Evidence for a second type of fibril branch point in fibrin polymer networks, the trimolecular junction

Mosesson, MW; DiOrio, James P.; Siebenlist, Kevin R.; Wall, J.; Hainfeld, J. F.

doi:10.1182/blood.v82.5.1517.bloodjournal8251517

Cited by 24 publications

(30 citation statements)

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“…However, the data extracted from the Casassa plots seem to indicate otherwise, in agreement with previous observations showing the strong Ca 2ϩ -dependence of the B-b interaction (Marx, 1988, and references therein), so at least this phenomenon should not be relevant under our experimental conditions. As for branching, it could be excluded if it happens only as a consequence of lateral aggregation; EM evidence to the contrary has been presented (Mosesson et al, 1993), but at higher ionic strengths (I ϭ 0.3-0.4) than the one used in our study (I ϭ 0.15).…”

Section: Models For Fibrin Polymerizationmentioning

confidence: 47%

Polymerization of Rod-Like Macromolecular Monomers Studied by Stopped-Flow, Multiangle Light Scattering: Set-Up, Data Processing, and Application to Fibrin Formation

Bernocco

Ferri

Cuniberti

et al. 2000

Biophysical Journal

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Many biological supramolecular structures are formed by polymerization of macromolecular monomers. Light scattering techniques can provide structural information from such systems, if suitable procedures are used to collect the data and then to extract the relevant parameters. We present an experimental set-up in which a commercial multiangle laser light scattering photometer is linked to a stopped-flow mixer, allowing, in principle, the time-resolved extrapolation of the weight-average molecular weight M(w) and of the z-average square radius of gyration (z) of the polymers from Zimm-like plots. However, if elongated structures are formed as the polymerization proceeds, curved plots rapidly arise, from which M(w) and (z) cannot be recovered by linear fitting. To verify the correctness of a polynomial fitting procedure, polydisperse collections of rod-like or worm-like particles of different lengths, generated at various stages during bifunctional polycondensations of rod-like macromolecular monomers, were considered. Then, the angular dependence of their time-averaged scattered intensity was calculated in the Rayleigh-Gans-Debye approximation, with random and systematic noise also added to the data. For relatively narrow size distributions, a third-degree polynomial fitting gave satisfactory results across a broad range of conversion degrees, yielding M(w) and (z) values within 2% and no greater than 10-20%, respectively, of the calculated values. When more broad size distributions were analyzed, the procedure still performed well for semiflexible polymers, but started to seriously underestimate both M(w) and (z) when rigid rod-like particles were analyzed, even at relatively low conversion degrees. The data were also analyzed in the framework of the Casassa approximation, from which the mass per unit length of the polymers can be derived. These procedures were applied to a set of data taken on the early stages of the thrombin-catalyzed polymerization of fibrinogen, a rod-like macromolecule approximately 50 nm long. The polymers, grown in the absence of Ca(2+) by rate-limiting amounts of thrombin, appeared to be characterized by a much broader size distribution than the one expected for a classical Flory bifunctional polycondensation, and they seem to behave as relatively flexible worm-like double-stranded chains. Evidence for the formation of fibrinogen-fibrin monomer complexes is also inferred from the time dependence of the mass/length ratio. However, our data are also compatible with the presence of limited amounts of single-stranded structures in the very early stages, either as a secondary, less populated pathway, or as transient intermediates to the classical double-stranded fibrils.

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Section: Models For Fibrin Polymerizationmentioning

confidence: 47%

Polymerization of Rod-Like Macromolecular Monomers Studied by Stopped-Flow, Multiangle Light Scattering: Set-Up, Data Processing, and Application to Fibrin Formation

Bernocco

Ferri

Cuniberti

et al. 2000

Biophysical Journal

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“…It is not clear on experimental grounds how these abnormalities contribute to thin fibrin fiber formation. It appears to us that this may be directly related to the tendency for increased Dusart fibrinogen self-association before its conversion to fibrin, an event that may lead to enhanced linear fibrinogen fibril formation and concomitant reduction in "trimolecular" fibrin network branch junctions (43,44). Dextran, which is known to induce a thick fiber network structure (34)(35)(36), normalized the abnormal Dusart thin fiber structure (8), but ac- celerated Dusart fibrinogen ␥ chain cross-linking was not normalized (Fig.…”

Section: Discussionmentioning

confidence: 99%

The relationship between the fibrinogen D domain self-association/cross-linking site (gammaXL) and the fibrinogen Dusart abnormality (Aalpha R554C-albumin): clues to thrombophilia in the "Dusart syndrome".

Mosesson¹,

Siebenlist²,

Hainfeld³

et al. 1996

J. Clin. Invest.

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Cross-linking of fibrinogen at its COOH-terminal gamma chain cross-linking site occurs in the presence of factor XIIIa due to self-association at a constitutive D domain site ("gammaXL"). We investigated the contribution of COOH-terminal regions of fibrinogen Aalpha chains to the gammaXL site by comparing the gamma chain cross-linking rate of intact fibrinogen (fraction I-2) with that of plasma fraction I-9, plasmic fraction I-9D, and plasmic fragment D1, which lack COOH-terminal Aalpha chain regions comprising approximately 100, approximately 390, and 413 residues, respectively. The cross-linking rates were I-2 > I-9 > 1-9D = D1, and indicated that the terminal 100 or more Aalpha chain residues enhance gammaXL site association. Fibrinogen Dusart, whose structural abnormality is in the COOH-terminal "alphaC" region of its Aalpha chain (Aalpha R554C-albumin), is associated with thrombophilia ("Dusart Syndrome"), and is characterized functionally by defective fibrin polymerization and clot structure, and reduced plasminogen binding and tPA-induced fibrinolysis. In the presence of XIIIa, the Dusart fibrinogen gamma chain cross-linking rate was about twice that of normal, but was normalized in proteolytic fibrinogen derivatives lacking the Aalpha chain abnormality, as was reduced plasminogen binding. Electron microscopy showed that albumin-bound Dusart fibrinogen "alphaC" regions were located in the vicinity of D domains, rather than at their expected tethered location near the fibrinogen E domain. In addition, there was considerable fibrinogen aggregation that was attributable to increased intermolecular COOH-terminal Aalpha chain associations promoted by untethered Dusart fibrinogen aC domains. We conclude that enhanced Dusart fibrinogen self-assembly is mediated through its abnormal alphaC domains, leads to increased gammaXL self-association and gamma chain cross-linking potential, and contributes to the thrombophilia that characterizes the "Dusart Syndrome."

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“…The branching process is accompanied by elongation and thickening of the fibrin fibres, rather than an independent event. There are two classifications of branch junctions when forming a three‐dimensional (3D) clot network (Figure A) (Mosesson et al ., ). The first, known as a ‘bilateral junction’, occurs when a double‐stranded protofibril combines laterally with another one, resulting in a four‐stranded fibril, which then again diverges into the original two separate protofibrils.…”

Section: Fibrin Fibre Formation and Its Potential Influence On Fractumentioning

confidence: 97%

Structural properties of fracture haematoma: current status and future clinical implications

Wang

Friis

Glatt

et al. 2016

J Tissue Eng Regen Med

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Blood clots (haematomas) that form immediately following a bone fracture have been shown to be vital for the subsequent healing process. During the clotting process, a number of factors can influence the fibrin clot structure, such as fibrin polymerization, growth factor binding, cellular infiltration (including platelet retraction), protein concentrations and cytokines. The modulation of the fibrin clot structure within the fracture site has important clinical implications and could result in the development of multifunctional scaffolds that mimic the natural structure of a haematoma. Artificial haematoma structures such as these can be created from the patient's own blood and can therefore act as an ideal bone defect filling material for potential clinical application to accelerate bone regeneration. Copyright © 2016 John Wiley & Sons, Ltd.

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Evidence for a second type of fibril branch point in fibrin polymer networks, the trimolecular junction

Cited by 24 publications

References 0 publications

Polymerization of Rod-Like Macromolecular Monomers Studied by Stopped-Flow, Multiangle Light Scattering: Set-Up, Data Processing, and Application to Fibrin Formation

Polymerization of Rod-Like Macromolecular Monomers Studied by Stopped-Flow, Multiangle Light Scattering: Set-Up, Data Processing, and Application to Fibrin Formation

The relationship between the fibrinogen D domain self-association/cross-linking site (gammaXL) and the fibrinogen Dusart abnormality (Aalpha R554C-albumin): clues to thrombophilia in the "Dusart syndrome".

Structural properties of fracture haematoma: current status and future clinical implications

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