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.     

Prophylaxis of postoperative deep vein thrombosis: selective use of low-dose heparin in high-risk patients.

Administration of prophylactic low-dose subcutaneous heparin to prevent postoperative deep vein thrombosis is expensive, entails treating many patients unnecessarily, and causes some side effects. By using a predictive index a population of patients who are at particularly high risk of developing postoperative deep vein thrombosis may be identified preoperatively. Prophylaxis was given only to these patients, resulting in an incidence of deep vein thrombosis of 3.8% compared with 16.1% in previous studies in which no specific prophylaxis was given. By limiting prophylaxis to the group of patients identified by the predictive index as being at high risk of developing postoperative deep vein thrombosis results may be obtained that are as good as those expected from treating the whole population. Thus many patients are saved from exposure to low-dose subcutaneous heparin.     

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.     

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.     

Prophylaxis of postoperative leg vine thrombosis by low dose subcutaneous heparin or peroperative calf muscle stimulation: a controlled clinical trial.

In a randomized, controlled clinical trial of two methods of preventing postoperative leg vein thrombosis patients undergoing major surgery were divided into three groups. One received intermittent electrical calf muscle stimulation during surgery, the second subcutaneous heparin calcium 5000 IU every eight hours for six days, and the third no specific prophylaxis. Leg vein thrombosis was detected by the 125-I-fibrinogen uptake test. Neither method was effective in patients undergoing open bladder or prostatic surgery. Stimulation did not reduce the incidence of leg vein thrombosis in patients with malignant disease undergoing laparotomy, but heparin calcium was highly successful in this group (P smaller than 0-001). When the laparotomy was for a benign condition, however, both heparin calcium (P smaller than 0-001) and stimulation (P smaller than 0-01) were effective.     

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.     

Diagnosis and treatment of venous thromboembolism by consultants in Scotland.

A questionnaire was sent to 508 consultants in Scotland likely to encounter deep vein thrombosis and pulmonary embolism to assess their current standard practice in diagnosis and treatment of these disorders. Replies were received from 358 (70.5%). In deep vein thrombosis 47% and in pulmonary embolism 33% of consultants usually depended on clinical observation alone for diagnosis. In deep vein thrombosis 37% used venography to supplement clinical diagnosis and in pulmonary embolism 13% used angiography and 53% used isotopic scanning. Almost all consultants treated deep vein thrombosis (95%) and pulmonary embolism (99%) with anticoagulants. Most consultants (81%) gave heparin by intravenous infusion. Although many consultants gave intravenous heparin for more than three days (49.5% in deep vein thrombosis and 61% in pulmonary embolism), 25% of these consultants did not use any laboratory monitoring of heparin''s effect. Large numbers of consultants gave warfarin for more than three months (20% in deep vein thrombosis and 47% in pulmonary embolism). There was a significant tendency to give heparin (p less than 0.01) and warfarin (p less than 0.001) for longer periods in pulmonary embolism than in deep vein thrombosis. This survey shows a widely varying practice and underlines the need for further controlled studies to provide clear guidance in the management of deep vein thrombosis and pulmonary embolism.     

Low-molecular-weight heparin and prevention of postoperative deep vein thrombosis.

The efficacy of low-molecular-weight heparin as a prophylactic agent was assessed in 150 consecutive patients over the age of 40 undergoing major abdominal surgery. Fifty of these patients received 1250 activated partial thromboplastin time (APTT) units of low-molecular-weight heparin every 12 hours: three developed isotopic deep vein thrombosis, which was confirmed by phlebography in two cases. The other 100 patients received a single injection of 1850 APTT units of low-molecular-weight heparin. Three of them developed isotopic deep vein thrombosis; phlebography failed to confirm the presence of thrombi in each case. None of the 150 patients studied died from fatal or contributory pulmonary emboli. Low-molecular-weight heparin was not associated with any increase in preoperative or postoperative bleeding. The effect of equal amounts of postoperative bleeding. The effect of equal amounts of low-molecular-weight heparin and unfractionated heparin on the coagulation mechanism during surgery was investigated in another 30 patients. The clotting assays and results of in-vivo platelet function tests indicated that both preparations produced similar effect. Intragroup comparisons, however, showed significant differences in the anti-factor Xa activity, lipoprotein lipase release, and plasma prekallikrein concentrations. A single injection of low-molecular-weight heparin daily is a convenient way of preventing deep vein thrombosis in high-risk patients undergoing major abdominal surgery.     

Assessment of Short-term Anticoagulant Administration after Cardiac Infarction

This report describes the design and results of a controlled trial of anticoagulant drugs in the treatment of patients admitted to hospital suffering from acute myocardial infarction. A total of 1,427 patients were allocated at random to therapy with high-dosage or low-dosage anticoagulants. The high-dosage regimen was 36 hours of heparin administration and phenindione in doses to maintain the thrombotest level between 10 and 20%. The mean phenindione dosage was 72 mg./day. The low-dosage regimen consisted of 1-mg. tablets of phenindione. Therapy was continued for 28 days.There was no significant reduction in the mortality in the high-dosage group. Among the 712 patients allocated to high dosage 115 (16·2%) died before the 29th day of the trial. Of the 715 patients allocated to low dosage 129 (18%) died. This difference between these mortality rates could have occurred by chance.There was a significant reduction in the frequency of clinically evident thromboembolic complications (systemic artery occlusion, leg vein thrombosis, and pulmonary embolism) among patients in the high-dosage group. This did not, however, materially affect the difference in mortality from all causes.     

Failure of low-dose heparin to improve efficacy of peroperative intermittent calf compression in preventing postoperative deep vein thrombosis.

The possible benefits of adding a low-dose heparin regimen to the technique of peroperative intermittent calf compression for preventing deep vein thrombosis (D.V.T.) were assessed in a randomized trial in 84 surgical patients. The efficacy of peroperative intermittent calf compression was not enhanced by a low-dose heparin regimen, but neither was it worsened. Age, weight, duration, operation, and malignant disease did not affect the relative effectiveness of the two regimens of prophylaxis. The results confirmed that venous stasis is the principal cause of D.V.T.     

Increased Incidence of Deep Vein Thrombosis after Myocardial Infarction in Non-smokers

Out of 102 patients with cardiac infarction admitted to the coronary care unit at this hospital and not treated with anticoagulants 30 (29%) developed isotopic evidence of deep vein thrombosis. Of the 65 smokers only 7 (11%) developed a deep vein thrombosis, whereas of the 37 non-smokers 23 (62%) developed a deep vein thrombosis. This difference is highly significant (P < 0·00001).     

Low-dose heparin prophylaxis against fatal pulmonary embolism.

A prospective randomised controlled trial in 500 patients over the age of 50 who were undergoing major surgery showed that low-dose subcutaneous heparin was an effective prophylactic measure against fatal pulmonary embolism. None of the 252 patients who received perioperative heparin cover died of fatal pulmonary embolism while eight of the 236 who did not receive heparin prophylaxis died of fatal pulmonary embolism. These results were statiscally significant (P less than 0.01).     

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.     

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.     

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.     

Fluctuation of thrombin-antithrombin III complex in patients with acute myocardial infarction: influence of low-dose heparin administration.

The haemostatic parameters were studied within 14 days of acute myocardial infarction (AMI) in 103 patients randomly allocated into a group receiving low-dose heparin or into a group treated without anticoagulants. Patients with isotopic evidence of deep vein thrombosis were excluded from the analysis. An important formation of thrombin-antithrombin III complex (TAT) in the plasma was detected in the early stage of the disease. It was accompanied by an activation of plasma intrinsic fibrinolysis (IF), an elevation of fibrinogen and its degradation products (FDP) and a reduction of extrinsic plasma fibrinolytic activity (EF) together with normal levels of factor X, antithrombin III (AT III), protein C and alpha-2-antiplasmin. Sequentially studies periods of the disease revealed a diminution of TAT complex concentration in the plasma on the seventh day of AMI together with a rise of the both plasma fibrinolytic activities (IF, EF) as well as an elevation of fibrinogen and its degradation products, returning to the initial values on the 14 day of AMI. In the patients treated with heparin the augmentation of TAT complex in the plasma was prolonged until the fifth day of AMI. Moreover, heparin administration was connected with significantly higher levels of AT III and protein C along with a lower concentration of factor X and FDP on the seventh day of the disease. The fluctuation of fibrinolytic activities (IF, EF) in the plasma was heparin-independent. The present results indicate that low-dose heparin treatment modulates the plasmatic fluctuation of TAT complex as well as factor X, AT III and protein C levels in patients with acute myocardial infarction.     

Femoral vein thrombosis and total hip replacement.

Of 160 patients who underwent total hip replacement, 81 developed venographic evidence of thrombi in the operated leg. In 46 cases (57%) the thrombus originated from the femoral vein, and in 43 of these the exact site of origin was defined by venography. In 34 cases (74%) the thrombus arose from the wall of the femoral vein at the level of the lesser trochanter. This region was studied by intraoperative venography in eight patients undergoing total hip replacement, and in every case severe distortion of the common femoral vein was observed, producing almost total occlusion. We suggest that intraoperative damage to the femoral vein results from manipulation of the leg, and that this is one reason why the operation is followed by a high incidence of deep vein thrombosis in the upper femoral region.     

Cerebral haemorrhagic infarction in young patients with hereditary protein C deficiency: evidence for "spontaneous" cerebral venous thrombosis.

Among 53 patients with hereditary protein C deficiency belonging to 20 families three women were encountered who, aged 27, 34, and 38 respectively, had had cerebral haemorrhagic infarction, probably due to intracranial venous thrombosis. All three had also had venous thrombosis of the leg and pulmonary embolism either before or after their cerebral infarction. One patient sustained cerebral infarction while receiving an oral contraceptive, but infarction in the two others occurred "spontaneously." One patient also had an intraventricular and subarachnoid haemorrhage during the induction phase of coumarin treatment, which was assumed to have resulted from haemorrhagic infarction of the chorioid plexus, analogous to coumarin provoked haemorrhagic skin necrosis in protein C deficiency. Hereditary protein C deficiency should be considered in young patients with acute or subacute cerebral symptoms, especially if they have a family or personal history of venous thromboembolism.     

Incidences of fatal postoperative pulmonary embolism after prophylaxis with dextran 70 and low-dose heparin: an international multicentre study.

A total of 4352 patients were admitted to a prospective'' randomised multicentre trial comparing the prophylactic efficacy of dextran 70 and low-dose heparin against fatal pulmonary embolism after elective operations for general, orthopaedic, urological, and gynaecological conditions. Out of 3984 patients correctly admitted, 1993 were allocated to receive dextran 70 and 1991 to receive low-dose heparin. Withdrawal of prophylaxis because of bleeding or technical difficulties occurred more often in the heparin group, but allergic reactions were more common in the dextran group. Of the 75 patients who died within 30 days after operation, 38 had been given dextran and 37 low-dose heparin. Necropsy was performed in 33 and 32 of these cases respectively. In six patients in each group pulmonary embolism was the sole or a contributory cause of death. Of these, five patients in the dextran group and two in the heparin group had received a full course of prophylaxis. There was no statistically significant difference between the two treatment groups in the incidence of fatal pulmonary embolism after a full course of prophylaxis.     

Prevention of Early Postoperative Deep Vein Thrombosis by Passive Exercise of Leg during Surgery

A clinical trial assessed the effect of passive exercise of the lower limb during surgery on the incidence of early postoperative deep vein thrombosis. Thrombosis was diagnosed by means of the ¹²⁵I-fibrinogen uptake test. Passive exercise of the lower limb during the operation was achieved by using a motorized foot mover designed for use on supine subjects, and by pedalling only one leg each patient acted as his own control.In a sequential statistical analysis, 47 patients were required to reach the 5% level of significance. Thrombosis was detected in 11 control (unpedalled) legs alone, and in only one pedalled leg alone. Two patients developed thrombosis bilaterally. The investigation shows that the incidence of early thrombosis in legs which were exercised during surgery was reduced by 77%.