EFFECTS OF LOCALLY ADMINISTERED ARGATROBAN ON RESTENOSIS AFTER BALLOON ANGIOPLASTY: EXPERIMENTAL AND CLINICAL STUDY

1. This study was undertaken to evaluate the preventive effects of locally administered argatroban, a competitive inhibitor of thrombin-induced platelet activation, on restenosis after balloon angioplasty. 2. A hydrogel-coated balloon catheter was immersed three times in argatroban/saline solution (1 mg/mL) for 60 s, inflated to a pressure of 606 kPa and left in the rabbit common carotid artery for 1 min. The same procedure was performed, without drug, as a control. The pharmacokinetics of delivered argatroban in the arterial wall were assessed using [¹⁴C]-argatroban. Platelet deposition 2h after balloon injury was quantified by fluorescence studies using antiplatelet antibody. Vascular smooth muscle cell (VSMC) proliferation 3 days after balloon injury was assessed by immunohistochemical staining for proliferative cell nuclear antigen (PCNA). In a clinical study, we divided 50 elective patients into two groups: argatroban and control. 3. In the experimental study, the mean quantities of argatroban at 0, 2 and 6 h after deflation wer. 24.63, 0.49 and 0.11 nmol/g wet weight of artery, respectively. Argatroban was undetected 24 h after deflation. Two hours after deflation, argatroban-treated arteries showed less platelet adhesion than saline-treated controls. The mean number of PCNA-positive cells was 16.9 and 43.8% in the argatroban and control groups, respectively (P < 0.01). In the clinical study, the mean late gain loss was 8.2 and 27.3% in the argatroban and control groups, respectively (P < 0.05). The mean late restenosis rate was 11.1 and 41.4% in the argatroban and control groups, respectively (P<0.05). 4. These data suggest that blood coagulation plays a significant role in VSMC proliferation after balloon injury and that locally administered argatroban using hydrogel-coated balloon catheter may prevent post-percutaneous transluminal coronary angioplast. restenosis.     

Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency

A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis.     

阿加曲班联合依达拉奉对后循环急性脑梗死患者神经功能恢复及血清Hcy、CXCL16和TGF-β1的影响

目的探究阿加曲班联合依达拉奉对后循环急性脑梗死患者神经功能恢复及血清同型半胱氨酸(Hcy)、CXC趋化因子配体16(CXCL16)、转化生长因子β1(TGF-β1)的影响。方法选取本院2017年1月—2019年3月收治的后循环急性脑梗死患者123例作为研究对象,按照随机数字表法分为联合治疗组、阿加曲班组和依达拉奉组,各41例。吸氧、预防感染、抗凝、稳定斑块等常规对症治疗基础上,阿加曲班组给予阿加曲班治疗,依达拉奉组给予依达拉奉治疗,联合治疗组给予阿加曲班联合依达拉奉治疗。治疗14天后,比较三组治疗效果、治疗前和治疗14天后后循环血流动力学指标[大脑后动脉、椎动脉、基底动脉收缩期峰血流速度(Vs)、阻力指数(RI)]、血清脑神经损伤标志物[神经元特异性烯醇化酶(NSE)、多胺氧化酶(PAO)、S-100β蛋白]、血清炎性因子(Hcy、CXCL16、TGF-β1)水平、神经功能(NIHSS评分)、日常生活能力(ADL评分)及不良反应。结果联合治疗组总有效率高于阿加曲班组和依达拉奉组,治疗14天后NIHSS评分、ADL评分优于阿加曲班组和依达拉奉组(P0.05),三组不良反应发生率比较差异无统计学意义(P0.05)。治疗14天后三组大脑后动脉、椎动脉、基底动脉Vs升高,且联合治疗组高于阿加曲班组和依达拉奉组,RI降低,且联合治疗组低于阿加曲班组、依达拉奉组。治疗14天后三组血清NSE、PAO、S-100β水平降低,联合治疗组降低幅度最高(P0.05)。治疗14天后,三组血清Hcy、CXCL16、TGF-β1水平降低,联合治疗组低于阿加曲班组、依达拉奉组(P0.05)。结论阿加曲班联合依达拉奉治疗后循环急性脑梗死临床疗效显著,可有效改善脑血流状态,抑制神经损伤,同时缓解机体炎症状态,提高患者神经功能及日常生活能力,保证治疗安全性。     

小剂量阿加曲班治疗TOAST分型下急性缺血性卒中的疗效分析

目的〖KG*2〗观察小剂量阿加曲班治疗不同病因分型下急性缺血性卒中患者的有效性与安全性。 〖HTH〗方法〖KG*2〗回顾性分析发病48 h内的急性缺血性卒中患者124例,按愿意接受阿加曲班治疗的患者依据TOAST（Trial of Org 10172 in Acute Stroke Treatment）分型分为大动脉粥样硬化型(large-artery atherosclerosis,LAA)42例,心源性栓塞型(cardiac embolism,CE)39例,小动脉闭塞型(small artery occlusion,SAO)38例。入院后7 d内每天给予阿加曲班注射液20 mg,同时联合阿斯匹林100 mg等常规治疗。于治疗前与治疗后7 d、14 d美国国立卫生院卒中（National Institutes of Health Stroke Scale,NHISS）量表、Barthel指数（Barthel Index,BI）评定量表评分,比较近期临床疗效;观察住院期间消化道、皮肤黏膜、颅内等部位出血以及病情恶化、死亡等不良事件发生情况。 〖HTH〗结果〖KG*2〗3组治疗后NHISS评分均呈下降趋势,BI指数均呈升高趋势,CE组变化幅度最大,组间、时间点、组间·时间点交互作用差异有统计学意义（P＜0.05）。CE组治疗总有效率高于LAA组和SAO组,差异有统计学意义（P＜0.05）。3组不良事件发生率差异无统计学意义（P＞0.05）。 〖HTH〗结论〖KG*2〗TOAST病因分型下的急性缺血性卒中患者早期联合应用小剂量阿加曲班治疗均可获益,且不增加出血风险,其中CE类型疗效最佳。     

连续性血液净化中阿加曲班与枸橼酸钠的抗凝效果及安全性比较

 目的 比较阿加曲班和枸橼酸钠在连续性肾脏替代治疗(continuous renal replacement therapy,CRRT)中的有效性和安全性。方法 选取2018-09至2019-05医院行CRRT治疗的患者132例,随机分为阿加曲班组60例和枸橼酸钠组72例,分别给予阿加曲班和枸橼酸钠抗凝治疗,阿加曲班组监测体内活化凝血时间(activated clotting time,ACT),枸橼酸钠监测ACT及血钙,同时记录两组患者透析前后血常规、血生化指标,尿素下降率、滤器及管路凝血情况,以及治疗后24 h内组织器官出血情况。结果 两组患者透析前ACT均在正常范围内,阿加曲班组ACT 5 min、2 h和4 h均显著升高,差异有统计学意义(P＜0.05),透析1 h后ACT显著下降至正常范围;枸橼酸钠组透析4 h和透析后ACT均无明显变化。枸橼酸钠组透析前、透析中、透析后体内游离钙均无明显变化;透析中体外游离钙均低于同时间体内游离钙水平。两组患者治疗前后血红蛋白及血小板较治疗前均无明显变化,血肌酐水平均显著下降,差异有统计学意义(P＜0.05)。两组患者治疗时间、URR值、管路滤器凝血情况及出血事件对比差异无统计学意义。结论 阿加曲班和枸橼酸钠在CRRT治疗中均为有效和安全的抗凝剂。对有高出血风险的患者选择枸橼酸钠更佳。     

阿加曲班对实验性大鼠脑出血周围组织神经元损伤的保护作用

目的研究阿加曲班对大鼠实验性大脑内出血的脑保护作用及其可能机制。方法选择SD大鼠60只,按随机数字法分为假手术组(1 2只)、脑出血组(12只)和阿加曲班治疗组(治疗组,36只)。治疗组又按注射阿加曲班1.0、1.5、2.0 mg/kg剂量分为治疗1组(12只)、治疗2组(12只)和治疗3组(12只)。观察应用阿加曲班前后脑出血大鼠神经功能缺损变化情况;应用免疫组织化学和Western blot法,观察阿加曲班干预前后大鼠大脑血肿周围组织中神经元烯醇化酶(NSE)、胶质纤维酸性蛋白(GFAP)阳性神经元数目的变化,以及NSE、诱导型一氧化氮合酶和GFAP表达水平的变化。结果与假手术组和治疗组比较,脑出血组大鼠血肿周围组织中NSE阳性神经元数目明显减少,GFAP阳性神经元数目明显增多,差异有统计学意义(P0.05,P0.01)。与脑出血组比较,治疗组大鼠血肿周围组织中NSE表达水平明显升高,而诱导型一氧化氮合酶及GFAP表达水平明显降低,差异有统计学意义(P0.05,P0.01)。结论阿加曲班可以有效拮抗大鼠脑出血血肿周围组织中NSE的丢失,其机制可能与阿加曲班降低神经元活性氧含量以及抑制炎性反应等作用有关。     

小剂量阿加曲班在连续性血液净化治疗中的应用

目的 探讨小剂量阿加曲班在连续性肾脏替代治疗(continuous renal replacement therapy,CRRT)中的抗凝效果和出血事件.方法 给予67例CRRT患者小剂量阿加曲班,首剂0.1 μg/kg,微量泵持续追加0.05 μg/(kg*min),测定实施治疗前、治疗结束后1 h、结束后2 h及治疗中每2 h凝血功能,采用评分方法 评价血滤器凝血和穿刺(置管)处出血及血肿情况.结果 血滤器凝血情况治疗前后无明显差异,穿刺(置管)处未见明显出血及血肿,活化部分凝血酶时间(APTT)和血浆凝血酶原时间(PT)治疗后1 h与治疗前有显著差异(P＜0.05);治疗后2 h与治疗前无差异.治疗1 h时同时检测动脉端和静脉端PT和APTT值,两者差异有统计学意义(P＜0.05).结论 达到治疗抗凝效果时,所需阿加曲班剂量较小,且未发生出血事件,故小剂量阿加曲班用于连续性肾脏替代治疗抗凝效果安全可靠.     

Treatment of heparin-induced thrombocytopenia in cardiovascular patients

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated syndrome associated with heparin exposure, a falling platelet count and a high risk of thrombosis. Cardiovascular patients are at increased risk of HIT due to wide use of heparin in this population. Should HIT be suspected, heparin must be avoided in most situations, and anticoagulation with an alternative anticoagulant should be instituted. Preferred agents include the direct thrombin inhibitors argatroban and lepirudin, whilst bivalirudin or desirudin (other direct thrombin inhibitors) can be used in some situations. The indirect thrombin inhibitors, danaparoid and fondaparinux, can also be considered at times. These agents and their use in cardiac patients, including patients with acute coronary syndrome, percutaneous coronary interventions, acute ST elevation myocardial infarction or cardiac surgery, will be reviewed.     

Treatment of intracardiac thrombi with argatroban

Intracardiac thrombi are well known complications associated with diverse cardiac diseases and venous thromboembolism. Therapeutic recommendations like thrombolysis, surgical thrombectomy, or treatment with low molecular heparin and intravenous unfractionated heparin based on small numbers of patients or retrospective case series have failed to reach a consensus. We report on the use of argatroban, a new direct thrombin inhibitor in 4 patients with intracardiac thrombi. Therapy was effective in all patients with complete resolution of thrombi. Treatment was complicated by recurrent strokes with complete neurological recovery in one patient. Therapy of intracardiac thrombi by argatroban is safe and effective. The drug requires no dosage adjustments for age, sex, or renal impairment, including in dialysis-dependent patients. Argatroban has been found to increase predictably activated partial thromboplastin time (aPTT) and activated clotting time (ACT) in a dose-dependent manner.     

凝血酶对人皮肤成纤维细胞增殖作用的研究

目的：观察不同浓度的凝血酶对成纤维细胞的刺激作用,以及阿加曲班对这种刺激的抑制作用。方法：采用贴壁法进行人皮肤成纤维细胞原代培养,并传代、鉴定。用MTT法检测不同浓度凝血酶刺激后的成纤维细胞活力。用氯胺T法检测不同浓度凝血酶刺激后的细胞上清中羟脯氨酸含量。用免疫组化的方法检测凝血酶刺激后的成纤维细胞中α-平滑肌肌动蛋白（α-SMA）的表达情况。在培养液中加入阿加曲班后重复上述检测。结果：①培养的细胞为典型的成纤维细胞形态,波形蛋白单克隆抗体免疫组化染色呈阳性;②加入不同浓度凝血酶的各组吸光值均高于不加凝血酶组（A组）（P〈0.01）,加入阿加曲班和凝血酶的各组吸光值与A组无显著性差异（P〉0.05）;③加入不同浓度凝血酶的各组细胞上清中羟脯氨酸含量均高于不加凝血酶组（A组）（P〈0.01）,加入阿加曲班和凝血酶的各组上清中羟脯氨酸含量与A组相比无统计学差异（P〉0.05）;④凝血酶刺激后的成纤维细胞中有α-SMA的表达,加入阿加曲班后此种表达被抑制。结论：凝血酶能诱导成纤维细胞增殖、胶原分泌量增加,能刺激成纤维细胞表达α-SMA,使成纤维细胞转变为肌成纤维细胞。阿加曲班能抑制凝血酶的这种作用。