Publications by authors named "Kerrie Smith"

Factor XIIIA (FXIIIA) is a transglutaminase that cross-links intra- and extracellular protein substrates. FXIIIA is expressed as an inactive zymogen, and during blood coagulation, it is activated by removal of an activation peptide by the protease thrombin. No such proteolytic FXIIIA activation is known to occur in other tissues or the intracellular form of FXIIIA.

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Bleeding complications secondary to surgery, trauma, or coagulation disorders are important causes of morbidity and mortality. Although fibrin sealants are considered to minimize blood loss, this is not widely adopted because of its high cost and/or risk for infection. We present a novel methodology employing nonantibody fibrinogen-binding proteins, termed Affimers, to stabilize fibrin networks with the potential to control excessive bleeding.

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Objective: To establish the cellular source of plasma factor (F)XIII-A.

Approach And Results: A novel mouse floxed for the gene, FXIII-A (Flox), was crossed with myeloid- and platelet-cre-expressing mice, and cellular FXIII-A mRNA expression and plasma and platelet FXIII-A levels were measured. The platelet factor 4-cre.

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An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk.

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Factor XIIIa (FXIIIa) introduces covalent γ-glutamyl-ε-lysyl crosslinks into the blood clot network. These crosslinks involve both the γ and α chains of fibrin. The C-terminal portion of the fibrin α chain extends into the αC region (210-610).

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A novel class of potent FXIII-A inhibitors containing a (±) cis-bisamido epoxide pharmacophore is described. The compounds display highly potent inhibition of FXIII-A (IC50 = 5-500 nM) in an in vitro assay. In contrast to other types of previously described covalent transglutaminase inhibitors, the bis-amido epoxides exhibited no measurable reactivity with glutathione, therefore possibly rendering this class of compounds suitable for future in vivo investigations.

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Transglutaminase activity has been widely implicated in bone deposition. A predominant role has been proposed for factor (F)XIII-A and a subsidiary role suggested for the homologous protein, transglutaminase 2. Full-length FXIII-A is an 83kDa protransglutaminase that is present both in plasma and also in haematopoietic and connective tissue lineages.

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The global increase in obesity-induced type 2 diabetes (T2DM) represents a burden for healthcare systems worldwide. Of particular concern is the increased morbidity associated with T2DM, in particular cardiovascular disease (CVD), leading to premature death. Obesity initially leads to the development of insulin resistance in adipose and other tissues.

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Diabetes is associated with hypofibrinolysis by mechanisms that are only partially understood. We investigated the effects of in vivo plasminogen glycation on fibrinolysis, plasmin generation, protein proteolytic activity, and plasminogen-fibrin interactions. Plasma was collected from healthy controls and individuals with type 1 diabetes before and after improving glycemia.

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Formation of a stable fibrin clot is dependent on interactions between factor XIII and fibrin. We have previously identified a key residue on the αC of fibrin(ogen) (Glu396) involved in binding activated factor XIII-A(2) (FXIII-A(2)*); however, the functional role of this interaction and binding site(s) on FXIII-A(2)* remains unknown. Here we (1) characterized the functional implications of this interaction; (2) identified by liquid-chromatography-tandem mass spectrometry the interacting residues on FXIII-A(2)* following chemical cross-linking of fibrin(ogen) αC389-402 peptides to FXIII-A(2)*; and (3) carried out molecular modeling of the FXIII-A(2)*/peptide complex to identify contact site(s) involved.

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Background And Method: Increased plasma clot density and prolonged lysis times are associated with cardiovascular disease. In this study, we employed a functional proteomics approach to identify novel clot components which may influence clot phenotypes.

Results: Analysis of perfused, solubilised plasma clots identified inflammatory proteins, including complement C3, as novel clot components.

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Fibrinogen αC residues 242-424 have been shown to have a major regulatory role in the activation of factor XIII-A(2)B(2) (FXIII-A(2)B(2)); however, the interactions underpinning this enhancing effect have not been determined. Here, we have characterized the binding of recombinant (r)FXIII-A subunit and FXIII-A(2)B(2) with fibrin(ogen) and fibrin αC residues 233-425. Using recombinant truncations of the fibrin αC region 233-425 and surface plasmon resonance, we found that activated rFXIII-A bound αC 233-425 (K(d) of 2.

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