Low molecular weight heparin in prevention of perioperative thrombosis.

OBJECTIVE--To determine whether prophylactic treatment with low molecular weight heparin reduces the incidence of thrombosis in patients who have had general or orthopaedic surgery. DESIGN--Meta-analysis of results from 52 randomised, controlled clinical studies (29 in general surgery and 23 in orthopaedic surgery) in which low molecular weight heparin was compared with placebo, dextran, or unfractionated heparin. SUBJECTS--Patients who had had general or orthopaedic surgery. INTERVENTION--Once daily injection of a low molecular weight heparin compared with placebo, dextran, or unfractionated heparin. MAIN OUTCOME MEASURES--Incidence of deep venous thrombosis, pulmonary embolism, major haemorrhages, and death. RESULTS--The results confirm that low molecular weight heparins are more efficacious for the prophylactic treatment of deep venous thrombosis than placebo (common odds ratio 0.31, 95% confidence interval 0.22 to 0.43; p < 0.001) and dextran (0.44, 0.30 to 0.65; p < 0.001). The results suggest that low molecular weight heparins are also more efficacious than unfractionated heparin (0.85, 0.74 to 0.97; p = 0.02), with no significant difference in the incidence of major haemorrhages (1.06, 0.93 to 1.20; p = 0.62). CONCLUSIONS--Low molecular weight heparins seem to have a higher benefit to risk ratio than unfractionated heparin in preventing perioperative thrombosis. However, it remains to be shown in a suitably powered clinical trial whether low molecular weight heparin reduces the risk of fatal pulmonary embolism compared with heparin.     

Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin.

OBJECTIVE--To evaluate the efficacy and safety of two subcutaneous prophylactic regimens for postoperative deep vein thrombosis after total hip replacement. DESIGN--Prospective open randomised multicentre trial. SETTING--28 European departments of orthopaedic surgery. INTERVENTION--All patients had bilateral phlebography 10 days after surgery. 31 patients receiving low molecular weight heparin and 29 receiving unfractionated heparin were excluded from the efficacy analysis for various reasons. PATIENTS--349 patients undergoing total hip replacement between September 1988 and May 1989. 174 patients received subcutaneously a low molecular weight heparin (Fraxiparine) with anti-factor Xa activity of 41 IU/kg/day for three days, then 62 IU/kg/day from day 4 to day 10. 175 patients received subcutaneous unfractionated heparin at intervals of eight hours; doses were adjusted to maintain the activated thromboplastin time at two to five seconds above control values. MAIN OUTCOME MEASURE--Total incidence of deep vein thrombosis and incidence of proximal deep vein thrombosis on bilateral phlebography. RESULTS--The total incidence of deep vein thrombosis was 16% in patients receiving unfractionated heparin and 12.6% in patients receiving low molecular weight heparin (p = 0.45), and the incidence of thrombosis of the proximal veins was 13.1% and 2.9% respectively (p less than 0.001). Four patients receiving unfractionated heparin and one receiving low molecular weight heparin developed pulmonary embolism. The incidence of bleeding complications was low and comparable in the two groups. CONCLUSION--Low molecular weight heparin is at least as effective as unfractionated heparin in preventing deep vein thrombosis and is more effective at preventing thrombosis of the proximal veins in patients undergoing hip replacement. Low molecular weight heparin is not more likely to cause bleeding complications and is simpler to give than unfractionated heparin.     

Experimental studies on the antithrombotic and haemorrhagic effects of heparin and a low molecular weight heparin derivative

Antithrombotic, haemorrhagic and anticoagulant effects of unfractionated heparin (UH) and the low molecular weight heparin fragment KABI 2165 were studied in rats. In stasis-induced venous thrombosis of the jugular vein intravenous injection of both, UH and KABI 2165, either reduced significantly the size of thrombi or completely prevented thrombus formation in a dose-dependent manner. The dose of KABI 2165 required for prevention of thrombus formation showed a marked anticoagulant activity measured by APTT which was in the same range as that of the equieffective dose of UH. After administration of antithrombotically effective doses only UH caused a significant prolongation of bleeding time after standardized incision of the tail. KABI 2165 produced haemorrhagic effects at about 4-fold higher doses only than those required for the antithrombotic action.     

Free radical generation during chemical depolymerization of heparin

Low-molecular weight heparins (LMWHs), as compared with unfractionated heparin (UFH), present superior bioavailability, much longer plasma half-life, and lower incidence of side effects. For these reasons, over the past two decades LMWHs have become the drugs of choice for the treatment of deep venous thrombosis, pulmonary embolism, arterial thrombosis, and unstable angina. Furthermore, their use in acute ischemic stroke is currently under study. LMWHs are obtained by UFH depolymerization, which can be performed using various methods, including nitrous acid depolymerization, cleavage by beta-elimination of benzyl ester, enzymatic depolymerization, and peroxyl radical-dependent depolymerization. This article addresses the chemical depolymerization, obtained by free radical attack (mainly hydroxyl radical), of heparin. The electron spin resonance (ESR) spectroscopy, coupled to the spin trapping technique, was employed to study this reaction. Free radical-mediated heparin depolymerization was performed under different chemical conditions. The final products of the reactions were purified and classified on the basis of their molecular weight and other characteristics. The level of heparin fragmentation was different depending on the type of depolymerization reaction used. Moreover, the level of reproducibility and the resulting radical species were different for every type of reaction performed.     

香豆乙酯与华法林预防髋膝关节手术后下肢深静脉血栓形成的效果比较

目的:比较香豆乙酯与华法林预防髋膝关节手术后下肢深静脉血栓形成的疗效。方法:选取我院行髋膝关节手术患者38例,随机分为实验组和对照组,每组19例。对照组给予低分子量肝素及香豆乙酯片治疗;实验组给予低分子量肝素及华法林治疗。观察并比较两组患者的临床效果、下肢深静脉血栓的发生率及不良反应的发生情况。结果:实验组总有效率(94.7%)高于对照组(68.4%),差异有统计学意义(P0.05);实验组患者下肢深静脉血栓发生率(5.3%)低于对照组(21.1%),差异有统计学意义(P0.05);实验组不良反应发生率(15.8%)低于对照组(42.1%),差异有统计学意义(P0.05)。结论:与双香豆乙酯相比,华法林预防髋膝关节手术患者下肢深静脉血栓形成的效果更显著,且并发症较少。     

Low-molecular-weight heparin (dalteparin) effectively prevents thrombosis in a rat model of deep arterial injury

Unfractionated heparin is often used to prevent thrombosis in microvascular surgery, but a major drawback of heparin therapy is increased bleeding. Low-molecular-weight heparins prevent venous thrombosis as effectively as heparin and have better bioavailability and a longer plasma half-life, which explains the increased use of low-molecular-weight heparins as substitutes for heparin in clinical practice. However, the ability of low-molecular-weight heparins to prevent arterial thrombosis has been debated. In this study, the authors compared the antithrombotic and antihemostatic effects of heparin and the low-molecular-weight heparin dalteparin in a rat model of arterial thrombosis. A segment of the left common carotid artery was isolated between vascular clamps and opened longitudinally. An endarterectomy was performed and the arteriotomy was closed with a running suture. The antithrombotic effect (vascular patency 31 minutes after reperfusion) and the surgical bleeding were measured. Groups of 10 rats were treated in a blind, random fashion with intravenous injection of one of the following substances 1 minute before clamp release. Three groups received a bolus of heparin (20, 60, or 180 IU anti-factor Xa/kg), three groups received dalteparin (60, 180, or 540 IU anti-factor Xa/kg), and one group was treated with vehicle (saline). Heparin 180 IU/kg produced a distinct antithrombotic effect compared with the control group (p = 0.03), but it also significantly increased the surgical bleeding to 2.0 g compared with 1.5 g in the control group (medians, p = 0.01). Dalteparin 180 and 540 IU/kg also produced a powerful antithrombotic effect (p = 0.01 and p = 0.03, respectively). In contrast to heparin, 180 IU/kg dalteparin did not increase the surgical bleeding (median, 1.5 g; p = 0.37 versus controls). Dalteparin 540 IU/kg increased the median surgical bleeding to 2.6 g (p = 0.06 versus controls). The nonsignificant difference may be explained by the great interindividual variation of surgical bleeding in the high-dose dalteparin group. Dalteparin prevented arterial thrombosis as effectively as unfractionated heparin. In contrast to heparin, dalteparin did not increase the surgical bleeding, which indicates that dalteparin instead of heparin can be used to prevent thrombosis in microvascular surgery.     

Anticoagulant and antithrombotic effects of low molecular weight heparin

Low molecular weight heparin (Mr 8 kDa) was prepared from conventional heparin (Mr 18 kDa) by the chromatography on DEAE-sephadex with the recovery of 56%. Low molecular weight heparin had less affinity to antithrombin III than unfractionated heparin and had less anticoagulant and anti-IIa activities. The anti-Xa activity of low molecular weight heparin exceed by 17% the activity of conventional heparin. In the experiments on rats it was determined that the biological half-life of low molecular weight heparin exceed two-fold that of the unfractionated heparin. In the modified model of the arteriovenous shunt thrombosis in normal and nephrotic syndrome rats it was shown that the low molecular weight heparin was the most efficient antithrombotic remedy in normal and decreased level of antithrombin III in the organism.     

Statins Improve the Resolution of Established Murine Venous Thrombosis: Reductions in Thrombus Burden and Vein Wall Scarring

Despite anticoagulation therapy, up to one-half of patients with deep vein thrombosis (DVT) will develop the post-thrombotic syndrome (PTS). Improving the long-term outcome of DVT patients at risk for PTS will therefore require new approaches. Here we investigate the effects of statins—lipid-lowering agents with anti-thrombotic and anti-inflammatory properties—in decreasing thrombus burden and decreasing vein wall injury, mediators of PTS, in established murine stasis and non-stasis chemical-induced venous thrombosis (N = 282 mice). Treatment of mice with daily atorvastatin or rosuvastatin significantly reduced stasis venous thrombus burden by 25% without affecting lipid levels, blood coagulation parameters, or blood cell counts. Statin-driven reductions in VT burden (thrombus mass for stasis thrombi, intravital microscopy thrombus area for non-stasis thrombi) compared similarly to the therapeutic anticoagulant effects of low molecular weight heparin. Blood from statin-treated mice showed significant reductions in platelet aggregation and clot stability. Statins additionally reduced thrombus plasminogen activator inhibitor-1 (PAI-1), tissue factor, neutrophils, myeloperoxidase, neutrophil extracellular traps (NETs), and macrophages, and these effects were most notable in the earlier timepoints after DVT formation. In addition, statins reduced DVT-induced vein wall scarring by 50% durably up to day 21 in stasis VT, as shown by polarized light microscopy of picrosirius red-stained vein wall collagen. The overall results demonstrate that statins improve VT resolution via profibrinolytic, anticoagulant, antiplatelet, and anti-vein wall scarring effects. Statins may therefore offer a new pharmacotherapeutic approach to improve DVT resolution and to reduce the post-thrombotic syndrome, particularly in subjects who are ineligible for anticoagulation therapy.     

Low-molecular-weight heparins in the treatment of venous thromboembolism

Venous thromboembolism is a common disease that is associated with considerable morbidity if left untreated. Recently, low-molecular-weight heparins (LMWHs) have been evaluated for use in acute treatment of deep venous thrombosis and pulmonary embolism. Randomized studies have shown that LMWHs are as effective as unfractionated heparin in the prevention of recurrent venous thromboembolism, and are as safe with respect to the occurrence of major bleeding. A pooled analysis did not show substantial differences among different LMWH compounds used, but no direct comparison of the different LMWHs is currently available. Finally, in patients with pulmonary embolism, there is a relative lack of large studies of daily practice. It could be argued that large prospective studies, in patients who were treated with LMWHs from the moment of diagnosis, are needed.     

Cost-utility of enoxaparin compared with unfractionated heparin in unstable coronary artery disease

Background  

Low molecular weight heparins hold several advantages over unfractionated heparin including convenience of administration. Enoxaparin is one such heparin licensed in the UK for use in unstable coronary artery disease (unstable stable angina and non-Q wave myocardial infarction). In these patients, two large randomised controlled trials and their meta-analysis showed small benefits for enoxaparin over unfractionated heparin at 30–43 days and potentially at one year.     

Probing structural selectivity of synthetic heparin binding to Stabilin protein receptors

As one of the most widely used drugs worldwide, heparin is an essential anticoagulant required for surgery, dialysis, treatment of thrombosis, cancer, and general circulatory management. Stabilin-2 is a scavenger clearance receptor with high expression in the sinusoidal endothelium of liver. It is believed that Stabilin-2 is the primary receptor for the clearance of unfractionated and low molecular weight heparins in the liver. Here, we identify the modifications and length of the heparin polymer that are required for binding and endocytosis by both human Stabilin receptors: Stabilin-2 and its homolog Stabilin-1 (also found in liver endothelium). Using enzymatically synthesized (35)S-labeled heparan sulfate oligomers, we identified that sulfation of the 3-OH position of N-sulfated glucosamine (GlcNS) is the most beneficial modification for binding and endocytosis via both Stabilin receptors. In addition, our data suggest that a decasaccharide is the minimal size for binding to the Stabilin receptors. These findings define the physical parameters of the heparin structure required for efficient clearance from blood circulation. These results will also aid in the design of synthetic heparins with desired clearance rates.     

Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation

The antiphospholipid syndrome (APS) is defined by thrombosis and recurrent pregnancy loss in the presence of antiphospholipid (aPL) antibodies and is generally treated with anticoagulation therapy. Because complement activation is essential and causative in aPL antibody-induced fetal injury, we hypothesized that heparin protects pregnant APS patients from complications through inhibition of complement. Treatment with heparin (unfractionated or low molecular weight) prevented complement activation in vivo and in vitro and protected mice from pregnancy complications induced by aPL antibodies. Neither fondaparinux nor hirudin, other anticoagulants, inhibited the generation of complement split products or prevented pregnancy loss, demonstrating that anticoagulation therapy is insufficient protection against APS-associated miscarriage. Our data indicate that heparins prevent obstetrical complications in women with APS because they block activation of complement induced by aPL antibodies targeted to decidual tissues, rather than by their anticoagulant effects.     

低分子肝素与普通肝素在介入手术中安全性与疗效的比较

肝素已经普遍用于冠状动脉介入术中,但是由于在应用过程中抗凝效果个体差异大、出血风险相对较高、并发症等问题的日益显现,已经引起了医生们的注意。相对而言,低分子肝素具有抗凝作用强、出血风险低、并发症发生率相对较低、无需实验室监测等优点,进而越来越广泛的在冠状动脉介入术中担当重要角色。普通肝素与低分子肝素在冠状动脉介入术中的有效性与安全性的比较是值得我们去探讨的,知道普通肝素与低分子肝素的优缺点后,可使我们在冠状动脉介入术中更好的选择抗凝药物,使手术的成功率大大提高,降低术后并发症的发生,减轻患者的痛苦。本文结合普通肝素与低分子肝素的药理作用及相关临床研究的结果,分析比较了普通肝素与低分子肝素在冠状动脉介入术中的有效性与安全性。     

低分子量肝素钠的制备与临床应用

低分子肝素有抗凝血、抗血栓、调血脂、抗肿瘤等作用,与普通肝素相比具有皮下注射吸收好、半衰期长、生物利用率高,与血浆、血小板亲和力小、出血副作用少等优点.对低分子肝素的制备、质量检测和临床应用的研究进展进行了综述.     

Search for the heparin antithrombin III-binding site precursor.

The last step of heparin biosynthesis is thought to involve the action of 3-O-sulfotransferase resulting in the formation of an antithrombin III (ATIII) binding site required for heparin's anticoagulant activity. The isolation of a significant fraction of heparin chains without antithrombin III-binding sites and having low affinity for ATIII suggests the presence of a precursor site, lacking the 3-O-sulfate group. Porcine mucosal heparin was depolymerized into a mixture of oligosaccharides using heparin lyase. One of these oligosaccharides was derived from heparin's ATIII-binding site. In an effort to find the ATIII-binding site precursor, the structures of several minor oligosaccharides were determined. A greater than 90% recovery of oligosaccharides (on a mole and weight basis) was obtained for both unfractionated and affinity-fractionated heparins. An oligosaccharide arising from the ATIII-binding site precursor was found that comprised only 0.8 mol % of the oligosaccharide product mixture. This oligosaccharide was only slightly enriched in heparin having a low affinity for ATIII and only slightly disenriched in high affinity heparin. The small number of these ATIII-binding site precursors, found in unfractionated and fractionated heparins, suggests the existence of a low ATIII affinity heparin may not simply be the result of the incomplete action of 3-O-sulfotransferase in the final step in heparin biosynthesis. Rather these data suggest that some earlier step, involved in the formation of placement of these precursor sites, may be primarily responsible for high and low ATIII affinity heparins.     

Serum Fibrin/Fibrinogen Degradation Products Associated with Postoperative Pulmonary Embolus and Venous Thrombosis

A total of 76 “high-risk” surgical patients were studied for evidence of venous thromboembolic disease. Episodes of deep vein thrombosis and of pulmonary embolism were related to changes in blood levels of fibrin degradation products (F.D.P.). When diagnosed either by ordinary clinical means or by venography and isotope scanning significantly raised F.D.P. levels were found in all cases. Serum F.D.P. estimations are unlikely to help in detecting deep vein thrombosis, but may prove valuable in diagnosing pulmonary embolism.     

Effect of non-fractionated and low-molecular heparin on the functional state of mast cells]

The state of the mast-cell population of rats treated with unfractionated and low-molecular weight heparins under stress conditions has been comparatively studied by the morphometrical assay. The stress was produced by 60 min immobilization followed by intravenous injection of unfractionated (UF) or low-molecular weight (LMW) heparin. The stress-induced heparin release from mast cells resulted in a 3.3-fold decrease of the index of saturation with heparin and in a significant increase of granulolysis and degranulation. The mast cell secretory status reached the preinjection level within 20 min in rats with UF heparin injected (15 unit/200 g). At the same time mast cells of rats with LMW heparin have no such ability. The data obtained indicate that LMW heparin in contrast to UF heparin cannot be accumulated (or accumulated very slowly) by mast cells. This fact as well as low affinity of LMW heparin to endothelium and blood platelets promote its preservation in blood for a long time.     

低分子肝素钙联合银杏达莫注射液应用于股骨粗隆间骨折术后下肢深静脉血栓形成的疗效观察

目的:探讨低分子肝素钙联合银杏达莫注射液应用于股骨粗隆间骨折术后下肢深静脉血栓形成的治疗效果。方法:选择2015年6月至2016年12月间我院骨科收治的股骨粗隆间骨折的患者80例,按随机数字表法分为研究组和对照组,每组各40例。两组患者均接受手术治疗,对照组术后应用低分子肝素钙6000IU治疗,皮下注射,2次/d;研究组在此基础上应用银杏达莫注射液20 m L治疗,静脉滴注,1次/d,疗程均为10 d。观察两组患者术后下肢深静脉血栓发生率、髌骨上极上15 cm周径、髌骨下极下15 cm周径及肿胀率,治疗前后凝血酶原时间(PT)、活化部分凝血活酶时间(APPT)、D-2聚体(D-D)水平和血液流变学检查指标。结果:治疗期间研究组下肢深静脉血栓发生率为2.50%,显著低于对照组的15.00%(P0.05)。治疗后两组患者髌骨上极上15cm周径、髌骨下极下15 cm周径均轻微增高,与治疗前比较无统计学差异(P0.05)。两组患者髌骨上极上15 cm肿胀率、髌骨下极下15 cm肿胀率比较无统计学差异(P0.05)。治疗后2d研究组患者PT、APPT显著高于对照组,D-D显著低于对照组(P0.05),治疗后10 d研究组PT、APPT显著高于对照组,D-D显著低于对照组(P0.05)。治疗后2 d、治疗后10 d研究组全血低切、全血高切、血浆黏度、红细胞压积、红细胞聚集指数和纤维蛋白原显著低于对照组(P0.05)。结论:低分子肝素钙联合银杏达莫注射液可以降低血液凝固性,改善血液流变学,对预防股骨粗隆间骨折下肢深静脉血栓形成有良好的疗效。     

Deep venous thrombosis and pulmonary embolus after face lift: a study of incidence and prophylaxis

Deep venous thrombosis and pulmonary embolus are known risks of surgery. However, the incidence of these conditions in face lift is unknown. In this study, the incidence of deep venous thrombosis/pulmonary embolus after face lift is studied and factors associated with thromboembolic complications are evaluated. One-third of the active members of the American Society for Aesthetic Plastic Surgery were randomly selected. Participating surgeons completed a one-page survey providing information on face-lift procedures during a 12-month study period. A response rate of 80 percent was achieved, with 273 of the 342 surgeons responding to the survey. A total of 9937 face-lift procedures were reported in the 1-year study period. There were 35 patients with deep venous thrombosis (0.35 percent), 14 patients with pulmonary embolus (0.14 percent), and 1 patient death in the series. Although 43.5 percent of patients underwent face lift under general anesthesia, 83.7 percent of deep venous thrombosis/pulmonary embolus events occurred with general anesthesia. For prophylaxis for deep venous thrombosis/pulmonary embolus, 19.7 percent of the surgeons used intermittent compression devices, 19.6 percent used thromboembolic disease hose or Ace wraps, and 60.7 percent used no prophylaxis. Of patients developing deep venous thrombosis/pulmonary embolus, 4.1 percent were treated prophylactically with intermittent compression devices, 36.7 percent with thromboembolic disease hose/Ace wraps, and 59.2 percent with no prophylaxis. It was found that deep venous thrombosis/pulmonary embolus after face lift is a measurable complication experienced by one of nine surgeons surveyed. Deep venous thrombosis/pulmonary embolus is more likely to occur when the procedure is performed under general anesthesia. The majority of plastic surgeons surveyed used no prophylaxis for deep venous thrombosis when performing face-lift procedures. Intermittent compression devices were associated with significantly fewer thromboembolic complications, whereas Ace wrap/thromboembolic disease hose afforded no protection against deep venous thrombosis/pulmonary embolus when used alone. In conclusion, aesthetic surgeons should consider adopting intermittent compression devices when performing face lift under general anesthesia.     

Inhibition of coagulation and platelet adhesion to extracellular matrix by unfractionated heparin and a low molecular weight heparin

In 7 healthy volunteers, the effect of a single i.v. injection of 52 mg (7,500 IU) of an unfractionated heparin (UFH) and of 52.5 mg (5,000 anti XaU) of a low molecular weight heparin (LMWH) on coagulation parameters and platelet function has been studied. Thrombin-induced platelet aggregation was inhibited after the injection of both heparins. There was no significant change of ADP or collagen-induced aggregation after LMWH of UFH. Platelet adhesion to bovine extracellular matrix was not inhibited by UFH but was significantly reduced after addition in vitro and ex vivo after administration of LMWH. Further investigation should establish the time course of LMWH effects on platelet adhesion. A long duration of this effect could be partially correlated with the antithrombotic effects of LMWH.