[Optimal duration of anticoagulant treatment of venous thromboembolism].

RECURRENT THROMBOSIS VERSUS ANTICOAGULANT-RELATED BLEEDING: The optimal duration of anticoagulation for venous thromboembolism depends on the balance between the risk of thrombosis if anticoagulation is stopped, and the risk of bleeding if patients remain on treatment. In the past decade, five large well designed trials have been completed which have compared different durations of anticoagulation for the treatment of various categories of patients with venous thrombosis. In conjunction with the findings of a number of other prospective studies, these trials have helped to identify risk factors for recurrent venous thrombosis and anticoagulant-related bleeding, and have led to a better understanding of the optimal duration of therapy for individual patients.

Influence of exogenous factor VIIa on thrombin generation in cord plasma of full-term and pre-term newborns.

Factor (F) VIIa has been used to treat adults and children with a variety of bleeding disorders. The results from these studies cannot be extrapolated to newborns because their hemostatic system differs significantly from adults, which may influence the effects of FVIIa on thrombin (IIa) generation. We compared the effects of FVIIa concentrates on IIa generation in plasmas from adults, full-term newborns and pre-term newborns.

New insights into the size and stoichiometry of the plasminogen activator inhibitor type-1.vitronectin complex.

Plasminogen activator inhibitor-type 1 (PAI-1) is the primary inhibitor of endogenous plasminogen activators that generate plasmin in the vicinity of a thrombus to initiate thrombolysis, or in the pericellular region of cells to facilitate migration and/or tissue remodeling. It has been shown that the physiologically relevant form of PAI-1 is in a complex with the abundant plasma glycoprotein, vitronectin. The interaction between vitronectin and PAI-1 is important for stabilizing the inhibitor in a reactive conformation.

Type 1 plasminogen activator inhibitor binds to fibrin via vitronectin.

Type 1 plasminogen activator inhibitor (PAI-1), the primary inhibitor of tissue-type plasminogen activator (t-PA), circulates as a complex with the abundant plasma glycoprotein, vitronectin. This interaction stabilizes the inhibitor in its active conformation In this report, the effects of vitronectin on the interactions of PAI-1 with fibrin clots were studied. Confocal microscopic imaging of platelet-poor plasma clots reveals that essentially all fibrin-associated PAI-1 colocalizes with fibrin-bound vitronectin.

Anticoagulation in pregnancy.

The use of anticoagulants during pregnancy for prevention and treatment of venous thromboembolism and prevention of systemic embolism in patients with valvular heart disease presents several problems. This article discusses the complications associated with warfarin, unfractionated heparin, and low-molecular-weight heparin as well as the benefits of each. While a literature review turned up only limited data, the authors extrapolated from existing data recommendations for treatment during pregnancy, finding that oral warfarin should be replaced by heparin during pregnancy, especially from the 6th to the 12th week and near term.

Identification of the mechanism responsible for the increased fibrin specificity of TNK-tissue plasminogen activator relative to tissue plasminogen activator.

TNK-tissue plasminogen activator (TNK-t-PA), a bioengineered variant of tissue-type plasminogen activator (t-PA), has a longer half-life than t-PA because the glycosylation site at amino acid 117 (N117Q, abbreviated N) has been shifted to amino acid 103 (T103N, abbreviated T) and is resistant to inactivation by plasminogen activator inhibitor 1 because of a tetra-alanine substitution in the protease domain (K296A/H297A/R298A/R299A, abbreviated K). TNK-t-PA is more fibrin-specific than t-PA for reasons that are poorly understood. Previously, we demonstrated that the fibrin specificity of t-PA is compromised because t-PA binds to (DD)E, the major degradation product of cross-linked fibrin, with an affinity similar to that for fibrin.

Expression and synthesis of alternatively spliced variants of Dp71 in adult human brain.

Transcripts encoding the 70-75 kDa C-terminal protein product of the dystrophin gene (Dp71) are alternatively spliced to generate multiple protein products in a number of adult human tissues. In this report, reverse transcriptase-polymerase chain reaction was used to clone and characterize a subpopulation of truncated Dp71 transcripts in adult human brain tissue which did not contain exons 71-74, resulting in an in-frame deletion of 330 bp encoding the syntrophin-binding domain. These truncated Dp71 transcripts are also alternatively spliced for exon 78.

Postthrombotic syndrome after hip or knee arthroplasty: a cross-sectional study.

Background: Although the incidence of the postthrombotic syndrome (PTS) has been addressed in patients with symptomatic deep vein thrombosis (DVT), less information is available on the incidence in patients who develop asymptomatic DVT after major hip or knee arthroplasty.

Objectives: To determine whether symptomatic PTS occurs more frequently in patients who develop DVT after hip or knee arthroplasty than those who are free of DVT and to provide an estimate of the incidence of PTS in patients who had undergone major hip or knee arthroplasty and had proximal DVT, distal (calf) DVT, or no DVT.

Design And Setting: A cross-sectional study conducted at the Hamilton Health Sciences Corporation, Hamilton, Ontario, and the Academic Medical Centre, Amsterdam, the Netherlands.

Using ethnicity as a classification variable in health research: perpetuating the myth of biological determinism, serving socio-political agendas, or making valuable contributions to medical sciences?

There is a need for a valid way to classify the human species consistently and reliably, be it to highlight similarities between human populations such as intelligence or physical capacity, to dispel myths about group differences, or to discover 'novel' risk factors for diseases. In contrast to racial divisions, which are usually based on differences in skin colour and physical features, ethnicity is a complex concept which has both socio-cultural and biological components. However, because of the relative vagueness of the term, the interpretation of the 'Ethnicity' construct is not simple, and its definition is often unique to the research project at hand.

Optimal dosing of subcutaneous unfractionated heparin for the treatment of deep vein thrombosis.

Twice-daily, inpatient, subcutaneous unfractionated heparin is at least as effective and safe as continuous intravenous unfractionated heparin for the treatment of acute deep vein thrombosis. Subcutaneous unfractionated heparin therefore may be suitable for outpatient treatment of deep vein thrombosis. The purpose of this study was to develop a dosing nomogram for a dose each 12 hours (2 doses per day) 12-hourly subcutaneous unfractionated heparin that is suitable for outpatient treatment of acute deep vein thrombosis.

The emerging role of low-molecular-weight heparin in cardiovascular medicine.

Although unfractionated heparin is widely used in the treatment of acute coronary syndromes, it has several pharmacokinetic, biophysical, and biological limitations. The practical advantages and success of low-molecular-weight heparin administered subcutaneously without laboratory monitoring for the treatment of venous thromboembolism have prompted a number of randomized studies investigating the efficacy and safety of these agents in patients with acute coronary syndromes. This article will review the limitations of unfractionated heparin and the mechanisms by which low-molecular-weight heparin overcomes these limitations, as well as the results of recent trials involving low-molecular-weight heparin in the management of patients with acute coronary syndromes.

The binding of unfractionated heparin and low molecular weight heparin to thrombin-activated human endothelial cells.

The binding of unfractionated heparin to endothelium is thought to be responsible for the rapid and saturable phase of unfractionated heparin clearance. Thrombin can induce endothelial cells to express and/or secrete a number of heparin binding proteins that have the potential to increase the binding of unfractionated heparin and to a lesser extent the binding of low molecular weight heparin. To explore this possibility, we examined the binding of unfractionated heparin and low molecular weight heparin to thrombin-activated endothelial cells.

Thrombosis and anticoagulation.

Most of the major advances in thrombosis research have occurred in the last 50 years, reflecting progress in biomedical sciences and clinical trials methodology. Improved understanding of the mechanisms of thrombogenesis has led to the discovery of a plethora of new antithrombotic agents that target many of the key steps in blood coagulation and platelet activation. Although most of these compounds are still under development, low-molecular-weight heparins (LMWH), glycoprotein (GP) IIb/IIIa receptor antagonists, and inhibitors of the adenosine diphosphate (ADP) receptor on platelets have already established their niche in the clinic.

Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis.

Context: Despite years of use in coronary artery disease (CAD) and several studies of its effectiveness, the role of oral anticoagulants (OAs) remains controversial.

Objective: To determine the effects of long-term OA therapy, stratified by the intensities of anticoagulation and aspirin therapy, on outcomes in patients with CAD.

Data Sources: Studies were identified by MEDLINE, EMBASE, and CURRENT CONTENTS searches (1960-July 1999) and by reviewing reference lists and inquiring with experts and pharmaceutical companies.

Low rates of preventive practices in patients with peripheral vascular disease.

Background: Patients with peripheral vascular disease (PVD) have a three-fold increased risk of myocardial infarction, stroke and death. Recently, a number of therapies have been demonstrated to prevent morbidity or mortality in patients with PVD or other arterial disease. Given the scarcity of data on the preventive practice patterns of this high risk patient group, the in-hospital management of patients admitted to hospital for a peripheral vascular intervention was reviewed.

A novel approach to arterial thrombolysis.

Achieving early, complete, and sustained reperfusion after acute myocardial infarction does not occur in approximately 50% of patients, even with the most potent established thrombolytic therapy. Bleeding is observed with increased concentrations of thrombolytics as well as with adjunctive antithrombotic and antiplatelet agents. A novel approach to enhance thrombolytic therapy is to inhibit the activated form of thrombin-activatable fibrinolysis inhibitor (TAFI), which attenuates fibrinolysis in clots formed from human plasma.

Comparison of heparin- and dermatan sulfate-mediated catalysis of thrombin inactivation by heparin cofactor II.

Heparin and dermatan sulfate activate heparin cofactor II (HCII) comparably, presumably by liberating the amino terminus of HCII to bind to exosite I of thrombin. To explore this model of activation, we systematically substituted basic residues in the glycosaminoglycan-binding domain of HCII with neutral amino acids and measured the rates of thrombin inactivation by the mutants. Mutant D, with changes at Arg(184), Lys(185), Arg(189), Arg(192), Arg(193), demonstrated a approximately 130-fold increased rate of thrombin inactivation that was unaffected by the presence of glycosaminoglycans.

Cardiovascular and cancer mortality among Canadians of European, south Asian and Chinese origin from 1979 to 1993: an analysis of 1.2 million deaths.

Background: Cardiovascular disease and cancer are important health problems worldwide, yet our knowledge of these conditions is derived principally from populations of European descent. To investigate ethnic variations in major causes of death in Canada, the authors examined total and cause-specific mortality among European, south Asian, and Chinese Canadians.

Methods: Canadians of European, south Asian and Chinese origin were identified in the Canadian Mortality Database by last name and country of birth and in the population census by self-reported ethnicity.

Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells.

Alterations in the cellular redox potential by homocysteine promote endothelial cell (EC) dysfunction, an early event in the progression of atherothrombotic disease. In this study, we demonstrate that homocysteine causes endoplasmic reticulum (ER) stress and growth arrest in human umbilical vein endothelial cells (HUVEC). To determine if these effects reflect specific changes in gene expression, cDNA microarrays were screened using radiolabeled cDNA probes generated from mRNA derived from HUVEC, cultured in the absence or presence of homocysteine.