Inhibition of platelet-surface-bound proteins during coagulation under flow II: Antithrombin and heparin

Miyazawa, Kenji; Fogelson, Aaron L.; Leiderman, Karin

doi:10.1016/j.bpj.2022.10.038

Cited by 9 publications

(2 citation statements)

References 48 publications

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“…A major motivation for the current study is to explore the effectiveness of platelet-surface anticoagulant reactions in the regulation of thrombin generation under flow. To our knowledge, our studies are the first to examine the effect of TFPI- and antithrombin (AT)-mediated inhibition occurring directly on platelet surfaces with modeling (we studied AT inhibition with and without heparin in a companion study ( 32 )). The key new additions to the model in this paper are that 1) FV can be partially activated to FV-h by FXa, 2) FV-h can bind FXa to form active prothrombinase on the platelet surface, 3)

can directly bind to FV-h in the fluid or bound to the platelet surface, and 4)

can bind directly to FXa that is bound to the platelet surface.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of platelet-surface-bound proteins during coagulation under flow I: TFPI

Miyazawa¹,

Fogelson²,

Leiderman³

2023

Biophysical Journal

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can directly bind to FV-h in the fluid or bound to the platelet surface, and 4)

can bind directly to FXa that is bound to the platelet surface.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of platelet-surface-bound proteins during coagulation under flow I: TFPI

Miyazawa¹,

Fogelson²,

Leiderman³

2023

Biophysical Journal

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“…Iduronic acid can also be used for the synthesising of fragment analogues of heparin. Heparin is a common anticoagulant drug which greatly enhances the effect of the inhibitor antithrombin, by improving binding with target enzymes, making this a valuable medical requirement (Miyazawa et al 2023). Iduronic acid can also be produced though chemical synthesis but this is a lengthy and expensive process (Lahaye and Ray 1996;Lahaye 1998;Kraan 2012).…”

Section: Introductionmentioning

confidence: 99%

Biochemical characterisation of a PL24 ulvan lyase from seaweed-associated Vibrio sp. FNV38

Rodrigues,

Jouanneau,

Fernandez-Fuentes

et al. 2023

J Appl Phycol

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Ulvan is a green macroalgal cell wall polysaccharide that has tremendous potential for valorisation due to its unique composition of sulphated rhamnose, glucuronic acid, iduronic acid and xylose. Several potential applications such as production of biofuels, bioplastics and other value-added products necessitate the breakdown of the polysaccharide to oligomers or monomers. Research on ulvan saccharifying enzymes has been continually increasing over the last decade, with the increasing focus on valorisation of seaweed biomass for a biobased economy. Lyases are the first of several enzymes that are involved in saccharifying the polysaccharide and several ulvan lyases have been structurally and biochemically characterised to enable their effective use in the valorisation processes. This study investigates the whole genome of Vibrio sp. FNV38, an ulvan metabolising organism and biochemical characteristics of a PL24 ulvan lyase that it possesses. The genome of Vibrio sp. FNV38 has a diverse CAZy profile with several genes involved in the metabolism of ulvan, cellulose, agar, and alginate. The enzyme exhibits optimal activity at pH 8.5 in 100 mM Tris–HCl buffer and 30 °C. However, its thermal stability is poor with significant loss of activity after 2 h of incubation at temperatures above 25 °C. Breakdown product analysis reveals that the enzyme depolymerised the polysaccharide predominantly to disaccharides and tetrasaccharides.

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Studying the Effects of Oral Contraceptives on Coagulation Using a Mathematical Modeling Approach

Kent,

Leiderman,

Nelson

et al. 2024

Mathematical Modeling for Women’s Health

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The use of oral contraceptives (OCs) is known to increase the risk of thrombosis, but the mechanisms underlying this risk and the determinants of the tests that assess this risk are not fully understood. In this study, we used a mathematical model to study the effects of an OC containing levonorgestrel (lev) on blood clotting. Lev is reported to change the plasma levels of blood clotting factors. The mathematical model used in this study simulates coagulation reactions in a small injury under flow, takes clotting factors as inputs, and outputs time courses of the coagulation enzyme thrombin. To study the effects of lev, we created a virtual patient population with factor levels before and after lev use based on published patient data and conducted simulations to predict thrombin response for each individual virtual patient. After analyzing the simulated thrombin, we found that changes in factor levels due to lev increased the amount and speed of thrombin generation for all virtual patients. This suggested that the factor level changes alone can heighten the prothrombotic state of the model system. We extended the model to include generation of the inhibitor activated protein C (APC), so we could test the effects of lev on the systems’ sensitivity to APC. In line with literature reports, the use of lev increased the APC sensitivity, which correlates with increased thrombosis risk.

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Inhibition of platelet-surface-bound proteins during coagulation under flow II: Antithrombin and heparin

Cited by 9 publications

References 48 publications

Inhibition of platelet-surface-bound proteins during coagulation under flow I: TFPI

Inhibition of platelet-surface-bound proteins during coagulation under flow I: TFPI

Biochemical characterisation of a PL24 ulvan lyase from seaweed-associated Vibrio sp. FNV38

Studying the Effects of Oral Contraceptives on Coagulation Using a Mathematical Modeling Approach

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