低分子肝素对进展性缺血性脑卒中预防作用的探讨

目的 探讨低分子肝素对进展性缺血性脑卒中的预防作用。方法 将起病在72小时内的203例脑梗死患者随机分成低分子肝素治疗组及常规治疗组。低分子肝素组在常规治疗的基础上加用低分子肝素0．4ml,每日2次腹部皮下注射,连续5－10天。治疗前后检测纤溶酶原和凝血因子X活性及血液流变学各项指标,同时对进展性缺血性脑卒中患者的神经功能缺损进行评分。结果 低分子肝素组11例发生进展性缺血性脑卒中,常规治疗组23例,两组比较有显著性差异（P＜0．05）;低分子肝素组发生的进展性卒中其进展的严重程度比常规治疗组轻（P＜0．01）;近期预后较常规治疗组好（P＜0．05）;低分子肝素治疗能明显降低纤溶酶原和凝血因子X活性及血液流变学各项指标。结论 低分子肝素治疗能降低进展性缺血性脑卒中发生率,有利于进展性缺血性脑卒中患者神经功能的恢复。     

A low molecular weight heparin compared with unfractionated heparin

A 6000 daltons low molecular weight heparin (LMWH) was compared with unfractionated mucosal heparin in vitro and in vivo. Despite unimpressive specifications by clotting assays in vitro, the LMWH gave high and sustained activity in vivo by anti-Factor Xa assays, following subcutaneous injection. However, activity measured by APTT and calcium thrombin time assays was at least as high as occurred following unfractionated heparin. On the basis of clotting assays, there seems no reason to expect a lower incidence of haemorrhagic side-effects following the clinical use of this LMWH. The study also strikingly demonstrates the inadequacy of in vitro clotting assays for assessing the in vivo behaviour of LMWH.     

Inhibition of low molecular weight heparin by protamine chloride in vivo

To determine the antagonization of anticoagulant and lipolytic effects of a low molecular weight [LMW] heparin preparation protamine chloride was given intravenously after i.v. injection of LMW or normal heparin. The effects of normal heparin on factor Xa, thrombin, aPTT, lipoprotein [LPL] and hepatic triglyceride lipase [HTGL] activities were neutralized immediately by i.v. protamine. The inhibition of thrombin and aPTT by LMW heparin were also abolished, whereas the effects on LPL and HTGL were counteracted to 80% and on factor Xa only to 40% by i.v. protamine chloride. No rebound of the anticoagulant or lipolytic effect was detected. It is assumed that haemorrhagic complication during therapy can be antagonized by protamine chloride. The incomplete inhibitory effect of protamine chloride on LPL, HTGL and factor Xa activities of LMW heparin indicate that protamine chloride requires more than 14 saccharide units in the heparin molecule for interaction.     

The disappearance of a low molecular weight heparin fraction (CY 216) differs from standard heparin in rabbits

In previous studies, we have reported that standard heparin (SH) was cleared by two mechanisms, a saturable mechanism which predominated at low doses (<100 anti-factor Xa U/kg) and a non-saturable mechanism which predominated at higher doses, when the first mechanism became saturated. In this study, we examined the importance of these two mechanisms in the disappearance of a low molecular weight heparin fraction (LMWH) (CY 216), by comparing the pharmacokinetics and the pharmacodyna-mics of a wide range of doses of SH and CY 216 (1.5 to 500 anti-factor Xa U/kg) Pharmacokinetics was measured as the disappearance of ¹²⁵I-radiolabelled SH or CY 216. Pharmacodynamics was measured as the disappearance of the anti-factor Xa activity of SH and CY 216. We found that the saturable mechanism contributed little to the disappearance of CY 216 and that it was cleared predominantly by the non-saturable mechanism at all doses tested. Thus, at low doses (<100 anti-factor Xa U/kg), SH was cleared more rapidly than CY 216, whereas at higher doses, CY 216 was cleared more rapidly than SH. We conclude that the mechanism of disappearance of LMWH's differ significantly from those of SH, and that this difference may explain the apparent prolonged anticoagulant activity of LMWH's within the therapeutic range doses.     

低分子肝素与辛伐他汀治疗缺血性脑梗死的疗效比较

目的 探讨低分子肝素及辛伐他汀对缺血性脑梗死的疗效差异,为临床用药提供科学指导.方法 160例缺血性脑梗患者随机分为低分子肝素组和辛伐他汀组各80例,在常规治疗的基础上,低分子肝素组给予肝素皮下注射治疗,辛伐他汀组口服辛伐他汀治疗,对两种药物的临床疗效进行对比研究.结果 低分子肝素组的临床总有效率明显高于辛伐他汀组,差异有统计学意义(P＜0.05).结论 低分子肝素治疗缺血性脑梗死疗效显著,值得临床推广.     

Comparative study of thrombolysis by high and low molecular weight urokinase in an in vitro perfusion system

Two urokinase preparations of different molecular weights were standardized against the International Reference Preparation for Urokinase and compared in an in vitro whole blood perfusion system using thrombi formed with whole blood and ¹²⁵I-fibrinogen. Plasminogen was added to one group and normal saline to the other. Thrombolysis, as well as plasminogen and plasmin inhibitor levels were monitored over a 60 minute period following the addition of the urokinase to the perfusion mediums. There was a high correlation as well as no significant difference found between the percents lysis caused by the high and low molecular weight urokinase. Added plasminogen resulted in a rapid decrease of plasmin inhibitors in both urokinase groups. In the saline groups this decrease was highly negatively correlated with the percent lysis. It is concluded that both high and low molecular weight urokinase behave similarly in an in vitro whole blood thrombolytic perfusion system over the time period studied.     

Low molecular weight heparin for deep vein thrombosis in glioma patients

The treatment and secondary prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism, a common complication in patients with malignant glioma, has remained controversial. We treated 11 patients with malignant glioma and DVT prospectively with low molecular weight heparin (LMWH) at 175 IU/kg for 10 days and then for 3 months at 100 IU/kg. No patient developed bleeding complications or any other severe side effects of LMWH treatment. Two patients had a dose reduction of LMWH to 75 IU/kg because of chemotherapy-induced thrombocytopenia. One patient developed progressive DVT and nonlethal pulmonary embolism on day 14 of LMWH 100 IU/kg. After increasing the dose to 175 IU/kg he had no further recurrence. One patient had recurrence of DVT after a fracture of the leg affected by DVT at 8 months after the diagnosis of DVT and 5 months after the end of LMWH therapy. LMWH therapy may be safe and effective in the treatment and secondary prophylaxis of DVT in patients with malignant glioma. Received: 4 January 2002, Received in revised form: 18 April 2002, Accepted: 23 April 2002 Correspondence to Dr. F. Schmidt     

低分子肝素钙治疗急性脑梗死的疗效观察

目的观察低分子肝素钙（LMWHCa）治疗急性脑梗死的疗效和安全性。方法选用48例急性脑梗死病人,其中24例用常规治疗为对照组,治疗组24例除常规治疗外,加用LMWHCa4100抗Xa国际单位腹部皮下注射,bid,连续10d为1疗程。治疗前后分别作神经功能评分、血液流变学观察和PT、AFTT、TT、Fg。结果治疗组神经功能恢复、血液流变学改善均明显优于对照组（P〈0．05）。治疗组用药后Fg降低,PT延长,与对照组比较差异显著（P〈0．01或P〈0．05）,两组治疗前后的TT、APTI变化不明显;治疗组有2例出现皮下淤斑。结论脑梗死急性期给予低分子肝素钙治疗安全和有效。     

The effects of heparin and low molecular weight heparins on bone

Recent clinical trials have shown that the risk of developing osteoporosis is substantially lower when low molecular weight heparins (LMWHs) are used in place of unfractionated heparin. While the reason(s) for this difference has not been fully elucidated, studies with animals have suggested that heparin causes bone loss by both decreasing bone formation and increasing bone resorption. In contrast, LMWHs appear to cause less bone loss because they only decrease bone formation. Whether all LMWHs decrease bone formation and therefore cause bone loss is unknown. For example, preliminary in vitro studies with the synthetic pentasaccaride, Fondaparinux, have suggested that it may not decrease bone formation and thus, may have no deleterious effects on bone. Further studies are required in order to determine if all LMWHs cause bone loss equally.     

Anticoagulant effects of two types of low molecular weight heparin administered subcutaneously

Two types of LMW heparin were prepared by gel filtration of standard heparin (LMW fraction) and by degradation of heparin by nitrous acid (LMW fragment), respectively. The effects on factor Xa inhibition (XaI), APTT, platelet aggregation and AT III level of these preparations were studied after subcutaneous administration to humans and compared with those of standard heparin. At a dose of 5000 IU (XaI) the LMW fraction and LMW fragment induced peak plasma XaI activity of 0.32 IU/ml and 0.41 IU/ml respectively, compared to 0.07 IU/ml for heparin. Still 11.5 h after administration both LMW preparations gave higher activities than heparin ever induced. Following administration of 10,000 IU (XaI) of the LMW fragment the plasma peak XaI activity was 0.81 IU/ml. This prolonged the APTT from 36 sec to 46 sec only. The half-lives of the XaI activity in plasma were between 3 and 4 hours. No effect on platelet aggregation or AT-III level was demonstrated.     

低分子肝素对TIA患者黏附分子及血小板指标的影响

目的观察低分子肝素对短暂性脑缺血发作(TIA)患者黏附分子及血小板指标的影响。方法选取本院收治的68例(TIA)患者为研究对象,按照随机分配的原则分为对照组和观察组各34例,对照组进行常规治疗,观察组在对照组基础上加用低分子肝素,比较2组治疗前后的血清黏附分子及血小板指标。结果治疗前2组血清黏附分子及血小板指标比较,差异无统计学意义(P0.05),而治疗后2d、5d及7d观察组PLT均高于对照组,其他血清黏附分子及血小板指标均低于对照组,差异有统计学意义(P0.05)。结论低分子肝素可显著改善短暂性脑缺血发作患者的黏附分子及血小板指标。     

Anticoagulant and lipolytic effects of a low molecular weight heparin fraction

The lipolytic and anticoagulant actions of a 4000 dalton low molecular weight (LMW) heparin were compared with unfractionated mucosal heparin after intravenous and various subcutaneous doses in man. I.v. injection of 100 USP units/kg body weight lipoprotein lipase (LPL) activity, and inhibition of factor Xa decreased with a half life twice as long after LMW heparin compared to normal heparin (p < 0.05). There were no differences in half lives for HTGL activity, thrombin inhibition and on aPTT. The area under the activity time curve (AUC) of LPL and factor Xa was double with LMW heparin (p < 0.05). S.c. administration showed that the AUC of LMW heparin on the factor Xa inhibition was 10 times larger compared to normal heparin. LPL activity was released comparable to normal heparin. The effects on HTGL were three times larger compared to normal heparin. There were no differences in half lives. The data show that in contrast to normal heparin LMW heparin is rapidly and completely absorbed from the subcutaneous depots. The pharmacodynamic data of LPL activity and factor Xa inhibition suggest similar release mechanisms.     

低分子肝素对大鼠大脑皮层神经细胞缺血再灌注损伤的保护作用

目的研究低分子肝素(low molecular weight heparin,LMWH)对大鼠大脑皮层神经细胞缺血再灌注损伤的保护作用及其可能机制。方法体外培养新生大鼠大脑皮层神经细胞,建立缺血再灌注模型,MTT法检测细胞活力,Annexin V-FITC、PI双染流式测细胞凋亡率,荧光分光光度计法测定细胞内钙离子浓度。结果低分子肝素可提高缺血再灌注损伤的神经细胞活力,降低细胞凋亡率和细胞内钙离子浓度。结论低分子肝素对缺血再灌注损伤的大鼠大脑皮层神经细胞有保护作用,其机制可能与LMWH降低细胞内钙离子浓度有关。     

Discordance between the anti-Xa activity and the antithrombotic activity of an ultra-low molecular weight heparin fraction

The relationship between the in vivo antithrombotic effect of heparin and ex vivo anti-Xa activity has been investigated using an animal thrombosis model. Three low molecular weight heparins were compared with the standard heparin from which they were fractionated. All four heparins showed a dose-dependent antithrombotic effect enabling the relative antithrombotic and anti-Xa activities to be compared over a dosage range. A correlation between ex vivo anti-Xa heparin levels and antithrombotic effect was demonstrated for the standard (MW 16,000), intermediate (MW 7,600) and low (MW 4,600) molecular weight heparins but not for the ultra-low molecular weight (MW 3,000) fraction. The lack of relationship between anti-Xa activity and inhibition of thrombosis for the very low molecular weight fraction indicates that a very high anti-Xa activity (measured in vitro or ex vivo) is not always predictive of in vivo antithrombotic efficacy. These findings suggest that other properties of low molecular weight heparins contribute to their antithrombotic effectiveness.     

动脉内接触性溶栓治疗急性缺血性脑卒中

目的探讨急性缺血性脑卒中动脉内接触性溶栓治疗的安全性和有效性。方法对178例急性缺血性脑卒中病人在起病后2～24h进行尿激酶超选择性动脉内接触性溶栓,尿激酶用量50～130万U(平均85万U)。结果颈内动脉系统血管闭塞117例,椎-基底动脉系统闭塞30例,脑血管造影未见明显异常31例。闭塞的颈内动脉再通14例,大脑中动脉再通29例,大脑中动脉分支再通30例,椎-基底动脉系统再通20例。11例因血管狭窄明显,溶栓后给予球囊扩张、支架置入术。临床症状完全恢复正常或明显好转108例,并发脑出血6例,消化道出血15例。结论超选动脉内接触性溶栓可使血栓局部迅速达到较高的血药浓度,疗效好,见效快,用药总量小,并发症少。     

缺血性脑卒中超早期选择性动脉溶栓治疗

目的评价超早期选择性脑动脉溶栓疗法(SIT)对急性缺血性脑卒中的疗效及安全性.方法32例急性缺血性脑卒中患者起病至溶栓时间介于1～6小时.尿激酶用量87.66±17.63万单位.溶栓前先用微导丝通过血栓到达血栓远端,导丝撤出后,将导管置于靶血管闭塞点或患侧颈内动脉进行溶栓治疗.结果颈内动脉闭塞12例,3例完全再通,2例部分再通.大脑中动脉闭塞20例,19例完全再通.治疗后3个月神经功能恢复率为81%(26/32).4例合并无症状性脑出血均痊愈.血管再闭塞1例(经重复造影证实).结论超早期SIT治疗可使闭塞血管再通.溶栓后并发无症状性脑出血患者临床可恢复正常.SIT是目前治疗急性缺血性脑卒中有效的治疗手段.     

Comparative study of antithrombotic effect of a low molecular weight heparin and unfractionated heparin in an ex vivo model of deep arterial injury

Thrombosis after plaque rupture triggers the onset of acute coronary events. The treatment of choice for patients with acute coronary syndromes is conventional unfractionated heparin. Low molecular weight heparin has recently been reported to be as effective and even safer than unfractionated heparin. In this study, the effects of the low molecular weight heparin reviparin and unfractionated heparin on thrombus formation were examined under dynamic conditions using an extracorporeal perfusion chamber in a porcine model. Thrombus formation was assessed by the deposition of porcine ¹²³I-fibrin(ogen) and autologous ¹¹¹In-platelets on porcine tunica media at high and low shear rates. Reviparin reduced the fibrinogen molecules deposited on injured vessels at high shear rates (252±80 molecules×10¹²/cm² for reviparine (200 U/kg/hour) vs. 624±70×10¹²/cm² for unfractionated heparin (200 U/kg/hour) (p<0.05). At low shear rates, fibrinogen deposition was also significantly reduced by reviparin (130±15 molecules×10¹²/cm²) compared to unfractionated heparin (192±40×10¹²/cm² at 200 U/kg/hour; p<0.05). No change in platelet deposition was detected after heparin administration in either treatment group. In conclusion, the low molecular weight heparin reviparin has a higher antithrombotic potential than unfractionated heparin. Reviparin may have advantages over unfractionated heparin in treatment and prevention of acute coronary syndromes.     

Signs of thrombin generation in pediatric cardiac catheterization with unfractionated heparin bolus or subcutaneous low molecular weight heparin for antithrombotic cover

Introduction: Thrombosis is one of the most frequent adverse events after cardiac catheterization, which can be reduced by anticoagulation with unfractionated heparin (UFH) in both children and adults. Low molecular weight heparin (LMWH) might possibly offer advantages. Laboratory signs of thrombin generation during pediatric cardiac catheterization, with unfractionated heparin (UFH) bolus or subcutaneous LMWH for thrombosis prophylaxis, were determined in a first step to investigate the potential of LMWH for antithrombotic cover. Materials and methods: Signs of thrombin generation (D-dimer and F₁₊₂), anti-Xa activity and activated clotting time (ACT) were measured in 65 patients with congenital heart disease. A total of 40 patients were treated with a UFH bolus of 100 IU/kg bodyweight and, in 25 children, enoxaparin was subcutaneously administered at a dosage of 1/1.6 mg/kg bodyweight. Results: The dose to plasma activity of enoxaparin was more consistent than in the UFH group. Only a slight elevation of F₁₊₂ was found in some patients, which was a little higher in the enoxaparin group, but no difference of incidence of increased F₁₊₂ generation was detected between the two groups. D-dimer was elevated in three children after UFH bolus application, but no such effect was observed in any child after LMWH administration. Conclusions: Application of LMWH was equally efficacious during pediatric cardiac catheterization than UFH bolus administration, as determined by plasma levels and markers of clotting activation. In contrast to UFH bolus, no further monitoring was necessary after the application of LMWH during cardiac catheterization due to a consistent dose to plasma activity.