Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

This article about currently available antiplatelet drugs is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). It describes the mechanism of action, pharmacokinetics, and pharmacodynamics of aspirin, reversible cyclooxygenase inhibitors, thienopyridines, and integrin alphaIIbbeta3 receptor antagonists. The relationships among dose, efficacy, and safety are thoroughly discussed, with a mechanistic overview of randomized clinical trials.

Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

This article concerning the pharmacokinetics and pharmacodynamics of vitamin K antagonists (VKAs) is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). It describes the antithrombotic effect of the VKAs, the monitoring of anticoagulation intensity, and the clinical applications of VKA therapy and provides specific management recommendations. Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh the risks, burdens, and costs.

Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

This chapter describes the pharmacology of approved parenteral anticoagulants, including the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin factor Xa and other clotting factors. Heparin also binds to cells and other plasma proteins, endowing it with unpredictable pharmacokinetic and pharmacodynamic properties, and can lead to nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis.

Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

Since publication of the seventh American College of Chest Physicians (ACCP) supplement on antithrombotic and thrombolytic therapy, the results of clinical trials have provided important new information on the management of thromboembolic disorders, and the science of developing recommendations has advanced. In the accompanying supplement, we provide the new and updated recommendations and review several important changes that we have made in our guideline development process. We again made a conscious effort to increase the participation of female authors and contributors from outside North America, the latter reflecting the widespread use and dissemination of these guidelines internationally.

Current anticoagulant therapy--unmet clinical needs.

Heparin and the vitamin K antagonist warfarin have been in clinical use for more than 50 years. However, both are associated with several well-documented drawbacks that limit their use. Warfarin can be administered orally, making it the agent of choice for long-term management of thromboembolic conditions, but frequent coagulation monitoring is necessary because of its unpredictable anticoagulant effect--the result, in part, of food and drug interactions-and its narrow therapeutic window.

Predictors of in-hospital mortality following operative management of hip fractures.

Objective: To identify predictors of in-hospital mortality and hospital stay following hip fractures.

Design: Retrospective cohort study of 185 consecutive patients.

Setting: Tertiary Care University Hospital.

High and low pressure irrigation in contaminated wounds with exposed bone.

Background: Irrigation and debridement are essential in the initial management of traumatic wounds. The relative efficicacy of low pressure irrigation compared with high pressure irrigation remains unclear.

Aims: The purpose of this study was to examine the time dependent efficacy of both high and low pressure lavage in removing adherent bacteria from traumatic wounds with exposed bone.

Fibrinolytic response to venous occlusion is decreased in patients after Kawasaki disease.

Impaired fibrinolysis is considered a sensitive marker of endothelial dysfunction. Persistent endothelial dysfunction occurs in some patients following Kawasaki disease. The aim of the present study was to assess whether impaired fibrinolysis is present in long-term survivors of Kawasaki disease.

Neutralization of interleukin-11 activity decreases osteoclast formation and increases cancellous bone volume in ovariectomized mice.

The issue of whether interleukin-11 (IL-11) contributes to bone loss during states of estrogen deficiency has not been previously determined. We therefore randomized ovariectomized (OVX) mice to once daily interperitoneal injections of either sheep anti-murine IL-11 Ab or normal sheep IgG (NSIgG) for 21 days, and then determined the effects on bone using bone histomorphometry. Here we report that treatment of OVX mice with anti-IL-11 Ab significantly increases both trabecular width and cancellous bone volume.

Heparin acts synergistically with interleukin-11 to induce STAT3 activation and in vitro osteoclast formation.

We have previously demonstrated that long-term heparin treatment causes cancellous bone loss in rats due in part to an increase in the number of osteoclasts lining the trabecular bone surface. In the present study, we investigated this phenomenon by examining the ability of heparin to synergistically enhance interleukin-11 (IL-11)-induced osteoclast formation. Treatment of murine calvaria and bone marrow cells with IL-11 was found to induce the formation of tartrate-resistant acid phosphatase-positive (TRAP(+)) multinucleated cells (MNCs) in a dose-dependent fashion.

Long-term treatment with sodium warfarin results in decreased femoral bone strength and cancellous bone volume in rats.

The issue of whether long-term sodium warfarin therapy results in decreased bone density is controversial. To address this question, we randomized rats to once daily subcutaneous injections of either sodium warfarin (0.20 or 0.

Decreased concentrations of heparinoids are required to inhibit thrombin generation in plasma from newborns and children compared to plasma from adults due to reduced thrombin potential.

Thrombin generation is decreased and delayed in plasma from newborns and children compared to adults. We hypothesized that lower doses of heparinoid anticoagulants are required to give similar thrombin generation in newborn (umbilical cord) and child plasmas compared to that of adults. Thrombin generation was performed in either the absence or presence of unfractionated heparin (UFH), low molecular weight heparin (LMWH) or a covalent antithrombin-heparin complex (ATH).

Decrease in sensitivity of D-dimer for acute venous thromboembolism after starting anticoagulant therapy.

D-dimer testing is useful for the exclusion of acute venous thromboembolism (VTE). Anticoagulant therapy is expected to reduce D-dimer levels in patients with thrombosis and, consequently, it may not be safe to use D-dimer levels to exclude VTE after anticoagulant therapy has been started. The objectives of this study were to estimate the decrease in D-dimer levels after 24 h of heparin therapy and, applying this estimate to the results of a recent study, to calculate the expected reduction in sensitivity.

Incorporation of vitronectin into fibrin clots. Evidence for a binding interaction between vitronectin and gamma A/gamma' fibrinogen.

Vitronectin is an abundant plasma protein that regulates coagulation, fibrinolysis, complement activation, and cell adhesion. Recently, we demonstrated that plasma vitronectin inhibits fibrinolysis by mediating the interaction of type 1 plasminogen activator inhibitor with fibrin (Podor, T. J.

Vimentin exposed on activated platelets and platelet microparticles localizes vitronectin and plasminogen activator inhibitor complexes on their surface.

Type 1 plasminogen activator inhibitor (PAI-1), the primary inhibitor of tissue-type plasminogen activator (t-PA), is found in plasma and platelets. PAI-1 circulates in complex with vitronectin (Vn), an interaction that stabilizes PAI-1 in its active conform. In this study, we examined the binding of platelet-derived Vn and PAI-1 to the surface of isolated platelets.

New anticoagulant drugs.

Arterial and venous thrombosis are major causes of morbidity and mortality. Arterial thrombosis is the most common cause of myocardial infarction, stroke, and limb gangrene. Venous thrombosis leads to potentially fatal pulmonary embolism and to post-phlebitic syndrome.

Low molecular weight heparin administered once versus twice daily in patients with venous thromboembolism: a meta-analysis.

Background: Low molecular weight heparin is as effective and safe as unfractionated heparin for treatment of acute venous thromboembolism. It is uncertain whether low molecular weight heparin should be administered once-daily or twice-daily in this setting.

Method: A meta-analysis of randomized studies which directly compared once- and twice-daily administration of low molecular weight heparin for the treatment of acute venous thromboembolism was performed.

Conformational changes in thrombin when complexed by serpins.

Thrombin possesses two positively charged surface domains, termed exosites, that orient substrates and inhibitors for reaction with the enzyme. Because the exosites also allosterically modulate thrombin's activity, we set out to determine whether the structure or function of the exosites changes when thrombin forms complexes with antithrombin, heparin cofactor II, or alpha(1)-antitrypsin (M358R), serpins that utilize both, one, or neither of the exosites, respectively. Using a hirudin-derived peptide to probe the integrity of exosite 1, no binding was detected when thrombin was complexed with heparin cofactor II or alpha(1)-antitrypsin (M358R), and the peptide exhibited a 55-fold lower affinity for the thrombin-antithrombin complex than for thrombin.

New anticoagulants.

Background: Heparin and coumarins have been in clinical use for more than 50 years. Low-molecular-weight heparins (including a heparinoid), developed 25 years ago, have been used clinically for more than a decade.

Methods: In the last 10 years, several new anticoagulants that target almost every step in the coagulation pathway have been developed.

Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement.

Background: With the best prophylactics now available, venous thromboembolism after total knee replacement remains substantial (25% to 27%). Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent inhibitor of factor VIIa/tissue factor complex that has the potential to reduce this risk. The present study was performed to determine an efficacious and safe dose of rNAPc2 for prevention of venous thromboembolism after elective, unilateral total knee replacement.

Anticoagulation of the Elderly Patient.

The optimal management of various thromboembolic and vascular disorders often entails the use of long term oral anticoagulant therapy. These disorders are generally more prevalent in the elderly than in the young. Hemorrhage is the most common complication of anticoagulant therapy.