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A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery.

There is experimental evidence that low-molecular-weight fractions of heparin are as effective as the standard form but cause less bleeding. We therefore performed a double-blind, randomized trial comparing PK10169 low-molecular-weight heparin with placebo for the prevention of venous thrombosis in patients undergoing elective hip surgery. Prophylactic treatment with a fixed dose was begun postoperatively and continued for 14 days. Fifty patients in each treatment group underwent surveillance with [125I]fibrinogen leg scanning and impedance plethysmography. In the first 24 patients, venography was performed only if either surveillance test was positive. Because the rate of venous thrombosis detected in those patients was unexpectedly low, venography was requested in the remaining 76 patients, even if the screening tests were negative. In this latter group, venous thrombosis occurred in 4 patients (10.8 percent) given PK10169 heparin and 20 patients (51.3 percent) given placebo (P = 0.0002); the corresponding rates for proximal-vein thrombosis were 5.4 percent and 23.1 percent, respectively (P = 0.029). In the entire group of 100 patients, venous thrombosis occurred in 12 percent of those given PK10169 heparin and 42 percent of those given placebo (P = 0.0007), and the corresponding rates for proximalvein thrombi were 4 percent and 20 percent, respectively (P = 0.014). The observed hemorrhagic rate was 4 percent in each treatment group. We conclude that prophylaxis with fixed-dose PK10169 heparin is effective and safe for patients undergoing elective hip replacement.

Aged↗

Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.

BACKGROUND: Abnormalities in the number and function of platelets may contribute to thromboembolic complications in patients with essential thrombocythemia. We assessed whether maintaining the platelet count below 600,000 per cubic millimeter with hydroxyurea reduces the incidence of thrombosis in patients with essential thrombocythemia and a high risk of thrombosis. METHODS: A total of 114 patients with essential thrombocythemia (77 women and 37 men; median age, 68 years; range, 40 to 85) and a median platelet count of 788,000 per cubic millimeter (range, 533,000 to 1,240,000 per cubic millimeter) were randomly assigned to receive hydroxyurea (56 patients) or no myelosuppressive therapy (58 patients). Ninety-seven (85 percent) were over 60 years old, and 52 (46 percent) had had thrombosis. The two groups were matched for age, sex, and platelet count at randomization. Antiplatelet prophylaxis with aspirin or ticlopidine was not stopped. Follow-up lasted a median of 27 months in both groups. RESULTS: Two patients (3.6 percent) treated with hydroxyurea had thrombotic episodes (one stroke and one myocardial infarction), whereas 14 patients (24 percent) in the control group had thrombotic episodes (one stroke, five transient ischemic attacks, five peripheral arterial occlusions, one deep-vein thrombosis, and two cases of superficial thrombophlebitis). The difference (20.4 percentage points; 95 percent confidence interval, 8.5 to 32 percent) was statistically significant (chi-square with Yates' correction, 8.3; 1 df; P = 0.003). CONCLUSIONS: Hydroxyurea is effective in preventing thrombosis in high-risk patients with essential thrombocythemia.

Adult↗

A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group.

BACKGROUND: The efficacy and safety of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis is still a matter of debate. METHODS: Using a two-by-two factorial design, we randomly assigned 400 patients with proximal deep-vein thrombosis who were at risk for pulmonary embolism to receive a vena caval filter (200 patients) or no filter (200 patients), and to receive low-molecular-weight heparin (enoxaparin, 195 patients) or unfractionated heparin (205 patients). The rates of recurrent venous thromboembolism, death, and major bleeding were analyzed at day 12 and at two years. RESULTS: At day 12, two patients assigned to receive filters (1.1 percent), as compared with nine patients assigned to receive no filters (4.8 percent), had had symptomatic or asymptomatic pulmonary embolism (odds ratio, 0.22; 95 percent confidence interval, 0.05 to 0.90). At two years, 37 patients assigned to the filter group (20.8 percent), as compared with 21 patients assigned to the no-filter group (11.6 percent), had had recurrent deep-vein thrombosis (odds ratio, 1.87; 95 percent confidence interval, 1.10 to 3.20). There were no significant differences in mortality or the other outcomes. At day 12, three patients assigned to low-molecular-weight heparin (1.6 percent), as compared with eight patients assigned to unfractionated heparin (4.2 percent), had had symptomatic or asymptomatic pulmonary embolism (odds ratio, 0.38; 95 percent confidence interval, 0.10 to 1.38). CONCLUSIONS: In high-risk patients with proximal deep-vein thrombosis, the initial beneficial effect of vena caval filters for the prevention of pulmonary embolism was counterbalanced by an excess of recurrent deep-vein thrombosis, without any difference in mortality. Our data also confirmed that low-molecular-weight heparin was as effective and safe as unfractionated heparin for the prevention of pulmonary embolism.

Aged↗

The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism.

BACKGROUND: Several small studies have indicated an association between deep venous thrombosis or pulmonary embolism and a subsequent diagnosis of cancer, but the subject is controversial. METHODS: We conducted a nationwide study of a cohort of patients with deep venous thrombosis or pulmonary embolism that was drawn from the Danish National Registry of Patients for the years 1977 through 1992. The occurrence of cancer in the cohort was determined by linkage to the Danish Cancer Registry. The expected number of cancer cases was estimated on the basis of national age-, sex-, and site-specific incidence rates. RESULTS: A total of 15,348 patients with deep venous thrombosis and 11,305 patients with pulmonary embolism were identified. We observed 1737 cases of cancer in the cohort with deep venous thrombosis, as compared with 1372 expected cases (standardized incidence ratio, 1.3; 95 percent confidence interval, 1.21 to 1.33). Among the patients with pulmonary embolism, the standardized incidence ratio was 1.3, with a 95 percent confidence interval of 1.22 to 1.41. The risk was substantially elevated only during the first six months of follow-up and declined rapidly thereafter to a constant level slightly above 1.0 one year after the thrombotic event. Forty percent of the patients given a diagnosis of cancer within one year after hospitalization for thromboembolism had distant metastases at the time of the diagnosis of cancer. There were strong associations with several cancers, most pronounced for those of the pancreas, ovary, liver (primary hepatic cancer), and brain. CONCLUSIONS: An aggressive search for a hidden cancer in a patient with a primary deep venous thrombosis or pulmonary embolism is not warranted.

Aged↗

Venous duplex imaging: should it replace hemodynamic tests for deep venous thrombosis?

Noninvasive diagnosis of deep venous thrombosis has traditionally relied on detection of alterations in venous hemodynamics. Although phleborheography is among the most sensitive tests, it is inadequate for diagnosing infrapopliteal and nonocclusive proximal thrombi and for surveillance of patients at high risk for deep venous thrombosis. Venous duplex imaging is a new technique being rapidly accepted, however, without the same critical analysis given to previous diagnostic modalities. The purpose of this study is to evaluate the diagnostic acumen of venous duplex imaging compared to phleborheography and ascending phlebography in two distinct patient groups, and to determine whether patient selection, and thus the location or magnitude of thrombi have significant influence on these diagnostic tests. One hundred ten extremities in 103 patients were prospectively evaluated with venous duplex imaging, phleborheography, and ascending phlebography within the same 24-hour period. Patients were categorized into one of two groups: Diagnostic--patients evaluated because of clinical suspicion of acute deep venous thrombosis; and Surveillance--patients at high risk of postoperative deep venous thrombosis after total joint replacement, but not symptomatic. Patients in the diagnostic group had a greater frequency of deep venous thrombosis (p less than 0.001) and significantly more occluding above-knee thrombi (p = 0.054) compared to those in the surveillance group. Phleborheography detected 73% (27/37) of above-knee thrombi in the diagnostic group compared to 29% (2/7) in the surveillance group (p = 0.036). This difference was not noted with venous duplex imaging, which detected 100% of above-knee thrombi in both diagnostic and surveillance groups and 78% (7/9) of all below-knee thrombi.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗

Deep venous thrombosis in the baboon: an experimental model.

Experimental models of deep venous thrombosis, heretofore, have not been available for laboratory studies. This investigation establishes a novel model of venous thrombosis by inhibiting the protein C system combined with venous stasis and subtle venous injury. Ten adolescent baboons were studied in pairs, with one animal receiving saline solution (B2, B4, B6, B8, B10) and one being exposed to thrombogenic reagents (B1, B3, B5, B7, B9). These reagents represented a combination of a monoclonal antibody (HPC4) to protein C, 1 to 4 mg/kg administered over 5 minutes, and tumor necrosis factor administered over 3 minutes at a dose of 150 micrograms/kg through a catheter placed into the left superficial femoral vein with distal ligation. To encourage stasis, a pediatric size blood pressure cuff was inflated to 40 mm Hg on the right thigh for 50 minutes of every hour during the first experimental day (day 1) in B5 to B10. The animals were observed for a 6-hour period on day 1 and then for an 11- to 15-day period until sacrifice. Hemodynamic and hematologic parameters were recorded along with duplex imaging of the iliac veins and inferior vena cava on a daily basis. Venography was performed on day 1, day 4, and the day of sacrifice. At sacrifice the entire iliac and vena caval system was carefully dissected, opened, and photographed. Experimental animals given the HPC4 and tumor necrosis factor developed left iliac vein thrombosis extending into the inferior vena cava. Duplex imaging, venography, and autopsy revealed that control animals receiving saline solution never developed comparable thrombus. Experimental subjects exhibited thrombus on duplex imaging by day 4 (B1), day 3 (B3), day 2 (B5), 120 minutes (B7), and 360 minutes (B9) after receiving HPC4 and tumor necrosis factor. Venograms performed on day 1 exhibited thrombus in B5, B7, and B9. The extent of thrombus, the timing of its occurrence, and its effect on the animals' left leg followed a dose-dependent relationship for the animals in which the occlusive blood pressure cuff was used. Significantly greater declines in blood pressure, white blood cell count, and platelet count were found in affected animals given HPC4 and tumor necrosis factor reagents as compared to control subjects. All affected animals demonstrated the appearance of fibrin split products and a markedly prolonged prothrombin time. This investigation, for the first time, establishes a reproducible model of deep venous thrombosis involving inhibition of protein C that will facilitate further laboratory studies on venous thrombosis.

Animals↗

Evaluation of thrombolysis in a porcine model of chronic deep venous thrombosis: an endovascular model.

PURPOSE: The advancement of catheter-based interventions for vascular recanalization has underscored the need for an experimental animal model of vascular thrombosis that can be used for the evaluation of interventional therapies. In this model, a porcine model of deep venous thrombosis with a novel endovascular technique was described, and the efficacy of thrombolytic therapy with urokinase was evaluated. METHODS: An endovascular device that consisted of a tapered polytetrafluoroethylene graft attached within a self-expanding nitinol stent was delivered to bilateral common iliac veins in 20 pigs. Venous thrombosis occurred as a result of flow stasis created by the intrastent stenosis. Catheter-directed pulse-spray thrombolysis with urokinase (250,000 units) and heparin (5000 IU) was performed on one limb while the contralateral limb received control saline solution. Thrombolysis was performed in 1 hour (n = 4), 8 hours (n = 4), 3 days (n = 4), 7 days (n = 4), and 14 days (n = 4) after the stent-graft deployment. Venography and intravascular ultrasound were used to evaluate the efficacy of thrombolysis. Light microscopy was used for histologic analysis of the thrombus. RESULTS: Complete thrombolysis was achieved in groups with deep vein thrombosis that were younger than 1 day. Angioplasty of the tapered stent-grafts in the completely thrombolysed iliac vein was successful in restoring venous flow. The efficacy of thrombolysis in 3-day, 7-day, and 14-day groups was 86% +/- 7%, 73% +/- 13%, and 42% +/- 23%, respectively. The thrombolytic efficacy was enhanced to 92% +/- 16% and 86% +/- 18% (P <.05) in 3-day and 7-day groups, respectively, when doses of the pulse-spray thrombolysis were doubled. Increased dosages of the thrombolytic agent, however, did not significantly enhance the thrombus dissolution in the 14-day group. CONCLUSION: The thrombolytic efficacy of urokinase correlated with the chronicity of deep venous thrombosis in our model. An increased dose of urokinase may be used to enhance the efficacy of thrombolysis in a 1-week-old thrombus.

Animals↗

Hypercoagulability. Should every patient with venous thrombosis be tested?

Tests for anticoagulant protein deficiencies have a low predictive value for venous thrombosis in the general population. Such testing should be done only in patients with recurrent thrombosis, a family history of thrombosis, or atypical features such as young age at presentation or unusual site. Decreased fibrinolysis is another defect often seen in patients with venous thrombosis, but it lacks sufficient specificity to have a high predictive value. The presence of antiphospholipid antibodies has a fairly high predictive value, and testing beyond the partial thromboplastin time may be justified in patients who have (1) arterial thrombosis or (2) a history of fetal demise or recurrent spontaneous abortions.

Animals↗

Successful local low-dose urokinase treatment of acquired thrombosis early after cardiothoracic surgery.

BACKGROUND AND OBJECTIVE: Recent surgery (<or=10 days) is considered an absolute contraindication for thrombolytic therapy. We report the successful use of low doses of urokinase locally infused to dissolve an intravascular thrombosis in the early postoperative period after congenital heart surgery. PATIENTS: Two children, with catheter-related intravascular thrombosis after cardiac surgery, received urokinase treatment within 24 hrs and 6 days of surgery, respectively. SETTING: Tertiary, 11-bed, pediatric intensive care unit. INTERVENTIONS: Urokinase was administered through the catheter close to the site of thrombosis with a bolus of 4400 units/kg followed by a continuous infusion of 1300 units x kg(-1) x hr(-1). MAIN RESULTS: Thrombosis resolved completely in both patients after 3 days of therapy. Signs of systemic thrombolysis were not observed. CONCLUSIONS: A short course of local low-dose urokinase is feasible and seems to be effective for thrombolysis of catheter-related thrombosis early after cardiothoracic surgery. It was not associated with bleeding in the two cases presented. Further studies are required to confirm the safety of this approach and to define optimal dosing.

Journal Article↗

Co-segregation of thrombosis with the factor V Q506 mutation in an extended family with resistance to activated protein C.

The activated protein C (APC) resistance phenotype results from a mutation at one of the cleavage sites of factor V by APC (Q506). We describe a large family with an APC resistance phenotype and without any other detectable coagulation defect, including eight subjects who had developed deep venous thrombosis (mean age of the first thrombosis episode 29 years; range 17-55 years). The factor V Q506 mutation was detected in the seven patients with thrombosis who could be tested and in 13 asymptomatic subjects (mean age 17 years; range 5-33 years). The APC resistance was detectable in only 10 heterozygotes among the 19 tested. These data suggest that, in affected families, the risk for the factor V Q506 mutation carriers to develop thrombosis may be very high and that factor V genotyping must be performed in patients with thrombosis even without any detectable APC resistance phenotype.

Adult↗

The risk factors in central venous catheter-related thrombosis.

Catheter-related venous thrombosis is one of the most important complications of central venous catheters. The aim of this prospective study was to assess the risk factors that may be important in the development of catheter-related thrombosis. Multiple lumen (n = 20) and single lumen (n = 24) polyurethane catheters were inserted to the subclavian vein by the infraclavicular approach in 44 consecutive patients. All variables that may be significant for the development of thrombosis related to the patient, the catheter, the insertion technique and the solution administered through the line were recorded. Eighteen of 44 patients (40%) were found to have venous thrombosis. Two factors were found to correlate significantly with the development of central venous catheter-related thrombosis, namely the number of vein punctures (one vs two punctures, P < 0.01) and the composition of solution (fluid replacement vs total parenteral nutrition, P = 0.01).

Adolescent↗

Aortic and iliac thrombosis associated with angiosarcoma of skeletal muscle in a dog.

A seven-year-old, neutered male greyhound was presented with a history of episodic shifting hindlimb lameness and pain. Ischaemic necrosis of areas of the hindlimb digits and skin and a firm swelling within the medial right thigh musculature were found on physical examination. Investigation demonstrated thrombosis of the terminal aorta and right external iliac artery with ischaemic necrosis of muscular and dermal tissue distal to the sites of thrombosis. The dog was euthanased due to poor prognosis. Necropsy findings were of a poorly differentiated invasive sarcoma of the skeletal muscle of the proximal right hindlimb, thrombosis of the aorta and right external iliac artery and secondary renal glomerulopathy. Immunohistochemistry of the neoplastic tissue indicated angiosarcoma based on expression of CD31 and factor VIII-related antigen. Thrombosis was considered likely to be due to systemic hypercoagulability because of the presence of altered flow characteristics and endothelial damage in the vascular tumour bed. Aortoiliac thrombosis, paraparesis and hindlimb ischaemia are unusual sequelae of angiosarcoma in the dog.

Animals↗

Prevention of deep vein thrombosis by intermittent pneumatic compression of calf.

A consecutive, randomly allocated, controlled clinical trial of the prophylactic effect of intermittent pneumatic compression of the calf on the incidence of postoperative deep vein thrombosis showed that in patients without malignant disease there was a highly significant reduction in the incidence of thrombosis. In patients with malignant disease the incidence of thrombosis was higher than in those without, and there was no reduction in incidence by the application of intermittent compression. In the absence of malignant disease, severity of operation and the age of the patient were the most significant aetiological factors. We found no relation between the incidence of deep venous thrombosis and obesity, length of preoperative stay, location of hospital, or duration of anaesthesia. We suggest that intermittent pneumatic compression as used in this trial is a safe, effective, and extremely practical method of preventing postoperative deep vein thrombosis in patients not suffering from malignant disease.

Adult↗

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.

Administration, Oral↗

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 (125)I-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%.

Adult↗

Decision analysis model of prolonged oral anticoagulant treatment in factor V Leiden carriers with first episode of deep vein thrombosis.

OBJECTIVE: To assess the risks and benefits of oral anticoagulant treatment extended beyond 3 months after a first episode of deep vein thrombosis in patients who carry factor V Leiden mutation. Such patients have over twice the risk of recurrence after the recommended treatment period, but more information is required before widespread genetic screening can be recommended. DESIGN: A decision analysis Markov model (with data extracted form literature) representing the risks of developing symptomatic venous thromboembolism, the risks of major bleeding, and the efficacy of anticoagulant treatment. SUBJECTS: A hypothetical cohort of 1000 carriers of factor V Leiden recovering from a first episode of deep vein thrombosis in the lower limbs. MAIN OUTCOME MEASURES: Risks and benefits of, firstly, stopping oral anticoagulation 3 months after first episode of thrombosis with reinitiation of treatment only after recurrent thrombosis and, secondly, extension of oral anticoagulation up to 1 to 5 years. RESULTS: Despite consistent biases in favour of extended oral anticoagulation, analysis revealed that among factor V carriers the number of major haemorrhages induced by oral anticoagulants would exceed that of clinical pulmonary emboli prevented over the entire range of duration of anticoagulation (1 to 5 years). On the other hand, the number of recurrent deep vein thrombi prevented would exceed that of iatrogenic major bleedings. CONCLUSION: The lack of evidence of a net clinical benefit of prolonged oral anticoagulation, at least beyond 1 year, among patients recovering from acute deep vein thrombosis does not support the decision to promote widespread genetic screening programmes to detect the factor V mutation.

Administration, Oral↗

Radionuclide plethysmography and Tc-99m red blood cell venography in venous thrombosis: comparison with contrast venography.

Radionuclide plethysmography (RPG) is a new technique that uses Tc-99m labelled red blood cells to ascertain changes in venous volumes by detecting the change in counts in response to the inflation and deflation of proximal thigh cuffs. Diagnosis of ileofemoral venous occlusion is possible using this technique, which also provides kinetic data of venous outflow. A range of normal values was defined in 19 subjects for per cent change in venous capacitance and venous outflow. Twenty-one patients with suspected deep venous thrombosis were studied prospectively using RPG, radionuclide venography (RV), and contrast venography (CV) to establish the usefulness of RPG alone and in combination with RV in the diagnosis of deep venous thrombosis. RPG proved to be a reliable technique for the diagnosis of ileofemoral venous thrombosis (sensitivity, 91%; specificity, 100%). RV was less sensitive (73%) and less specific (93%) in diagnosing that condition. When RPG is used as the criterion for the detection of ileofemoral vein thrombosis and RV is used as the criterion for the detection of calf vein thrombosis, the combined techniques show improved sensitivity (92%) and specificity (93%) for the detection of all deep venous thromboses.

Adult↗

Chronic inflammatory bowel disease, deep-venous thrombosis and antithrombin activity.

Of 34 patients with chronic inflammatory bowel disease (CIBD), 4 developed well-documented episodes of deep-venous thrombosis. All 4 patients had active disease at the time of thrombosis. This group was studied to determine if the tendency to deep-venous thrombosis in patients with CIBD was associated with reduced antithrombin activity by measuring the concentration of three thrombin inhibitors, antithrombin III (AT III), alpha 2-macroglobulin (alpha 2 M) and alpha 1-antitrypsin. 2 patients had low AT III levels and 10 had low alpha 2 M levels. 2 patients who developed deep-venous thrombosis had significantly low levels of both AT III and alpha 2 M. It is suggested that in patients with diseases predisposing to thrombosis and associated with low AT III levels, the measurement of alpha 2 M in addition to AT III may predict those particularly at risk.

Antithrombin III↗