Functional analysis of fibrin γ-chain cross-linking by activated factor XIII: determination of a cross-linking pattern that maximizes clot stiffness

Standeven, Kristina F.; Carter, Angela Maria; Grant, Peter J.; Weisel, John W.; Chernysh, Irina N.; L, Másová; Lord, Susan T.; Ariëns, Robert A. S.

doi:10.1182/blood-2007-01-066837

Cited by 100 publications

(108 citation statements)

References 30 publications

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“…Using a fibrinogen mutant (-3X) unable to generate - crosslinks [30] and studying clot microrheology using magnetic tweezers, fibrin -chain crosslinking was shown to significantly increase clot stiffness (storage modulus, G') by 1.4-fold and significantly decrease clot deformation (loss modulus, G'') by 1.4-fold compared to uncross-linked clots [31]. This was suggested to be most likely be due to increased fibre tautness observed by electron microscopy in clot formed in the presence of FXIII [31].…”

Section: Fibrin - Chains Cross-linkingmentioning

confidence: 99%

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Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ′ as thrombomobulin II

Duval

Ariëns

2017

Matrix Biology

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ReuseUnless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ÔØ Å ÒÙ× Ö ÔØ A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractFibrin is an important matrix protein that provides the backbone to the blood clot, promoting tissue repair and wound healing. Its precursor fibrinogen is one of the most heterogenous proteins, with an estimated 1 million different forms due to alterations in glycosylation, oxidation, single nucleotide polymorphisms, splice variation and other variations. Furthermore, ligation by transglutamimase factor XIII (cross-linking) adds to the complexity of the fibrin network. The structure and function of the fibrin network is in part determined by this natural variation in the fibrinogen molecule, with major effects from slice variation and cross-linking. This mini-review will discuss the direct effects of fibrinogen EC and fibrinogen ' splice variation on clot structure and function and also discuss the additional role of fibrinogen ' as thrombomodulin II. Furthermore, the effects of crosslinking on clot function will be described. Splice variation and cross-linking are major determinants of the structure and function of fibrin and may therefore impact on diseases affecting bleeding, thrombosis and tissue repair.

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Section: Fibrin - Chains Cross-linkingmentioning

confidence: 99%

“…These studies used whole clot rheology by torsion pendulum [30] and single fibre measurement by atomic microscopy [33], and showed an increase in fibre and clot stiffness of around 40% due to -chain cross-linking.…”

Section: Fibrin - Chains Cross-linkingmentioning

confidence: 99%

Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ′ as thrombomobulin II

Duval

Ariëns

2017

Matrix Biology

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“…Fibrinogen is a heteromultimeric protein composed of three different chains (α, β, and γ) and plays an essential role in coagulation during which it is cleaved by thrombin to generate fibrin (17). The fibrinogen γ-chain (49 kDa) that was immunoprecipitated migrated as an ∼80 kDa entity, suggesting that it may represent covalently crosslinked γ-chain dimers that are generated in the conversion of soft clots to hard clots (18). Previous studies showing that polyclonal rabbit antibodies directed against fibrinogen react with matrix proteins in human aneurysmal tissues (13), combined with a report that IgG isolated from human AAA specimens recognize an 80 kDa band in aneurysmal extracts (14), prompted us to further investigate fibrinogen as a candidate self-antigen in elastaseinduced AAA.…”

Section: Significancementioning

confidence: 99%

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Zhou

Yan

Bertram

et al. 2013

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

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Abdominal aortic aneurysm (AAA) is a common vascular disease associated with high mortality rate due to progressive enlargement and eventual rupture. There is currently no established therapy known to alter the rate of aneurysmal expansion. Thus, understanding the processes that initiate and sustain aneurysmal growth is pivotal for the development of medical therapies aimed at halting disease progression. Using an elastase-induced AAA mouse model that recapitulates key features of human AAA, we previously reported that a natural IgG antibody directs alternative pathway complement activation and initiates the inflammatory process that culminates in aneurysmal development. The target of this natural antibody, however, was unknown. Herein we identify a natural IgG that binds to fibrinogen deposited in elastaseperfused aortic tissues, activates the complement lectin pathway (LP), and induces AAA. Moreover, we establish that alterations in the glycosylation patterns of this antibody critically affect its ability to activate the LP in vivo. We find that LP activation precedes the alternative pathway and absence of the LP complement protein mannan-binding lectin abrogates elastase-induced AAA. In human AAA tissues the mouse anti-fibrinogen antibody recognizes epitopes that localize to the same areas that stain positively for mannan-binding lectin, which suggests that the complement LP is engaged in humans as well. Lastly, we demonstrate that circulating antibodies in a subset of AAA patients react against fibrinogen or fibrinogen-associated epitopes in human aneurysmal tissues. Our findings support the concept that an autoimmune process directed at aortic wall self-antigens may play a central role in the immunopathogenesis of AAA.A bdominal aortic aneurysm (AAA) is a common vascular disorder that affects ∼5% of men and ∼1.5% of women ages 65 and older (1, 2). Rupture of AAA presents a medical emergency that accounts for 15,000 deaths annually in the United States (3). Currently, surgical repair represents the only treatment option for large AAAs, whereas surgery in small AAAs offers no clear overall long-term survival advantage (4, 5). Thus, medical management, to inhibit or reverse the progression of small AAAs, has received increasing attention. Major challenges remain in the development of therapeutic agents that impede aneurysm expansion, as our understanding of the pathophysiology underlying this disease is incomplete.One of the defining characteristics of AAA is inflammation accompanied by a cellular infiltrate that is predominantly lymphocytic (6-8). The elastase-induced AAA mouse model recapitulates many key features of human AAA, including the inflammatory response (9). We previously established with this model that aneurysm development requires factor B and properdin of the complement alternative pathway (AP) (10, 11). We showed that mice deficient in B cells (and hence antibodies), called μMT mice, are protected against aneurysm formation. Reconstitution with natural IgG, but not IgM, from wild-type mice res...

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“…Sheets were seen with all combinations of fibrinogens and thrombin, both with and without any added Factor XIIIa, a transglutaminase that stabilizes monomer-monomer association (28). On the scale of light microscopy ( Fig.…”

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confidence: 99%

Ultrathin self-assembled fibrin sheets

Falvo

Millard²,

Eastwood

et al. 2008

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

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Fibrin polymerizes into the fibrous network that is the major structural component of blood clots and thrombi. We demonstrate that fibrin from three different species can also spontaneously polymerize into extensive, molecularly thin, 2D sheets. Sheet assembly occurs in physiologic buffers on both hydrophobic and hydrophilic surfaces, but is routinely observed only when polymerized using very low concentrations of fibrinogen and thrombin. Sheets may have been missed in previous studies because they may be very short-lived at higher concentrations of fibrinogen and thrombin, and their thinness makes them very difficult to detect. We were able to distinguish fluorescently labeled fibrin sheets by polymerizing fibrin onto micropatterned structured surfaces that suspended polymers 10 m above and parallel to the cover-glass surface. We used a combined fluorescence/atomic force microscope system to determine that sheets were Ϸ5 nm thick, flat, elastic and mechanically continuous. Video microscopy of assembling sheets showed that they could polymerize across 25-m channels at hundreds of m 2 /sec (Ϸ10 13 subunits/s⅐M), an apparent rate constant many times greater than those of other protein polymers. Structural transitions from sheets to fibers were observed by fluorescence, transmission, and scanning electron microscopy. Sheets appeared to fold and roll up into larger fibers, and also to develop oval holes to form fiber networks that were ''preattached'' to the substrate and other fibers. We propose a model of fiber formation from sheets and compare it with current models of end-wise polymerization from protofibrils. Sheets could be an unanticipated factor in clot formation and adhesion in vivo, and are a unique material in their own right.clot ͉ fiber ͉ monomolecular sheet ͉ network ͉ thrombus B ecause of the central role of fibrin in the clotting of blood during wound healing and in the formation of pathogenic vascular thrombi, the polymerization of fibrin has been actively studied since the mid-19th century (1). The parent protein, fibrinogen, is an elongated, sausage-shaped dimeric molecule with symmetry around a central globular domain (2-6). Cleavage and removal of the small peptides-fibrinopeptide A and later B-from fibrinogen by the enzyme thrombin expose specific binding sites (''knobs'') on fibrin that allow binding to corresponding regions (''holes'') on neighboring fibrin molecules (7-11). Fibrin can then self-associate to form elongated, sometimes twisted, often highly branched fibers and fiber networks that, together with platelets and blood cells, form clots in response to vascular injury (1,(12)(13)(14)(15). Fibrin fibers are elastic and adhesive and show very high extensibility (16,17). Recent studies suggest that these properties derive, at least in part, from the properties of the fibrin molecule itself (18-21). Exhaustive studies of fibrin polymerization in vitro have been carried out with purified components since the 1940s (e.g., 22, 23), but several details of fibrin assembly into fibers and fibe...

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Functional analysis of fibrin γ-chain cross-linking by activated factor XIII: determination of a cross-linking pattern that maximizes clot stiffness

Cited by 100 publications

References 30 publications

Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ′ as thrombomobulin II

Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ′ as thrombomobulin II

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Ultrathin self-assembled fibrin sheets

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