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.     

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.     

Peri-procedural anticoagulation management of mechanical prosthetic heart valve patients

Introduction

To estimate the three-month cumulative incidence of thromboembolism and bleeding among mechanical heart valve (MHV) patients receiving peri-procedural anticoagulation management, consecutive MHV patients referred to the Mayo Clinic Thrombophilia Center for peri-procedural anticoagulation management over the seven-year period, 1997-2003, were followed for three months for thromboembolism, bleeding and vital status.

Materials and Methods

Warfarin was stopped 4-5 days prior to the procedure, and re-started after the procedure as soon as hemostasis was assured. The decision to provide bridging therapy with low molecular weight (LMWH) or unfractionated (UFH) heparin was individualized and based on the estimated risks of TE and bleeding.

Results

556 MHV patients (372 aortic only, 136 mitral only, 48 with multiple valves) underwent 580 procedures. The three-month cumulative incidence of thromboembolism was 0.9% which included: cerebral ischemia (n = 3), unstable angina (n = 1), acute myocardial infarction (n = 1). None were fatal. The cumulative incidence of major bleeding was 3.6% and fatal in 0.2%. The incidence of major bleeding events did not differ by postoperative anticoagulant strategy whether LMWH (3.7%), UFH (6.1%), or no heparin (2.4%) was used (p = 0.26).

Conclusions

The three-month cumulative incidence of thromboembolism among MHV patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Whereas bleeding exceeds thromboembolic complications, our current practice is to restart warfarin as soon as possible post-procedure. Post-procedural heparin use is reserved for patients with the highest thromboembolic risk (mitral MHV, multiple MHVs, MHV with prior stroke or atrial fibrillation) waiting at least 48 hours before initiating.     

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.     

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。     

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.     

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     

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。     

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。     

低分子肝素联合丹参注射液治疗急性脑梗死的效果分析

目的探讨低分子肝素和丹参注射液联合治疗急性脑梗死的临床效果。方法选取2012-12—2015-01我院诊治的急性脑梗死患者95例,随机分为研究组(n=48例)和对照组(n=47例),对照组实施基础治疗与丹参注射液,观察组加用低分子肝素治疗。比较2组治疗前后血液流变情况、神经功能改变情况(NIHSS评分),并评定临床疗效、并发症情况。结果2组治疗后血液流变学指标(纤维蛋白原、红细胞比积、血浆黏度、全血低切黏度、全血高切黏度)均明显低于治疗前(P0.05),且研究组较对照组降低更明显(P0.05);治疗后7、14、28d2组NIHSS评分均较治疗前明显降低(P0.05),且研究组各时点NIHSS评分较对照组更低(P0.05);研究组与对照组总有效率分别为91.67%和74.47%,研究组高于对照组(P0.05);2组并发症发生情况无明显差异(P0.05)。结论低分子肝素联合丹参注射液治疗急性脑梗死,患者脑部循环明显改善,效果显著,值得推广。     

Comparative effects of heparin and PK 10169, a low molecular weight fraction, in a canine model of arterial thrombosis

The comparative properties of heparin and PK 10169, a low molecular weight fraction, were studied using an antithrombotic test in anaesthetized dogs. The antithrombotic properties of the two compounds were evaluated by measuring inhibition of thrombus formation following transluminar stimulation of coronary artery with anodal current and by measuring anticoagulant properties, anti Xa and anti IIa activities. The results show that PK 10169 displayed significant antithrombotic activities above 0.625 mg/kg and was equipotent at 2.5 mg/kg s.c. with heparin 10 mg/kg s.c. No correlation could be observed between antithrombotic/anti Xa ratio of both compounds. Moreover it was shown that, unlike heparin, PK 10169 s.c. was devoid of obvious anticoagulant properties and induced a negligible anti IIa activity contrasting with a high anti Xa level. A similar dissociation between anti Xa and anti IIa activities was observed following i.v. administration of 2.5 mg/kg of PK 10169 but not with heparin. This low molecular weight heparin fraction might thus be regarded as a potential arterial antithrombotic agent devoid of appreciable anticoagulant effect.     

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.     

The effect of low molecular weight heparin on experimental thrombosis and haemostasis--the influence of production method

Three low molecular weight heparins prepared by enzymatic depolymerization, chemical degradation, and fractionation, respectively were studied in experimental thrombosis and haemostasis models in vivo and in biological assays in vitro. The three low molecular weight heparins, which had comparable molecular weight distributions, showed very similar activities both in vitro and in vivo. All three showed dose dependent thromboprophylactic effect. The antithrombotic effects of the low molecular weight heparins and conventional heparin administered in the same dose (30 XaI u/kg b.w.) did not differ. Neither LMW heparin nor conventional heparin (60 or 90 XaI u/kg b.w.) showed significant effects on the haemostatic plug formation time in the rabbit mesenteric microcirculation.

These experiments confirm that low molecular weight heparins are potential antithrombotic drugs, which by intravenous administration have effects similar to those of standard heparin. The method of preparation seems to be of no or minor importance, at least if the molecular weight distributions of the products are similar.     

急性脑血管病患者血浆低分子量肝素浓度监测

目的 研究脑血管病患者急性期（10d内）及亚急性期（4周内）血浆低分子量肝素（LMWH）浓度,了解LMWH样物质水平的自然变化趋势,并观察LMMH治疗干预后体内LMWH血浓度的变化以及出血副反应与浓度之间的关系。方法 应用发色底物法抗FXa测定法对84例急性脑血管病患者的血浆LMWH浓度进行动态观察。结果 脑梗死患者与脑出血患者血浆LMWH浓度在0.3-0.4之间,相比无显著性差异。应用LMWH治疗的脑梗死患者血浆LMWH浓度高于非治疗组,且有显著差异性。血浆LMWH浓度与出血副反应有一定的相关性。结论 监测血浆LMWH浓度有益于防止出血副反应,为个体化给药提供了基础。     

In vitro comparison of dabigatran, unfractionated heparin, and low-molecular-weight heparin in preventing thrombus formation on mechanical heart valves

Introduction

Lifelong oral anticoagulation (OAC) therapy is required for the prevention of thromboembolic events after implantation of an artificial heart valve. Thromboembolism and anticoagulant-related bleedings account for ≈ 75% of all complications experienced by heart valve recipients (2-9% of patients per year). The present study investigated the efficacy of dabigatran, a new direct thrombin inhibitor for oral use, as compared to unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in preventing thrombus formation on mechanical heart valves in vitro.

Material and Methods

Blood (230 ml) from healthy young male volunteers was anticoagulated either by dabigatran (1 μmol/l), UFH (150 IU), or LMWH (100 IU). Mechanical heart valve prostheses were placed in an in vitro thrombosis tester and exposed to the anticoagulated blood samples under continuous circulation at a rate of 75 beats per minute.

Results

In whole blood with no anticoagulant, the apparatus completely clotted in 15-20 minutes. When blood was treated with dabigatran, the mean thrombus weight was 164 ± 55 mg, in the UFH group 159 ± 69 mg, and in the LMWH group 182 ± 82 mg (p-value: 0.704). Electron microscopy showed no significant difference in thrombus formation in any group.

Conclusisons

Dabigatran was as effective as UFH and LMWH in preventing thrombus formation on mechanical heart valves in our in vitro investigation. Thus, we hypothesize that dabigatran etexilate might potentially be a useful and competitive orally administered alternative to UFH and LMWH for recipients of alloplastic heart valve prostheses.     

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。