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You searched for subject:(direct thrombin inhibitors). Showing records 1 – 3 of 3 total matches.

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McMaster University

1. Yeh, Calvin Hsiung. FUNCTIONAL STUDIES WITH DIRECT ORAL ANTICOAGULANTS: INVESTIGATION OF THE REGULATION OF KEY BLOOD COAGULATION PROTEASES.

Degree: PhD, 2016, McMaster University

Intrinsic structural and conformational mechanisms regulate the functional specificity of the coagulation system. The study of these structure-function relationships is important for understanding the strategies used in the management of clinical thrombosis. Previous studies have shown that the central enzyme in clotting, thrombin, is sequestered inside of a clot, and protected from the natural downregulator antithrombin (AT). This is problematic for anticoagulants like heparin which depend on AT. Subsequently, it was found that the key upstream propagator of thrombin, the prothrombinase enzyme complex, is also resistant to the AT-heparin. Our data show that further upstream of prothrombinase, the intrinsic tenase is only moderately protected, while there is no protection at the level of the initiator complex, extrinsic tenase. This protection phenomenon possibly reflects steric and allosteric mechanisms that ensure maximal activation of the coagulation system once a threshold stimulus is achieved. These mechanisms likely evolved as a result of conformational rearrangement, as evidenced by the proteolytic activation of thrombin activity following proteolysis of prothrombin. Indeed, subtle differences in the structural interaction of ligands with the active site can lead to substantial differences in enzyme activity. The binding of rivaroxaban and apixaban to factor Xa is nearly identical; both interact with the active site with comparable affinity. Despite this, a 3-fold faster rate of the rivaroxaban on-rate yields significantly greater prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT), global tests of coagulation. These small differences in ligand interaction also have allosteric consequences. Structural differences between the direct thrombin inhibitors dabigatran and argatroban yield divergent exosite-mediated thrombin binding to physiologic ligands like yA-fibrin, y'-fibrin, factor Va, and factor VIII, interactions that govern clot-mediated protection from AT inhibition, and the various functions of thrombin. These divergent effects were robust and ligand-dependent, suggesting conserved energetic scaffolds within the thrombin molecule that govern allosteric changes throughout the molecule. Because proteolysis of prothrombin yields significant allosteric and structural rearrangement that capacitates the active site for substrate recognition amd catalytic ability, we investigated the role of Ser195, a key residue in the thrombin catalytic triad in also regulating thrombin allostery. Site directed mutagenesis of Ser195 to Ala yielded a significant increase in the flexibility of the entire thrombin molecule, as evidenced by increased potency of dabigatran and argatroban in terms of their capacity to modulate exosite binding through the active site, and increased interexosite cooperative and competitive allostery. Together, these studies represent an advance in our understanding of the consequences of both small molecule ligation of coagulation proteases, as well as the… Advisors/Committee Members: Weitz, Jeffrey I., Biochemistry and Biomedical Sciences.

Subjects/Keywords: Coagulation; Proteases; Enzyme kinetics; Direct oral inhibitors; Dabigatran; Argatroban; Thrombin; Heparin; Factor Xa; Prothrombinase

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Yeh, C. H. (2016). FUNCTIONAL STUDIES WITH DIRECT ORAL ANTICOAGULANTS: INVESTIGATION OF THE REGULATION OF KEY BLOOD COAGULATION PROTEASES. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/19502

Chicago Manual of Style (16th Edition):

Yeh, Calvin Hsiung. “FUNCTIONAL STUDIES WITH DIRECT ORAL ANTICOAGULANTS: INVESTIGATION OF THE REGULATION OF KEY BLOOD COAGULATION PROTEASES.” 2016. Doctoral Dissertation, McMaster University. Accessed March 05, 2021. http://hdl.handle.net/11375/19502.

MLA Handbook (7th Edition):

Yeh, Calvin Hsiung. “FUNCTIONAL STUDIES WITH DIRECT ORAL ANTICOAGULANTS: INVESTIGATION OF THE REGULATION OF KEY BLOOD COAGULATION PROTEASES.” 2016. Web. 05 Mar 2021.

Vancouver:

Yeh CH. FUNCTIONAL STUDIES WITH DIRECT ORAL ANTICOAGULANTS: INVESTIGATION OF THE REGULATION OF KEY BLOOD COAGULATION PROTEASES. [Internet] [Doctoral dissertation]. McMaster University; 2016. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/11375/19502.

Council of Science Editors:

Yeh CH. FUNCTIONAL STUDIES WITH DIRECT ORAL ANTICOAGULANTS: INVESTIGATION OF THE REGULATION OF KEY BLOOD COAGULATION PROTEASES. [Doctoral Dissertation]. McMaster University; 2016. Available from: http://hdl.handle.net/11375/19502


University of Illinois – Chicago

2. Patel, Vardhaman. Direct Thrombin Inhibitors: Use and Consequences in Patients with Heparin-Induced Thrombocytopenia.

Degree: 2015, University of Illinois – Chicago

Heparin-induced thrombocytopenia (HIT) is an immunologic response to heparin exposure that may lead to thrombosis. Argatroban and bivalirudin are two commonly used direct thrombin inhibitors (DTIs) for the prevention of thrombosis in patients with HIT. However, DTIs may lead to major bleeding events. Data on the use and consequences of DTIs is limited. Of note, patients with suspected HIT are of interest in the thesis, as current guidelines recommend the initiation of DTI treatment at the time of clinical suspicion of HIT. This thesis focused on the identification of suspected HIT, and the use and consequences of direct thrombin inhibitors (DTI) for the treatment of suspected HIT. First, algorithms based on diagnostic codes, medications and diagnostic tests were developed and validated to identify patients with suspected HIT. An algorithm based only on the timing of medication and diagnostic tests was recommended for the identification of suspected HIT from claims data, as it was observed to have the highest positive predictive value and sensitivity. Second, the rates of thrombosis, major bleeding, amputation and mortality were compared between argatroban-treated and bivalirudin-treated patients using administrative claims data obtained from the University HealthSystem Consortium. The difference in the likelihood of thrombosis, amputation and mortality between the two DTI groups was not statistically significant. However, bivalirudin-treated patients were more likely to experience major bleeding than argatroban-treated patients. Third, the use of bivalirudin for the treatment of suspected HIT (off-label use) increased from one-third to half of DTI-treated patients from 2010 to 2012. Patients treated by surgeons or specialists were more likely to receive off-label bivalirudin compared to patients treated by primary care. In addition, hepatic impairment and skin infection increased the odds of patients to receive bivalirudin over argatroban. In conclusion, the off-label use of bivalirudin should be scrutinized for medical necessity due to the higher risk of bleeding than argatroban, except in patients with hepatic impairment. Advisors/Committee Members: Walton, Surrey M. (advisor), Schumock, Glen T. (committee member), Lee, Todd A. (committee member), Galanter, William L. (committee member), Nutescu, Edith A. (committee member), Hohmann, Samuel F. (committee member).

Subjects/Keywords: 1; comparative effectiveness; 2; direct thrombin inhibitors; 3; argatroban; 4; bivalirudin; 5; thrombosis; 6; major bleeding; 7; safety; 8; off-label; 9; algorithms; 10; validity

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Patel, V. (2015). Direct Thrombin Inhibitors: Use and Consequences in Patients with Heparin-Induced Thrombocytopenia. (Thesis). University of Illinois – Chicago. Retrieved from http://hdl.handle.net/10027/19794

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Patel, Vardhaman. “Direct Thrombin Inhibitors: Use and Consequences in Patients with Heparin-Induced Thrombocytopenia.” 2015. Thesis, University of Illinois – Chicago. Accessed March 05, 2021. http://hdl.handle.net/10027/19794.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Patel, Vardhaman. “Direct Thrombin Inhibitors: Use and Consequences in Patients with Heparin-Induced Thrombocytopenia.” 2015. Web. 05 Mar 2021.

Vancouver:

Patel V. Direct Thrombin Inhibitors: Use and Consequences in Patients with Heparin-Induced Thrombocytopenia. [Internet] [Thesis]. University of Illinois – Chicago; 2015. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10027/19794.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Patel V. Direct Thrombin Inhibitors: Use and Consequences in Patients with Heparin-Induced Thrombocytopenia. [Thesis]. University of Illinois – Chicago; 2015. Available from: http://hdl.handle.net/10027/19794

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation


Virginia Commonwealth University

3. Verghese, Jenson. SYNTHESIS AND BIOCHEMICAL STUDIES ON SULFATED MONOMERS OF LOW MOLECULAR WEIGHT LIGNINS.

Degree: MS, Medicinal Chemistry, 2009, Virginia Commonwealth University

Anticoagulants are used as the first line therapy for management and prevention of thrombotic disorders. Thrombin and factor Xa have been the prime targets for regulation of the coagulation cascade. In this work, a small library of 17 benzofuran derivatives were synthesized and screened against thrombin and factor Xa. The derivatives that displayed inhibitory potential were docked on the exosite-II of factor Xa using a docking protocol that was developed in our research group. These compounds were based on the β-5 structural unit found in the oligomer -'CDSO3‘, which was prepared in our lab and was found to inhibit both thrombin and factor Xa by an exosite-II mediated allosteric disruption of the catalytic triad.The results revealed that these β-5 like derivatives are inhibitory against thrombin and factor Xa, although their potency is weak. Thrombin and factor Xa appear to recognize different structural features suggesting a significant selectivity in recognition. Furthermore, a slight preference for the benzofuran scaffold was observed with factor Xa. Probing the mechanism of inhibition using Michaelis-Menten kinetics reveal that these compounds display uncompetitive inhibition of these proteases and the mechanism of inhibition is allosteric. Docking of these compounds on factor Xa were done using GOLD (Genetic algorithm for ligand docking) and the results, explain the observed inhibition profile. The computed docked poses also give an idea of the residues on the exosite-II of factor Xa critical for inhibition. The molecules studied here are radically different in terms of structure and mechanism of inhibition from any other ligand described in literature. This represents an opportunity to discover novel molecules with a possibly different pharmacological and toxicological profile. Advisors/Committee Members: Umesh Desai.

Subjects/Keywords: Anticoagulants; Medicinal Chemistry; Direct FXa and Thrombin Inhibitors; Chemicals and Drugs; Medicine and Health Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Verghese, J. (2009). SYNTHESIS AND BIOCHEMICAL STUDIES ON SULFATED MONOMERS OF LOW MOLECULAR WEIGHT LIGNINS. (Thesis). Virginia Commonwealth University. Retrieved from https://doi.org/10.25772/JW8N-J921 ; https://scholarscompass.vcu.edu/etd/1868

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Verghese, Jenson. “SYNTHESIS AND BIOCHEMICAL STUDIES ON SULFATED MONOMERS OF LOW MOLECULAR WEIGHT LIGNINS.” 2009. Thesis, Virginia Commonwealth University. Accessed March 05, 2021. https://doi.org/10.25772/JW8N-J921 ; https://scholarscompass.vcu.edu/etd/1868.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Verghese, Jenson. “SYNTHESIS AND BIOCHEMICAL STUDIES ON SULFATED MONOMERS OF LOW MOLECULAR WEIGHT LIGNINS.” 2009. Web. 05 Mar 2021.

Vancouver:

Verghese J. SYNTHESIS AND BIOCHEMICAL STUDIES ON SULFATED MONOMERS OF LOW MOLECULAR WEIGHT LIGNINS. [Internet] [Thesis]. Virginia Commonwealth University; 2009. [cited 2021 Mar 05]. Available from: https://doi.org/10.25772/JW8N-J921 ; https://scholarscompass.vcu.edu/etd/1868.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Verghese J. SYNTHESIS AND BIOCHEMICAL STUDIES ON SULFATED MONOMERS OF LOW MOLECULAR WEIGHT LIGNINS. [Thesis]. Virginia Commonwealth University; 2009. Available from: https://doi.org/10.25772/JW8N-J921 ; https://scholarscompass.vcu.edu/etd/1868

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

.