Subcutaneous injections and intravenous infusion of sodium salt of heparin in the treatment of thrombosis of deep veins of the lower extremities

Ninety-four patients with deep vein thrombosis of inferior limbs were randomly allocated to receive sodium heparin either by subcutaneous injections or by continuous intravenous infusion for six days. No significant difference was observed in the therapeutic efficiency as judged by phlebographic examinations and in rate of symptomatic pulmonary embolism between the two groups. There was one instance of major bleeding in the subcutaneous group. Minor bleedings occurred in 10 of the 48 patients treated with subcutaneous heparin and in 13 of the 46 patients receiving intravenous heparin. The results showed that subcutaneous injections of sodium heparin are as effective and safe as continuous intravenous infusion of this drug in the treatment of deep vein thrombosis.     

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.     

Effect of intravenous dextran 70 and pneumatic leg compression on incidence of postoperative pulmonary embolism.

The incidence of pulmonary embolism and deep vein thrombosis was measured in 50 matched pairs of patients undergoing common surgical procedures with preoperative and postoperative ventilation-perfusion lung scans and the fibrinogen uptake test. One patient in each pair was treated with intravenous dextran 70 and pneumatic leggings. The incidence of pulmonary embolism among the treated patients was significantly reduced from 24% to 8%, but the incidence of deep vein thrombosis was not significantly reduced (34% to 24%).     

Collaborative overview of randomised trials of antiplatelet therapy--III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialists' Collaboration.

OBJECTIVE--To determine the efficacy of antiplatelet therapy as prophylaxis against deep venous thrombosis or pulmonary embolism in surgical and high risk medical patients. DESIGN--Overviews of all randomised trials of antiplatelet therapy that could have been available by March 1990 and in which deep venous thrombosis was assessed systematically. SETTING--53 trials (total 8400 patients) of an average of two weeks of antiplatelet therapy versus control in general or orthopaedic surgery; nine trials (600 patients) of antiplatelet therapy versus control in other types of immobility; 18 trials (1000 patients) of one antiplatelet regimen versus another. RESULTS--Overall, a few weeks of antiplatelet therapy produced a highly significant (2P < 0.00001) reduction in deep venous thrombosis. 25% of patients allocated antiplatelet therapy versus 34% of appropriately adjusted controls had deep venous thrombosis detected by systematic fibrinogen scanning or venography, representing prevention in about 90 patients per 1000 allocated antiplatelet therapy. There was an even greater proportional reduction in pulmonary embolism: such emboli were detected among 47 (1.0%) antiplatelet allocated patients versus an adjusted control total of 129 (2.7%), representing prevention among about 17 patients per 1000 treated (2P < 0.00001). In analyses confined to surgical trials, the proportional reductions were similar and separately significant for nonfatal pulmonary embolism (0.7% antiplatelet therapy v 1.8% control; 2P < 0.00001) and for deaths attributed to pulmonary embolism (0.2% v 0.9%; 2P = 0.0001). There was a slight but non-significant excess of deaths from other causes (1.0% v 0.7%), which made the difference in total mortality nonsignificant, though still favourable (1.2% v 1.5%). Information on adding antiplatelet therapy to heparin was limited but, at least for pulmonary embolism, suggested more protection from the combination than from heparin alone. The proportional reduction in the odds of suffering a deep venous thrombosis was roughly the same in patients having general surgery, traumatic orthopaedic surgery, and elective orthopaedic surgery (and in medical patients who were at increased risk of thromboembolism). For pulmonary embolism the numbers affected were smaller, but again the reductions were highly significant both in general surgery (16 (0.5%) v 58 (1.7%) pulmonary emboli; 2P < 0.0001) and in orthopaedic surgery (28 (2.7%) v 63 (6.1%) pulmonary emboli; 2P < 0.0002). CONCLUSION--It had previously been supposed that antiplatelet therapy did not influence venous thromboembolism, and many surgeons and physicians do not use it routinely for thromboprophylaxis, even for patients who are at substantial risk of deep venous thrombosis or pulmonary embolism. These results indicate that antiplatelet therapy--either alone or, for greater effect, in addition to other proved forms of thromboprophylaxis (such as subcutaneous heparin)--should be considered.     

Preventing thromboembolism after myocardial infarction: effect of low-dose heparin or smoking.

A trial of low-dose subcutaneous heparin to prevent thromboembolic complications after myocardial infarction was carried out in 78 patients. Of the 37 heparin-treated patients only two (5%) developed evidence of leg vein thrombosis, while 14 (34%) of the 41 controls did so, and five controls developed pulmonary emboli. Leg vein thrombosis developed in 12 (50%) of the 24 controls who did not smoke cigarettes but in only two (13%) of the 17 controls who were cigarette smokers. Non-smokers who have a myocardial infarction should be given low-dose heparin subcutaneously to prevent leg vein thrombosis and pulmonary embolism.     

Ion-pairing reversed-phased chromatography/mass spectrometry of heparin

Heparin and heparin-derived components are widely applied anticoagulant drugs used for amongst other applications medical treatment of deep vein thrombosis and pulmonary embolism. Depolymerisation of native heparin results in complex mixtures of sulfated linear oligosaccharides that are usually not well characterised. In order to further characterise such mixtures, two on-line ion-pairing reverse-phased chromatography electrospray ionisation (ESI) mass spectrometry methods have been developed. One of the systems allows the determination of more than 200 components in a medium molecular weight heparin preparation, whereas the other system can be used to separate isomeric heparin oligosaccharides after previous separation according to size. This latter system allows semi-preparative isolation of isomeric heparin oligosaccharides. The experimental setup includes on-line cation exchange in order to prevent the ion-pairing reagent from entering the mass spectrometer.     

Effectiveness of long term oral anticoagulation treatment in preventing venous thrombosis in hereditary protein S deficiency.

In eight of 14 patients who were deficient in protein S and who belonged to two unrelated families thrombosis presented as thrombophlebitis in seven and deep vein thrombosis in six, complicated by pulmonary embolism in four and leg ulcers in two. In four patients superficial thrombophlebitis preceded deep vein thrombosis by one to 11 years. Post-thrombotic varicose veins and venous insufficiency had developed in four patients. In three of those and in a fourth patient symptomatic superficial thrombophlebitis, deep vein thrombosis, and pulmonary embolism did not recur while they were taking oral anticoagulant treatment for six to 12 years. The anticoagulation intensity corresponded to international normalised ratio values of over 2.5. It is concluded that the benefits of anticoagulant treatment for patients with congenital thrombotic disease are great, and thus it is necessary to make an early diagnosis and treat patients at risk of developing thrombosis.     

肾病综合征合并肺栓塞的临床研究进展

肾病综合征是一种临床常见疾病,其患者体内常呈高凝状态,极易发生血栓栓塞事件,而其中以肾静脉血栓、肺动脉栓塞和 下肢深静脉血栓最为常见。由于肺动脉栓塞早期缺乏特征性的临床表现,病情隐匿,所以极易误诊或漏诊,发现时患者病情往往 已十分严重,致死率极高。目前,对于肾病综合征合并肺栓塞的发生率国内外报道不一,尚无准确的流行病学资料,而对于其发病 原因、危险因素、早期诊断及是否需要预防性抗凝治疗等均存在争议,本文主要结合文献对肾病综合征合并肺栓塞的流行病学、 病因及发病机制、诊断、高危因素和治疗进行了综述,尤其是对目前争议较大的肾病综合征合并肺栓塞患者是否需要早期抗凝治 疗。     

Failure of low-dose heparin to prevent significant thromboembolic complications in high-risk surgical patients: interim report of prospective trial. Groote Schuur Hospital Thromboembolus Study Group.

The efficacy of low-dose subcutaneous heparin (5000 IU eight-hourly) is being studied in a single-centre, prospective randomised trial of patients aged over 40 submitted to major elective intra-abdominal surgery. The trial end-points are the objectively defined incidence and extent of deep vein thrombosis (as seen on uptake of 125I-labelled fibrinogen, Doppler ultrasonography, and bilateral ascending phlebography) and non-fatal pulmonary embolus (as measured by preoperative spirometry and preoperative and postoperative chest radiography and perfusion lung scanning performed on a routine, unselected basis). An interim analysis of the first 200 patients indicates that low-dose heparin significantly reduces the incidence of calf-vein thrombosis but does not reduce the incidence of proximal segment thrombosis or non-fatal pulmonary embolism. Thus the routine use of low-dose heparin prophylaxis in all major surgical procedures in patients aged over 40 may not be advisable.     

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.     

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.     

Heparin in the Prevention of Deep Vein Thrombosis after Myocardial Infarction

A trial of continuous intravenous heparin in the prevention of deep vein thrombosis was undertaken in 48 patients who had suffered a myocardial infarction. Of the 24 control patients who did not receive heparin seven (29%) developed calf vein thrombosis as detected by the radioactive fibrinogen technique. None of the 24 heparinized patients had any evidence of venous thrombosis. This difference is significant at the 1% level.     

Cost-effectiveness of enoxaparin versus warfarin prophylaxis against deep-vein thrombosis after total hip replacement.

OBJECTIVE: To compare the efficacy and cost-effectiveness of enoxaparin, a low-molecular-weight heparin derivative, with that of low-dose warfarin in the prevention of deep-vein thrombosis (DVT) after total hip replacement. DATA SOURCES: English-language articles on enoxaparin and warfarin prophylaxis is patients undergoing total hip replacement published from January 1982 to December 1992. STUDY SELECTION: Four trials of enoxaparin (involving 567 patients) and six trials of warfarin (involving 630) met the following criteria: randomized controlled trial, prophylaxis started no later than 24 hours after surgery and continued for at least 7 days, warfarin dose monitored and adjusted appropriately, enoxaparin dosage 30 mg twice daily, and DVT confirmed by bilateral venography. DATA EXTRACTION: Rates of DVT, cost of prophylaxis, diagnosis and treatment per patient, rate of pulmonary embolism (PE), number of deaths and incremental cost-effectiveness (cost per life-year gained). DATA SYNTHESIS: The pooled rate of DVT was 13.6% with enoxaparin (95% confidence interval [CI] 10.9% to 16.3%) and 20.6% with warfarin (95% CI 17.4% to 23.8%). At a cost of $19.55 per day for enoxaparin the total cost per patient, including prophylaxis and management of DVT, exceeded that per patient receiving warfarin by about $121. For every 10,000 patients treated the use of enoxaparin will prevent 47 cases of DVT, 3 cases of PE and 4 deaths. Thus, the estimated incremental cost-effectiveness of enoxaparin is $29 120 per life-year gained. CONCLUSION: On the basis of current Canadian cost-effectiveness guidelines the results of this study would be considered moderate to strong evidence to adopt enoxaparin prophylaxis against DVT after total hip replacement. However, because of the limited data the estimates are uncertain. Future trials should compare enoxaparin and warfarin and incorporate a prospective economic appraisal.     

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。     

Dextran 70 in prophylaxis of thromboembolic disease after surgery: a clinically oriented randomized double-blind trial.

A randomized double-blind trial of prophylaxis of thromboembolism in surgical patients judged by clinical morbidity has been completed. Altogether 831 patients over 40 years of age who underwent elective surgery of the stomach, biliary system, or colon received either dextran 70 or normal saline before the operation. Thirteen of the 435 patients on saline and three of the 396 on dextran developed pulmonary embolism. Eight of these 16 patients died of pulmonary embolism--seven in the saline group and one in the dextran group. As detected either clinically or by 125I-fibrinogen scanning the incidence of deep vein thrombosis was similar in the two groups. There was no increased incidence of excessive bleeding in patients on dextran though clinical impression suggested that some patients on dextran bled excessively. This trial showed that dextran 70 administered by intravenous drip during operation is effective in preventing pulmonary embolism and, in particular, reducing mortality from this cause. It seems to be as effective as subcutaneous heparin but is easier to administer and places less of a burden on nursing services.     

Subcutaneous calcium heparin versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective randomised trial.

One hundred patients with phlebographically proved acute deep vein thrombosis of the legs were prospectively randomised into two treatment groups to compare the safety and efficacy of subcutaneous calcium heparin versus intravenous sodium heparin administered by constant infusion pump. The dose of heparin was determined by daily measurement of the kaolin cephalin clotting time. Treatment was maintained for up to 14 days, after which phlebography was repeated. Of 49 patients who received subcutaneous calcium heparin, two showed an increase in thrombus size, while eight showed complete lysis. In the 47 patients who received intravenous sodium heparin thrombus increased in size in 13 while only one showed evidence of complete lysis. These differences were significant. There were no significant differences between the two groups in the incidence of serious complications, although almost half of those receiving intravenous heparin had some minor problem with the constant infusion pump and just over half of those receiving subcutaneous heparin had some bruising at the injection site. This study showed that subcutaneous calcium heparin was more effective in helping lyse existing thrombus and preventing its propagation than intravenous sodium heparin.     

关节置换术后抗凝药物预防深静脉血栓及相关并发症的临床研究进展

抗凝药物有助于预防全髋关节置换术和全膝关节置换术后深静脉血栓形成,临床上最常使用的传统抗凝药物如低分子肝素、华法林等可以起到很好的预防效果。目前有一类新的口服抗凝药物已经用于临床,为关节置换术后患者带来了一种更方便、安全和有效预防血栓的治疗选择。本篇综述主要针对传统抗凝药物低分子肝素及维生素K拮抗剂,直接凝血酶抑制剂达比加群,以及选择性Xa因子抑制剂利伐沙班和阿哌沙班,对迄今为止传统抗凝药物在全髋关节置换术和全膝关节置换术患者中的临床使用经验、优缺点、以及新型口服抗凝药物最新临床用药进展进行综述,为关节置换术后患者预防深静脉血栓提供用药参考。     

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.     

Fixed minidose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery.

A prospective study was carried out to see whether a small fixed dose of warfarin (1 mg daily) given before operation (mean 20 days) would prevent deep vein thrombosis in patients having major gynaecological surgery. One hundred and four patients were randomised into three groups: fixed minidose warfarin; full dose oral anticoagulation; and no treatment (controls). There was a significantly lower incidence of deep vein thrombosis in the minidose warfarin and full dose anticoagulant treatment groups (9% (3/32) and 3% (1/35) respectively) than in the controls (30%; 11/37) but no significant difference between the two anticoagulant treatment groups. Prothrombin time and the activated partial thromboplastin time were normal on the day of surgery in the warfarin treatment group, whereas times were prolonged in the group given full dose anticoagulation. Mean haemoglobin concentrations fell in all three groups after operation but the fall was significantly less in the minidose warfarin treatment group than after full dose anticoagulation. The benefit from full dose oral anticoagulant prophylaxis, based on a preoperative international normalised ratio of 1.5-2.5 with rabbit brain Manchester reagent, was similar to the protection achieved in an oral anticoagulant treatment group controlled with human brain Manchester comparative reagent at a similar level of anticoagulation. The lack of disturbance of normal haemostasis at the time of operation together with a significant reduction in deep vein thrombosis may encourage surgeons to introduce minidose prophylaxis with warfarin.     

Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis.

OBJECTIVE--To compare the efficacy and safety of low molecular weight heparins and unfractionated heparin in the initial treatment of deep venous thrombosis for the reduction of recurrent thromboembolic events, death, extension of thrombus, and haemorrhages. DESIGN--Meta-analysis of results from 16 randomised controlled clinical studies. SUBJECTS--2045 patients with established deep venous thrombosis. INTERVENTION--Treatment with low molecular weight heparins or unfractionated heparin. MAIN OUTCOME MEASURES--Incidences of thromboembolic events (deep venous thrombosis or pulmonary embolism, or both); major haemorrhages; total mortality; and extension of thrombus. RESULTS--A significant reduction in the incidence of thrombus extension (common odds ratio 0.51, 95% confidence interval 0.32 to 0.83; P = 0.006) in favour of low molecular weight heparin was observed. Non-significant trends also in favour of the low molecular weight heparins were observed for the recurrence of thromboembolic events (0.66, 0.41 to 1.07; P = 0.09), major haemorrhages (0.65, 0.36 to 1.16; P = 0.15), and total mortality (0.72, 0.46 to 1.4; P = 0.16). CONCLUSIONS--Low molecular weight heparins seem to have a higher benefit to risk ratio than unfractionated heparin in the treatment of venous thrombosis. These results, however, remain to be confirmed by using clinical outcomes in suitably powered clinical trials.