Incubation of human platelets, human neutrophils, or highly metastatic mouse lymphoma cells with sulfate-labeled extracellular matrix (ECM) results in heparanase-mediated release of labeled heparan sulfate cleavage fragments (0.5 less than Kav less than 0.85 on Sepharose 6B). This degradation was inhibited by native heparin both when brought about by intact cells or their released heparanase activity. Degradation of heparan sulfate in ECM may facilitate invasion of normal and malignant cells through basement membranes. The present study tested the heparanase inhibitory effect of nonanticoagulant species of heparin that might be of potential use in preventing heparanase mediated extravasation of bloodborne cells. For this purpose, we prepared various species of low-sulfated or low-mol-wt heparins, all of which exhibited less than 7% of the anticoagulant activity of native heparin. N-sulfate groups of heparin are necessary for its heparanase inhibitory activity but can be substituted by an acetyl group provided that the O-sulfate groups are retained. O-sulfate groups could be removed provided that the N positions were resulfated. Total desulfation of heparin abolished its heparanase inhibitory activity. Heparan sulfate was a 25-fold less potent heparanase inhibitor than native heparin. Efficiency of low-mol-wt heparins to inhibit degradation of heparan sulfate in ECM decreased with their main molecular size, and a synthetic pentasaccharide, representing the binding site to antithrombin III, was devoid of inhibitory activity. Similar results were obtained with heparanase activities released from platelets, neutrophils, and lymphoma cells. We propose that heparanase inhibiting nonanticoagulant heparins may interfere with dissemination of bloodborne tumor cells and development of experimental autoimmune diseases.

BACKGROUND AND PURPOSE Although medications can significantly reduce the risk of recurrent stroke, little is known about the extent to which such therapies are given to nursing home residents. We sought to evaluate the extent to which people of color were less likely to receive pharmacological agents in the treatment of recurrent stroke while living in US nursing homes. METHODS We identified 19 051 residents with a recent hospitalization and primary discharge diagnosis of 434 or 436 in 5 states from 1992 to 1996; of these, 7053 had concomitant conditions indicating anticoagulant therapy. We considered aspirin, dipyridamole, ticlopidine, or warfarin alone or in combination as secondary drug prevention. Generalized linear models provided estimates of the absolute difference in prevalence estimates of the receipt of agents used for the prevention of recurrent stroke between each race-ethnicity group adjusted for potential confounders. RESULTS Variability in use of any treatment was observed by race-ethnicity ranging from 58% of American Indians receiving therapy to only 39% of Asian/Pacific Islanders. Among residents with an indication for anticoagulant therapy, the absolute estimated crude differences indicated that residents of color were less likely than non-Hispanic whites to receive warfarin. After controlling for confounding, Asian/Pacific Islanders, blacks, and Hispanics eligible for anticoagulant therapy received warfarin less often than non-Hispanic white residents. CONCLUSIONS Overall, only half of our elderly population received any pharmacological agent for secondary prevention of stroke. Interventions designed to improve the pharmacological management of recurrent stroke regardless of race are needed in the nursing home setting.

Venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, is the result of an imbalance among procoagulant, anticoagulant and profibrinolytic processes. This imbalance reflects a complex interplay between genetic and environmental or acquired risk factors. Genetic thrombophilic defects influence the risk of a first episode of thrombosis. How these defects influence the risk of recurrence in patients whose first episode of venous thromboembolism was unprovoked is less certain. Thus, when anticoagulants are stopped, patients with unprovoked venous thromboembolism have a risk of recurrence of at least 7% to 10% per year, even in the absence of an underlying thrombophilic defect. Consequently, there is a trend toward longer durations of anticoagulation therapy for these patients, which is problematic given the limitation of existing anticoagulants. This chapter provides an overview of the thrombophilic defects and how they influence the risk of venous thromboembolism. The chapter also details advances in anticoagulant therapy, focusing on new inhibitors of factor Xa and thrombin. In Section I, Dr. Saskia Middeldorp describes the various thrombophilic defects and reviews their relative importance in the pathogenesis of a first episode of venous thromboembolism. She then discusses the influence of these defects on the risk of recurrent thrombotic events in patients with unprovoked venous thromboembolism and in those whose thrombosis occurred in association with a known risk factor, such as surgery. In Section II, Dr. William Geerts reviews the pharmacology of new parenteral and oral factor Xa inhibitors and describes the results of the Phase II and III clinical trials with these agents. He then provides perspective on the potential advantages and drawbacks of these drugs for the prevention and treatment of venous thromboembolism. In Section III, Dr. John Heit focuses on direct thrombin inhibitors. He discusses their mechanism of action and compares and contrasts their pharmacological profiles prior to describing the results of Phase II and III clinical trials. Dr. Heit then provides perspective on the potential advantages and limitations of these drugs relative to existing anticoagulants.

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect thrombin inhibitors, and coumarins, such as warfarin, which modulate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagatran, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.

Despite the progress made in the development of cardiopulmonary bypass (CPB) equipment, systemic anticoagulation with unfractionated heparin and post-bypass neutralization with protamine are still used in most perfusion procedures. However, there are a number of situations where unfractionated heparin, protamine or both cannot be used for various reasons. Intolerance of protamine can be addressed with extracorporeal heparin removal devices, perfusion with (no) low systemic heparinization and, to some degree, by perfusion with alternative anticoagulants. Various alternative anticoagulation regimens have been used in cases of intolerance to unfractionated heparin, including extreme hemodilution, low molecular weight heparins, danaparoid, ancrod, r-hirudin, abciximab, tirofiban, argatroban and others. In the presence of heparin-induced thrombocytopenia (HIT) and thrombosis, the use of r-hirudin appears to be an acceptable solution which has been well studied. The main issue with r-hirudin is the difficulty in monitoring its activity during CPB, despite the fact that ecarin coagulation time assessment is now available. A more recent approach is based on selective blockage of platelet aggregation by means of monoclonal antibodies directed to GPIIb/IIIa receptors (abciximab) or the use of a GPIIb/IIIa inhibitor (tirofiban). An 80% blockage of the GPIIb/IIIa receptors and suppression of platelet aggregation to less than 20% allows the giving of unfractionated heparin and running CPB in a standard fashion despite HIT and thrombosis. Likewise, at the end of the procedure, unfractionated heparin is neutralized with protamine as usual and donor platelets are transfused if necessary. GPIIb/IIIa inhibitors are frequently used in interventional cardiology and, therefore, are available in most hospitals.

OBJECTIVES Hospital administrative data were analyzed to assess treatment patterns, in-hospital mortality, rates of hemorrhagic events and thrombus propagation, utilization of health care resources, and hospital costs associated with various treatments during inpatient care for venous thromboembolism (VTE). STUDY DESIGN Data from inpatient records were collected for deep venous thrombosis (DVT) and pulmonary embolism (PE) encounters at 132 US hospitals between January 1999 and December 2000. Patients receiving the most frequently employed treatments were compared with respect to demographics, related procedures and diagnostics, length of stay, adverse events, in-hospital mortality, and hospital costs. RESULTS A total of 953 primary DVT and 3933 primary PE admissions were identified. Most admissions involved treatment with unfractionated heparin and vitamin K antagonist (UFH/VKA, 64.2% of admissions), followed by UFH with VKA and low-molecular-weight heparin (UFH/LMWH/VKA, 14.4%), and LMWH/VKA (12.9%). Compared with those treated with UFH/VKA, patients treated with LMWH/VKA experienced higher anticoagulant costs (dollar 540 vs. dollar 106), but lower total hospital costs (dollar 5198 vs. dollar 5977) and shorter lengths of stay (4.4 vs. 5.7 days for those without PE and 5.7 vs. 6.7 days for those with PE). CONCLUSIONS UFH/VKA was the most common regimen used to treat VTE. In spite of its higher medication cost, however, treatment with LMWH/VKA was associated with significantly shorter hospital stays and lower total hospitalization costs, compared with UFH/VKA.

Unfractionated heparin (UFH) has been used as an antithrombotic agent in the treatment of various clinical entities for over 60 years. Low-molecular-weight heparin (LMWH) com- pounds have gradually replaced UFH for these indications as they have several advantages, including subcutaneous administration and the lack of need for laboratory monitoring. Ever since their introduction, there has been discussion about whether LMWH compounds differ in their efficacy and safety. The best answer is given by direct comparison of two or more preparations; however, such trials are very scarce. Comparison using classical meta-analysis is limited as only a small number of trials with the respective low-molecular-weight heparin compounds are available. The objective of the present analysis has been to use a novel way of plotting the odds ratios of the different studies to compare the efficacy and safety of different LMWH compounds in the initial treatment of patients with venous thromboembolism. Classical meta-analysis revealed reductions in safety and efficacy of 30--40% in favour of LMWHs. Contrasting the log odds ratios of efficacy and safety indicated that there is no conclusive evidence that LMWHs have intrinsic different safety and efficacy profiles.