The molecular physiology and pathology of fibrin structure/function

Standeven, Kristina F.; Ariëns, Robert A. S.; Grant, Peter J.

doi:10.1016/j.blre.2005.01.003

Cited by 134 publications

(114 citation statements)

References 123 publications

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“…1,2 The N-termini of the fibrinogen (AaBbg) 2 chains form the central E region, which extends via a coil-coiled region to two terminal D regions. A flexible portion of the Aa chain, the aC region, extends from the ends of the D regions and is tethered to the central E region.…”

Section: Introductionmentioning

confidence: 99%

Ranking reactive glutamines in the fibrinogen αC region that are targeted by blood coagulant factor XIII

Mouapi

Bell

Smith

et al. 2016

Blood

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Key Points• FXIIIa exhibits a preference for Q237 in crosslinking reactions within fibrinogen aC (233-425) followed by Q328 and Q366.• None of the reactive glutamines in aC 233-425 (Q237, Q328, and Q366) are required to react first before the others can crosslink.Factor XIIIa (FXIIIa) introduces covalent g-glutamyl-«-lysyl crosslinks into the blood clot network. These crosslinks involve both the g and a chains of fibrin. The C-terminal portion of the fibrin a chain extends into the aC region (210-610). Crosslinks within this region help generate a stiffer clot, which is more resistant to fibrinolysis. Fibrinogen aC (233-425) contains a binding site for FXIIIa and three glutamines Q237, Q328, and Q366 that each participate in physiological crosslinking reactions. Although these glutamines were previously identified, their reactivities toward FXIIIa have not been ranked. Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry and nuclear magnetic resonance (NMR) methods were thus used to directly characterize these three glutamines and probe for sources of FXIIIa substrate specificity. Glycine ethyl ester (GEE) and ammonium chloride served as replacements for lysine. Mass spectrometry and 2D heteronuclear single quantum coherence NMR revealed that Q237 is rapidly crosslinked first by FXIIIa followed by Q366 and Q328. Both N-GEE could be crosslinked to the three glutamines in aC (233-425) with a similar order of reactivity as observed with the MALDI-TOF mass spectrometry assay. NMR studies using the single aC mutants Q237N, Q328N, and Q366N demonstrated that no glutamine is dependent on another to react first in the series. Moreover, the remaining two glutamines of each mutant were both still reactive. Further characterization of Q237, Q328, and Q366 is important because they are located in a fibrinogen region susceptible to physiological truncations and mutation. The current results suggest that these glutamines play distinct roles in fibrin crosslinking and clot architecture. (Blood. 2016;127(18):2241-2248

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Section: Introductionmentioning

confidence: 99%

Ranking reactive glutamines in the fibrinogen αC region that are targeted by blood coagulant factor XIII

Mouapi

Bell

Smith

et al. 2016

Blood

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“…Genetic and environmental factors determining fibrin structure have been extensively studied in recent years (detailed reviews in references 14,15 ). In brief, fibrin with a tight network conformation is observed under circumstances with increased plasma fibrinogen concentration (genetically determined or raised in association with age, female gender, infection, inflammation, hypertension, diabetes and hyperlipidemia), as well as in the presence of increased thrombin (or prothrombin) concentration.…”

Section: See Page 2567mentioning

confidence: 99%

“…12 Also, fibrin formed with a recombinant fibrinogen truncated at A␣ chain residue 251 was less stiff and digested faster in plasmin-catalyzed experiments than control fibrin formed with recombinant fibrinogen with common A␣ chains containing 610 amino acid residues, although the fibrin formed from the truncated fibrinogen was composed of thinner and denser fibers, with more branch points, than the control fibrin. 13 Regarding mechanisms, little is known about the relationships between fibrin's mechanical properties and rate of fibrinolysis.Genetic and environmental factors determining fibrin structure have been extensively studied in recent years (detailed reviews in references 14,15 ). In brief, fibrin with a tight network conformation is observed under circumstances with increased plasma fibrinogen concentration (genetically determined or raised in association with age, female gender, infection, inflammation, hypertension, diabetes and hyperlipidemia), as well as in the presence of increased thrombin (or prothrombin) concentration.…”

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confidence: 99%

Fibrin Gel Architecture Influences Endogenous Fibrinolysis and May Promote Coronary Artery Disease

Silveira

Hamsten

2006

ATVB

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A n altered fibrin network architecture has been associated with premature coronary artery disease (CAD). 1,2 Hypofibrinolysis, ie, impaired dissolution of fibrin in blood clots, is another common finding in such patients. Hypofibrinolysis is associated with elevated activity of inhibitors of the fibrinolytic process, particularly of plasminogen activator inhibitor-1 (PAI-1) 3 and thrombin activatable fibrinolysis inhibitor (TAFI), 4 but it is also influenced by the characteristics of the fibrin network itself. 5,6 However, previous studies on fibrin architecture, its regulation, and implications for CAD have been hampered by imperfect and/or incomplete methodology. Thus, the relationships between fibrin structure, fibrinolytic function, and premature CAD warrant further thorough examination. This issue of Arteriosclerosis, Thrombosis, and Vascular Biology features a comprehensive investigation of physical and viscoelastic characteristics of fibrin clots formed ex vivo from plasma samples, their relationships to fibrinolysis rate, and potential role in CAD. 7 See page 2567Both the morphology and mechanical properties of fibrin influence susceptibility to fibrinolysis. Fibrin structure is generally assessed by using liquid permeation, light scattering, scanning electron microscopy, and confocal microscopy, from which variables such as the fiber thickness, length and density, and the number of branch points and porosity of the network are derived. 8 Blunted fibrinolysis is associated with a tight fibrin structure composed of thin and short fibers with increased number of branch points, and small pores. 5,6 Individual thick fibers are actually lysed at a slower rate, 9 but tight network configurations display a significantly higher fiber density compared with loose structures, which renders them more difficult to be lysed because there are more fibers to be processed 6 and increased restriction to the permeation of fibrinolytic factors through the network.The mechanical properties of fibrin can be quantified by determining the response to forces to which fibers are subjected. 10 Either static or dynamic measurements can be made, oscillatory motion being an example of the latter. Recording of the oscillations of a torsion pendulum attached to a sample (clot) on careful application of shear forces allows calculations of the storage modulus, which reflects the stiffness or resistance of the clot to deformation. 11 In general, clots with increased stiffness are digested more slowly by plasmin than less stiff clots. This was clearly shown in experiments in which the stiffness of the clot and its resistance to fibrinolysis increased in parallel on addition of factor XIII, whereas inhibitors of the factor XIII-catalyzed reactions greatly reduced both clot stiffness and lytic resistance. 12 Also, fibrin formed with a recombinant fibrinogen truncated at A␣ chain residue 251 was less stiff and digested faster in plasmin-catalyzed experiments than control fibrin formed with recombinant fibrinogen with common A␣ chains contain...

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“…Non-covalent, self-association of fibrin monomers produces a loose clot. This is subsequently covalently cross-linked by factor XIIIa, which enhances the structural integrity of the growing thrombus [18]. In essence, activated platelets are the 'platform of all action' (Fig.…”

Section: Propagationmentioning

confidence: 99%

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

Henry¹,

Desai²

2008

CHAMC

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Physiologic clotting is a defensive action. The new cell-based model of hemostasis proposes three steps -initiation, amplification and propagation -occurring on specific cell surfaces to generate a thrombus in a tightly regulated manner. The initiation phase relies on key players including tissue factor (TF), factor VIIa (fVIIa), platelets, Ca 2+ , phospholipids, and factor X/Xa (fX/fXa). Exposure of TF on sub-endothelial and other blood cells triggers a coagulation response, which may have to be inhibited to prevent a deleterious thrombotic effect. Inhibiting TF-initiated coagulation, akin to 'nipping coagulation in the bud', is predicted to have major advantages, including a more efficient separation of the antithrombotic and hemorrhagic responses. The availability of crystal structures of TF, fVIIa and TFfVIIa complex makes structure-based drug design feasible. Although no initiation phase small molecule inhibitor has reached the clinic as yet, several molecules have displayed promise. We discuss recent results on the discovery of inhibitors of the initiation phase with special emphasis on peptides, peptidomimetics and organic small molecules.Key Words: Anticoagulants, coagulation, factor VIIa, tissue factor, thrombin, factor Xa, Enzyme Inhibition, small molecule inhibitors. CELL-BASED HEMOSTASISPhysiologic clotting is a defensive action preventing excessive loss of blood and infiltration of microbes. The physiologic mechanism that produces this defensive reaction is an enzymatic cascade ( Fig. 1), proposed nearly 50 years ago [1,2]. In vivo, the enzymatic reactions occur on specific cell surfaces. The cell-dependent coagulation cascade is proposed to proceed sequentially in three stepsinitiation, amplification and propagation -on specific cell surfaces to generate a thrombus in a tightly regulated manner [3][4][5]. InitiationTissue factor (TF) is an integral membrane protein present on several extravascular cells [6] and is the most important initiator of coagulation. Under normal conditions, it is sequestered from circulating proteinases, especially factor VII (fVII), thus preventing inappropriate initiation of clotting. Vascular injury exposes TF to blood, resulting in rapid complex formation with free activated fVII (fVIIa) on TF-bearing cells (Fig. 1). It is believed that some fVIIa is always present in blood (~1-2%), which can rapidly interact with TF to initiate clotting. The formation of TF/fVIIa complex activates the circulating factor X (fX) to fXa, the formation of which can induce further production of fVIIa and fXa [7][8][9]. The TF/fVIIa complex can also activate factor IX (fIX) to fIXa [10][11][12], which in turn can result in more fXa. The earliest fXa formed remains localized to the site of TF-bearing cells, yet is free enough to form the prothrombinase complex with factor Va (fVa). The small amount of the prothrombinase complex so formed is responsible for the initial production of thrombin from prothrombin [12]. The in vivo source of the initial fVa needed for the assembly of p...

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The molecular physiology and pathology of fibrin structure/function

Cited by 134 publications

References 123 publications

Ranking reactive glutamines in the fibrinogen αC region that are targeted by blood coagulant factor XIII

Ranking reactive glutamines in the fibrinogen αC region that are targeted by blood coagulant factor XIII

Fibrin Gel Architecture Influences Endogenous Fibrinolysis and May Promote Coronary Artery Disease

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

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