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In this phase 1 study, a chemically modified RNA interference therapy designed to target antithrombin was administered to participants with hemophilia A or B. Antithrombin levels decreased and the generation of thrombin increased.

Antithrombin (AT), a glycoprotein, plays a key role in anticoagulation by inhibiting coagulation proteases. It is also the primary mediator of heparin's anticoagulant effect, with heparin binding amplifying AT activity up to 1000-fold. Deficiency in AT contributes to a hypercoagulable state associated with adverse clinical outcomes, including morbidity and mortality. Hereditary AT deficiency (hATD) is a rare autosomal dominant disorder caused by mutations in the gene encoding AT ( SERPINC1 ), resulting in decreased AT levels or activity. As the most thrombogenic inherited thrombophilia, hATD confers a lifetime venous thromboembolism (VTE) risk of up to 85%, with similar annual VTE incidence in both pediatric and adult patients. Management of hATD often includes AT concentrate (ATc) therapy in high-risk clinical settings. Although ATc has a long history of use in adults, pediatric use has been largely off-label and guided by extrapolation from adult data. In August 2025, the U.S. Food and Drug Administration (FDA) approved an expanded indication for antithrombin III concentrate (human) to include pediatric patients with hATD, representing the first product specifically approved for this population. In light of this recent shift in the treatment landscape, this review provides a timely synthesis of the current clinical understanding and evidence-informed strategies to optimize AT therapy in the management of pediatric hATD.

Vitamin K antagonists are the only oral anticoagulants approved for long-term treatment of patients with a cardiac valve replacement. This study aims to test a new dosing regimen for dabigatran etexilate in patients with a mechanical bileaflet valve. Patients aged ≥18 years and ≤75 years, either undergoing implantation of a mechanical bileaflet valve (aortic or mitral or both) during the current hospital stay or having undergone implantation a mitral bileaflet valve >3 months before randomization, will be randomized between dabigatran etexilate or warfarin (in a ratio of 2:1) in an open-label design. Initial doses of dabigatran will be based on the estimated creatinine clearance, and the doses will be adjusted based on measuring trough dabigatran plasma levels to achieve levels ≥50 ng/mL at steady state. Doses will range between 150 mg twice a day and 300 mg twice a day. Warfarin management and target international normalized ratio will be according to current practice guidelines at the discretion of the treating physicians. The plan is to treat 270 patients with dabigatran etexilate for a total study population of approximately 405 patients. Clinical efficacy and safety outcomes will be analyzed in an exploratory manner. RE-ALIGN is the first study to test an alternative to warfarin in patients with mechanical heart valves. A definitive phase III study will be planned based on the results of this study.

The Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) programme was designed to assess the comparative safety and effectiveness of radial versus femoral access and of bivalirudin versus unfractionated heparin with optional glycoprotein IIb/IIIa inhibitors in patients with the whole spectrum of acute coronary syndrome undergoing invasive management. Here we describe the prespecified final 1-year outcomes of the entire programme. MATRIX was a programme of three nested, randomised, multicentre, open-label, superiority trials in patients with acute coronary syndrome in 78 hospitals in Italy, the Netherlands, Spain, and Sweden. Patients with ST-elevation myocardial infarction were simultaneously randomly assigned (1:1) before coronary angiography to radial or femoral access and to bivalirudin, with or without post-percutaneous coronary intervention infusion or unfractionated heparin (one-step inclusion). Patients with non-ST-elevation acute coronary syndrome were randomly assigned (1:1) before coronary angiography to radial or femoral access and, only if deemed eligible to percutaneous coronary intervention after angiography (two-step inclusion), entered the antithrombin type and treatment duration programmes. Randomisation sequences were computer generated, blocked, and stratified by intended new or current use of P2Y12 inhibitor (clopidogrel vs ticagrelor or prasugrel), and acute coronary syndrome type (ST-elevation myocardial infarction, troponin-positive, or troponin-negative non-ST-elevation acute coronary syndrome). Bivalirudin was given as a bolus of 0·75 mg/kg, followed immediately by an infusion of 1·75 mg/kg per h until completion of percutaneous coronary intervention. Heparin was given at 70–100 units per kg in patients not receiving glycoprotein IIb/IIIa inhibitors, and at 50–70 units per kg in patients receiving glycoprotein IIb/IIIa inhibitors. Clinical follow-up was done at 30 days and 1 year. Co-primary outcomes for MATRIX access and MATRIX antithrombin type were major adverse cardiovascular events, defined as the composite of all-cause mortality, myocardial infarction, or stroke up to 30 days; and net adverse clinical events, defined as the composite of non-coronary artery bypass graft-related major bleeding, or major adverse cardiovascular events up to 30 days. The primary outcome for MATRIX treatment duration was the composite of urgent target vessel revascularisation, definite stent thrombosis, or net adverse clinical events up to 30 days. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01433627. Between Oct 11, 2011, and Nov 7, 2014, we randomly assigned 8404 patients to receive radial (4197 patients) or femoral (4207 patients) access. Of these 8404 patients, 7213 were included in the MATRIX antithrombin type study and were randomly assigned to bivalirudin (3610 patients) or heparin (3603 patients). Patients assigned to bivalirudin were included in the MATRIX treatment duration study, and were randomly assigned to post-procedure infusion (1799 patients) or no post-procedure infusion (1811 patients). At 1 year, major adverse cardiovascular events did not differ between patients assigned to radial access compared with those assigned to femoral access (14·2% vs 15·7%; rate ratio 0·89, 95% CI 0·80–1·00; p=0·0526), but net adverse clinical events were fewer with radial than with femoral access (15·2% vs 17·2%; 0·87, 0·78–0·97; p=0·0128). Compared with heparin, bivalirudin was not associated with fewer major adverse cardiovascular (15·8% vs 16·8%; 0·94, 0·83–1·05; p=0·28) or net adverse clinical events (17·0% vs 18·4%; 0·91, 0·81–1·02; p=0·10). The composite of urgent target vessel revascularisation, stent thrombosis, or net adverse clinical events did not differ with or without post-procedure bivalirudin infusion (17·4% vs 17·4%; 0·99, 0·84–1·16; p=0·90). In patients with acute coronary syndrome, radial access was associated with lower rates of net adverse clinical events compared with femoral access, but not major adverse cardiovascular events at 1 year. Bivalirudin with or without post-procedure infusion was not associated with lower rates of major adverse cardiovascular events or net adverse clinical events. Radial access should become the default approach in acute coronary syndrome patients undergoing invasive management. Italian Society of Invasive Cardiology, The Medicines Company, Terumo, amd Canada Research Chairs Programme.

Objectives To determine the incremental net health benefits of dabigatran etexilate 110 mg and 150 mg twice daily and warfarin in patients with non-valvular atrial fibrillation and to estimate the cost effectiveness of dabigatran in the United Kingdom.Design Quantitative benefit-harm and economic analyses using a discrete event simulation model to extrapolate the findings of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study to a lifetime horizon.Setting UK National Health Service.Population Cohorts of 50 000 simulated patients at moderate to high risk of stroke with a mean baseline CHADS2 (Congestive heart failure, Hypertension, Age≥75 years, Diabetes mellitus, previous Stroke/transient ischaemic attack) score of 2.1.Main outcome measures Quality adjusted life years (QALYs) gained and incremental cost per QALY of dabigatran compared with warfarin.Results Compared with warfarin, low dose and high dose dabigatran were associated with positive incremental net benefits of 0.094 (95% central range −0.083 to 0.267) and 0.146 (−0.029 to 0.322) QALYs. Positive incremental net benefits resulted for high dose dabigatran in 94% of simulations versus warfarin and in 76% of those versus low dose dabigatran. In the economic analysis, high dose dabigatran dominated the low dose, had an incremental cost effectiveness ratio of £23 082 (€26 700; $35 800) per QALY gained versus warfarin, and was more cost effective in patients with a baseline CHADS2 score of 3 or above. However, at centres that achieved good control of international normalised ratio, such as those in the UK, dabigatran 150 mg was not cost effective, at £42 386 per QALY gained.Conclusions This analysis supports regulatory decisions that dabigatran offers a positive benefit to harm ratio when compared with warfarin. However, no subgroup for which dabigatran 110 mg offered any clinical or economic advantage over 150 mg was identified. High dose dabigatran will be cost effective only forpatients at increased risk of stroke or for whom international normalised ratio is likely to be less well controlled.

Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1+/− rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1+/− rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1+/− rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury.

There is a clinical need for safe new oral anticoagulants. The safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939--a novel, oral, direct Factor Xa (FXa) inhibitor--were investigated in this single-center, placebo-controlled, single-blind, parallel-group, multiple-dose escalation study. Healthy male subjects (aged 20-45 years, body mass index 18.6-31.4 kg/m(2)) received oral BAY 59-7939 (n=8 per dose regimen) or placebo (n=4 per dose regimen) on days 0 and 3-7. Dosing regimens were 5 mg once, twice (bid), or three times daily, and 10 mg, 20 mg, or 30 mg bid. There were no clinically relevant changes in bleeding time or other safety variables across all doses and regimens. There was no dose-related increase in the frequency or severity of adverse events with BAY 59-7939. Maximum inhibition of FXa activity occurred after approximately 3 h, and inhibition was maintained for at least 12 h for all doses. Prothrombin time, activated partial thromboplastin time, and HepTest were prolonged to a similar extent to inhibition of FXa activity for all doses. Dose-proportional pharmacokinetics (AUC(tau, norm) and C(max, norm)) were observed at steady state (day 7). Maximum plasma concentrations were achieved after 3-4 h. The terminal half-life of BAY 59-7939 was 5.7-9.2 h at steady state. There was no relevant accumulation at any dose. BAY 59-7939 was safe and well tolerated across the wide dose range studied, with predictable, dose-proportional pharmacokinetics and pharmacodynamics and no relevant accumulation beyond steady state. These results support further investigation of BAY 59-7939 in phase II clinical trials.

Treatment with antithrombin (AT)-III is indicated for patients with sepsis or hereditary AT deficiency. The purpose of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of 2 AT-III formulations in healthy Korean volunteers to satisfy the regulatory requirements for bioequivalence for marketing purposes. A single-center, single-dose, open-label, randomized, 2-period, 2-sequence crossover study was conducted in healthy Korean volunteers. Blood samples for the drug analysis were collected for up to 216 hours after drug administration. Participants received either the test or reference formulation of AT-III 100 U/kg IV for 20 minutes in the first period and the alternative formulation in the second period. Both the AT-III activity and antigen (Ag) were measured for the analysis of pharmacokinetic properties, and the prothrombin time and the activated partial thromboplastin time were assessed for the analysis of pharmacodynamic properties. Because AT-III is an endogenous compound, the analysis used data corrected from baseline values. The tolerability of the 2 formulations was also assessed based on physical examinations including vital sign measurements, laboratory tests, and 12-lead ECG. Of the 20 subjects enrolled (mean [SD] age, height, and weight, 25.3 [2.3] years, 175.3 [4.5] cm, and 67.4 [6.3] kg, respectively), 19 completed both treatment periods; 1 subject withdrew consent for personal reasons. The observed mean (SD) Cmax, AUClast, and AUC0–∞ of AT-III activity were, respectively, 279.24% (35.92), 14,364.10 (2325.25) %·h, and 17,526.38 (3150.81) %·h with the test formulation and 249.75% (31.96), 12,962.95 (1897.52) %·h, and 15,957.67 (3189.21) %·h with the reference formulation. The observed mean (SD) Cmax, AUClast, and AUC0–∞ of AT-III Ag were 62.58 (5.66) mg/dL, 3051.94 (401.87) mg/dL·h, and 3639.80 (726.01) mg/dL·h, respectively, with the test formulation and 58.63 (5.27) mg/dL, 2805.08 (272.38) mg/dL·h, and 3340.00 (428.46) mg/dL·h with the reference formulation. The geometric mean ratios (90% CI) of the log-transformed data for AT-III activity between the 2 formulations were 1.11494 (1.08994–1.14053) for Cmax, 1.11305 (1.05435–1.17503) for AUClast, and 1.11527 (1.03754–1.19889) for AUC0–∞; corresponding values for AT-III Ag were 1.08802 (1.06258–1.11405), 1.10905 (1.05804–1.16242), and 1.11460 (1.02058–1.21726). During the study period, 8 adverse events were reported, and all were transient, mild, and resolved completely during the treatment period. The results of the present study showed that these 2 AT-III formulations met the regulatory criteria for pharmacokinetic bioequivalence with respect to AT-III activity and Ag in these healthy Korean subjects. ClinicalTrials.gov identifier: NCT00846274.

In a randomized trial, dabigatran (110 mg per day or 150 mg per day) was no more effective than aspirin (100 mg per day) in preventing a second stroke after an embolic stroke of undetermined source. The occurrence of major bleeding was similar in the two treatment groups.

Antithrombin (AT) deficiency is a rare hereditary thrombophilia with a mean prevalence of 0.02 % in the general population, associated with a more than ten-fold increased risk of venous thromboembolism (VTE). Within this multicenter retrospective clinical analysis, female patients with inherited AT deficiency were evaluated concerning the type of inheritance and extent of AT deficiency, medical treatment during pregnancy and postpartally, VTE risk as well as maternal and neonatal outcome. Statistical analysis was performed with SPPS for Windows (19.0). A total of 18 pregnancies in 7 patients were evaluated, including 11 healthy newborns ≥37th gestational weeks (gw), one small for gestational age premature infant (25th gw), two late-pregnancy losses (21st and 28th gw) and four early miscarriages. Despite low molecular weight heparin (LMWH) administration, three VTE occurred during pregnancy and one postpartally. Several adverse pregnancy outcomes occurred including fetal and neonatal death, as well as severe maternal neurologic disorders occurred. Patients with substitution of AT during pregnancy in addition to LMWH showed the best maternal and neonatal outcome. Close monitoring with appropriate anticoagulant treatment including surveillance of AT levels might help to optimize maternal and fetal outcome in patients with hereditary AT deficiency.