Clot Architecture Is Altered in Abdominal Aortic Aneurysms and Correlates With Aneurysm Size

Scott, Daniel; Prasad, Priya; Philippou, Helen; Rashid, ST; Sohrabi, Soroush; Whalley, Daniel; Kordowicz, Andy; Tang, Quen; West, Robert; Johnson, Anne B.; Woods, Janet; Ajjan, Ramzi; Ariëns, Robert A. S.

doi:10.1161/atvbaha.111.236786

Cited by 55 publications

(62 citation statements)

References 41 publications

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“…Yet, because activated platelets degranulate within the clot [39], there is a potential for diffusion/convection of biomolecules through the canaliculi. Overall, these findings suggest possible continual cycles of fibrin deposition and degradation within the luminal layer, indicative of an active remodeling and renewal of the fibrin matrix [13,54]. Whether fibrin deposition within the luminal layer could eventually become dense enough to exclude further cellular infiltration (thus rendering the layer more inert) remains to be proven, although findings by Tong et al [12] for older luminal layers having few erythrocytes supports this possibility.…”

Section: Prominent Role Of the Luminal Layer In Ilt Activitymentioning

confidence: 78%

“…Interestingly, plasma samples from AAA patients form denser, lower porosity clots that resist fibrinolysis more than controls, with the degree of resistance correlating with aneurysm size [13]. These findings appear to be independent of fibrinogen or changes in thrombin generation; yet, other agents such as lipoprotein (a) or activated factor XII (fXIIa) may affect clot structure independent of thrombin [13]. Notably, lipoprotein (a) is elevated in AAA plasma versus control [14], and fXII activity correlates with aneurysm size [15].…”

Section: Hemodynamics and Ilt Developmentmentioning

confidence: 99%

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Biochemomechanics of Intraluminal Thrombus in Abdominal Aortic Aneurysms

Wilson

Virag

Achille

et al. 2013

Journal of Biomechanical Engineering

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Most computational models of abdominal aortic aneurysms address either the hemodynamics within the lesion or the mechanics of the wall. More recently, however, some models have appropriately begun to account for the evolving mechanics of the wall in response to the changing hemodynamic loads. Collectively, this large body of work has provided tremendous insight into this life-threatening condition and has provided important guidance for current research. Nevertheless, there has yet to be a comprehensive model that addresses the mechanobiology, biochemistry, and biomechanics of thrombus-laden abdominal aortic aneurysms. That is, there is a pressing need to include effects of the hemodynamics on both the development of the nearly ubiquitous intraluminal thrombus and the evolving mechanics of the wall, which depends in part on biochemical effects of the adjacent thrombus. Indeed, there is increasing evidence that intraluminal thrombus in abdominal aortic aneurysms is biologically active and should not be treated as homogeneous inert material. In this review paper, we bring together diverse findings from the literature to encourage next generation models that account for the biochemomechanics of growth and remodeling in patient-specific, thrombus-laden abdominal aortic aneurysms.

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Section: Prominent Role Of the Luminal Layer In Ilt Activitymentioning

confidence: 78%

Section: Hemodynamics and Ilt Developmentmentioning

confidence: 99%

Biochemomechanics of Intraluminal Thrombus in Abdominal Aortic Aneurysms

Wilson

Virag

Achille

et al. 2013

Journal of Biomechanical Engineering

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“…Abnormal weak fibrin clots were formed from the plasma of people with hemophilia, 95 while clots from the plasma of patients with abdominal aortic aneurisms were dense and fibrinolytically resistant. 96 Altered fibrin clot structure associated with a resistance to fibrinolysis was observed in in vitro clots made from the plasma of patients with ischemic stroke, 97 patients with venous thromboemolism, 98 and in smokers. 99 The importance of the structure and properties of fibrin clots formed at the sites of injury during wound healing and inflammation has been underestimated.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of fibrin polymerization and clinical implications

Weisel

Litvinov

2013

Blood

400

363

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Research on all stages of fibrin polymerization, using a variety of approaches including naturally occurring and recombinant variants of fibrinogen, x-ray crystallography, electron and light microscopy, and other biophysical approaches, has revealed aspects of the molecular mechanisms involved. The ordered sequence of fibrinopeptide release is essential for the knob-hole interactions that initiate oligomer formation and the subsequent formation of 2-stranded protofibrils. Calcium ions bound both strongly and weakly to fibrin(ogen) have been localized, and some aspects of their roles are beginning to be discovered. Much less is known about the mechanisms of the lateral aggregation of protofibrils and the subsequent branching to yield a 3-dimensional network, although the aC region and B:b knob-hole binding seem to enhance lateral aggregation. Much information now exists about variations in clot structure and properties because of genetic and acquired molecular variants, environmental factors, effects of various intravascular and extravascular cells, hydrodynamic flow, and some functional consequences. The mechanical and chemical stability of clots and thrombi are affected by both the structure of the fibrin network and cross-linking by plasma transglutaminase. There are important clinical consequences to all of these new findings that are relevant for the pathogenesis of diseases, prophylaxis, diagnosis, and treatment. (Blood. 2013;121(10):1712-1719 IntroductionFibrin polymer is an end product of the enzymatic cascade of blood clotting. In vivo formation of the polymeric fibrin network, along with platelet adhesion and aggregation, are the key events in salutary stopping of bleeding at the site of injury (hemostasis) as well as in pathological vascular occlusion (thrombosis). Fibrin polymerization comprises a number of consecutive reactions, each affecting the ultimate structure and properties of the fibrin scaffold. These properties determine the development and outcomes of various diseases, such as heart attack, ischemic stroke, cancers, trauma, surgical and obstetrical complications, hereditary and acquired coagulopathies, and thrombocytopathies. In addition to providing a better understanding of the pathogenesis of such disorders, the knowledge of the molecular mechanisms of fibrin formation provides a foundation for new diagnostic tools and therapeutic approaches. Fibrinopeptide releaseFibrinogen is 45 nm-long and made up of 6 paired polypeptide chains (Aa Bb g) 2 held together by 29 disulfide bonds. There are now crystal structures of large parts of fibrinogen, including the g-and b-nodules, the coiled coil, and the central nodule.1 Still missing in the crystal structures are the flexible NH 2 -terminal (N-terminal) ends of the Aa-chains and the carboxyl-terminal (C-terminal) portion of the Aa-chain, but modern simulation techniques make possible partial computational reconstructions of these parts of fibrin(ogen) (Figure 1).Fibrin polymerization is initiated by the thrombin cleavage of fibrinopeptides A (...

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“…Laser scanning confocal microscopy was performed as previously described [21,22]. In brief, plasma samples were diluted 1/6 with TBS and incubated with 0.6 U/ml of human thrombin (Calbiochem; Nottingham, UK), 50 g/ml AlexaFluor 488 fibrinogen (Invitrogen; Paisley, UK) and 5mMCaCl2 (final concentration), in a final volume of 60 l. The reaction mixture was transferred into the channel of an uncoated Ibidi slide (Ibidi GmbH, München, Germany) and left in a humidity chamber for 4 h at room temperature.…”

Section: Laser Scanner Confocal Microscopymentioning

confidence: 99%

Fibrin clot structure in patients with congenital dysfibrinogenaemia

Casini

Duval

Pan

et al. 2016

Thrombosis Research

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Article:Casini, A, Duval, C orcid.org/0000-0002-4870-6542, Pan, X et al. (3 more authors) (2016) Fibrin clot structure in patients with congenital dysfibrinogenaemia. Thrombosis Research, https://doi.org/10.1016/j.thromres. 2015.11.008 © 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless 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. ABSTRACTThe clinical phenotype of patients with congenital dysfibrinogenaemia is highly heterogeneous, from absence of symptoms to mild bleeding, or thrombosis. A few mutations are associated with a specific phenotype, but generally the clinical course is not predictable. We investigated whether fibrin clot properties are correlated with the patient's phenotype and/or genotype. Ex vivo plasma fibrin clot characteristics, including turbidity, fibrinolysis, clot permeability and fibrin fibre density assessed by laser scanner confocal microscopy were investigated in 24 genotyped patients with congenital dysfibrinogenaemia compared to normal pool plasma. Compared to normal pool plasma, the patients were characterised by slower fibrin polymerisation (lag time, 345.10 ± 22.98 vs. 166.00 s), thinner fibrin fibres (maximum absorbance, 0.15 ± 0.01 vs. 0.31), prolonged clot lysis time (23.72 ± 0.97 vs. 20.32 min) and larger clot pore size (21.5 × 10−9 ± 4.48 × 10−9 vs. 7.96 × 10−9 cm2). Laser scanning confocal microscopy images confirmed disorganised fibrin networks in all patients. Patients with tendency to bleed showed an increased permeability compared to asymptomatic patients (p=0.01) and to patients with a thrombotic history (p=0.02) while patients with thrombotic history had a tendency to have a prolonged clot lysis time. Fibrin clot properties were similar among hotspot mutations. Further studies including a larger number of patients are needed to evaluate whether analysis of permeability and clot lysis time may help to distinguish the clinical phenotype in these patients and to assess differences according to the genotype.

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Clot Architecture Is Altered in Abdominal Aortic Aneurysms and Correlates With Aneurysm Size

Cited by 55 publications

References 41 publications

Biochemomechanics of Intraluminal Thrombus in Abdominal Aortic Aneurysms

Biochemomechanics of Intraluminal Thrombus in Abdominal Aortic Aneurysms

Mechanisms of fibrin polymerization and clinical implications

Fibrin clot structure in patients with congenital dysfibrinogenaemia

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