低分子肝素的抗凝与抗血栓作用

目的研究低分子肝素的抗凝特点及抗栓作用。方法分别测定其抗Xa因子与抗IIa因子的比率(FXa/FIIa);全凝血时间（CT）、复钙时间（RT）、凝血酶原时间（PT）、凝血酶时间（TT）、活化的部分凝血活酶时间（APTT）;制备体内、体外血栓。结果低分子肝素FXa/FIIa<1,对RT、TT的延长作用明显低于肝素,对CT、PT、ATPP无影响;在两种血栓模型中,低分子肝素组的血栓重均低于肝素组。结论低分子肝素对凝血系统的作用低于肝素;而其抗栓作用大于肝素。     

糖皮质激素联合低分子肝素钠对IgA肾病小鼠的疗效观察

摘要：目的初步探索糖皮质激素（GC）联合低分子肝素钠（LMWH）对IgA肾病（IgAN）小鼠的疗效及可能的作用机制。方法应用“口服牛血清白蛋白（SBA）加葡萄球菌肠毒素B（SEB）尾静脉注射”法复制小鼠IgAN模型。设正常组、模型组、泼尼松组、低分子肝素纽、泼尼松联合低分子肝素钠组5组。实验结束取血、尿及肾组织标本,测24h尿蛋白含量、凝血功能（血浆凝血酶原时间PT、活化部分凝血活酶时间APTT）、肾功能（肌酐、尿素氮）,观察肾脏病理变化、系膜区IgA沉积及转化生长因子-β（TGF-f1）、血小板衍化生长因子（PDGF）表达情况,比较各组小鼠蛋白含量、凝血功能、肾功能、肾脏病理等的差异。结果模型组小鼠蛋白含量、肾功能、肾脏病理变化、系膜区IgA荧光强度、TGF-β、PDGF表达均明显高于正常组,PT、APTT低于正常组。泼尼松、LMWH组及联合治疗组上述指标除凝血功能外均低于模型组（P〈0．05）,联合治疗组除凝血功能外均低于单用泼尼松及LMWH组（P〈0．05）,联合治疗组凝血功能指标较泼尼松组增高（P〈0．05）,与LMWH组比较无明显差异。泼尼松组与LMWH组比较后者凝血功能指标升高（P〈0．05）,其余指标无明显差异。结论泼尼松能明显减少IgAN小鼠的蛋白尿、改善肾功能、’肾脏病理、IgA沉积程度,但也能加重高凝状态,LMWH不但能改善凝血功能和肾功能,减轻蛋白尿,还能通过抑制系膜细胞增生和基质沉积起到抑制肾小球硬化的作用,两者联合应用能进一步减少蛋白尿,肾功能及肾脏病理改善亦较单用泼尼松及LMWH明显,对肾病本身的高凝状态及泼尼松所致的凝血异常均有明显改善作用,在IgAN治疗中,泼尼松低分子肝素钠联合应用的疗效优于单用泼尼松及LMWH。     

低分子肝素与肝素在血液灌流中的疗效比较

目的 观察低分子肝素在血液灌流中的抗凝效果,并评估引起出血的危险性. 方法 回顾分析106例中毒患者,分为LMWH组55例和SH组51例. LMWH组血液灌流时给予低分子肝素,于血液灌流前一次性静脉注射,体质量<60 kg给予0.3 mL,≥60 kg者给予0.4 mL;SH组给予肝素,先使灌流器肝素化,然后首剂静脉注射20 mg,以后每30 min追加5 mg,结束前30 min停用,如有凝血则追加5 mg. 结束时分别静脉注射等量鱼精蛋白中和. 结果LMWH组出现灌流器凝血1例(1.81%),SH组为8例(15.69%),两组差异有统计学意义(P<0.05). LMWH组活化部分凝血活酶时间(APTT)、凝血酶时间(TT)、血浆凝血酶原时间(PT)波动小,SH组APTT、TT、PT明显延长,波动大,易出血. 结论 低分子肝素是血液灌流较理想的抗凝药.     

毕赤酵母表达去氨普酶及其突变体的溶栓活性研究

目的：研究毕赤酵母表达野生型去氨普酶（DSPAwt）及其突变体F195和QNRR的溶栓活性,为开发新型溶栓类药物奠定基础。方法：以阿替普酶（rt-PA）和中国仓鼠卵巢细胞表达野生型DSPAα1为阳性对照,采用大鼠动-静脉旁路血栓模型,通过对血栓重量、出血时间、大鼠凝血指标凝血酶时间（TT）、凝血酶原时间（PT）、活化部分凝血酶原时间（APTT）和纤维蛋白降解产物D-二聚体的测定考察毕赤酵母表达DSPAwt及其两种突变体的溶栓活性。结果：DSPAwt及其突变体F195和QNRR在0.7mg/kg和1.5mg/kg剂量下均有一定的溶栓活性,其中DSPAwt溶栓作用较弱,有效动物数少,溶栓率较低,相同剂量突变体F195和QNRR溶栓作用显著增强,溶栓效果与DSPAα1接近。此外,不同剂量各样品均能在一定程度上延长大鼠出血时间,延长大鼠血浆TT、PT和APTT,提高血浆中D-二聚体含量。结论：通过酵母表达系统有望获得具有高溶栓活性的突变型DSPA,从而开发成新一代溶栓类药物。     

红花黄色素联合低分子肝素钙预防骨科术后下肢深静脉血栓形成分析

目的：探析红花黄色素与低分子肝素钙预防骨科术后下肢深静脉血栓形成效果分析。方法：选取2013年6月～2014年6月我院择期骨科手术治疗的患者84例,随机分为两组,每组42例,观察组联合应用红花黄色素与低分子肝素钙,对照组仅给予低分子肝素钙,比较两组患者术后下肢深静脉血栓形成（DVT）的发生率;比较两组的凝血酶原时间（PT）、凝血酶时间（TT）、凝血活酶时间（APTT）、血小板计数（PLT）等指标。结果：观察组发生DVT 2例（4.8%）,对照组发生DVT 7例（16.7%）,差异有统计学意义（X2=4.82,P<0.05）;两组治疗后各项凝血功能指标、血小板指标均有改善,观察组的凝血酶原时间（PT）、凝血酶时间（TT）、凝血活酶时间（APTT）、血小板计数（PLT）等指标显著优于对照组,差异有统计学意义（P<0.05）。结论：红花黄色素与低分子肝素钙可显著降低骨科术后下肢深静脉血栓形成的发生率,效果确切。     

蝮蛇毒血小板抑制因子对动脉血栓形成的影响及机制研究

目的：探讨皖南蝮蛇毒血小板抑制因子（AHV-PI）对家兔动脉血栓形成的影响及可能机制。方法：新西兰家兔24只,随机分成假手术组、动脉血栓模型组、阳性对照组（奥扎格雷钠,5mg/kg）,AHV-PI（0.1mg/kg）实验组共4组,每组6只。应用70%FeCl3溶液化学损伤的方法来制备家兔颈动脉血栓模型,采用血栓弹力仪（TEG）描计血栓弹力图,比浊法测定家兔血小板聚集率,ELISA测定各组血浆中α颗粒膜蛋白（GMP-140）和血栓素B2（TXB2）水平,光镜和透射电镜分别观察动脉血栓形成和血小板形态的改变。结果：AHV-PI实验组与模型组相比,血栓弹力图凝血时间（R）值和血凝块形成时间（K）值延长（P〈0.01和P〈0.05）,Alpha角度、最大幅度（MA）和凝血指数（CI）减小（P〈0.05和P〈0.01）;血小板聚集率的各项指标均明显降低（P〈0.05）;血浆中GMP-140和TXB2含量降低（P〈0.01）。AHV-PI实验组光镜下动脉内未见血栓形成,血小板电镜显示血小板形态基本规则,与模型组相比伪足较少,α-颗粒和致密颗粒无明显减少,胞浆空泡化现象减轻。结论：AHV-PI可以通过抑制血小板聚集,防止动脉血栓的形成,其机制可能与之保护血小板超微结构,减少血小板脂质代谢和颗粒内容物的释放有关。     

低分子肝素的抗血栓作用

研究了低分子肝素 (lowmoleculerweightheparin ,LMWH)的抗血栓作用 .研究表明 ,静脉注射LMWH (40 0、2 0 0IU/kg)能明显降低家兔高、中、低切比粘度 (P <0 .0 1) ,并显著降低家兔体内实验性血栓湿重及干重 (P <0 .0 0 1) ;静脉注射LMWH 40 0、2 0 0IU/kg及 30 0、15 0IU/kg能分别抑制家兔及小鼠ADP诱导的血小板聚集作用 (P <0 .0 0 1) .实验证明 ,相对分子质量为 6 40 0的低分子肝素有抗血栓作用 .     

低分子肝素钙防治老年下肢骨折术后深静脉血栓形成86例

目的探讨低分子肝素钙预防老年下肢骨折术后下肢深静脉血栓形成的效果。方法选取172例老年下肢骨折手术患者,随机均分为两组,试验组予低分子肝素钙抗凝治疗,对照组未采取任何抗凝措施,两组均于术后7d内用彩色多普勒超声检测双下肢深静脉血栓形成情况,并检测凝血指标。结果试验组下肢深静脉血栓发生率为6.98%,对照组为23.26%,经χ2检验,P〈0.05;试验组有4例（4.65%）、对照组有2例（2.33%）出现活化部分凝血活酶时间（APTT）延长。结论对于老年下肢骨折患者,低分子肝素钙能降低术后下肢深静脉血栓形成的危险,且使用安全。     

低分子肝素对胎儿生长受限患者脂代谢的影响与其疗效的相关性分析

目的探讨低分子肝素（LMWH）对于胎儿生长受限患者脂代谢的影响与其疗效的相关性。方法49例胎儿生长受限患者随机分为2组,对照组应用低分子右旋糖酐加复方丹参、LMWH组应用低LMWH治疗。治疗前、治疗后1周及终止妊娠前,行彩色超声检查,监测胎儿生长情况和脐血流变化,同时监测各项脂代谢指标和凝血指标,记录新生儿情况并进行随访。结果与对照组比较,LMWH组治疗后血清TG、TC、LDL显著降低,HDL则显著升高（P〈0.05）,脐血流指标明显改善,胎儿生长各项指标均显著增加,新生儿胎龄显著延长,出生体重及身长明显增加,差异均有统计学意义（P〈0.05）。2组新生儿窒息、早产、胎死宫内和新生儿死亡发生率比较差异无统计学意义（P〉0.05）。对照组足月小样儿发生率明显高于LMWH组（P〈0.05）,新生儿转重症监护病房（NICU）几率明显升高（P〈0.05）。结论低分子肝素对于胎儿生长受限的治疗作用与其对患者脂代谢的影响相关,通过降低血脂可有效改善患者胎盘血液供应,促进胎儿生长发育。     

低分子量肝素及其临床应用

1916年Molean首先发现肝素的抗凝作用，至今已有半个多世纪。肝素不仅具有抗凝、抗血栓作用，还具有抗炎、抗过敏、抗病毒和降血脂等作用。临床应用表明，肝素是一种有效的防治深部静脉血栓（DVT）、肺栓塞（＊E）以及其它血栓的药物，但应用时常伴有出血、血小板减少及骨质疏松等副作用。7O年代中期和80年代初期，有人发现从标准肝素（SH）中分离出的分子量较小的肝素片段，同样具有SH的抗Xa因子（FXa）作用，产生与SH相似的抗血栓作用，而对活化部分凝血活酶时间（aPTT）影响不大，出血可能性小LI。。；低分子肝素（LMWH）是通…     

低抗凝肝素来源低分子肝素口服制剂的研究

以生产肝素的副产品——低抗凝肝素为原料,采用亚硝酸控制解聚法制得了低分子肝素,分子量为5300,抗凝活性为39.2u/mg,测定了理化指标。以对家兔实验性血栓形成的影响为药效学指标,确定低分子肝素口服制剂的处方组成为低分子肝素、油酸、牛胆盐。研究了所制备的低分子肝素胶囊对家兔血液流变学及血栓形成的影响,并试用于部分动脉粥样硬化症志愿者,表明该胶囊可有效地改善家免和动脉粥样硬化症志愿者血液流变性质,抑制血栓形成。     

高抗血栓活性的低分子肝素

以生产肝素的副产品──低抗凝活性肝素为原料，采用亚硝酸控制解聚法制得低分子肝素（ＬＭＷＨ）；在固定ｐＨ值和亚硝酸用量的条件下，探明ＬＭＷＨ分子量与反应温度和时间呈反变。测定了产物的理化常数，抗凝效价和抗ＦＸａ活性。以大鼠颈动脉血栓模型研究证明分子量为５３００ｄ的产物具有较强的抗栓活性；此外对琼脂所致大鼠足跖肿胀、棉球所致小鼠炎症性肉芽肿组织增生都具有显著抑制作用。以抗ＦＸａ活性为检测指标，研究了家兔一次静脉注射的药物动力学，结果显示ＬＭＷＨ的生物半衰期ｔ（１／２）约为肝素的３倍，全身清除率Ｃｌｓ比肝素小，血药－时曲线下面积ＡＵＣ和表观分布容积Ｖ比肝素大。以对家兔实验性血栓形成的影响为药效学指标，确定了ＬＭＷＨ口服胶囊的配方组成及其对家兔血液流变学及实验性血栓形成的影响。     

Comparative study on the in vitro and in vivo activities of heparinoids derivative investigated on the animal model.

In this study we compared the antithrombotic and anticoagulant properties of sodium and calcium derivatives of pentosan polysulfate (Na-PPS, Ca-PPS), unfractionated heparin (UFH), and low-molecular-weight heparin (Fraxiparin). The antithrombotic effects of these agents have been investigated in an experimental thrombosis model in which rat mesenteric venules with a diameter of 20-30 microm were injured by well-defined argon laser lesions. Furthermore, the in vivo and in vitro anticoagulant activities [activated partial thromboplastin time (aPTT), Heptest] of these agents have been studied. Thrombus formation was significantly inhibited after s.c. injection of Na-PPS and Ca-PPS in doses >10 mg/kg. The duration of the antithrombotic effect lasted 8 h for Na-PPS and 12 h for Ca-PPS. After oral administration of Na-PPS, an antithrombotic effect was not observed. Oral application of Ca-PPS in doses >20 mg/kg significantly inhibited thrombus formation. Na-PPS and Ca-PPS markedly prolonged clotting time in aPTT and Heptest in concentrations ranging from 0.01 to 0.2 mg/ml rat PTT. Two h after s.c. administration of these agents in a dose of 10 mg/kg, the aPTT increased threefold and the Heptest 2.5-fold compared with controls. After oral application of 50 mg/kg Na-PPS and Ca-PPS, no effect on the coagulation test could be measured. Intravenous injection of UFH prolonged the Heptest after 1 min and the aPTT after 30 min. In ex vivo studies of aPTT and Heptest performed in rat plasma between 2 and 24 h after s.c. injection of 0.2 mg/kg Fraxiparin, no inhibition of any coagulation test was measured. The antithrombotic effect of 0.2 mg/kg Fraxiparin after s.c. injection was significant. Intravenous injection of 20 U/kg UFH significantly inhibited thrombus formation. The smallest antithrombotic effect was after i.v. injection of UFH.     

相对小分子质量肝素在左心导管术中的应用

目的：比较相对小分子质量肝素（ＬＭＷＨ）和普通肝素（ＵＦＨ）预防左心导管术中血栓形成和出血并发症的发生率。方法：行左心导管术４２６例按导管号随机分成两组,分别于动脉鞘管内给予ＬＭＷＨ或ＵＦＨ,ＬＭＷＨ按９５ＩＵ／ｋｇ,ＵＦＨ按５０ＩＵ／ｋｇ体重给药。观察术中及术后血栓,出血现象的发生率,部分病人动态检测出,凝血时间及凝血活酶时间。结果：ＬＭＷＨ组与ＵＦＨ组对比,总的全身出血现象发生率明显减少,分别     

General pharmacological properties of a low molecular weight heparin in rodents

The effects on central nervous system of a new low molecular weight heparin (OP/LMWH) were studied in mice and rats. The effect of OP/LMWH on respiration, blood pressure and heart rate was studied in guinea-pigs and rats. In these studies unfractionated heparin was used for comparison. OP/LMWH, up to 10 mg/kg/s.c., did not show any effect on central nervous system and did not increase the blood pressure, heart rate and respiration rate up to 10 mg/kg i.v. At the same dosages, heparin presented effects similar to those shown by OP/LMWH.     

Urinary protein C inhibitor as a therapeutic agent to disseminated intravascular coagulation (DIC): a comparison with low molecular weight heparin in rats with lipopolysaccharide-induced DIC

We compared urinary protein C inhibitor (uPCI) with low molecular weight heparin (LMWH) in terms of the effect on the pathophysiology of disseminated intravascular coagulation (DIC), such as hypercoagulation, induction of secondary fibrinolysis and organ failure, using lipopolysaccharide (LPS)-induced DIC in rats. The uPCI (0.5 and 1.0 mg/kg) administration significantly inhibited both the decrease in fibrinogen level and the increase in fibrin/fibrinogen degradation products (FDP) level, and the effects compared favorably with those of LMWH (100 and 200 IU/kg). Both uPCI (0.5 and 1.0 mg/kg) and a low dose of LMWH also inhibited the increases in the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), thrombin, and plasma kallikrein equally, but a high dose of LMWH did not inhibit the changes in those parameters. Furthermore, uPCI dose-dependently prevented the prolongation of activated partial thromboplastin time (APTT), while LMWH excessively prolonged APTT at a high dose. These results suggest that the preventive effect of uPCI on the pathophysiology of DIC compares favorably with that of LMWH, including the lack of a hemorrhagic reaction in contrast to LMWH.     

Effect of inhaled low molecular weight heparin on methacholine-induced bronchoconstriction

OBJECTIVES: Recent studies have shown that inhaled standard heparin exhibits protection towards various bronchoconstrictor stimuli in asthma including methacholine. Low molecular weight heparins (LMWH) (4000-5000 daltons) have higher bioavailability than standard heparins (12,000-16,000 daltons). It is possible that the anti-asthmatic activity of heparin may be molecular weight-dependent. The purpose of the present investigation was to study the effect of LMWH on methacholine-induced bronchoconstriction and to compare the effect of LMWH with that of standard heparin. SUBJECTS: Fifteen subjects (7 male, 8 female, mean age: 33 +/- 13 years, range: 20-65) with mild asthma were studied. METHOD: Methacholine bronchial provocation tests were performed in a single-blind, crossover, randomized order and repeated 45 minutes after placebo or aerosolized standard heparin (1.000 U/kg) or aerosolized LMWH (Enoksaparin, Clexane, 0.8 mg/kg). RESULTS: There was no significant difference in baseline FEV1 values between study days. The standard heparin and enoksaparin inhibited bronchoconstriction induced by methacholine. The geometric mean log PD20 values after placebo, standard heparin, and enoksaparin were 0.24 +/- 0.57 (1.74) mg/ml, 0.79 +/- 0.59 (6.17 mg/ml), 0.76 +/- 0.57 (5.75 mg/ml), respectively (p < 0.0009). Three subjects in standard heparin group and two subjects in enoksaparin group showed increased hyperreactivity, the others showed decreased bronchial hyperreactivity. The degree of protection offered by standard heparin and enoksaparin did not show any statistical difference. CONCLUSIONS: These data suggest that both inhaled LMWH and inhaled standard heparin play inhibitory roles in methacholine-induced bronchoconstriction.     

The effect of taurolidine on experimental thrombus formation

Venous thrombosis can be the source of emboli, a significant health risk encountered throughout surgical and medical clinics. Taurolidine is an antimicrobial agent used to prevent intraabdominal adhesion formation and sepsis in experimental and clinical trials. The aim of this study is to evaluate effect of taurolidine on experimental thrombus formation and make a comparison with low-molecular weight heparin. Four groups of ten Wistar-Albino rats (300-350 g) were used; with the first and second groups each being administered 10 and 20 mg of taurolidine, the third group low-molecular weight heparin and the fourth group saline solution (control group) respectively. Experimental thrombus formation was performed in rats in the area of the abdominal inferior vena cava by using a combination of stasis and hypercoagulability described by Wessler et al. [Wessler, S., Reimer, S.M., Sheps, M.C., 1959. Biologic assay of a thrombosis inducing activity in human serum. J. Appl. Physiol. 14:943-946.]. Thrombocyte count, the weight of thrombus, prothrombin time and activated partial thromboplastin time and activities of coagulation factors were measured and compared across groups. Thrombus weights in the taurolidine treated groups were lower than the control group and greater than the low-molecular weight heparin treated group. Taurolidine was found to decrease activities of coagulation factors V, VIII, IX, XI and XII. Taurolidine showed no effect on activated partial thromboplastin time and prothrombin time values; however, it decreased thrombus weight, but not as much as low-molecular weight heparin. The cause of these findings in our study may be related to the minimized effect of taurolidine on factor II, VII, and X activities. These effects likely render the agent ineffective in the prevention of venous thrombosis. Taurolidine was found to be less effective than low-molecular weight heparin in prevention of thrombus formation.     

Toxic and mutagenic effects of a low molecular weight heparin in rats

Acute, subacute, chronic toxicity and mutagenicity studies of a new low molecular weight heparin (OP/LMWH) were carried out in rats. The LD50 values resulted lower by i.m. and s.c. route than after i.p. and i.v. administration. OP/LMWH given by subcutaneous route in subacute and in chronic toxicity produced no significant adverse effects at 5 mg/kg, only marginal effects at 10 mg/kg and moderate effects at the dose of 20 mg/kg. In these studies, unfractionated heparin at 10 mg/kg by s.c. route was used for comparison. At 10 mg/kg, heparin presented effects similar to those shown by OP/LMWH at 20 mg/kg. OP/LMWH did not show any mutagenic activity when compared with mutagenic standards.