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Direct-thrombin inhibitors

Hayden N Box, Sean Shahrestani, Michael H Huo
Venous thromboembolic disease (VTED) is a major cause of morbidity and mortality after total knee arthroplasty (TKA). Current VTED prophylaxis protocols consist of early mobilization, mechanical compression devices, and pharmacologic agents. Venous phasic flow-regulated below-knee devices are generally favored, but the optimal duration and method of mechanical prophylaxis is unknown. Risk stratification models have been developed to guide pharmacologic prophylaxis. For patients with standard VTED risk profile, aspirin has become increasingly popular...
March 7, 2018: Journal of Knee Surgery
José Francisco Kerr Saraiva
Atrial fibrillation (AF) is an established risk factor for a first or recurrent stroke. Despite proven efficacy in preventing stroke in patients with AF, warfarin is underused, partly due to safety concerns. Recent randomized trials have shown that non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran (a direct thrombin inhibitor) and apixaban, edoxaban, and rivaroxaban (factor Xa inhibitors) are not only non-inferior or superior to warfarin but also demonstrate a decreased risk of cerebrovascular bleeding among patients with AF and moderate to high risk of stroke...
February 27, 2018: Cardiology and Therapy
Jackie Pratt, Philip Crispin
OBJECTIVES: To evaluate the dilute Russell viper venom time (DRVVT) for the detection of direct-acting oral anticoagulants (DOACs) and to investigate the effect of DOACS on coagulation assays. METHODS: Patients on DOACs and controls had plasma levels determined by an anti-Xa assay and dilute thrombin clotting time. Levels were correlated with the DRVVT as well as thrombin clotting time (TCT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, protein C, protein S and antithrombin levels...
February 27, 2018: European Journal of Haematology
Marcello Di Nisio, Iris M Wichers, Saskia Middeldorp
BACKGROUND: The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the third update of a review first published in 2007. OBJECTIVES: To assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications...
February 25, 2018: Cochrane Database of Systematic Reviews
Michael Schuliga, Christopher Grainge, Glen Westall, Darryl Knight
Fibrosis causes irreversible damage to lung structure and function in restrictive lung diseases such as idiopathic pulmonary fibrosis (IPF). Extravascular coagulation involving fibrin formation in the intra-alveolar compartment is postulated to have a pivotal role in the development of pulmonary fibrosis, serving as a provisional matrix for migrating fibroblasts. Furthermore, proteases of the coagulation and plasminogen activation (plasminergic) systems that form and breakdown fibrin respectively directly contribute to pulmonary fibrosis...
February 20, 2018: International Journal of Biochemistry & Cell Biology
Katherine L Zaleski, James A DiNardo, Viviane G Nasr
Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ), a direct thrombin inhibitor, has found increasing utilization as a heparin alternative in the pediatric population, most commonly for the treatment of thrombosis secondary to heparin-induced thrombocytopenia. Due to the relative rarity of heparin-induced thrombocytopenia as well as the lack of Food and Drug Administration-approved indications in this age group, much of what is known regarding the pharmacokinetics and pharmacodynamics of bivalirudin in this population has been extrapolated from adult data...
February 14, 2018: Anesthesia and Analgesia
Daniel K Afosah, Stephen Verespy, Rami A Al-Horani, Rio S Boothello, Rajesh Karuturi, Umesh R Desai
Despite the development of promising direct oral anticoagulants, which are all orthosteric inhibitors, a sizable number of patients suffer from bleeding complications. We have hypothesized that allosterism based on the heparin-binding exosites presents a major opportunity to induce sub-maximal inhibition of coagulation proteases, thereby avoiding/reducing bleeding risk. We present the design of a group of sulfated benzofuran dimers that display heparin-binding site-dependent partial allosteric inhibition of thrombin against fibrinogen (ΔY = 55-75%), the first time that a small molecule (MW < 800) has been found to thwart macromolecular cleavage by a monomeric protease in a controlled manner...
February 3, 2018: Bioorganic & Medicinal Chemistry Letters
Martin Beiderlinden, Patrick Werner, Astrid Bahlmann, Johann Kemper, Tobias Brezina, Maximilian Schäfer, Klaus Görlinger, Holger Seidel, Peter Kienbaum, Tanja A Treschan
BACKGROUND: Argatroban or lepirudin anticoagulation therapy in patients with heparin induced thrombocytopenia (HIT) or HIT suspect is typically monitored using the activated partial thromboplastin time (aPTT). Although aPTT correlates well with plasma levels of argatroban and lepirudin in healthy volunteers, it might not be the method of choice in critically ill patients. However, in-vivo data is lacking for this patient population. Therefore, we studied in vivo whether ROTEM or global clotting times would provide an alternative for monitoring the anticoagulant intensity effects in critically ill patients...
February 9, 2018: BMC Anesthesiology
Yanyan Liu, Jianjie Fu, Wenxiao Pan, Qiao Xue, Xian Liu, Aiqian Zhang
The studies on the human toxicity of nanoparticles (NPs) are far behind the rapid development of engineered functionalized NPs. Fullerene has been widely used as drug carrier skeleton due to its reported low risk. However, different from other kinds of NPs, fullerene-based NPs (C60 NPs) have been found to have an anticoagulation effect, although the potential target is still unknown. In the study, both experimental and computational methods were adopted to gain mechanistic insight into the modulation of thrombin activity by nine kinds of C60 NPs with diverse surface chemistry properties...
January 2018: Journal of Environmental Sciences (China)
Heiko Rühl, Sara Reda, Jens Müller, Johannes Oldenburg, Bernd Pötzsch
Antithrombin (AT) activity tests are used for diagnosing hereditary AT deficiency, a main genetic determinant of thrombophilia. They are either based on inhibition of thrombin (FIIa) or activated factor X (FXa). FXa-based assays have been suggested to be preferable to FIIa-based assays due to their higher sensitivity for certain AT deficiency causing mutations. To assess the performance of these two methods in a real-world scenario, 745 consecutively collected samples from patients referred to our institute during a 3-month period for thrombophilia testing were analysed...
February 2018: Thrombosis and Haemostasis
Nicolas E Nunez-Navarro, Fabian M Santana, Loreto P Parra, Flavia C Zacconi
Factor Xa (FXa) plays a key role in haemostasis, it is a central part of the blood coagulation cascade which catalyzes the production of thrombin and leads to clot formation and wound closure. Therefore, FXa is an attractive target for the development of new anticoagulant agents. In this review, we will first describe the molecular features of this fundamental protein in order to understand its mechanism of action, an essential background for the design of novel inhibitors by means of synthetic organic chemistry or using peptides obtained from recombinant methodologies...
January 25, 2018: Current Medicinal Chemistry
Kathrin Feldmann, Maria Grandoch, Christina Kohlmorgen, Birte Valentin, Stephen Gerfer, Nadine Nagy, Anke Claudia Fender, Sonja Hartwig, Stefan Lehr, Jens Walter Fischer
No abstract text is available yet for this article.
August 2017: Atherosclerosis
Yun Gi Kim, Jong-Il Choi, Mi-Na Kim, Dong-Hyuk Cho, Suk-Kyu Oh, Hyungdon Kook, Hee-Soon Park, Kwang No Lee, Yong-Soo Baek, Seung-Young Roh, Jaemin Shim, Seong-Mi Park, Wan Joo Shim, Young-Hoon Kim
Spontaneous echo-contrast (SEC) and thrombus observed in trans-esophageal echocardiography (TEE) is known as a strong surrogate marker for future risk of ischemic stroke in patients with atrial fibrillation (AF) or atrial flutter (AFL). The efficacy of non-vitamin K antagonist oral anticoagulants (NOAC) compared to warfarin to prevent SEC or thrombus in patients with AF or AFL is currently unknown. AF or AFL patients who underwent direct current cardioversion (DCCV) and pre-DCCV TEE evaluation from January 2014 to October 2016 in a single center were analyzed...
2018: PloS One
Scott G Garland, Christina E DeRemer, Steven M Smith, John G Gums
OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of the factor Xa (FXa) inhibitor betrixaban for extended-duration prophylaxis of acute medically ill patients with venous thromboembolism (VTE) risk factors. DATA SOURCES: A MEDLINE/PubMed (January 1990 to October 2017) search was conducted using the following keywords: betrixaban, PRT054021, FXa inhibitor, novel oral anticoagulant, NOAC, direct oral anticoagulant, DOAC, and target specific oral anticoagulant, TSOAC...
January 1, 2018: Annals of Pharmacotherapy
Taizen Nakase, Junta Moroi, Tatsuya Ishikawa
BACKGROUND: Recently, non-vitamin K antagonist oral anticoagulants such as direct thrombin and direct factor Xa inhibitors have been prescribed for prevention of embolic stroke. While in Japan, argatroban, also a direct thrombin inhibitor, is available for the treatment of atherothrombotic stroke patients. This study aimed to explore whether there is any differences between direct thrombin and direct factor Xa inhibitors regarding the inhibiting effect against thrombogenesis in the clinical setting of acute ischemic stroke...
January 12, 2018: Clinical and Translational Medicine
Minna Voigtlaender, Florian Langer
In patients with solid tumours or haematological malignancies, venous thromboembolism (VTE) is a leading cause of death and significantly contributes to morbidity and healthcare resource utilization. Current practice guidelines recommend long-term anticoagulation with low-molecular-weight heparin (LMWH) as the treatment of choice for cancer-associated VTE, based on clinical trial data showing an overall improved safety and efficacy profile of LMWH compared to vitamin K antagonists. However, several open questions remain, e...
February 2018: VASA. Zeitschrift Für Gefässkrankheiten
Viraj Suvarna
Stroke prevention in atrial fibrillation (AF) has reached an exciting phase with a plethora of newer, potentially more efficacious and safer agents being introduced for physicians to select from. Dabigatran belongs to a class of anticoagulants called direct thrombin inhibitors, while rivaroxaban, apixaban, and edoxaban are direct Factor Xa inhibitors. Purely from a therapeutic endpoint perspective-based on the action of anticoagulants in reducing cardioembolic stroke-in clinical trials, one should look at whether a new anticoagulant in patients with AF prevents ischemic stroke...
October 2017: Journal of the Association of Physicians of India
Upinder Kaur, Sankha Shubhra Chakrabarti, Sukdev Manna, Indrajeet Singh Gambhir
Dabigatran is a newer oral direct thrombin inhibitor approved by the United States Food and Drug Administration and the European Medicines Agency (EMA). The proper dosage of the drug, the potential for adverse drug reactions and the nature of bleeds with use of this drug as with other novel oral anticoagulants (NOACs), in the elderly population are still areas of uncertainty. Despite the existence of a specific antibody, idarucizumab which is an antidote to dabigatran toxicity, management of dabigatran-induced bleeds is an undefined area especially in resource constrained settings...
January 2018: Therapeutic Advances in Drug Safety
M Cini, C Legnani, B Cosmi, S Testa, C Dellanoce, O Paoletti, R Marcucci, D Poli, R Paniccia, V Pengo, A Tripodi, G Palareti
INTRODUCTION: Several specific assays are commercially available to determine dabigatran anticoagulant activity. Aims of this multicenter and multiplatform study were to compare five methods for dabigatran measurement and investigate their performances in the low concentration range. METHODS: Dabigatran levels were analyzed in 295 plasma samples from patients enrolled in the START-Laboratory Register by the following methods using dedicated calibrators and controls: STA-ECA II (Diagnostica Stago), standard and low range Hemoclot Thrombin Inhibitors (Hyphen BioMed), Direct Thrombin Inhibitor Assay (Instrumentation Laboratory), Direct Thrombin Inhibitor Assay (Siemens), Technoclot DTI (Technoclone)...
January 3, 2018: International Journal of Laboratory Hematology
Deborah Siegal, Genmin Lu, Janet M Leeds, Mark Karbarz, Janice Castillo, Vandana Mathur, Athiwat Hutchaleelaha, Uma Sinha, Michael Kitt, Matt McClure, Stanley J Hollenbach, John T Curnutte, Pamela B Conley, Mark Crowther
Direct factor Xa (FXa) inhibitors lack a specific reversal agent for emergencies such as major bleeding or urgent surgery. Andexanet alfa, a modified, catalytically inactive, recombinant human FXa derivative, reverses anticoagulant effect by binding and sequestering FXa inhibitors. This original report of safety and dose-finding, phase 1 and 2 randomized, double-blind, placebo-controlled studies, investigated various doses of andexanet in healthy volunteers. Phase 1 evaluated the safety and pharmacokinetics of andexanet (n = 24) or placebo (n = 8)...
September 26, 2017: Blood Advances
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