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Prevention of major venous thromboembolism following total hip or knee replacement: a randomized comparison of low-molecular-weight heparin with unfractionated heparin (ECHOS Trial).

AIM: Venous thromboembolism remains a frequent complication after total hip or knee replacement surgery despite routine prophylaxis. However, the ability of pharmacologic thromboprophylaxis to prevent major venous thromboembolism, defined as proximal deep vein thrombosis, and/or pulmonary embolism, and/or death, has not been previously validated. METHODS: In a double-blind randomized study, 2018 patients, undergoing either total hip or knee replacement surgery, were allocated to receive subcutaneous preoperative reviparin (4,200 anti Xa IU) once daily or 7,500 IU unfractionated heparin twice daily, for a minimum of 11 days. The primary efficacy outcome was major venous thromboembolism, defined as the composite of venographically confirmed proximal deep vein thrombosis, and/or symptomatic pulmonary embolism and death, recorded up to day 14. RESULTS: The primary efficacy outcome was assessed in 1,628 patients and demonstrated a significant reduction in the reviparin group (3.4% [28 of 813 patients] compared with unfractionated heparin (5.5% [45 of 815]) (odds ratio, 0.61; 95% confidence interval, 0.38 to 0.99, P=0.04) by day 11 to 14. A significant reduction in venous thromboembolism was maintained up to 6-8 weeks (3.4% [28 of 813 reviparin patients] versus 5.6% [46 of 815 unfractionated heparin patients]) (odds ratio, 0.6; 95% confidence interval, 0.37 to 0.97, P=0.03). Major bleeding events occurred in 9 reviparin-treated patients (0.9%) and in 12 unfractionated heparin-treated patients (1.2%). CONCLUSIONS: Prophylaxis with reviparin significantly reduces the risk of major venous thromboembolism compared with unfractionated heparin in patients undergoing elective hip or knee replacement without increasing the risk of bleeding.

Adult↗

Heparins and mechanical methods for thromboprophylaxis in colorectal surgery.

BACKGROUND: Colorectal surgery implies higher risk of postoperative thromboembolic complications as deep venous thrombosis (DVT) and pulmonary embolism (PE) than general surgery. The best prophylaxis in general surgery is heparin and graded compression stockings. No systematic review on combination prophylaxis or on thrombosis prophylaxis in colorectal surgery has been published. OBJECTIVES: To compare the incidence of postoperative thromboembolism after colorectal surgery using prophylactic methods focussing on heparins and mechanical methods alone and in combinations. SEARCH STRATEGY: Electronic searches was performed in MEDLINE, EMBASE back to 1970. Abstract books from major congresses were handsearched as were reference lists from previously performed reviews. SELECTION CRITERIA: RCT or CCT comparing prophylactic interventions and/or placebo. Outcomes were ascending venography, 125 I-fibrinogen uptake test, ultrasound methods, pulmonary scintigraphy. Studies, using thermographic methods, other isotopic methods, plethysmographic methods, and purely clinical methods as the only diagnostic measure were excluded. 558 studies were identified - 477 were excluded. Only 3 of the identified studies focused exclusively on colorectal surgery. Studies of general surgery contain considerable numbers of colorectal patients. The authors of 66 studies in general and/or abdominal surgery were contacted for retrieving the results from the colorectal patients. Answers were received from very few. 19 studies entered this review. DATA COLLECTION AND ANALYSIS: All studies and all data extraction were performed independently by at least two of the authors. Outcome was deep venous thrombosis and/or pulmonary embolism. Analysis of bleeding complications were unfeasible. 12 meaningful outcomes were analysed by means of the fixed effects model with Peto Odds Ratios. MAIN RESULTS: Heparins versus no treatment: Any kind of heparincompared to no treatment or placebo (comparison 07.03, 11 studies). Heparin is better in preventing DVT and/or PE with a Peto Odds ratio at 0.32 (95% Confidence Interval 0.20-0.53) Unfractionated heparin versus low molecular weight heparin (comparison 08.03, 4 studies). The two treatments were found equally effective in preventing DVT and/or PE with a Peto Odds ratio 1.01 (95% Confidence Interval 0.67-1.52). Mechanical methods (comparison 10.3, 2 studies). The combination of graded compression stockings and LDH is better than LDH alone in preventing DVT and/or PE with a Peto Odds ratio at 4.17 (95% Confidence Interval 1.37-12.70). REVIEWER'S CONCLUSIONS: The optimal prophylaxis in colorectal surgery is the combination of graduated compression stockings and low-dose unfractionated heparin. The unfractionated heparin can be replaced with low molecular weight heparin.

Anticoagulants↗

Current diagnostic techniques for pulmonary embolism.

The diagnosis of venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary embolism (PE) and requires objective testing. The clinician uses a combination of risk factors and nonspecific clinical findings to identify patients who warrant such an evaluation. The recommended approach begins with ventilation/perfusion (V/Q) lung scans or lower extremity noninvasive studies by compression ultrasonography. Nondiagnostic V/Q scans or negative noninvasive studies require further testing. A high-probability V/Q scan or a positive noninvasive study warrant treatment. A normal V/Q scan excludes the diagnosis of PE. Helical computed tomography (CT) can diagnose PE of major vessels but is not sufficiently sensitive to exclude PE because of its poor sensitivity for subsegmental pulmonary vessels. Newer D-dimer assays have a high negative predictive value, but results vary with the specific assay and do not perform well in patients with cancer. Future studies are needed to validate magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA).

Humans↗

Occult pulmonary embolism: a common occurrence in deep venous thrombosis.

Ventilation-perfusion scans were used in a prospective study to determine the prevalence of occult pulmonary embolus in proven deep venous thrombosis. Fifty-eight patients without symptoms of pulmonary embolism, but with venographically proven deep venous thrombosis, were subjected to chest radiographs, 99mTc macroaggregated-albumin perfusion scans, and 133Xe ventilation scans. Of the 49 patients with deep venous thrombosis proximal to the calf veins, 17 (35%) had high-probability scans. Of all 58 patients, only 12 (21%) had normal scans. When the study population was compared with a group of 430 patients described in reports of pulmonary perfusion in asymptomatic persons, a significantly higher percentage of high-probability scans was found in the study population with deep venous thrombosis. Baseline ventilation-perfusion lung scanning is valuable for patients with proven above-knee deep venous thrombosis.

Adolescent↗

Diagnosis and treatment of deep vein thrombosis.

Deep vein thrombosis and pulmonary embolism are important clinical disorders that affect patients in many medical and surgical specialties. In North America, deep vein thrombosis results in hospitalization of up to 600,000patients per year. Pulmonary embolism is also a serious problem that occurs in more than 500,000patients per year, of whom approximately 200,000will die. Almost half of those patients who die will be terminally ill or suffer an incurable disease, but the remainder of the deaths occur in patients who other- wise could have recovered completely.'

Journal Article↗

Prevention effect of orally active heparin derivative on deep vein thrombosis.

The use of heparin as the most potent anticoagulant for the prevention of deep vein thrombosis and pulmonary embolism is nevertheless limited, because it is available to patients only by parenteral administration. Toward overcoming this limitation in the use of heparin, we have previously developed an orally active heparin-deoxycholic acid conjugate (LMWH-DOCA) in 10% DMSO formulation. The present study evaluates the anti-thrombogenic effect of this orally active LMWH-DOCA using a venous thrombosis animal model with Sprague-Dawley rats. When 5 mg/kg of LMWH-DOCA was orally administered in rats, the maximum anti-FXa activity in plasma was 0.35 +/- 0.02, and anti-FXa activity in plasma was maintained above 0.1 IU/ml [the minimum effective anti-FXa activity for the prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE)] for five hours. LMWH-DOCA (5 mg/kg, 430 IU/kg) that was orally administered reduced the thrombus formation by 56.3 +/- 19.8%;on the other hand, subcutaneously administered enoxaparin (100 IU/kg) reduced the thrombus formation by 36.4 +/- 14.5%. Also, LMWH-DOCA was effectively neutralized by protamine that was used as an antidote. Therefore, orally active LMWH-DOCA could be proposed as a new drug that is effective for the longterm prevention of DVT and PE.

Administration, Oral↗

Lysis of venous, pulmonary, prosthetic valvular, arterial, and ventricular clots.

Thrombolysis has been used for the treatment of diverse thrombotic conditions for almost 50 years. Treatment of deep venous thrombosis and pulmonary embolism have been extensively studied, and benefit has been demonstrated in some subgroups. More recently thrombolysis has been investigated for the treatment of prosthetic valvular, arterial, and ventricular mural thrombi.

Arteriovenous Shunt, Surgical↗

Recent advances in the management of venous thromboembolism.

Deep venous thrombosis and pulmonary embolism are frequently diagnosed in patients encountered in a primary-care practice. In the past 10 years, many important advances have been made regarding the management of these disorders. Risk factors have been better defined than in the past. Several new prophylactic measures--such as external pneumatic compression of the lower extremities, dihydroergotamine in combination with heparin, adjusted-dose heparin, and two-step warfarin therapy--can be used to help prevent deep venous thrombosis in surgical patients. The use of serial impedance plethysmography has expanded options for noninvasive diagnosis of deep venous thrombosis. Correlations between pulmonary embolism and ventilation-perfusion lung scan patterns have been clarified. Although much has been learned about heparin and warfarin that affect common management decisions, the indications for thrombolytic therapy for venous thromboembolism remain controversial. Finally, studies have shown that calf vein thrombi that are not detectable by impedance plethysmography and that show no evidence of proximal propagation by serial impedance plethysmography do not require treatment.

Anticoagulants↗

Heparin-induced thrombocytopenia in the emergency department.

We describe 3 patients who presented to the emergency department (ED) with stroke, deep venous thrombosis, or pulmonary embolism and renal failure after undergoing cardiac surgery 7 to 17 days earlier. Their onset of thrombosis after previous heparin exposure was temporally plausible for complications of heparin-induced thrombocytopenia, an immune-mediated thrombotic disorder triggered by heparin. The patients had normal platelet counts at presentation, yet each had circulating heparin-induced thrombocytopenia antibodies that were ultimately confirmed. Two patients had heparin reexposure in the ED, 1 of whom developed thrombocytopenia with new thrombosis and died. Alternative parenteral anticoagulation prevented further thrombosis in 2 patients. Because heparin use can be catastrophic in patients with heparin-induced thrombocytopenia, physicians should be vigilant in suspecting heparin-induced thrombocytopenia in patients with thrombosis after recent hospitalization or heparin exposure. Alternative anticoagulants are available for these at-risk patients.

Aged↗

[Prevalence of duplex ultrasonography detectable venous thrombosis in patients with suspected or acute pulmonary embolism].

OBJECTIVES: Duplex ultrasonography performance in detecting embolic foci has not been proven satisfactory compared with phlebography or autopsic findings. In case of suspected pulmonary embolism, the embolic focus is only discovered in 11 to 18% of the cases compared with more than 30% with phlebography. For overt acute pulmonary embolism, the discovery rate is in the 30 to 45% range versus 70 to 80% with phlebography or autopsy findings. This discrepancy might result from the fact that duplex ultrasonographic explorations are generally limited to the deep collectors at the cruropopliteal level. The purpose of this study was to assess the prevalence of duplex ultrasonography detected venous thrombosis in patients with suspected or acute pulmonary embolism when the exploration includes the entire venous system from the inferior vena cava to the ankles and examines not only the deep collectors but also the muscle and superficial networks. MATERIAL AND METHODS: This study included all patients with suspected pulmonary embolism referred to the emergency unit from January 1, 1995 through December 31, 1998. The patients' hospital files were used to determine the suspected pulmonary embolism population. The acute pulmonary embolism population was defined as the patients whose files contained documented proof of pulmonary embolism (highly probable ventilation/perfusion pulmonary scintigraphy, positive pulmonary angiography, positive proximal angioscan). Thrombosis of the deep venous collectors with or without associated superficial or muscular localization was classed as "deep venous thrombi" and superficial or muscular thrombosis without involvement of the deep collectors was classed as "other venous thrombi". Subpopliteal thrombosis was classed as distal and popliteal or suprapopliteal thrombosis as proximal. RESULTS: The suspected pulmonary embolism group included 352 patients, 118 men and 234 women aged 67.6 +/- 15.4 and 70.8 +/- 20.0 years respectively (m +/- SD). The acute pulmonary embolism group included 60 patients, 17 men and 43 women aged 66.2 +/- 12.5 and 69.7 +/- 16.6 years respectively. Overall prevalence of duplex-ultrasound detected venous thrombosis was 30.4% (107/352) (95%CI: 25.6-35.2) in the suspected pulmonary embolism group and 80% (48/60) (95%CI: 69.9-90.1) in the acute pulmonary embolism group. Deep venous thrombi reaching the collectors and proximal thrombi predominated. Prevalence of "other venous thrombi" and distal venous thrombi were 6.5% (23/352) and 11.4% (40/352) respectively in the suspected pulmonary embolism group and 15.0% (9/60) and 26.7% (16/60) in the acute pulmonary embolism group. The frequency of asymptomatic venous thrombosis of the lower limbs, irrespective of the localization, was 42.1% (45/107) in the suspected pulmonary embolism group and 52.1% (25/48) in the acute pulmonary embolism group. CONCLUSIONS: The prevalence of duplex-ultrasonography detected venous thrombosis in patients with suspected or proven pulmonary embolism found in this series was equivalent to the rates reported in phlebography and autopsy series. The prevalence was higher than usually reported for duplex-ultrasonography studies limited to the cruro-popliteal level. The difference came from the "other venous thrombi" and "distal deep venous thrombi" discovered by exploring the superficial and muscular networks and the calves. This study demonstrates the contribution of duplex-ultrasonography to the diagnostic strategy for pulmonary embolism.

Acute Disease↗

Thrombosis associated with procainamide-induced lupus anticoagulant.

A predisposition to thrombosis in patients with procainamide-induced lupus anticoagulants is previously unrecognized. We describe two patients treated with procainamide who experienced acute thromboembolic events temporally associated with development of the lupus anticoagulant. One patient had a deep venous thrombosis and pulmonary embolism, while the other patient had a cerebrovascular accident. In both patients, coagulation parameters corrected with interruption of procainamide therapy. We suggest that thrombosis may complicate treatment with procainamide in patients who develop the lupus anticoagulant.

Aged↗

Prophylaxis of thromboembolism in the neurosurgical patient: a review.

The incidence of postoperative thromboembolic complications in neurosurgical patients is 29 to 43%. However, anticoagulant treatment of these complications increases the inherent risk of hemorrhage into the operative site. We have reviewed the literature on the prophylaxis of deep vein thrombosis and pulmonary embolism; the incidence of thromboembolic complications, the mechanism of deep venous thrombosis, risk factors, and methods of prophylaxis for deep vein thrombosis are discussed in relation to possible prophylactic treatment of neurosurgical patients. We conclude from our review that low dose heparin therapy is indicated for patients undergoing elective neurosurgical procedures, especially for patients over the age of 40 and for patients under the age of 40 who are known to be at risk of developing thromboembolic complications.

Anticoagulants↗

[Antithrombin III deficiency and tendency to thrombosis (author's transl)].

Antithrombin III (AT III) was determined in 290 patients with deep venous thrombosis and/or pulmonary embolism by immunological methods (radial immunodiffusion, Laurell technique) and by biological activity (heparin cofactor activity and anti-Xa activity). Patients with venous thrombosis had a significantly lower AT III concentration, as determined by the immunological methods or biological method (heparin cofactor activity), than normal persons without any history of venous thrombosis. A decreased level of AT III was found in 27 patients. In these patients the immunoreactive antithrombin III was decreased to the same degree as biological activity (heparin cofactor activity or anti-Xa activity). Thirteen out of these 27 patients belonged to 9 families and, hence, congenital AT III deficiency can be assumed in these cases. The aetiology was unknown in the other half. Patients with AT III deficiency are prone to spontaneous and/or recurrent venous thrombosis. A high incidence of pulmonary embolism and particularly, of fatal pulmonary embolism is remarkable. In more than half of the patients the first thrombotic event occurred before the age of 35. The treatment of choice in such patients is with oral anticoagulants of the coumarin group.

Adult↗

Estrogen administration enhances thrombin generation in rats.

Venous thrombosis is a serious disorder that may be fatal if complicated by pulmonary embolism. Venous thrombosis is usually related to one of three factors: reduced blood flow, changes in vessel wall integrity, or changes in the blood composition. Factors leading to thrombosis are classified as either genetic or acquired. Puerperium and oral contraceptives are examples of the acquired factors. The risk of thrombosis during pregnancy is high compared to that in the overall population,. however, this increases by three to five times in puerperium. Deep vein thrombosis (DVT) complicated by pulmonary thromboembolism (PE) is considered the leading cause of maternal death in the United States and Europe [Am. J. Obstet. Gynecol. 164 (1991) 603; Obstet. Gynecol. 84 (1994) 240] and the third cause in Japan [M Ishikawa, Maternal mortality and pulmonary thromboembolism. Study on maternal mortality in Japan. Report from the Ministry of Health of Japan in Maternal and Child Health Research, 1996. p. 123-128]. Patients without history of familial thrombophilia have 14-fold higher risk of DVT during puerperium [Thromb. Haemost. 25 (1999) 610]. Little is known about the underlying mechanism of thrombotic disorders in puerperium. It is recognized that oral contraceptive estrogen enhances the risk of DVT [Am. J. Epidemiol. 133 (1991) 32]. However, there is little research regarding the relation between estrogen and blood coagulation, although it is known that plasma estrogen reaches extremely high levels near term. We assume that high-level plasma estrogen plays an important role in the blood coagulation activity that results in the occurrence of DVT. To assess this likely association, we studied the effects of high estrogen levels on coagulation in rat plasma.

Animals↗

Red blood cell methylfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study.

BACKGROUND: Moderate hyperhomocysteinaemia is a risk factor for venous thromboembolism. We do not know whether this risk depends on homocysteine itself or on components of the homocysteine remethylation pathway, such as methylfolate. We did a case-control study to analyse the relation between the major components of the homocysteine remethylation pathway and risk of venous thromboembolism. METHODS: We measured concentrations of homocysteine, methionine, and folate in plasma, total folate and methylfolate in red-blood cells, and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T genotype and other known risk factors for venous thromboembolic disease in 243 patients with deep vein thrombosis or pulmonary embolism and controls matched for sex and age. FINDINGS: Concentrations in plasma of homocysteine differed significantly between cases and controls. We noted a strong concentration-dependent association between concentrations of methylfolate in red-blood cells and risk of venous thromboembolism. The adjusted conditional odds ratio ranged from 1.0 for methylfolate 249 microg/L or greater to 7.1 (3.2-15.8) for methylfolate 141 microg/L or less. Methionine concentrations below the median were also independently associated with raised risk of venous thromboembolic disease, as were established risk factors such as high body-mass index, history of cancer, family history of thromboembolism, oral contraceptive use, and factor V Leiden mutation. Furthermore, the association between concentrations of methylfolate in red-blood cells and risk of thromboembolism varied according to MTHFR C677T genotype. INTERPRETATION: Measurement of methylfolate concentrations in red-blood cells might help to identify people at risk of venous thromboembolism.

Adult↗