New antithrombotic agents.

The development of new antithrombotic agents has been stimulated by clinical needs and by advances in biotechnology that have made it possible to produce drugs that target specific steps in thrombogenesis. Heparin has pharmacokinetic and biophysical limitations that are overcome by new anticoagulants. Of these, low-molecular-weight heparin and direct inhibitors of thrombin have been evaluated clinically.

A randomized controlled trial comparing plasma removal with white cell reduction to prevent reactions to platelets.

Background: Recent data suggest that most reactions to platelets are caused by white cell (WBC)-derived cytokines that accumulate in the plasma portion of the component during storage. On the basis of this theory, the effectiveness of two interventions to prevent reactions, poststorage WBC reduction and plasma depletion, were compared.

Study Design: A multiple crossover design was used, in which platelet components for transfusion to a patient randomly were WBC reduced after storage, or the plasma supernatant was removed.

Relationship of glucose and insulin levels to the risk of myocardial infarction: a case-control study.

Objective: To assess the relationship between dysglycemia and myocardial infarction in nondiabetic individuals.

Background: Nondiabetic hyperglycemia may be an important cardiac risk factor. The relationship between myocardial infarction and glucose, insulin, abdominal obesity, lipids and hypertension was therefore studied in South Asians-a group at high risk for coronary heart disease and diabetes.

Exosites 1 and 2 are essential for protection of fibrin-bound thrombin from heparin-catalyzed inhibition by antithrombin and heparin cofactor II.

Assembly of ternary thrombin-heparin-fibrin complexes, formed when fibrin binds to exosite 1 on thrombin and fibrin-bound heparin binds to exosite 2, produces a 58- and 247-fold reduction in the heparin-catalyzed rate of thrombin inhibition by antithrombin and heparin cofactor II, respectively. The greater reduction for heparin cofactor II reflects its requirement for access to exosite 1 during the inhibitory process. Protection from inhibition by antithrombin and heparin cofactor II requires ligation of both exosites 1 and 2 because minimal protection is seen when exosite 1 variants (gamma-thrombin and thrombin Quick 1) or an exosite 2 variant (Arg93 --> Ala, Arg97 --> Ala, and Arg101 --> Ala thrombin) is substituted for thrombin.

A histomorphometric evaluation of heparin-induced bone loss after discontinuation of heparin treatment in rats.

Although it is well established that long-term heparin therapy causes osteoporosis, it is unknown whether heparin-induced bone loss is reversible when heparin treatment is stopped. To address this question, we randomized rats to once daily subcutaneous injections of either unfractionated heparin (1.0 U/g or 0.

Venous thromboembolic events in pediatric patients. Diagnosis and management.

Venous thromboembolism is a rapidly increasing secondary complication in children being treated for serious, life-threatening, primary diseases. Most current management guidelines and recommendations for imaging techniques have been extrapolated from the results of trials in adults. This may be less than optimal for children as there are important differences.

A randomized trial comparing 5-mg and 10-mg warfarin loading doses.

Background: Warfarin sodium therapy is usually initiated with a loading dose to reduce the time required to elevate the international normalized ratio (INR). Warfarin loading doses are associated with early overanticoagulation and the development of a potential hypercoagulable state; they also may not hasten achieving an INR value between 2.0 and 3.

The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism.

This paper describes the role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Inability to compress the common femoral or popliteal vein is usually diagnostic of a first episode of deep venous thrombosis in symptomatic patients (positive predictive value of about 97%). Full compressibility of both of these sites excludes proximal deep venous thrombosis in symptomatic patients (negative predictive value of about 98%).

A novel antithrombin-heparin covalent complex: antithrombotic and bleeding studies in rabbits.

Heparin has been used extensively for prophylaxis and treatment of deep vein thrombosis. However, heparin has several limitations including a short intravenous half-life, inability to inhibit clot-bound thrombin, and bleeding. We have developed a covalent antithrombin-heparin complex (ATH) that has a longer intravenous half-life and greater anticoagulant activity than heparin.

Investigation of the anticoagulant mechanisms of a covalent antithrombin-heparin complex.

Recently, we developed a covalent antithrombin-heparin complex (ATH) as a possible treatment for respiratory distress syndrome. ATH reacted rapidly with thrombin and efficiently catalyzed the inhibition of either thrombin or factor Xa by exogenous antithrombin. In order to investigate mechanisms for the conjugate's unusual anticoagulant properties, changes in fluorescence due to covalent linkage or addition of exogenous antithrombin were studied in relation to reaction with thrombin derivatives or factor Xa.

The Study of Health Assessment and Risk in Ethnic groups (SHARE): rationale and design. The SHARE Investigators.

The Study of Health Assessment and Risk in Ethnic groups (SHARE) is a study to determine the risk factors for atherosclerosis among three ethnic populations in Canada. Three hundred and thirty South Asian Canadian, 320 Chinese Canadian and 320 European Canadian men and women between 35 and 75 years of age are being randomly sampled from communities in Hamilton and Toronto, Ontario and Edmonton, Alberta for assessment of conventional (i.e.

Perioperative management of long-term anticoagulation.

When the need for surgery arises, temporary interruption of long-term anticoagulation exposes patients to additional thrombotic risk. There is no consensus as to how perioperative anticoagulation should be managed in this setting. Based on an individual assessment of risk factors for arterial or venous thromboembolism and the risk of postoperative bleeding, this review outlines an approach to the perioperative management of anticoagulation that is designed to optimize patient safety and efficient delivery of health care.

Covalent heparin cofactor II-heparin and heparin cofactor II-dermatan sulfate complexes. Characterization of novel anticoagulants.

Heparin cofactor II is a naturally occurring anticoagulant that acts by specifically inhibiting thrombin and is facilitated by the binding of glycosaminoglycans such as heparin and dermatan sulfate. In vivo, heparin cofactor II-glycosaminoglycan complexes dissociate, leaving the inhibitor less active in its ability to function as a component of the anticoagulation pathway. We have produced permanently activated heparin cofactor II molecules by covalent linkage to either heparin or dermatan sulfate.

Direct thrombin inhibitors for treatment of arterial thrombosis: potential differences between bivalirudin and hirudin.

Given the central role of thrombin in arterial thrombogenesis, most treatment strategies for acute coronary syndromes are aimed at inhibiting its generation or blocking its activity. Although heparin has been widely used, it has limitations in the setting of arterial thrombosis. These limitations reflect the inability of heparin to inactivate thrombin bound to fibrin, a major stimulus for thrombus growth.

Homocysteine-dependent alterations in mitochondrial gene expression, function and structure. Homocysteine and H2O2 act synergistically to enhance mitochondrial damage.

Mitochondrial abnormalities have been identified in hepatocytes of patients with hyperhomocysteinemia and in endothelial cells from the aortas of rats with diet-induced hyperhomocysteinemia. However, the mechanism by which homocysteine affects mitochondria is unknown. In this report, homocysteine-induced expression of the mitochondrial electron transport chain gene, cytochrome c oxidase III/ATPase 6,8 (CO3/ATPase 6,8), was identified in a human megakaryocytic cell line DAMI using mRNA differential display.

A cross-Canada survey of prothrombin time testing: Does the establishment of local ISI values improve the accuracy of international normalized ratio reporting? Thrombosis Interest Group of Canada.

The international normalized ratio (INR) was established as a means of standardizing the prothrombin time regardless of the thromboplastin used in the individual laboratories. The INR is the prothrombin time ratio of the sample raised to the power of the International Sensitivity Index (ISI). Traditionally, the ISI is determined by using a manual clotting technique by comparing the test thromboplastin with a World Health Organization international reference thromboplastin with results from 60 patient samples standardized on warfarin, and 20 samples from normal volunteers.

Recent clinical trials in the treatment of venous thromboembolism and unstable angina with low molecular weight heparins.

Low molecular weight heparins (LMWHs) have a more predictable anticoagulant response, better bioavailability when administered by subcutaneous injection, and a longer plasma half-life than unfractionated heparin. Consequently, LMWHs can be administered by subcutaneous injection, once daily, without laboratory monitoring. When used in this way, LMWHS are as safe and effective as unfractionated heparin administered by continuous intravenous infusion with laboratory monitoring for the treatment of venous thrombosis and pulmonary embolism, and at least as safe and effective as unfractionated heparin for the treatment of unstable angina.

The effects of standard and low molecular weight heparin on bone nodule formation in vitro.

Previously, we demonstrated in a rat model of heparin-induced osteoporosis that low molecular weight heparin (LMWH) produces less bone loss than unfractionated heparin, and that only heparin increases osteoclast number and activity. In contrast, both heparin and LMWH were found to decrease osteoblast function to a similar extent, possibly because at the doses tested both agents produced maximal inhibition. To examine the relative effects of heparin and LMWH on osteoblast function more closely we used an in vitro bone nodule assay, together with measurements of alkaline phosphatase (ALP) activity.

Dysglycaemia: a cardiovascular risk factor.

Patients with diabetes have a 2-fold higher risk of developing cardiovascular disease than non-diabetic individuals. Moreover, recent epidemiologic studies have shown that this risk rises with the degree of hyperglycaemia, so that diabetic patients with poorly controlled glucose levels have a higher risk of cardiovascular disease than those with well-controlled glucose levels. Thus, in patients with diabetes, glucose level appears to be a continuous risk factor for cardiovascular disease.

Hirudin causes more bleeding than heparin in a rabbit ear bleeding model.

This study was undertaken to determine the appropriateness of the current practice of using the activated partial thromboplastin time (APTT) to select hirudin doses. A rabbit bleeding ear model was used to compare the effects of various doses of heparin and hirudin on the relationship between the APTT and bleeding. In addition, the effects of these agents on the thrombin clotting time (TCT) and factor Xa clotting time also were examined.

The relationship of antiphospholipid antibodies to thromboembolic events in pediatric patients with systemic lupus erythematosus: a cross-sectional study.

The purpose of this study was to evaluate pediatric patients with systemic lupus erythematosus (SLE) to determine 1) the incidence of thrombosis, 2) the incidence of antiphospholipid antibodies, and 3) whether there is an association between the presence of antiphospholipid antibodies and thrombosis. We performed a cross-sectional cohort study in 59 consecutive SLE patients who had been managed at rheumatology clinics in two pediatric hospitals. A history, questionnaire, and chart review were completed by the study nurse blinded to laboratory results.