot retraction by glycoprotein IIb/IIIa antagonists

Binding of fibrinogen to platelet glycoprotein (GP) IIb/IIIa induces clot retraction. Significant differences among GP IIb/IIIa antagonists were previously noted to inhibit thromboelastography in whole blood specimens. The relationship between efficacy of these agents and inhibition of clot retraction is unclear. Here, we use a plasma-free clot retraction assay to evaluate potency of GP IIb/IIIa antagonists to inhibit clot retraction and modulate platelet signaling, and to address whether these effects are realized in the clinically relevant dose range. The potencies for inhibition of clot retraction and aggregation are similar for antagonists with high affinity for resting platelets and slow off-rates, whereas lower affinity and fast off-rate antagonists are disproportionately less effective in blocking clot retraction. A positive correlation is observed between inhibition of clot retraction and inhibition of tyrosine dephosphorylation across a number of GP IIb/IIIa antagonist pharmacophores. For lower affinity and fast off-rate antagonists, the concentrations required for inhibition of clot retraction clearly exceed the clinical dose range. Site occupancy studies combined with clot retraction experiments addressed whether high affinity and slow off-rate compounds can alter clot retraction during the dosing interval. Binding studies using [3H] Roxifiban, a high affinity GP IIb/IIIa antagonist, indicate that occupancy of >95% of GP IIb/IIIa sites is required to inhibit clot retraction. This level of occupancy is not routinely achieved in the clinic and is not tolerated, at least for chronic therapy. These results suggest that inhibition of clot retraction is not necessary for efficacy of GP IIb/IIIa antagonists.     

A defined peptide that inhibits the formation of the glycoprotein IIb and IIIa complex

Collagen–platelet interaction plays an important role in hemostasis and pathological thrombosis. The proposed mechanism of the interaction was the activation of platelets→releasing of contents from granules→aggregation. The common end point is the platelets and fibrin aggregates. Platelet glycoprotein (GP) IIb/IIIa (the IIbβ3 integrin) complexes serve as a receptor for the binding of fibrinogen to form firmed aggregates. Blockading of GP IIb/IIIa has been proposed to prevent platelet aggregation independent of the substance(s) responsible for activating the platelets. The development of various forms of GP IIb/IIIa inhibitor has resulted in the inhibition of platelet aggregation, although studies of IIbβ3 receptor function and various GP IIb/IIIa inhibitors have demonstrated the potential for these agents to produce effects on other aspects of platelet function as well as having nonplatelet effects. This study investigated platelet inhibition provided by blocking the GP IIb/IIIa complex formation by using a peptide derived from the GP IIIa molecule. The peptide inhibits both types I and III collagen-induced platelet aggregation in a dose-dependent manner. The defined peptide interferes with the formation of the GP IIb/IIIa complex by inhibiting the binding of FITC–PAC-1 onto ADP-, type I collagen-, and type III collagen-activated platelets. However, P-selectin secretion is not affected by the peptide. In addition, the peptide is not interfering with the binding of FITC–PAC-1 to platelets that were preincubated with indomethacin. Results from this study may suggest that the defined peptide is an effective agent to block the interaction of types I and III collagen with platelets.     

Intrinsic activating properties of GP IIb/IIIa blockers

Potential intrinsic activating properties are probably the most controversially discussed issues with respect to GP IIb/IIIa blockers, especially since clinical trials with oral GP IIb/IIIa blockers revealed disappointing results. Based on the finding that currently clinically used GP IIb/IIIa blockers are ligand mimetics, experimental data are discussed, demonstrating an intrinsic activating effect of ligand mimetic GP IIb/IIIa blockers that potentially results in fibrinogen binding to alpha(IIb)beta(3) and in platelet aggregation. Furthermore, the inhibitory effect of aspirin on GP IIb/IIIa blocker-induced platelet aggregation is discussed as a clinically relevant finding. Finally, the potential association of GP IIb/IIIa blocker-induced thrombocytopenia with platelet activation is described.     

A new variant of thrombasthenia with abnormally glycosylated GP IIb/IIIa

A 15 year-aged Japanese girl with a life long mild purpura was found as a variant type of thrombasthenia. Basic tests revealed prolonged bleeding time, border-line clot retraction, no coagulation defect, no giant platelets and mild thrombocytopenia (70,000-110,000/microliters). Neither ADP, epinephrine nor collagen aggregated her platelet rich plasma. Thrombin (0.1U/ml) caused slightly decreased aggregation of her washed platelets and about 20% normal production of thromboxane B2. PAS-stained SDS-PAGE of her whole platelets showed markedly decreased GP IIb and IIIa. However, crossed immunoelectrophoresis (CIE) against anti-whole platelets antibody showed a normal amount of GP IIb/IIIa complex in her whole platelets solubilized with 1% Triton X-100. CIE using monospecific anti-GP IIb/IIIa complex antibody showed normal dissociation of the patient's GP IIb/IIIa complex into two new bands in the presence of EDTA. Crossed affino-immunoelectrophoresis with the first dimension containing Concanavalin A revealed that the patient's GP IIb/IIIa was much less shifted to the cathode than controls. Immunoprecipitation lines of her GP IIb/IIIa complex were excised from unstained CIE using anti-GP IIb/IIIa antibody and subjected to the silver-stained reduced SDS-PAGE, which showed two protein bands with molecular weights of 125KD and 108KD, corresponding to GP IIb alpha and GP IIIa, respectively. These results suggest that the platelets of this apparently thrombasthenic patient have an antigenically normal but abnormally glycosylated GP IIb/IIIa complex, which is functionally abnormal because of abnormal glycosylation.     

Heparin potentiation of collagen-induced platelet aggregation is related to the GPIIb/GPIIIa receptor and not to the GPIb receptor, as tested by whole blood aggregometry.

To determine whether heparin potentiation of platelet aggregation is related to platelet GP IIb/IIIa and GP Ib receptors, four series of experiments were performed on blood from normal volunteers. In the first experiment pretreatment with the monoclonal antibody 7E3 (MAb 7E3), which antagonizes at the GP IIb/IIIa receptor, potently inhibited the collagen-induced platelet aggregation (p less than 0.001). With heparin added to blood pretreated with MAb 7E3, the aggregation increased (p less than 0.005) to an extent similar to that when only saline was used for pretreatment. In the second experiment, monoclonal antibody 10E5 (MAb 10E5) and peptide RGDS, substances which also antagonize at the GP IIb/IIIa receptor, decreased collagen-induced platelet aggregation to an extent similar to that after pretreatment with MAb 7E3. Following pretreatment with RGDS, heparin increased platelet aggregation (p less than 0.03), while after pretreatment with antibody MAb 10E5 heparin did not enhance platelet aggregation. In the third experiment aurin, an inhibitor of von Willebrand factor and its interaction with the platelet GPIb receptor, decreased platelet aggregation dose-dependently. In the fourth experiment heparin enhanced platelet aggregation to a similar extent (p less than 0.005), regardless of pretreatment of the blood with saline, aurin or monoclonal antibody 6D1 (MAb 6D1), the latter an antagonist at the GP Ib receptor. In conclusion, the potentiation of collagen-induced platelet aggregation by heparin was not inhibited by MAb 7E3, RGDS, aurin or MAb 6D1, but was abolished by MAb 10E5, implying that the heparin effect is related to activation of the platelet GP IIb/IIIa receptor complex.     

Comparative study of antiplatelet drugs in vitro: distinct effects of cAMP-elevating drugs and GPIIb/IIIa antagonists on thrombin-induced platelet responses.

Among various categories of antiplatelet drugs, cAMP-elevating agents and GP IIb/IIIa antagonists have been reported to inhibit platelet aggregation stimulated by a wide variety of platelet agonists. To clarify the qualitative difference between these two agents, their effects on various platelet responses in washed platelets evoked by thrombin (0.05 U/mL) were compared in vitro. Two types of cAMP-elevating drugs, cilostazol (a phosphodiesterase III inhibitor) and prostaglandin E1 (an adenylate cyclase activator), both inhibited platelet aggregation, thromboxane A2 formation, and platelet factor 4 release in a concentration-dependent manner. In addition, both agents suppressed intracellular Ca++ elevation induced by thrombin. However, two classes of GP IIb/IIIa antagonists, abciximab (Fab fragment of antibody) and tirofiban (a synthetic compound), showed no inhibitory effects against thromboxane A2 formation and platelet factor 4 release, although these drugs inhibited platelet aggregation. Essentially the same results were obtained in platelet-rich plasma stimulated with high concentration (100 microM) of thrombin receptor activating peptide. In contrast to these different profiles on thromboxane A2 formation and release reaction, both cAMP-elevating agents and GP IIb/IIIa antagonists potently suppressed procoagulant activity in thrombin-stimulated platelets. These results suggest that the development of platelet procoagulant activity induced by thrombin is exclusively dependent on platelet aggregation or aggregation-dependent processes. These observations also indicate that cAMP-elevating agents possess wider inhibitory effects on platelet responses evoked by strong agonists than GP IIb/IIIa antagonists.     

Upregulation of GP IIb/IIIa receptors during platelet activation: influence on efficacy of receptor blockade

INTRODUCTION: GP IIb/IIIa inhibitor doses high enough to inhibit platelet macroaggregation may not completely prevent formation of microaggregates. Platelets contain an internal pool of GP IIb/IIIa receptors which externalizes with activation and supports microaggregation. This study assesses microaggregation in the presence of the two GP IIb/IIIa inhibitors abciximab and tirofiban. METHODS: Citrated whole blood was preincubated with abciximab (5 microg/ml), tirofiban (50 ng/ml), or saline as control and activated with TRAP (5 microM) or ADP (2 microM) at 37 degrees C under constant stirring. Microaggregate formation and receptor expression were determined with flow cytometry. RESULTS: Within few seconds after TRAP-activation the platelet count dropped from 266,000/microl to 20,000/microl, the number of microaggregates increased from 3700/microl to 10,100/microl and the mean number of GP IIb/IIIa receptors increased from 53,000 to 65,000/platelet. With TRAP+abciximab the platelet count dropped from 259,000 to 113,000/microl, microaggregates increased from 2500 to 9300/microl, GP IIb/IIIa receptors from 56,000 to 77,000/platelet. Platelet microaggregate formation was reversible. With TRAP and tirofiban platelet count dropped to only 190,000/microl, there was no increase in platelet microaggregates, receptors increased to 66,000/platelet. Platelet activation with ADP gave similar results. CONCLUSIONS: During the early phase of activation additional GP IIb/IIIa receptors externalize to the platelet surface. Abciximab does not block these new receptors sufficiently to prevent microaggregate formation. However, the number of unblocked receptors is not high enough to maintain a stable aggregate, microaggregation is reversible. With tirofiban there is no microaggregate formation, possibly because the inhibitor rapidly binds to newly externalized receptors.     

Abciximab therapy is associated with increased platelet activation and decreased heparin dosage in patients with acute myocardial infarction

The inhibition of the glycoprotein (GP) IIb/IIIa receptor for reducing periprocedural ischemic events in patients undergoing coronary intervention is known to influence platelet reactivity. Suboptimal doses of GP IIb/IIIa antagonists have been suggested to be prothrombotic and proinflammatory. This study was performed to observe platelet activation markers, whole blood aggregation and the dosage of unfractionated heparin (UFH) in the presence or absence of the GP IIb/IIIa inhibitor abciximab. Patients with acute myocardial infarction undergoing percutaneous coronary intervention were treated with (n = 15) or without (n = 15) abciximab. Platelet activation markers were flow cytometrically measured before and after PCI. Whole blood platelet aggregation was tested by a platelet function assay. The patients with abciximab showed a significant increase in platelet activation markers (P-selectin: 7.12 +/- 0.36 AU vs 11.05 +/- 0.79 AU) and a lower requirement of UFH to prolong aPTT > 60 sec during the infusion. 12 hours after infusion P-selectin level decreased (7.20 +/- 0.58 AU), whereas whole blood aggregation was increasing again. After stopping abciximab, requirement of UFH to prolong aPTT increased in the treated group to a greater extent to a level similar to the untreated group even when most of the platelets were still inhibited. The increased platelet activation found at the end of abciximab treatment points to a procoaguable condition that should be carefully monitored and treated by adapting anticoagulation and antiplatelet drugs.