Antithrombotic Agents (antithrombotic + agent)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Implementation of an Emergency Department,based Transient Ischemic Attack Clinical Pathway: A Pilot Study in Knowledge Translation

ACADEMIC EMERGENCY MEDICINE, Issue 11 2007
Michael D. Brown MD
Objectives To assess the feasibility of implementing an emergency department (ED),based transient ischemic attack (TIA) clinical pathway that uses computer-based clinical support, and to evaluate measures of quality, safety, and efficiency. Methods This was a prospective cohort study of adult patients presenting to a community ED with symptoms consistent with acute TIA. Adherence to the clinical pathway served as a test of feasibility. Compliance with guideline recommendations for antithrombotic therapy and vascular imaging were used as process measures of quality. The 90-day risk of recurrent TIA, stroke, or death provided estimates of safety. Efficiency was assessed by measuring the rate of uneventful hospitalization, defined as a hospital admission that did not result in any major medical event or vascular intervention such as endarterectomy or stent placement. Results Of the 75 subjects enrolled, physician adherence to the clinical pathway was 85.3%, and 35 patients (46.7%) were discharged home from the ED. Antithrombotic agents were prescribed to 68 (90.7%), and vascular imaging was performed in 70 (93.3%). The 90-day risk of recurrent TIA was seven out of 75 (9.3%; 95% confidence interval [CI] = 4.6% to 18.0%), one patient experienced stroke (1.3%; 95% CI = 0.2% to 7.2%), and three patients died (4.0%; 95% CI = 1.4% to 11.1%). Uneventful hospitalization occurred in 38 of 40 patients (95.0%). Conclusions Implementation of a clinical pathway for the evaluation and management of TIA using computer-based clinical support is feasible in a community ED setting. This pilot study in knowledge translation provides a design framework for further studies to assess the safety and efficiency of a structured ED-based TIA clinical pathway. [source]


Two novel monoclonal antibodies to VWFA3 inhibit VWF-collagen and VWF-platelet interactions

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2007
Y. ZHAO
Summary.,Background:,The interaction of collagen-von Willebrand factor (VWF)-GPIb is essential for platelet adhesion, especially under high shear conditions. VWF, which acts as a bridge between platelets and exposed subendothelium, interacts with collagen through its A3 domain, which is a new target for the antithrombotic agent. Objective:,To develop functional blockers that specifically inhibit VWF-dependent adhesion of platelets to collagen under high shear stress. Methods:,To develop murine antihuman VWF A3 monoclonal antibodies (mAbs) by standard hybridoma technology, and characterize their abilities to block interactions between VWF A3 and collagen as well as platelet function. Results:,Thirty anti-VWF-A3 mAbs were obtained. Among them, two mAbs, designated as SZ-123 and SZ-125, were found to inhibit VWF-collagen type III interaction. SZ-123 and SZ-125 inhibited the binding of purified human VWF (1.5 or 3 ,g mL,1) to human placenta collagen type III (IC50 = 0.07 ± 0.02 and 0.15 ± 0.03 ,g mL,1, respectively) or to calf skin collagen type III (IC50 = 0.48 ± 0.06 and 0.51 ± 0.07 ,g mL,1, respectively) coated on plates. Under flow shear condition (1000 s,1), SZ-123 and SZ-125 inhibited platelet adhesion on human placenta collagen- or calf skin collagen-coated surfaces. Both mAbs also inhibited platelet aggregation induced by ristocetin, botrocetin or bovine plasma. Conclusions:,SZ-123 and SZ-125 inhibited VWF-collagen and VWF-platelet interactions. [source]


The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007
Joachim Stangier
Aims The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. Methods Dabigatran etexilate or placebo was administered orally at single doses of 10,400 mg (n = 40) or at multiple doses of 50,400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. Results Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8,10 h and 14,17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (Vz/F) of 1860 l (range 1430,2400 l) and the apparent total clearance after oral administration (CLtot/F) of 2031 ml min,1 (range 1480,2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration,time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups. Conclusions These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted. [source]


Management of patients with non,ST-segment elevation acute coronary syndromes: Insights from the pursuit trial

CLINICAL CARDIOLOGY, Issue S5 2000
Dan J. Fintel M.D
The glycoprotein (GP) IIb-IIIa inhibitor eptifibatide (INTEGRILIN®, COR Therapeutics, Inc., South San Francisco, California, and Key Pharmaceuticals, Inc., Kenilworth, New Jersey) is a novel and highly potent antithrombotic agent indicated for the management of patients with non-ST-segment elevation acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention. The approval of eptifibatide for non-ST-segment elevation ACS was based on the positive results of the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. With enrollment of almost 11,000 patients, not only is the PURSUIT trial the largest trial of a GP IIb-IIIa inhibitor to date, but it is also the largest clinical study ever conducted in patients with non-ST-segment elevation ACS. The key feature of the PURSUIT trial is that patient management closely resembled standard clinical practice, because decisions about the use and timing of invasive cardiac procedures were made by the individual physicians rather than being prespecified in the study protocol. Eptifibatide therapy was associated with a significant reduction in the incidence of the primary endpoint,a composite of death or myocardial infarction at 30 days (14.2 vs. 15.7% in the placebo group; p = 0.042). Of importance is the fact that the beneficial effect of eptifibatide was independent of the management strategy pursued during study drug infusion (invasive or conservative), and it was achieved with few major safety concerns. These findings demonstrate that the use of eptifibatide should be considered for all patients presenting with signs and symptoms of intermediate- to high-risk non-ST-segment elevation ACS. [source]


Antiplatelet Therapy: Anti-Ischemic Benefits versus Bleeding Risk

JOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 2008
C. MICHAEL GIBSON M.D., F.A.C.C.
Balance between efficacy and safety is a major concern in therapeutic interventions of patients with acute coronary syndromes. Identifying and managing the risks that may negatively affect this balance can potentially minimize the incidence of morbidity and/or mortality among patients with acute coronary syndromes. Unstable angina and non-ST-elevation myocardial infarction are potentially life-threatening disorders and a major cause of hospitalization and emergency medical care. At the time of presentation, the use of algorithms that provide reasonable assessment of a patient's risk of cardiovascular events, such as the Thrombolysis in Myocardial Infarction risk score, can help clinicians identify which patients will most likely benefit from a specific strategy. The ultimate goal of treatment for non-ST-elevation myocardial infarction is to reduce short- and long-term morbidity and mortality, as well as salvage myocardial cells and cardiac function. Pharmacologic intervention with antiplatelet and/or antithrombotic agents has proven to be effective in achieving this goal in numerous outcome studies. However, clinicians must balance anti-ischemic efficacy with the need to minimize the risk of serious bleeding complications (e.g., hemorrhage). Issues related to safety include timing of the dose, duration of infusion, drug compatibility, errors in estimating a patient's weight and/or age, failure to adjust the dosage based upon renal function, and errors in drug preparation. [source]


Ultrasound screening for asymptomatic deep vein thrombosis after major orthopaedic surgery: the VENUS study

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 7 2007
S. M. SCHELLONG
Summary.,Background:,Venography is currently used to assess the incidence of deep vein thrombosis (DVT) in dose-finding and confirmatory trials of new antithrombotic agents. Centrally adjudicated, complete compression ultrasound (CCUS) could be a non-invasive alternative to venography. Objectives:,A substudy of two, similarly designed, phase IIb trials of a novel, oral anticoagulant for the prevention of venous thromboembolism after elective hip or knee arthroplasty was undertaken to validate CCUS against venography. Patients/Methods:,Patients received study drugs until mandatory, bilateral venography was performed 7 ± 2 days after surgery. CCUS was performed within 24 h after venography by sonographers blinded to the venography result. Sonographers were trained and certified for the standardized examination and documentation procedure. Venograms and sonograms were adjudicated centrally at different sites by two independent readers; discrepancies between readers were resolved by consensus. Results:,A total of 1104 matching pairs of evaluable venograms and sonograms were obtained from the participants of the two trials (n = 1435): 19% of venograms and 20% of sonograms were not evaluable. The observed frequency of any DVT was 18.9% with venography and 11.5% with CCUS. Sensitivity of CCUS compared with venography was 31.1% for any DVT (95% confidence interval 23.4, 38.9), 21.0% (2.7, 39.4) for proximal DVT, and 30.8% (23.1, 38.6) for distal DVT. The figures for specificity were 93.0% (91.0, 95.1), 98.7% (98.0, 99.5), and 93.3% (91.5, 95.3), respectively. Conclusions:,Based on these results, centrally adjudicated CCUS will be unable to replace venography for DVT screening early after major orthopaedic surgery in studies evaluating anticoagulant drugs. [source]


Effects of factor XI deficiency on ferric chloride-induced vena cava thrombosis in mice

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2006
X. WANG
Summary.,Background:,Increased plasma levels of coagulation factor (F) XI are a risk factor for venous thrombosis. Objective:,To further explore the relationship between FXI and venous thrombosis, we evaluated FXI-deficient and wild-type mice in a ferric chloride (FeCl3)-induced vena cava thrombosis model. Methods and Results:,Thrombosis was induced by 3-min topical application of filter papers containing increasing concentrations of FeCl3 and the thrombus was measured at 30 min. In contrast to wild-type mice, FXI-deficient mice failed to form a thrombus with 5% FeCl3, and were partially protected against 7.5% and 10% FeCl3, respectively. The protective effect was substantially stronger than a high dose of heparin (1000 units kg,1, i.v.), clopidogrel (30 mg kg,1, p.o.) or argatroban (30 mg kg,1, i.p.). These antithrombotic agents resulted in off-scale bleeding in a tail bleeding time assay, whereas the bleeding time of FXI-deficient mice was unchanged compared to wild-type mice. In addition to its known effect on the coagulation cascade, enhanced clot lysis was demonstrated in FXI-deficient mouse and human plasma compared to those supplemented with FXIa. Conclusion:,Given the strong antithrombotic efficacy (possibly contributed by strong anticoagulant activity associated with increased fibrinolytic activity) and mild bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable therapeutic strategy to treat or prevent venous thrombosis. [source]


Association of the antagonism of von Willebrand factor but not fibrinogen by platelet ,IIb,3 antagonists with prolongation of bleeding time

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2005
T. AOKI
Summary.,Background:,The ,IIb,3 antagonists inhibit platelet aggregation and are used as antithrombotic agents for cardiothrombotic disease. The present study investigates the correlation of inhibition of fibrinogen and von Willebrand factor (VWF) binding by ,IIb,3 antagonists with the inhibition of platelet aggregation and prolongation of bleeding time (BT). Methods:,Inhibition of fibrinogen and VWF binding were assessed in a purified ,IIb,3 -binding assay. As an in vitro cell-based assay, platelet aggregation and VWF-mediated adhesion studies were performed using human platelets. In vivo effects on BT were measured using a template device in dogs at the same time as an ex vivo aggregation study was performed. Results:,In vitro studies demonstrated that the antiaggregatory effects of ,IIb,3 antagonists correlate with their inhibition of fibrinogen binding, but not VWF. Interestingly, the effects of ,IIb,3 antagonists on BT could be differentiated from the inhibition of platelet aggregation. Furthermore, this differentiation was strongly correlated with the different inhibitory potencies between fibrinogen and VWF binding, as well as that between VWF-mediated adhesion and aggregation. Conclusions:,Our study provides novel evidence showing that the inhibitory effect of ,IIb,3 antagonists on VWF, but not fibrinogen binding, correlates with their ability to prolong BT. [source]


Prevention of venous thromboembolism after acute ischemic stroke

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2005
P. W. KAMPHUISEN
Summary., Venous thromboembolism (VTE) is a common complication after acute ischemic stroke. When screened by 125I fibrinogen scanning or venography, the incidence of deep-vein thrombosis (DVT) in stroke patients is comparable with that seen in patients undergoing hip or knee replacement. Most stroke patients have multiple risk factors for VTE, like advanced age, low Barthel Index severity score or hemiplegia. As pulmonary embolism is a major cause of death after acute stroke, the prevention of this complication is of crucial importance. Prospective trials have shown that both unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are effective in reducing DVT and pulmonary embolism in stroke patients. Current guidelines recommend the use of these agents in stroke patients with risk factors for VTE. Some clinicians are concerned that the rate of intracranial bleeding associated with thromboprophylaxis may outweigh the benefit of prevention of VTE. Low-dose LMWH and UFH seem, however, safe in stroke patients. Higher doses clearly increase the risk of cerebral bleeding and should be avoided for prophylactic use. Both aspirin and mechanical prophylaxis are suboptimal to prevent VTE. Graduated compression stockings should be reserved to patients with a clear contraindication to antithrombotic agents. [source]


Synthetic selective inhibitors of coagulation factor Xa strongly inhibit thrombin generation without affecting initial thrombin forming time necessary for platelet activation in hemostasis

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2004
M. Ieko
Summary., DX-9065a and JTV-803, synthetic selective inhibitors of activated factor X (FXa), have recently been demonstrated as strongly effective antithrombotic agents in animal thrombosis models, yet with a low risk of bleeding. The aim of the present study was to elucidate these characteristics. Using a chromogenic assay with purified coagulation factors, 73.9% of thrombin generation was suppressed by the addition of DX-9065a (0.20 µm) and 75.7% by JTV-803 (0.18 µm). Inhibition by argatroban (0.19 µm) was less (36.0%) and initial thrombin forming time (T50), the time required to generate 50% thrombin activity in vitro, which is considered important for platelet aggregation in hemostasis, was significantly prolonged by argatroban. In contrast, DX-9065a and JTV-803 had no apparent influence on T50, suggesting that initial thrombin was formed immediately, as in the control. We also investigated platelet aggregation in defibrinated plasma induced by tissue factor, to clarify whether initial thrombin contributes to hemostasis. Aggregation was not affected by the addition of either FXa inhibitor, whereas it was significantly reduced by argatroban. Our results suggest that initial thrombin, which is formed despite the presence of a FXa inhibitor, can activate platelets. We concluded that DX-9065a and JTV-803 are able to inhibit thrombin generation significantly without affecting the formation of initial thrombin for platelet activation, which may contribute to hemostasis through the preservation of normal bleeding time. [source]


Prevention of venous thromboembolism after major orthopedic surgery: ,new' clinical trials for new antithrombotic agents

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2003
P. Mismetti
No abstract is available for this article. [source]


Safety of plasmin in the setting of concomitant aspirin and heparin administration in an animal model of bleeding

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2003
S. Sadeghi
Summary., Plasmin is a direct thrombolytic which has been shown to have a strikingly favorable benefit to risk profile in comparison with plasminogen activators, notably tissue plasminogen activator (t-PA). As heparin is known to increase the risk of hemorrhage when co-administered with a plasminogen activator, we asked whether adjunct antithrombotic agents such as aspirin and heparin would affect the safety of plasmin. Three groups of rabbits were administered plasmin at a dose (4 mg kg,1) designed to induce significant decreases in antiplasmin, fibrinogen and factor (F)VIII, to about 25, 40 and 40%, respectively, of baseline values, but not cause prolongation of the ear puncture bleeding time. In a blinded and randomized trial, the results show that an intravenous aspirin bolus plus heparin administered as a bolus followed by a maintenance continuous infusion did not significantly prolong the bleeding time during plasmin infusion. These data indicate that in the rabbit, concomitant use of aspirin plus heparin does not affect the safety of a therapeutic dose of plasmin. [source]


Progress in the design of low molecular weight thrombin inhibitors

MEDICINAL RESEARCH REVIEWS, Issue 1 2005
Stuti Srivastava
Abstract Intravascular thrombosis and its complication, embolism, is a leading cause of morbidity and mortality throughout the world. Past few decades have seen a great deal of progress in the development of antithrombotic agents, though the current treatment options are limited to heparin, LMW heparins, and warfarin. Detailed understanding of the biochemical and biophysical mechanisms of activation and regulation of blood coagulation have helped in developing specific inhibitors of enzymes, especially thrombin, within the coagulation cascade. Thrombin plays a central role in the coagulation cascade and so has become the primary target for the development of antithrombotic drugs. The review covers the main pharmacological aspects of haemostasis and thrombosis and provides an update on low molecular weight thrombin inhibitors along with the limitations of the prevalent antithrombotic agents. Recent developments in small molecule inhibitors of Protease Activated Receptor-1 (PAR-1) which can be helpful for the treatment of thrombotic and vascular proliferative disorders, have also been discussed. © 2004 Wiley Periodicals, Inc. [source]


The new Swedish Prescribed Drug Register,Opportunities for pharmacoepidemiological research and experience from the first six months,

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 7 2007
Björn Wettermark M.Sc.Pharm
Abstract Purpose To describe the content and potentials of the new Swedish national register on prescribed and dispensed medicines. Methods The Swedish Prescribed Drug Register contains information about age, sex and unique identifier of the patient as well as the prescriber's profession and practice. Information regarding drug utilization and expenditures for prescribed drugs in the entire Swedish population was extracted from the first six months July,December 2005 and compared with total drug sales in the country including OTC and hospital use. Results The total quantity of drugs sold in Sweden was 2666 million DDDs, corresponding to 1608 DDD/1000 inhabitants daily. The total expenditures were 1.6 billion Euro. The prescribed drugs, included in the register, accounted for 84% of the total utilization and 77% of the total expenditures. About half of all men and two-thirds of all women in the country purchased drugs. The proportion increased by age. The most common drugs for chronic treatment were diuretics among women (8.8% of the population) and antithrombotic agents among men (7.6%). Psychotropic drugs, corticosteroids and analgesics were more common among women, while men used antithrombotic agents, antidiabetic drugs, lipid lowering agents and ACE inhibitors to a greater extent. Conclusions The new register provides valuable data on exposure to drugs and is useful to study patterns of drug utilization. The possibilities for record linkage to other health registers gives from an international perspective good opportunities to explore drug and disease associations and the risks, benefits, effectiveness and health economical effects of drug use. Copyright © 2006 John Wiley & Sons, Ltd. [source]


Synthesis, Antiplatelet and Vasorelaxing Activities of Xanthone Derivatives

ARCHIV DER PHARMAZIE, Issue 1 2009
Kai-Wei Lin
Abstract A series of ,-aminoalkoxylxanthones was synthesized and tested in vitro for their ability to inhibit platelet aggregation and cause vasorelaxing action. Compounds 4, 5, 12, 17, and 18 showed significant antiplatelet effects on thrombin-, arachidonic acid (AA)-, collagen-, and platelet activating factor (PAF)-induced washed rabbit platelet aggregation and exhibited inhibition of primary and secondary aggregation induced by adenosine-5'-diphosphate (ADP) in human platelet-rich-plasma (PRP). Compounds 4, 17, and 18 revealed vasorelaxing activities in rat thoracic aorta. We concluded that these compounds may be developed as new antithrombotic agents. [source]


Differential expression of protease-activated receptors in monocytes from patients with primary antiphospholipid syndrome

ARTHRITIS & RHEUMATISM, Issue 3 2010
Chary López-Pedrera
Objective To investigate the expression of protease-activated receptors (PARs), their potential regulation by anticardiolipin antibodies (aCL), and their association with the expression of other molecules relevant to thrombosis in monocytes obtained from 62 patients with primary antiphospholipid syndrome (APS). Methods Monocytes were isolated from peripheral blood mononuclear cells by magnetic depletion of nonmonocytes. Expression of tissue factor (TF) and PARs 1,4 genes was measured by quantitative real-time reverse transcription,polymerase chain reaction. Cell surface TF and PARs 1,4 expression was analyzed by flow cytometry. For in vitro studies, purified normal monocytes were incubated with purified APS patient IgG, normal human serum IgG, or lipopolysaccharide, in the presence or absence of specific monoclonal antibodies anti,PAR-1 (ATAP2) or anti,PAR-2 (SAM11) to test the effect of blocking the active site of PAR-1 or PAR-2. Results Analysis of both mRNA and protein for the 4 PARs revealed significantly increased expression of PAR-2 as compared with the control groups. PAR-1 was significantly overexpressed in APS patients with thrombosis and in the control patients with thrombosis but without APS. PAR-3 expression was not significantly altered. PAR-4 expression was absent in all groups analyzed. In addition, we demonstrated a correlation between the levels of PAR-2 and the titers of IgG aCL, as well as parallel behavior of TF and PAR-2 expression. In vitro, IgG from APS patients significantly increased monocyte expression of PAR-1 and PAR-2. Inhibition studies suggested that there was direct cross-talk between TF and PAR-2, such that inhibition of PAR-2 prevented the aCL-induced expression of TF. Conclusion These results provide the first demonstration of increased expression of PARs in monocytes from patients with APS. Thus, PAR antagonists might have therapeutic potential as antithrombotic agents in APS. [source]


S-nitrosothiols as selective antithrombotic agents , possible mechanisms

BRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2010
MP Gordge
S-nitrosothiols have a number of potential clinical applications, among which their use as antithrombotic agents has been emphasized. This is largely because of their well-documented platelet inhibitory effects, which show a degree of platelet selectivity, although the mechanism of this remains undefined. Recent progress in understanding how nitric oxide (NO)-related signalling is delivered into cells from stable S-nitrosothiol compounds has revealed a variety of pathways, in particular denitrosation by enzymes located at the cell surface, and transport of intact S-nitrosocysteine via the amino acid transporter system-L (L-AT). Differences in the role of these pathways in platelets and vascular cells may in part explain the reported platelet-selective action. In addition, emerging evidence that S-nitrosothiols regulate key targets on the exofacial surfaces of cells involved in the thrombotic process (for example, protein disulphide isomerase, integrins and tissue factor) suggests novel antithrombotic actions, which may not even require transmembrane delivery of NO. [source]


Effect of low molecular weight heparin (dalteparin) and fondaparinux (Arixtra®) on human osteoblasts in vitro,

BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 2 2005
A. E. Handschin
Background: The prolonged administration of heparin for prevention and treatment of venous thromboembolism has been associated with a risk of heparin-induced osteoporosis. Fondaparinux is a new antithrombotic drug that specifically inhibits factor Xa. Because of the known interactions of other antithrombotic agents with bone remodelling, the effects of fondaparinux on human osteoblasts were analysed in vitro. Methods: Primary human osteoblast cell cultures were incubated with either the low molecular weight heparin dalteparin at concentrations of 30, 300 and 900 µg/ml or with fondaparinux at concentrations of 25, 50, 100, 150, 200 and 250 µg/ml. Cellular proliferation rate and protein synthesis were measured. Expression of genes encoding osteocalcin, collagen type I and alkaline phosphatase was examined by reverse transcriptase,polymerase chain reaction. Results: Incubation with dalteparin led to a significant, dose-dependent inhibition of osteoblast proliferation, inhibition of protein synthesis, and inhibited expression of phenotype markers (osteocalcin and alkaline phosphatase genes) after 3 and 7 days. No inhibitory effects were observed in the fondaparinux-treated cells. Conclusion: Fondaparinux did not inhibit osteoblast proliferation in vitro and may reduce the risk of heparin-induced osteoporosis associated with long-term heparin administration. Copyright © 2004 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source]


Evolution of Anticoagulant and Antiplatelet Therapy: Benefits and Risks of Contemporary Pharmacologic Agents and Their Implications for Myonecrosis and Bleeding in Percutaneous Coronary Intervention

CLINICAL CARDIOLOGY, Issue S2 2007
Hector M. Medina M.D., M.P.H.
Abstract Periprocedural myonecrosis, as evidenced by elevated creatine kinase,myocardial bound (CK-MB) levels, occurs in up to 25% of patients undergoing percutaneous coronary intervention (PCI) and has been linked with an increased risk of adverse short- and long-term clinical outcomes. Such myonecrosis arises from three main pathophysiological mechanisms: procedure-related complications, lesion-specific characteristics (e.g., large thrombus burden, plaque volume), and patient-specific characteristics (e.g., genetic predisposition, arterial inflammation). Periprocedural myonecrosis has not been definitively identified as the cause of postprocedural ischemic events, although agents that reduce or prevent thrombosis,including aspirin, thienopyridines, heparin, low-molecular-weight heparins, glycoprotein IIb/IIIa inhibitors, and direct thrombin inhibitors,have been shown to reduce the incidence of ischemic outcomes in this population, as have agents that reduce inflammation (aspirin, statins). At the same time, antithrombotic agents are known to increase the risk of bleeding and the use of transfusions, which have likewise been associated with worse outcomes in these patients. Thus, optimal management of patients undergoing PCI represents a balance between minimizing the risk of ischemic outcomes and simultaneously minimizing the risk of major bleeding. It may be that patients who have only minor, untreated postprocedural elevations in CK-MB level (with no clinical or angiographic signs of ischemia) might have a better prognosis than patients who have normal CK-MB levels but who suffer major bleeding complications. Copyright © 2007 Wiley Periodicals, Inc. [source]