Sol Sherry Lecture in Thrombosis

Lóránd, L.

doi:10.1161/01.atv.20.1.2

Cited by 44 publications

(18 citation statements)

References 85 publications

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“…Clots are formed when the enzyme thrombin cleaves fibrinogen to generate fibrin monomers, which polymerize to produce a threedimensional network of fibers (1)(2)(3)(4)(5)(6)(7)(8). Fibrin is stabilized by ligation, ¶ the formation of intermolecular covalent bonds at specific sites with a transglutaminase, factor XIIIa, rendering the whole clot stiffer and resistant to fibrinolytic dissolution (9,10). The viscoelastic properties of clots and their major constituent fibrin are normally finely tuned to optimize how they stop bleeding while also minimizing their effect in cardiovascular disease, because bleeding occurs if clot stiffness is too low; a decreased rate of fibrinolysis and increased thrombosis and thromboembolism are generally associated with stiff and friable clots, although such relationships are complex (10 -14).…”

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confidence: 99%

The elasticity of an individual fibrin fiber in a clot

Collet

Shuman²,

Ledger³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

246

215

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A blood clot needs to have the right degree of stiffness and plasticity to stem the flow of blood and yet be digestable by lytic enzymes so as not to form a thrombus, causing heart attacks, strokes, or pulmonary emboli, but the origin of these mechanical properties is unknown. Clots are made up of a three-dimensional network of fibrin fibers stabilized through ligation with a transglutaminase, factor XIIIa. We developed methods to measure the elastic moduli of individual fibrin fibers in fibrin clots with or without ligation, using optical tweezers for trapping beads attached to the fibers that functioned as handles to flex or stretch a fiber. Here, we report direct measurements of the microscopic mechanical properties of such a polymer. Fibers were much stiffer for stretching than for flexion, as expected from their diameter and length. Elastic moduli for individual fibers in plasma clots were 1.7 ؎ 1.3 and 14.5 ؎ 3.5 MPa for unligated and ligated fibers, respectively. Similar values were obtained by other independent methods, including analysis of measurements of fluctuations in bead force as a result of Brownian motion. These results provide a basis for understanding the origin of clot elasticity.fibrinogen ͉ optical trap ͉ viscoelasticity ͉ microrheology ͉ cardiovascular B lood clots play an essential role by stopping bleeding, but they can also cause heart attacks and strokes. Clots are formed when the enzyme thrombin cleaves fibrinogen to generate fibrin monomers, which polymerize to produce a threedimensional network of fibers (1-8). Fibrin is stabilized by ligation, ¶ the formation of intermolecular covalent bonds at specific sites with a transglutaminase, factor XIIIa, rendering the whole clot stiffer and resistant to fibrinolytic dissolution (9, 10). The viscoelastic properties of clots and their major constituent fibrin are normally finely tuned to optimize how they stop bleeding while also minimizing their effect in cardiovascular disease, because bleeding occurs if clot stiffness is too low; a decreased rate of fibrinolysis and increased thrombosis and thromboembolism are generally associated with stiff and friable clots, although such relationships are complex (10 -14). Although much is known of fibrin assembly mechanisms (1)(2)(3)(4)(5)(6)(7)(8)(15)(16)(17)(18), the origin of clot viscoelasticity remains to be established.The elasticity of a fibrin clot, like that of rubber-like polymers, is characterized by very large deformability with essentially complete recovery (19). However, the elasticity of the fibrin clot cannot be rubber-like, because it is not a random-coil network made up of thin, highly flexible strands; instead, it is a network made up of thick branching fibers. As an example of how unrealistic such rubber-like models are, it can be calculated from clot stiffness that there would be an average of only one fibrin molecule per branch point for a rubber-like model (20), yet electron micrographs show that the clots used for these experiments commonly have Ϸ1 million fibrin molecules bet...

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mentioning

confidence: 99%

The elasticity of an individual fibrin fiber in a clot

Collet

Shuman²,

Ledger³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

246

215

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“…Removal of these peptides initiates a structural rearrangement between adjacent polypeptides, resulting in elongation and lateral aggregation of fibrin into a polymer that constitutes the mesh network of a clot [15] . Fibrin aggregates are strengthened by fXIII cross-linking [16] . fXIII introduces -( ␥ -glutamyl)lysine cross-bridges between adjacent ␣ -and ␥ -chains [16] .…”

Section: Physiological Coagulation/fibrinolytic Cascadementioning

confidence: 99%

“…Fibrin aggregates are strengthened by fXIII cross-linking [16] . fXIII introduces -( ␥ -glutamyl)lysine cross-bridges between adjacent ␣ -and ␥ -chains [16] .…”

Section: Physiological Coagulation/fibrinolytic Cascadementioning

confidence: 99%

<i>Staphylococcus aureus</i> Secretes Coagulase and von Willebrand Factor Binding Protein to Modify the Coagulation Cascade and Establish Host Infections

McAdow

Missiakas

Schneewind³

2012

J Innate Immun

146

121

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Clinical isolates of Staphylococcus aureus secrete coagulases, polypeptides that bind to and activate prothrombin, thereby converting fibrinogen to fibrin and promoting the clotting of plasma or blood. Two staphylococcal products, the canonical coagulase (Coa) as well as the recently identified von Willebrand factor binding protein (vWbp), promote similar modifications of the coagulation cascade during host infection. Staphylococcal binding to fibrinogen or fibrin is an important attribute of disease pathogenesis, which leads to the formation of abscesses and bacterial persistence in host tissues and also enables the pathogen to cause lethal sepsis. Circumstantial evidence suggests that the product of coagulase activity, staphylococci captured within a fibrin meshwork, enable this pathogen to disseminate as thromboembolic lesions and to resist opsonophagocytic clearance by host immune cells. In addition, the coagulation products of staphylococci appear to display discrete differences when compared to those of thrombin-mediated coagulation, the latter representing a key innate defense mechanism against many invading pathogens. Preclinical evidence suggests that inactivation or neutralization of coagulases may prevent the pathogenesis of staphylococcal infections, a strategy that could be used to combat the current epidemic of hospital-acquired infections with drug-resistant S. aureus isolates.

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“…Selected derivatives of 1,2,4-thiadiazoles, presently in discovery and development, may offer new treatment strategies as inhibitors of Factor XIIIa. In order to evaluate its pharmacokinetic (PK) profile and to facilitate the selection of drug candidates for drug discovery and development process, we developed and validated a simple and selective reversed-phase high-performance liquid chromatographic method (RP-HPLC) with UV detection for the determination of N- [6-(imidazo[1,2-d] [1,2,4]thiadiazol-3-ylamino)hexyl]-2-nitrobenzensulfonamide (5624) in rabbit plasma. The plasma protein precipitation and sample preparation was achieved by using acetonitrile, followed by organic phase evaporation to dryness and the residue reconstitution in the mobile phase.…”

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confidence: 99%

“…Chromatography was performed on a C18 column using a gradient of acetonitrile in water as a mobile phase. A chemically related compound, N- [6-(imidazo[1,2-d] [1,2,4]thiadiazol-3-ylamino)hexyl]naphthalene-1-sulfonamide (5422), was used as an internal standard. Limit of detection (LOD), based on signal to noise ratio > 3, was 0.2 M (on-column amount of about 7 ng), while limit of quantification (LOQ), based on signal to noise ratio > 10, was 0.5 M (on-column amount of about 20 ng).…”

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confidence: 99%