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Direct Thrombin Inhibitor (direct + thrombin_inhibitor)
Selected AbstractsEtiology of thrombocytopenia in all patients treated with heparin productsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2005Damian A. Laber Abstract:,Purpose:,To characterize the cause of thrombocytopenia in all patients treated with heparin products, to determine the incidence of heparin-induced thrombocytopenia (HIT) in unselected hospitalized patients, and to have modern data of the magnitude of this problem. Methods:,Retrospective hospital-based cohort study. During a random 2-month period, we reviewed the medical records of all patients treated with heparin agents, screened them for thrombocytopenia, and determined the cause of it. Results:,Out of 674 patients who received heparin products, 110 (16%) had thrombocytopenia. The most common causes included cancer chemotherapy, surgery, sepsis, and medications. Three patients met the clinical criteria for HIT. One had antibodies for heparin-platelet factor-4, and received a direct thrombin inhibitor. The other two individuals had a clinical syndrome that resembled immune HIT, but were not tested for HIT antibodies. One suffered a thrombotic episode that led to the death of her fetus. The other died of a possible thromboembolism. Conclusions:,This study provides evidence-based data for the differential diagnosis of thrombocytopenia after treatment with heparin products. Our findings suggest that increased awareness of the HIT syndrome might reduce morbidity and mortality. Patients exposed to heparin products, who develop thrombocytopenia, should not be overlooked. [source] Deep Hypothermic Circulatory Arrest and Bivalirudin Use in a Patient With Heparin-Induced Thrombocytopenia and Antiphospholipid SyndromeJOURNAL OF CARDIAC SURGERY, Issue 1 2007Kay B. Leissner M.D. Methods: Bivalirudin was used during CPB and deep hypothermic circulatory arrest (DHCA) for resection of multiple right atrial masses in a patient with HIT II and antiphospholipid antibodies syndrome (APS). Anticoagulation was monitored with the activated clotting time (ACT) and a target ACT of 450 seconds or greater was maintained. Results: Surgical removal of multiple right atrial masses was successful and there was no evidence of thromboembolic events. Clot was noticed in the cardiotomy and venous reservoir after CPB was discontinued and the system flushed. The postoperative course was uneventful. Conclusions: Anticoagulation was successfully managed with bivalirudin, a new short-acting, and direct thrombin inhibitor. Further studies are necessary to evaluate the safety of bivalirudin during DHCA. [source] Experimental metastasis and primary tumor growth in mice with hemophilia AJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2006F. LANGER Summary., During experimental lung metastasis, tumor cells adhere to the pulmonary microvasculature and activate coagulation via surface-expressed tissue factor (TF), leading to local fibrin deposition and platelet aggregation. While interventional studies have demonstrated great efficacy of anticoagulants and antiplatelet agents in inhibiting metastasis, no information is available on how tumor biology may be affected by congenital bleeding disorders such as hemophilia A. We therefore used a syngeneic model to study experimental metastasis and primary tumor growth in factor VIII (FVIII)-deficient mice. By conventional reverse transcription-polymerase chain reaction, flow cytometry, and one-stage clotting assays, we demonstrated constitutive expression of TF mRNA, antigen, and procoagulant activity in the murine B16F10 melanoma cell line. In hemophilic mice, B16F10 lung metastasis was significantly (P < 0.001) enhanced by a single dose of human FVIII (100 U kg,1), suggesting that FVIII played a critical role during the early blood-borne phase of the metastatic cascade. In contrast, lung seeding was significantly (P < 0.05) reduced by lepirudin, a direct thrombin inhibitor, suggesting that thrombin generation contributed to pulmonary metastasis even in the absence of FVIII. Consistent with this finding, intravenous injection of B16F10 cell-evoked laboratory changes of a hemolytic thrombotic microangiopathy and consumptive coagulopathy in both hemophilic and non-hemophilic mice. Subcutaneous implantation of B16F10 cells into mice with hemophilia A gave rise to primary tumors in an exponential growth pattern similar to that observed in non-hemophilic mice. Although TF expression by B16F10 cells may promote thrombin-dependent metastasis in mice with hemophilia A, amplification of coagulation by host FVIII appears to be necessary for maximum lung seeding. [source] Antithrombotic properties of a direct thrombin inhibitor with a prolonged half-life and AT-mediated factor Xa inhibitory activityJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2003G. M. T. Vogel Summary., Rebound thrombin generation after successful thrombolysis might be related to (i) too short-term anticoagulant therapy and to (ii) the inability of heparin derivatives to inhibit clot-bound thrombin. To meet these shortcomings, a compound was synthesized, which consists of a pentasaccharide conjugated to a direct thrombin inhibitor. This compound (Org 42675) has a 10 times longer half-life compared with the original half-life of the direct thrombin inhibitor, while the thrombin inhibitory activity is maintained. An extra advantage of this product is the inhibitory activity on thrombin generation via antithrombin III (AT)-mediated factor (F)Xa inhibition. Org 42675 inhibited in vitro clot-bound thrombin with similar activity to the direct thrombin inhibitor argatroban. In experimental models in rats, Org 42675 showed on a molar base similar antithrombotic activity to unfractionated heparin, was more active than argatroban and was more active than fondaparinux sodium (AT-mediated FXa inhibitor) in arterial thrombosis. Finally, Org 42675 was far more active than the three reference compounds in an experimental thrombolysis model in rabbits. These properties of Org 42675, with its FXa and (clot-bound) thrombin inhibitory activity in combination with its long half-life, make this compound a powerful drug that is likely to be effective in the prevention of re-occlusion after successful thrombolysis in man. [source] The first two Japanese cases of severe type I congenital plasminogen deficiency with ligneous conjunctivitis: Successful treatment with direct thrombin inhibitor and fresh plasma,,AMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2009Takashi Suzuki A 71-year-old woman and her elder sister developed ligneous conjunctivitis after ocular surgery. Laboratory tests demonstrated that the proband and her sister had 6.6% and 8.1% of plasminogen activity, and 1.2 and 1.4 mg/dl of antigen, respectively. Thus, they were diagnosed as having severe type I plasminogen deficiency, for the first time, in Japan. DNA sequencing and PCR-RFLP analyses revealed that these two cases are homozygotes of a novel A-to-G mutation at the obligatory splicing acceptor site in intron-C. Both cases were satisfactorily treated with a direct thrombin inhibitor, topical Argatroban, and topical plasma obtained from their healthy family members. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Latest news and product developmentsPRESCRIBER, Issue 9 2008Article first published online: 21 MAY 200 Dabigatran launched Dabigatran (Pradaxa), an orally active direct thrombin inhibitor, has been introduced for the prophylaxis of venous thromboembolism in patients undergoing elective total hip or knee replacement. Treatment is initiated within four hours of surgery and continued for 10 days after knee replacement and 28-35 days after hip replacement. Dabigatran has been shown to be as effective and well tolerated as enoxaparin (Clexane). The launch was widely publicised in the lay media; the charity Lifeblood claimed it could help prevent tens of thousands of deaths. NICE is preparing a technology appraisal of the new agent but it has not announced a publication date. Loop diuretics may increase bone loss Continuous use of a loop diuretic appears to double the rate of bone loss in men compared with nonusers, an observational study suggests (Ann Intern Med 2008;168: 735-40). Up to five years' follow-up of 3269 men aged over 65 revealed that the mean rate of bone loss in the hip among those who did not use a loop diuretic was 0.33 per cent compared with 0.78 per cent among users and 0.58 per cent in those who had intermittently used a loop diuretic. Use of these agents should be included as a risk factor for fractures, the authors suggest. Rosuvastatin not for heart failure patients? Prescribers should pause before using rosuvastatin (Crestor). in patients with heart failure and ischaemic heart disease, the National Prescribing Centre (NPC). says. Commenting on the CORONA trial (N Engl J Med 2008; published online 5 Nov 2007; 10.1056/NEJMoa 0706201)., which found no reduction in cardiovascular events or mortality in older patients with systolic heart failure despite a reduction in LDL-C, the NPC says GPs should still consider evidence-based statins such as simvastatin in this patient group. The reason for the outcome of CORONA is unclear but the NPC points out that not all statins affect mortality equally. Rimonabant CV benefits sustained Two-year follow-up of the RIO-Europe trial has shown that the benefits of rimonabant (Acomplia). on weight loss and cardiovascular risk factors are sustained with continuing treatment (Eur Heart J 2008; published online doi: 10.1093/ eurheartj/ehn076). In addition to a dietary deficit of 600kcal per day, rimonabant 20mg per day achieved greater mean weight loss (5.5 vs 1.2kg). and improvements in waist circumference, HDL-cholesterol, triglycerides, fasting glucose and insulin levels, insulin resistance, and metabolic syndrome prevalence compared with placebo. Many patients discontinued treatment (placebo 42 per cent, rimonabant 45 per cent). but, although psychiatric events were more common with rimonabant during the first year, there was little difference in patients remaining in the second year. Early glatiramer cuts MS progression risk Early treatment with glatiramer acetate (Copaxone). appears to reduce the risk of progression to multiple sclerosis (MS), according to a study presented at the 60th Annual Meeting of the American Academy of Neurology in Chicago. Interim analysis of the PreCISE trial showed that, in patients with a single episode and MRI suggestive of MS, glatiramer was associated with a lower incidence of progression to a second episode of MS compared with placebo (25 vs 43 per cent). The placebo arm of the trial has now been stopped. NRT before quitting Beginning nicotine replacement therapy (NRT) before stopping smoking may double the six-month success rate compared with beginning treatment on the scheduled quit day, a meta-analysis suggests (Addiction 2008;103: 557-63). The analysis of four trials involving 755 participants found that starting NRT two to four weeks before the agreed quit date was twice as likely as the conventional strategy to achieve abstinence after six weeks and six months. Copyright © 2008 Wiley Interface Ltd [source] Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblastsARTHRITIS & RHEUMATISM, Issue 11 2009Galina S. Bogatkevich Objective Myofibroblasts are the principal mesenchymal cells responsible for tissue remodeling, collagen deposition, and the restrictive nature of lung parenchyma associated with pulmonary fibrosis. We previously reported that thrombin activates protease-activated receptor 1 (PAR-1) and induces a myofibroblast phenotype in normal lung fibroblasts resembling the phenotype of scleroderma lung myofibroblasts. We undertook this study to investigate whether a selective direct thrombin inhibitor, dabigatran, interferes with signal transduction in human lung fibroblasts induced by thrombin and mediated via PAR-1. Methods Lung fibroblast proliferation was analyzed using the Quick Cell Proliferation Assay. Expression and organization of ,-smooth muscle actin (,-SMA) was studied by immunofluorescence staining and immunoblotting. Contractile activity of lung fibroblasts was measured by a collagen gel contraction assay. Connective tissue growth factor (CTGF) and type I collagen expression was analyzed on Western blots. Results Dabigatran, at concentrations of 50,1,000 ng/ml, inhibited thrombin-induced cell proliferation, ,-SMA expression and organization, and the production of collagen and CTGF in normal lung fibroblasts. Moreover, when treated with dabigatran (1 ,g/ml), scleroderma lung myofibroblasts produced 6-fold less ,-SMA, 3-fold less CTGF, and 2-fold less type I collagen compared with untreated cells. Conclusion Dabigatran restrains important profibrotic events in lung fibroblasts and warrants study as a potential antifibrotic drug for the treatment of fibrosing lung diseases such as scleroderma lung disease and idiopathic pulmonary fibrosis. [source] The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007Joachim 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] Current concepts for the prevention of venous thromboembolismEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2005P. Bramlage Abstract Venous thromboembolism (VTE) is a major cause of morbidity and mortality worldwide and the annual incidence of VTE is 1 per 1000. The individual risk for venous thromboembolism may be substantially higher and is determined by expositional and dispositional factors. Unfractionated heparin and warfarin have been the mainstays for the prevention of VTE until the early 1980s. Bleeding complications and side effects limited the use of these agents and subsequently low molecular weight heparins (LMWH) were introduced into clinical practice. These are most commonly used for the prophylaxis and treatment of VTE today. In the last decade, the pace of development of further anticoagulants has accelerated with the introduction of new treatment regimens and new substances. In this context, novel drugs directed against clotting factor Xa (such as fondaparinux) and direct thrombin inhibitors (such as melagatran/ximelagatran) have been developed. Fondaparinux shows a favourable efficacy/safety profile and has been documented to be cost-effective compared to enoxaparin in the US and the UK. [source] Atrial fibrillation: insights from clinical trials and novel treatment optionsJOURNAL OF INTERNAL MEDICINE, Issue 6 2007Y. Blaauw Abstract., Blaauw Y, Crijns HJGM (University Hospital Maastricht, Maastricht, The Netherlands). Atrial fibrillation: insights from clinical trials and novel treatment options (Review). J Intern Med 2007; 262: 593,614. Atrial fibrillation (AF) is the most common encountered sustained arrhythmia in clinical practice. The last decade the result of large ,rate' versus ,rhythm' control trials have been published that have changed the current day practise of AF treatment. It has become clear that rate control is at least equally effective as a rhythm control strategy in ameliorating morbidity as well as mortality. Moreover, in each individual patient the risk of thromboembolic events should be assessed and antithrombotic treatment be initiated. There have also been great advances in understanding the mechanisms of AF. Experimental studies showed that as a result of electrical and structural remodelling of the atria, ,AF begets AF'. Pharmacological prevention of atrial electrical remodelling has been troublesome, but it seems that blockers of the renin angiotensin system, and perhaps statins, may reduce atrial structural remodelling by preventing atrial fibrosis. Clinical studies demonstrated that the pulmonary veins exhibit foci that can act as initiator and perpetuator of the arrhythmia. Isolation of the pulmonary veins using radiofrequency catheter ablation usually abolishes AF. The most promising advances in the pharmacological treatment of AF include atrial specific antiarrhythmic drugs and direct thrombin inhibitors. In the present review we will describe the results of recent experimental studies, discuss the latest clinical trials, and we will focus on novel treatment modalities. [source] Factor Xa or thrombin: is factor Xa a better target?JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2007J. ANSELL Summary., Existing vitamin K antagonists (VKAs) have drawbacks that limit their effectiveness, safety, and overall frequency of use. Oral anticoagulants in development with targeted action against individual coagulation factors, specifically direct factor (F) Xa and IIa inhibitors, appear to have pharmacokinetic and pharmacodynamic properties that overcome the limitations of the VKAs. Based on the theory of how coagulation factors interact, on the results of in vitro studies, and on clinical outcomes, there is accumulating evidence that FXa may represent a better target for inhibition than FIIa. This is based on an understanding of the amplified nature of coagulation factor interactions and fibrin formation, the need for smaller doses of an anticoagulant to block coagulation progression earlier in the sequence of reactions, the evidence for incomplete suppression of thrombin generation with direct thrombin inhibitors, evidence for rebound hypercoagulability with thrombin inhibitors, and clinical results with the indirect, parenteral, FXa inhibitor (fondaparinux), as well as early phase II results of new oral Xa and IIa inhibitors compared with enoxaparin. The latter studies, although not comparative, provide some evidence for the effectiveness and safety of Xa inhibitors at a range of doses not seen with the direct IIa inhibitors. [source] Laboratory tests for protein C deficiency,AMERICAN JOURNAL OF HEMATOLOGY, Issue 6 2010Bernard Khor Hereditary protein C deficiency is a hypercoagulable state associated with an increased risk for venous thrombosis. The recommended initial test for protein C is an activity (functional) assay, which may be clotting time based or chromogenic. The advantages and disadvantages of the various testing options are presented. The causes of acquired protein C deficiency are much more common than hereditary deficiency. Therefore, this article describes the appropriate steps to take when protein C activity is low, to confirm or exclude a hereditary deficiency. The causes of falsely normal results are also described, including lupus anticoagulants and direct thrombin inhibitors. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] Laboratory monitoring of new anticoagulants,AMERICAN JOURNAL OF HEMATOLOGY, Issue 3 2010Donna D. Castellone Maintaining a balance between bleeding and clotting has always been a challenge in treating coagulation disorders. A perturbation in that balance can be associated with substantial morbidity and mortality. As a result, anticoagulant monitoring is extremely important, and inappropriate testing may lead to complications. There are now a variety of new anticoagulant drugs in clinical use including several direct thrombin inhibitors (DTIs), such as argatroban, bivalirudin, and hirudin, as well as a Factor Xa inhibitor, fondaparinux. There are pitfalls associated with some of the currently used laboratory monitoring tests, and newer alternative laboratory monitoring tests have been investigated (Walenga and Hoppensteadt, Semin Thromb Hemost 2004;30:683,695). In addition, laboratory testing can assist with transitioning patients from DTI to warfarin therapy. Am. J. Hematol. 2010. © 2009 Wiley-Liss, Inc. [source] Evolution of Anticoagulant and Antiplatelet Therapy: Benefits and Risks of Contemporary Pharmacologic Agents and Their Implications for Myonecrosis and Bleeding in Percutaneous Coronary InterventionCLINICAL CARDIOLOGY, Issue S2 2007Hector 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] | ||||||||||||||||||||||