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Biomedical subjects

G Agnelli

Publications and source records attributed to G Agnelli.

At least 73 records · Page 4Linked to original sources
PubMed1998

Current role of venography in the diagnosis of deep-vein thrombosis.

The clinical diagnosis of deep vein thrombosis (DVT) is barely sensitive and specific. Thus, the clinical suspicion of DVT needs to be confirmed by objective testing. Venography has been for a long time the only reliable technique to confirm or rule-out the clinical suspicion of DVT. Furthermore, venography served as "gold standard" for the validation of non-invasive diagnostic methods for DVT. Among these methods, compressive real-time B-mode ultrasonography (CUS) has substantially reduced the need of performing venography, mainly in outpatients with clinical suspicion of DVT. However, indications for venography still remain in the three DVT patient categories. CUS is highly specific in patients with a first episode of clinically suspected DVT, so that positive patients can be treated with anticoagulants without any further testing. In CUS negative patients three options are available in order to rule-out clinically significant DVT: a) to repeat CUS at day 2 and 8; b) to associate D-dimer to CUS to rule-out DVT (negative D-dimer) or to reinforce surveillance (positive D-dimer); c) to perform venography on the same day. This last approach has been proposed in patients with negative CUS and high pretest clinical probability. CUS is highly specific in high risk patients with asymptomatic DVT and thus it could be used to make treatment decision in positive patients. However, CUS is less sensitive in asymptomatic than in symptomatic patients. Thus, venography remains the only available diagnostic technique to rule-out DVT in asymptomatic patients. In clinical practice, venography should be used on individual basis. In clinical research on DVT prophylaxis, venography should be used in the assessment of the end-point. However, three recent clinical trials on the prevention of post-discharge DVT has generated some uncertainty on the clinical relevance of asymptomatic venography detected DVT. Four to six weeks after discharge a high prevalence of venography detected DVT was observed, a finding disagreeing with the low incidence of clinically overt thromboembolic events at long-term follow-up. Two strategies are available in patients with recurrent symptomatic DVT: to follow-up patients with serial impedance plethysmograph and CUS after the first episode in order to pick-up a positive test in patients previously turned negative or to perform venography, a new intraluminal filling defect suggesting DVT recurrence.

Female↗
PubMed1997

Recombinant hirudin in the prevention of venous thromboembolism in patients undergoing elective hip surgery.

Venous thromboembolism is a major cause of mortality and morbidity in patients undergoing orthopedic surgery. In these patients systemic prophylaxis with anticoagulants appears to be the most effective approach to reduce venous thromboembolic events. Low-molecular-weight heparins (LMWHs) are the prophylactic agents of choice in patients undergoing elective hip replacement. However, their use is still associated with a 15% incidence of deep vein thrombosis (DVT); hence, there is a need for potentially more effective agents. Among these, hirudin and other selective thrombin inhibitors have recently been evaluated. The main pharmacologic properties of recombinant hirudin and the clinical trials carried out with this agent in the prevention of DVT in patients undergoing elective hip replacement are reviewed in this article. Overall, the results of these clinical trials are quite promising; they actually indicate that a b.i.d. subcutaneous injection of 15 or 20 mg of recombinant hirudin is an effective and safe prophylactic approach. Hirudin was more effective than unfractionated heparin, given at a low fixed dose, in two clinical trials and of a LMWH in one clinical trial. However, further studies are required to define the role of recombinant hirudin in the prevention of venous thromboembolism in orthopedic surgery patients.

Elective Surgical Procedures↗
PubMed1997

Fibrinogenolysis and thrombin generation after reduced dose bolus or conventional rt-PA for pulmonary embolism. The Coagulation Project Investigators of the Bolus Alteplase Pulmonary Embolism Group.

The aim of this study was to compare the effects on fibrinogenolysis and thrombin generation of two recombinant tissue-type plasminogen activator (rt-PA) regimens in patients with pulmonary embolism entering a randomised, controlled study with a 1:2 allocation ratio to rt-PA, 100 mg over 2 h (Group A) or rt-PA, 0.6 mg/kg, maximum dose 50 mg, over 15 min (Group B). In both groups the heparin infusion was stopped 2-4 h before starting thrombolytic treatment and resumed accordingly to the activated partial thromboplastin time (aPTT) or thrombin clotting time (TcT). Seventeen patients in Group A and 30 patients in Group B were evaluated before starting thrombolytic treatment and 2, 6 and 24 h after its end for the following parameters: aPTT, TcT, fibrinogen, fibrinogen degradation products (FDP), plasmin-alpha 2 antiplasmin (PAP) and thrombin-antithrombin III (TAT) complexes. The two groups had similar coagulation parameters at baseline. Two h after starting rt-PA, the aPTT was more prolonged in Group A than in Group B patients (P = 0.01). Patients in Group B showed less reduction in plasma fibrinogen levels at all study times after rt-PA treatment (P = 0.008). The increase in plasma FDP (P = 0.037) and PAP (P = 0.001) levels was lower at 2 and 6 h samples in Group B compared with Group A. TcT was prolonged (P = 0.003) and TAT increased (P = 0.001) during treatment without differences between the two groups. AUC0-24 of fibrinogen, FDP and PAP levels confirmed the statistically significant differences (P = 0.04) between the two groups over the entire 24 h period of the study. Three patients in Group A (17.6%) and three (10.0%) in Group B suffered major or other important bleeding. Our results indicate that the administration of weight-adjusted reduced-dose rt-PA bolus produces less impairment of blood coagulation than the FDA approved regimen.

Adult↗
PubMed1997

Pharmacokinetic optimisation of the treatment of deep vein thrombosis.

The current treatment for deep vein thrombosis is a 5- to 10-day course of heparin followed by 3 to 6 months of oral anticoagulants. Both heparin and oral anticoagulants present a high inter- and intra-individual variability and require individualisation and monitoring of their dosage. The pharmacokinetic properties of heparin have been difficult to assess through the radiolabelling procedures typically used for many other drugs. This is partially a result of the heterogeneous nature of heparin. Thus, the pharmacokinetics of heparin are expressed in terms of its pharmacodynamic activity. Improved coagulation test methodology coupled with the incorporation of patient factors such as bodyweight, height, baseline coagulation status, pretreatment heparin sensitivity and heparin concentrations, can be used to improve the accuracy of heparin dosage determination. Computer-based systems are now available to assist clinicians in quantitating dosage requirements, estimating bleeding risks, and storing patient dose-response relationships for future therapy monitoring. Low molecular weight heparin products might improve our ability to control anticoagulant therapy because drug concentration, as well as the effect on the clotting system, will be more predictable in patients receiving these products. In addition, low molecular weight heparins produce a more consistent, predictable anticoagulant response, and clinicians have a new pharmacological tool which may readily lend itself to patient-controlled, home-based anticoagulant pharmacotherapy. Where pharmacokinetics and pharmacodynamics could contribute to the optimisation of warfarin treatment is in the initiation of treatment, the estimation of the dosage required, the methods for drug monitoring, the assessment of unusual responses and the avoidance of drug interactions. Traditional pharmaco kinetic methods have limited applicability to the optimisation of warfarin therapy because there is no direct relationship between drug concentration and therapeutic effect. However, a variety of simple or sophisticated computer-assisted methods have been developed to help clinicians in individualising and monitoring warfarin treatment. New therapeutic approaches, such as direct thrombin inhibitors and thrombolytic agents, could overcome some limitations of the standard heparin plus oral anticoagulation therapy.

Animals↗
PubMed1997

Venous thromboembolism and cancer: a two-way clinical association.

Venous thromboembolism and cancer are linked by a two way clinical association: venous thromboembolism may be the presenting feature of an occult cancer and patients with clinically overt cancer may develop a venous thromboembolic complication at any stage of their disease. Patients with venous thromboembolism in the absence of conventional risk factors have a 10% likelihood of having cancer. However, the value of investigating for underlying malignant disease in patients with idiopathic venous thrombosis who are otherwise well is still undefined: intensive diagnostic screening versus routine management is under evaluation in a randomised prospective clinical trial. Patients with cancer are at a high risk of developing postoperative venous thromboembolism. Therefore, they require prophylactic measures comparable to those usually recommended for major orthopaedic surgery. Both retrospective and prospective studies have recently focused attention on the thromboembolic risk associated with chemo- and/or hormone therapy in cancer patients. A prospective, double-blind, randomised study showed that very-low-dose warfarin is an effective and safe method for the prevention of thromboembolism in patients with metastatic breast cancer receiving chemotherapy. The evidence of lowered cancer mortality in patients receiving low molecular weight heparins has renewed interest in the antithrombotic agents as antineoplastic drugs. A multicentre study aimed at investigating this fascinating hypothesis is now being carried out.

Anticoagulants↗
PubMed1996

Pharmacological activities of heparin chains: should our past knowledge be revised?

Unfractionated heparin is a heterogeneous mixture of sulphated polysaccharides. The anticoagulant activity of unfractionated heparin is mainly accounted for by its fractions with a sequence with binding affinity for antithrombin III. The interaction of heparin with antithrombin III markedly enhances the ability of the latter to inhibit factor Xa and thrombin. Only about one third of the unfractionated heparin molecules contain the high-affinity material and its distribution along the heparin molecules appears to be random-hence the development of low-molecular-weight heparins. Most of the saccharide chains of low-molecular-weight heparins are composed of less than 18 saccharides and have reduced ability to inhibit thrombin relative to their ability to inhibit factor Xa. The potential dissociation of anti-factor IIa activity and the anti-Xa activity provided the pharmacological background for the clinical development of low-molecular-weight heparins. During the last few years, evidence has accumulated on the importance of anti-factor IIa for the expression of the antithrombotic activity of low-molecular-weight heparins. This paper reviews the evidence and revises our knowledge about the pharmacological activity of the heparin chains.

Adult↗
PubMed1996

Distribution and occlusiveness of thrombi in patients with surveillance detected deep vein thrombosis after hip surgery.

Venous thromboembolism is a leading cause of in-hospital postoperative morbidity and mortality. Postoperative deep vein thrombosis (DVT) is usually asymptomatic. A number of studies have consistently shown that the non invasive diagnostic methods are inaccurate in the screening of asymptomatic DVT. Failure of non invasive diagnostic methods to detect thrombi in asymptomatic patients has been suggested to be due to the features of thrombi in these patients. The aim of this study was to assess the distribution and the occlusiveness of thrombi in a series of 321 asymptomatic hip surgery patients with adequate bilateral venography of the lower limbs. Venography was performed 10 +/- 1 days after hip surgery. DVT was found in 180 limbs (28.0%). The distribution of thrombi was as follows: 26 (14.4%) isolated proximal thrombi, 55 (30.6%) proximal and distal thrombi, 99 (55.0%) isolated calf thrombi. We found that 14 of the 81 proximal trombi (17.3%) involved the superficial femoral vein either as exclusive location or in association with calf veins. An involvement of common femoral, superficial femoral and popliteal vein was observed in 37 (45.7%), 39 (48.1%) and 44 (54.3%) cases of the 91 proximal DVT. These thrombi were non occlusive in 25 (67.6%), 22 (56.4%) and 26 (59.1%) limbs, respectively. An involvement of at least one peroneal, anterior tibial and posterior tibial veins was observed in 118, 13 and 89 cases of the 220 distal thrombi. These thrombi were non occlusive in 61 (51.7%), 10 (76.9%) and 30 (33.7%) of the cases. We conclude that the majority of thrombi found in asymptomatic hip surgery patients are non occlusive. In view of this, non invasive diagnostic methods based upon venous flow measurement will be unlikely to improve the diagnosis of asymptomatic DVT. The high incidence of isolated superficial femoral vein thrombosis necessitates that real-time B-mode ultrasonography should be performed examining the entire proximal venous system.

Aged↗
PubMed1996

Experimental pharmacology of hirunorm: a novel synthetic peptide thrombin inhibitor.

Enhanced thrombin activity has been associated with coronary thrombosis and with acute and long-term complications following coronary balloon angioplasty. Blocking thrombin activity with specific inhibitors is proposed as a promising antithrombotic therapy. We describe the anticoagulant and antithrombotic properties of hirunorm, a novel synthetic 26-aminoacid peptide thrombin inhibitor, in comparison with r-hirudin and hirulog-1. Hirunorm was equipotent to hirulog-1 and 1/30 as potent as r-hirudin in blocking alpha-thrombin amidolytic activity (IC50 = 10 +/- 2, 15 +/- 1 and 0.3 +/- 0.1 nM, respectively), but it did not affect trypsin, plasmin and t-PA activities at 10 microM. All the compounds inhibited clot-bound thrombin to clots prepared by thrombin hydrolysis of purified fibrinogen in buffer. Hirunorm and hirulog-1 showed similar species-dependent potency in doubling basal in vitro clotting times of human, rat and rabbit plasma (EC200 varied 70 to 200 nM for TT, 0.7 to 16 microM for aPTT and 0.8 to 17 microM for PT), while r-hirudin was always at least three times more active. When assayed by HPLC or by bioassay of the intact peptide, hirunorm was stable against alpha-thrombin and plasma hydrolases, but it was catabolized by rat liver and kidney enzymes. Venous thrombosis was produced in anaesthetized rats by vena cava ligation following a procoagulant serum injection. Intravenous and subcutaneous hirunorm inhibited venous thrombosis at doses (< or = 0.3 mg/kg) two-three times higher than those of r-hirudin. Hirulog-1 was as active as hirunorm only after i.v. infusion. Arterial thrombosis was obtained in the anaesthetized rat by chemical (FeCl2) stimulation of a common carotid and i.v. infused hirunorm (1-3 mg/kg/30 min) inhibited it dose-dependently; r-hirudin was partly active only at 3 mg/kg, but hirulog-1 was inactive at either dose. Full antithrombotic doses of hirunorm did not affect the bleeding time as measured from punctured mesenteric vessels, in anaesthetized rats. In conclusion, hirunorm is a potent peptide thrombin inhibitor endowed with antithrombotic activity in models of venous and arterial thrombosis.

Animals↗
PubMed1996

Post discharge clinically overt venous thromboembolism in orthopaedic surgery patients with negative venography--an overview analysis.

A high incidence of post-discharge venous thromboembolism in orthopaedic surgery patients has been recently reported drawing further attention to the unresolved issue of the optimal duration of the pharmacological prophylaxis. We performed an overview analysis in order to evaluate the incidence of late occurring clinically overt venous thromboembolism in major orthopaedic surgery patients discharged from the hospital with a negative venography and without further pharmacological prophylaxis. We selected the studies published from January 1974 to December 1995 on the prophylaxis of venous thromboembolism after major orthopaedic surgery fulfilling the following criteria: 1) adoption of pharmacological prophylaxis, 2) performing of a bilateral venography before discharge, 3) interruption of pharmacological prophylaxis at discharge in patients with negative venography, and 4) post-discharge follow-up of the patients for at least four weeks. Out of 31 identified studies, 13 fulfilled the overview criteria. The total number of evaluated patients was 4120. An adequate venography was obtained in 3469 patients (84.1%). In the 2361 patients with negative venography (68.1%), 30 episodes of symptomatic venous thromboembolism after hospital discharge were reported with a resulting cumulative incidence of 1.27% (95% C.I. 0.82-1.72) and a weighted mean incidence of 1.52% (95% C.I. 1.05-1.95). Six cases of pulmonary embolism were reported. Our overview showed a low incidence of clinically overt venous thromboembolism at follow-up in major orthopaedic surgery patients discharged with negative venography. Extending pharmacological prophylaxis in these patients does not appear to be justified. Venous thrombi leading to hospital re-admission are likely to be present but asymptomatic at the time of discharge. Future research should be directed toward improving the accuracy of non invasive diagnostic methods in order to replace venography in the screening of asymptomatic post-operative deep vein thrombosis.

Humans↗
PubMed1995

Prolonged antithrombin activity of low-molecular-weight heparins. Clinical implications for the treatment of thromboembolic diseases.

BACKGROUND: The mechanism for the efficacy of once- or twice-daily subcutaneous injections of low-molecular-weight heparins (LMWHs) for the treatment of venous thromboembolism has been difficult to explain. The confusion exists because the observation from experimental studies that the antithrombin activity of LMWHs is necessary for their antithrombotic effect is inconsistent with the reported short half-life of the antithrombin activity of LMWHs. Previous pharmacokinetic studies were performed with lower doses of LMWHs than have been used in contemporary trials, and antithrombin activity was assessed with the barely sensitive chromogenic assay. METHODS AND RESULTS: We performed a pharmacokinetic study to compare the relative half-lives of prophylactic and therapeutic doses of LMWHs assessing antithrombin activity with both the chromogenic and a more sensitive assay (plasma thrombin neutralization assay). An eight-way cross-over randomized study in healthy volunteers was performed. Enoxaparin (20 and 40 mg and 1 and 2 mg/kg) and nadroparin (7500 and 10,000 ICU and 225 and 450 ICU/kg) were administered subcutaneously. The maximal peak activity for aPTT ratio was 1.7. A dose-dependent peak activity was found for both antifactor Xa and antithrombin activities. Disappearance time of these activities after the highest dose of both LMWHs was longer than 16 hours. Overall mean antifactor Xa activity half-life was 4.6 hours. Overall mean antithrombin activity half-life was longer than 4 hours. CONCLUSIONS: Our results provide an explanation for the effectiveness of LMWHs administered either once or twice daily. High and sustained plasma antithrombin activity is achieved when LMWHs are administered in therapeutic doses used in contemporary trials with only a moderate prolongation of the aPTT.

Adult↗
PubMed1995

Thrombolytic and antithrombotic treatment in myocardial infarction: main achievements and future perspectives.

Several trials enrolling thousands of patients have demonstrated the beneficial effect of thrombolytic therapy on survival in patients with acute myocardial infarction. Three large trials have compared the effect of different thrombolytic agents on mortality from myocardial infarction: GISSI-2/International trial, ISIS-3, and GUSTO. In this last trial, treatment with accelerated t-PA and intravenous heparin resulted in a 14% relative reduction in mortality compared with streptokinase and intravenous or subcutaneous heparin. The results of the GUSTO trial renewed the interest toward new strategies for enhancing the speed and rate of coronary reperfusion. An improvement in coronary patency can be anticipated by adopting a variety of pharmacological approaches that include the development of more effective therapeutic regimens with the available thrombolytic agents, the development of more fibrin specific agents and the development of safer and more effective adjunctive antithrombotic agents to accelerate thrombolysis and to prevent rethrombosis.

Antithrombins↗
PubMed1995

Anticoagulation in the prevention and treatment of pulmonary embolism.

The anticoagulant agents commonly used in prevention and treatment of pulmonary embolism are unfractionated heparin, and more recently, low molecular weight heparins, and oral anticoagulants. Unfractionated heparin is the drug of choice for prophylaxis and short-term treatment of pulmonary embolism. Oral anticoagulants are used for prophylaxis in high risk patients and in long-term treatment of pulmonary embolism. Independent overview analysis of clinical trials in elective surgery showed a 60 to 70% reduction in the incidence of fatal pulmonary embolism in heparin-treated patients when they were compared with placebo-treated patients. Low dose heparin has also been shown to be effective in reducing venous thromboembolism after myocardial infarction and other serious medical disorders. In high risk patients prophylaxis with low molecular weight heparins or adjusted doses of unfractionated heparin is recommended. The objectives of treating patients with pulmonary embolism are to prevent death, to reduce morbidity from the acute event, and to prevent thromboembolic pulmonary hypertension. These objectives are achieved by the administration of heparin followed by oral anticoagulants. Heparin is generally administered for 7 to 10 days and is followed by oral anticoagulants. Although widely used and effective in the prevention and treatment of pulmonary embolism, unfractionated heparin has some pharmacological limitations. Heparin presents an aspecific "nonfunctional" binding to plasma proteins such as fibrinogen, factor VIII, vitronectin, and fibronectin. This aspecific binding limits the anticoagulant effect of unfractionated heparin and, is responsible for the heparin resistance observed in some patients with pulmonary embolism as well as of the high intersubject variability of the heparin-induced anticoagulant effect. Antithrombotic agents, such as low molecular weight heparins and pure thrombin inhibitors (hirudin and its analogues), do not specifically bind to plasma protein and they will probably improve the efficacy and practicality of the treatment of pulmonary embolism.

Anticoagulants↗