Distributed intraclot thrombolysis: mechanism of accelerated thrombolysis with encapsulated plasminogen activators.

BACKGROUND: The delivery of encapsulated plasminogen activators has demonstrated enhanced thrombolysis in vivo in several models. The mechanism of such improvement has not previously been established. OBJECTIVES: We explored in vitro the mechanism by which microencapsulation of streptokinase in polymeric microparticles accelerates clot digestion and reduces reperfusion times by as much as an order of magnitude in vivo. METHODS: The efficacy of microencapsulated streptokinase (MESK) was directly compared with identical dosages of unencapsulated streptokinase (FREE SK) at three initial pressure drops using clots formed of plasma or whole blood in 0.2-cm inner diameter glass capillary tubes. RESULTS: MESK demonstrated accelerated flow restoration compared with FREE SK for each condition in plasma (23.8 +/- 4.5% faster) and whole blood clots (17.2 +/- 9.2% faster). Images collected by light microscopy show sites of thrombolysis internal to the clot only with MESK while the spatial distribution of fluorescently labeled streptokinase by confocal microscopy confirms greater penetration of the encapsulated agent compared with unencapsulated streptokinase. Digestion thus proceeds in three dimensions rather than restricted to a two-dimensional lysis front. CONCLUSIONS: The improved clot penetration with MESK establishes enhanced transport with encapsulation and the concept of distributed intraclot thrombolysis as a basis for the accelerated dissolution observed with encapsulated plasminogen activators in vivo.     

Effect of urokinase antiserum on plasminogen activators: demonstration of immunologic dissimilarity between plasma plasminogen activator and urokinase

Antiserum against purified human urokinase was produced by immunization of Hartley strain guinea pigs. The antiserum was capable of neutralizing the plasminogen activator activity of the antigen and of native urokinase in human urine. The antiserum did not inhibit plasminogen activators of bacterial origin, i.e., streptokinase and staphylokinase; neither did it inhibit urokinase from nonprimate mammals, i.e., dog, pig, rabbit, guinea pig, nor tissue activator or tissue culture supernatants from porcine sources. Partial cross-reactivity against urokinase from primates, i.e., rhesus monkey and baboon, was noted as well as with supernatant from rhesus kidney tissue culture. In vitro studies showed lack of immunologic identity between human urokinase and human milk activator or human tissue activator from adrenal sources but demonstrated immunologic identity between human urokinase and the supernatant from human kidney tissue culture. In vivo studies in man failed to show detectable levels of urokinase activity in peripheral venous or renal venous blood under a variety of clinical states and when stimuli such as exercise, electroshock therapy, or nicotinic acid were used to enhance plasminogen activator activity in the plasma. The results establish that human plasma activator, milk activator, and tissue activator from the adrenals are immunologically distinct from human urokinase.     

艾通立早期静脉溶栓治疗急性脑梗死--附100例病例分析

目的：评价重组组织型纤溶酶原激活剂(rt-PA)艾通立对急性脑梗死早期静脉溶栓治疗的疗效及安全性，同时探讨国人应用rt-PA治疗的最佳剂量。方法：凡符合入选标准的患者随机分为A、B、C 3组，A组为rt-PA0．9mg／kg，B组为rt-PA 0．7mg／kg，C组作为对照组不用rt-PA。溶栓两组先将总量中的8mg静脉快速推入，剩余量在1h内用静脉泵输入，总量均不超过90mg。观察3组治疗后24h、90d神经功能缺损评分，及90d日常生活能力指数(Barthel)，同时观察3组治疗后30d脑出血率及病死率。结果：A组溶栓后24h和90d治愈及显效率为41．18％和76．47％，90d Barthel指数为95～100分者占58．82％，30d脑出血率为8．82％，病死率为5．88％。B组溶栓后24h和90d治愈及显效率为39．39％和69．70％，90d Barthel指数为95～100分者占54．55％，30d脑出血率为9．09％，病死率为9．09％。C组治疗后24h和90d治愈及显效率为21．21％和30．30％，90d Barthel指数为95～100分者占21．21％，30d病死率为9．09％。90d溶栓组显效率(73．13％)明显高于对照组(30．30％，P=0．0017)，严重致残率分别为13．43％和24．24％。结论：急性脑梗死静脉应用rt-PA溶栓治疗是安全有效的，国外0．9mg／kg的剂量也适用于国人。     

Liquid jets, accelerated thrombolysis: a study for revascularization of cerebral embolism.

A prior study has reported that a rapid recanalization therapy of cerebral embolism, using liquid jet impacts generated by the interaction of gas bubbles with shock waves, can potentially penetrate through thrombi in as little as a few microseconds with very efficient ablation (Kodama et al. 1997). The present study was undertaken to examine the liquid jet impact effect on fibrinolysis in a tube model of an internal carotid artery. First, the conditions for generating the maximum penetration depth of liquid jets in the tube were investigated. Gelatin was used to mimic thrombi. The shock wave was generated by detonating a silver azide pellet weighing about a few micrograms located in a balloon catheter. The collapse of the inserted gas bubbles and the subsequent liquid jet formation were recorded with high-speed photography. Second, thrombi were formed using fresh human blood from healthy volunteers. The fibrinolysis induced by the liquid jet impact with urokinase was explored. This was conducted under selected conditions based on the experiment using the gelatin. Fibrinolysis was calculated as the percentage of the weight loss of the thrombus. Fibrinolysis with urokinase alone and with a single liquid jet impact with urokinase was 1.9 +/- 3.7% (n = 16) and 20.0 +/- 9.0% (n = 35), respectively, for an incubation time of 60 min. Statistical differences were obtained between all groups (ANOVA). These results suggest that liquid jet impact thrombolysis has the potential to be a rapid and effective therapeutic modality in recanalization therapy for patients with cerebral embolism and other clinical conditions of intra-arterial thrombosis.     

Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) in acute lower limb ischaemia

For various reasons some patients are unable to undergo intra-arterial thrombolysis for acute limb ischaemia. This interventional case series study prospectively evaluated the effect of thrombolytic treatment with 100 mg recombinant tissue plasminogen activator (rt-PA), administered intravenously, in patients with acute thrombosis of the lower limb arteries and onset of symptoms within 12 h prior to treatment. During a 3-year period (2007-2009), 18 of 86 patients satisfied the inclusion criteria and were included in the study (age range 65-80 years; 11 women). Complete and partial thrombolysis was observed in eight (44.4%) and six (33.3%) patients, respectively. All patients experienced clinical improvement. There were no amputations during the 36-month follow-up period and no haemorrhagic complications in the first 30 days post-treatment. Five patients died (27.8%) during follow-up from unrelated causes. This small study demonstrated that thrombolytic treatment with intravenous rt-PA in selected patients with acute limb ischaemia is feasible.     

Endovascular treatment of acute limb ischemia: review of current plasminogen activators and mechanical thrombectomy devices

Acute limb ischemia occurs in 15% to 20% of patients with chronic peripheral arterial disease. Off-label use of tissue plasminogen activators is the most common approach for patients with ischemic limbs that can wait 24 to 48 hours to restore flow. In the past decade, mechanical thrombectomy devices that use aspiration, maceration, or ultrasound waves have been developed to allow more rapid restoration of flow. Combination therapy with both mechanical and pharmacologic thrombolysis has become commonplace without randomized data to support its use. This article reviews acute limb ischemia and data regarding pharmacologic and mechanical thrombolysis.     

Scapular motion is accelerated in asymptomatic individuals with dyskinesis: An observational study

IntroductionIndividuals with shoulder and upper extremity pathology often present with altered scapular motion. Few studies have looked at variations in scapular acceleration as a way of quantifying scapular motion. The purpose was to determine the effectiveness of wireless accelerometers for detecting changes in acceleration in individuals with scapular dyskinesis.Materials/methodsTwenty-seven asymptomatic college students (mean age 24 (SD ± 1.54), 65% female, 93% right handed) were visually screened for scapular dyskinesis using previously described criteria. Of the students recruited, fifteen students were determined to have scapular dyskinesis. After securing a wireless accelerometer (MyoResearch 3D DTS) on the dominate scapula, the participants performed five repetitions of standing scaption from 0 to 140°. Linear scapular accelerations along three orthogonal axes (frontal-y, transverse-z, and sagittal-x) were collected. Intraclass correlation coefficients (ICC_{3, k}) were used to determine the between day intra-rater reliability while a one-way analysis of variance was used to determine differences in acceleration between those with and without dyskinesis.ResultsThere was good between day intra-rater reliability for the average of all three axes (ICC = 0.79) and for the x and y axes (ICC > 0.78). Reliability was poor (ICC = 0.31) for the z-axis. There was a significant increase in overall acceleration of the scapula in those with dyskinesis (p = .039). There was also a significant increase in acceleration along the y-axis for those with dyskinesis (p = .003) but not for the other axes (p > .16).ConclusionWireless accelerometers reliably quantify scapular acceleration in healthy individuals. In a healthy population with dyskinesis, the overall magnitude of scapular acceleration was greater when compared to a healthy group without dyskinesis.     

Use of transesophageal echocardiography during thrombolysis with tissue plasminogen activator of a thrombosed prosthetic mitral valve.

Inadequate anticoagulation in patients with mechanical prosthetic heart valves can result in a significant incidence of thromboembolic complications. An even more life-threatening complication is massive thrombosis of the valve itself. Thrombolytic therapy was given to a moribund 22-year-old woman with intractable heart failure caused by a thrombosed St. Jude prosthetic mitral valve (St. Jude Medical, Inc., St. Paul, Minn.). Although this form of therapy has been used before, this is the first report of a case in which transesophageal echocardiography was performed during thrombolytic therapy to continually record successful thrombolysis of the clotted prosthetic valve. Serial imaging during thrombolysis displayed progressive dissolution of the thrombus and progressive improvement in valve function. Transesophageal echocardiography is helpful in the diagnosis of prosthetic valve thrombosis and has the ability to monitor continually the effect of treatment with thrombolysis. Although thrombolytic therapy with recombinant tissue plasminogen activator is effective in treating prosthetic valve thrombosis, it carries a high risk for serious thromboembolic complications and thus should be reserved for critically ill patients who are too sick to undergo immediate surgery.     

Alpha 2-antiplasmin supplementation inhibits tissue plasminogen activator-induced fibrinogenolysis and bleeding with little effect on thrombolysis.

Tissue plasminogen activator (t-PA) causes fibrinogen proteolysis when alpha 2-antiplasmin levels fall, and this may contribute to t-PA-induced hemorrhage. Because clot-bound plasmin is protected from alpha 2-antiplasmin inhibition, we tested the possibility that alpha 2-antiplasmin supplementation would block t-PA-induced fibrinogenolysis and bleeding without affecting thrombolysis. When added to human or rabbit plasma, alpha 2-antiplasmin inhibits t-PA-induced fibrinogenolysis, but hat little effect on the lysis of 125I-fibrin clots. To examine its effect in vivo, rabbits with preformed 125I-labeled-jugular vein thrombi were randomized to receive t-PA, t-PA and alpha 2-antiplasmin, or saline. alpha 2-Antiplasmin infusion produced a modest decrease in t-PA-induced thrombolysis (from 40.2% to 30.1%, P = 0.12), but reduced fibrinogen consumption from 87% to 27% (P = 0.0001), and decreased blood loss from standardized ear incisions from 5,594 to 656 microliter (P < 0.0001). We hypothesize that alpha 2-antiplasmin limits t-PA-induced hemorrhage by inhibiting fibrinogenolysis and subsequent fragment X formation because (a) SDS-PAGE and immunoblot analysis indicate less fragment X formation in alpha 2-antiplasmin treated animals, and (b) when added to a solution of fibrinogen and plasminogen clotted with thrombin in the presence of t-PA, fragment X shortens the lysis time in a concentration-dependent fashion. These findings suggest that fragment X incorporation into hemostatic plugs contributes to t-PA-induced bleeding. By blocking t-PA-mediated fibrinogenolysis, alpha 2-antiplasmin supplementation may improve the safety of fibrin-specific plasminogen activators.     

穿支动脉区孤立性梗死静脉溶栓治疗研究

目的 对比穿支动脉区孤立性梗死与其他类型脑梗死经静脉rtPA溶栓治疗后出血转化及神经功能结局的差异,明确穿支动脉区孤立性梗死静脉溶栓的安全性和有效性.方法 回顾分析了浙江大学医学院附属第二医院神经内科前瞻性收集的2009.06-2011.04期间接受静脉rtPA溶栓治疗的缺血性中风患者资料,包括性别、年龄、既往史、溶栓时间、基线NIHSS、血压、血糖、电解质、凝血谱、心电图、头颅MRI、颅内外MRA(或CTA)等,按照中国缺血性中风亚型(CISS)标准1予以病因分组.结果 共75例患者接受静脉rtPA治疗,年龄(67.4±12.7)岁,女性25例,占33.3％;溶栓前NIHSS(12.3±6.4)分;发病至溶栓时间:(239.6±97.5)min; 72例(96％)在24 h接受多模式MRI复查.共24例(32％)示溶栓后出血转化,4例(5.3％)为症状性出血.22例(29.3％)患者为穿支动脉区域孤立性梗死,仅1例(1.3％)发生出血转化.Logistic回归分析发现,穿支动脉区孤立性梗死明显降低溶栓后的出血转化风险(OR=0.075,95％CI:0.008～0.663; P=0.020).并发现,82％的穿支动脉区孤立性梗死患者的1月mRS评分≤2,其神经功能结局较其梗死好(P＜0.01).结论 穿支动脉区域孤立梗死患者相对于其他类型脑梗死患者在经静脉rtPA溶栓治疗后,显示出更低的出血转化率和较好的神经功能结局,故对 此类患者的静脉溶栓治疗可更积极.     

小剂量重组组织型纤溶酶原激活剂静脉加速给药法治疗急性心肌梗死

目的评价小剂量重组组织型纤溶酶原激活剂（rt-PA）50 mg加速给药法对急性心肌梗死（AMI）溶栓的疗效及安全性.方法共入选符合条件的患者236例.随机分为观察组与对照组,观察组120例：小剂量rt-PA加速给药,rt-PA给予8 mg静脉注射,继之42 mg在60分钟内静脉滴注;对照组116例：rt-PA给予8 mg静脉注射,继之42 mg在90分钟内静脉滴注;所有患者均给予静脉肝素治疗,以用药后临床2小时再通指标为主要终点.结果观察组冠脉再通率高于对照组（84.1%vs 70.7%,P＜0.05）两组出血率无差别,两组各有1例颅内出血,但差异无统计学意义.结论小剂量rt-PA加速给药治疗AMI疗效更好,且同样安全.