Abnormal Fibrin Clot Architecture in Nephrotic Patients Is Related to Hypofibrinolysis: Influence of Plasma Biochemical Modifications

1999 ◽  
Vol 82 (11) ◽  
pp. 1482-1489 ◽  
Author(s):  
Zohar Mishal ◽  
Claude Lesty ◽  
Manoucher Mirshahi ◽  
Jacqueline Peynet ◽  
Alain Baumelou ◽  
...  
Keyword(s):  
Fibrin Clot ◽  
Albumin Level ◽  
Morphological Properties ◽  
Plasma Modification ◽  
Fibrin Gels ◽  
Pharmacological Prevention ◽  
Fibrin Network ◽  
Lysis Rate ◽  
Thrombotic Complications ◽  
Fibrin Fiber

SummaryPorosity, viscoelasticity and morphological properties of plasma fibrin from 16 nephrotic patients and 16 healthy volunteers were compared. Nephrotic patients were characterized by formation of tight and rigid plasma fibrin gels which resulted in a slower rate of fibrin lysis studied either under pressure-driven permeation or diffusional transport of fibrinolytic agents. These latter findings indicated that both abnormal fibrin network conformation and abnormal fibrin fiber structure were involved in hypofibrinolysis. Albumin supplementation up to 40 mg/ml partially restored normal fibrin architecture and increased the rate of fibrinolysis in these patients. Multiparametric analysis showed that nephrotic patients were mainly characterized by a low plasma albumin level (R = -0.85), a low albumin to fibrinogen ratio (R = -0.89) and a high resistance to lysis (R = -0.82). High triglycerides level was the only plasma modification related to the slower fibrin lysis rate (R = -0.54). High fibrin rigidity (G’) was the only fibrin parameter simultaneously related to the nephrotic state (R = 0.75) and the lysis resistance (R = -0.71). After eliminating the effects of age, albumin and fibrinogen levels, low fibrin porosity (Ks) and low fiber mass-length ratio (μ) were the main features of the nephrotic state. These findings are discussed in relation to both the pathophysiology of thrombotic complications in nephrotic syndrome and their pharmacological prevention.

A novel natural mutation AαPhe98Ile in the fibrinogen coiled-coil affects fibrinogen function

2014 ◽  
Vol 111 (01) ◽  
pp. 79-87 ◽  
Author(s):  
Zuzana Riedelová-Reicheltová ◽  
Roman Kotlín ◽  
Jiří Suttnar ◽  
Věra Geierová ◽  
Tomáš Riedel ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Coiled Coil ◽  
Fibrin Clot ◽  
Coiled Coil Region ◽  
Platelet Aggregometry ◽  
Sds Page ◽  
Lysis Rate ◽  
Thrombotic Complications ◽  
Natural Mutation ◽  
And Function

SummaryThe aim of this study was to investigate the structure and function of fibrinogen obtained from a patient with normal coagulation times and idiopathic thrombophilia. This was done by SDS-PAGE and DNA sequence analyses, scanning electron microscopy, fibrinopeptide release, fibrin polymerisation initiated by thrombin and reptilase, fibrinolysis, and platelet aggregometry. A novel heterozygous point mutation in the fibrinogen Aα chain, Phe98 to Ile, was found and designated as fibrinogen Vizovice. The mutation, which is located in the RGDF sequence (Aα 95–98) of the fibrinogen coiled-coil region, significantly affected fibrin clot morphology. Namely, the clot formed by fibrinogen Vizovice contained thinner and curled fibrin fibers with reduced length. Lysis of the clots prepared from Vizovice plasma and isolated fibrinogen were found to be impaired. The lysis rate of Vizovice clots was almost four times slower than the lysis rate of control clots. In the presence of platelets agonists the mutant fibrinogen caused increased platelet aggregation. The data obtained show that natural mutation of Phe98 to Ile in the fibrinogen Aα chain influences lateral aggregation of fibrin protofibrils, fibrinolysis, and platelet aggregation. They also suggest that delayed fibrinolysis, together with the abnormal fibrin network morphology and increased platelet aggregation, may be the direct cause of thrombotic complications in the patient associated with pregnancy loss.

scholarly journals A novel missense mutation in the FGB g. 3354 T>A (p. Y41N), Fibrinogen Caracas VIII

2011 ◽  
Vol 105 (04) ◽  
pp. 627-634 ◽  
Author(s):  
Héctor Rojas ◽  
Michael Meyer ◽  
Oscar Castillo ◽  
Arlette De Sáez Ruiz ◽  
John Weisel ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Fibrin Clot ◽  
Polymerization Process ◽  
Confocal Laser ◽  
Fibrinogen Concentration ◽  
Thrombin Time ◽  
Normal Range ◽  
Amino Terminal ◽  
Fibrin Network ◽  
Β Chain

SummaryA novel dysfibrinogenaemia with a replacement of Tyr by Asn at Bβ41 has been discovered (fibrinogen Caracas VIII). An asymptomatic 39-year-old male was diagnosed as having dysfibrinogenaemia due to a mildly prolonged thrombin time (+ 5.8 seconds); his fibrinogen concentration was in the low normal range, both by Clauss and gravimetric determination, 1.9 g/l and 2.1 g/l, respectively. The plasma polymerization process was slightly impaired, characterised by a mildly prolonged lag time and a slightly increased final turbidity. Permeation through the patients´ clots was dramatically increased, with the Darcy constant around four times greater than that of the control (22 ± 2 x10–9 cm2 compared to 6 ± 0.5 x10–9 cm2 in controls). The plasma fibrin structure of the patient, by scanning electron microscopy, featured a mesh composed of thick fibres (148 ± 50 nm vs. 120 ± 31 nm in controls, p<0.05) and larger pores than those of the control fibrin clot. The viscoelastic properties of the clot from the patient were also altered, as the storage modulus (G‘, 310 ± 30) was much lower than in the control (831 ± 111) (p ≤0.005). The interaction of the fibrin clot with a monolayer of human microvascular endothelial cells, by confocal laser microscopy, revealed that the patients´ fibrin network had less interaction with the cells. These results demonstrate the significance of the amino terminal end of the β chain of fibrin in the polymerisation process and its consequences on the clot organisation on the surface of endothelial cells.

Fibrinogen and factor XIII at the intersection of coagulation, fibrinolysis and inflammation

2014 ◽  
Vol 112 (10) ◽  
pp. 649-658 ◽  
Author(s):  
Berthold Hoppe
Keyword(s):  
Innate Immunity ◽  
Factor Xiii ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Coagulation Factors ◽  
Fibrin Clot ◽  
Biologically Active ◽  
Gel Formation ◽  
Fibrin Gel ◽  
Fibrin Network

SummaryFibrinogen and factor XIII are two essential proteins that are involved directly in fibrin gel formation as the final step of a sequence of reactions triggered by a procoagulant stimulus. Haemostasis is the most obvious function of the resulting fibrin clot. Different variables affect the conversion of fibrinogen to fibrin as well as the mode of fibrin polymerisation and fibrin crosslinking, hereby, critically influencing the architecture of the resulting fibrin network and consequently determining its mechanical strength and resistance against fibrinolysis. Due to fibrinogen’s structure with a multitude of domains and binding motifs the fibrin gel allows for complex interactions with other coagulation factors, with profibrinolytic as well as antifibrinolyic proteins, with complement factors and with various cellular receptors. These interactions enable the fibrin network to control its own further state (i. e. expansion or degradation), to influence innate immunity, and to function as a scaffold for cell migration processes. During the whole process of fibrin gel formation biologically active peptides and protein fragments are released that additionally influence cellular processes via chemotaxis or by modulating cell-cell interactions. Thus, it is not surprising that fibrinogen and factor XIII in addition to their haemostatic function influence innate immunity as well as cell-mediated reactions like wound healing, response to tissue injury or inflammatory processes. The present review summarises current knowledge of fibrinogen’s and factor XIII’s function in coagulation and fibrinolysis giving special emphasis on their relation to inflammation control.

scholarly journals Fibrin gels and their clinical and bioengineering applications

2008 ◽  
Vol 6 (30) ◽  
pp. 1-10 ◽  
Author(s):  
Paul A Janmey ◽  
Jessamine P Winer ◽  
John W Weisel
Keyword(s):  
Mechanical Properties ◽  
Wound Healing ◽  
Cell Migration ◽  
Network Architecture ◽  
Blood Clotting ◽  
Reaction Conditions ◽  
Fibrin Gels ◽  
Physiological Conditions ◽  
Small Strains ◽  
Fibrin Network

Fibrin gels, prepared from fibrinogen and thrombin, the key proteins involved in blood clotting, were among the first biomaterials used to prevent bleeding and promote wound healing. The unique polymerization mechanism of fibrin, which allows control of gelation times and network architecture by variation in reaction conditions, allows formation of a wide array of soft substrates under physiological conditions. Fibrin gels have been extensively studied rheologically in part because their nonlinear elasticity, characterized by soft compliance at small strains and impressive stiffening to resist larger deformations, appears essential for their function as haemostatic plugs and as matrices for cell migration and wound healing. The filaments forming a fibrin network are among the softest in nature, allowing them to deform to large extents and stiffen but not break. The biochemical and mechanical properties of fibrin have recently been exploited in numerous studies that suggest its potential for applications in medicine and bioengineering.

scholarly journals Influence of Fibrin Network Conformation and Fibrin Fiber Diameter on Fibrinolysis Speed

2000 ◽  
Vol 20 (5) ◽  
pp. 1354-1361 ◽  
Author(s):  
J. P. Collet ◽  
D. Park ◽  
C. Lesty ◽  
J. Soria ◽  
C. Soria ◽  
...  
Keyword(s):  
Fiber Diameter ◽  
Fibrin Network ◽  
Fibrin Fiber

scholarly journals BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

2017 ◽  
Vol 117 (02) ◽  
pp. 295-302 ◽  
Author(s):  
Katie A. Greenhalgh ◽  
Mark W. Strachan ◽  
Saad Alzahrani ◽  
Paul D. Baxter ◽  
Kristina F. Standeven ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Plasma Clot ◽  
Lysis Time ◽  
Increased Risk ◽  
Fibrin Network ◽  
Clot Lysis Time ◽  
Fibrin Clots

SummaryBoth type 2 diabetes (T2DM) and Bß448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BßArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BßArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BßArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BßArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bß448Lys was longer than Bß448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bß448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bß448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bβ448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BβArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies.

Multicomponent proton spin–spin relaxation of fibrin gels with magnetically oriented and randomly oriented fibrin fiber structures

2003 ◽  
Vol 93 (10) ◽  
pp. 6736-6738 ◽  
Author(s):  
Michihiro Takeuchi ◽  
Masaki Sekino ◽  
Kikuo Yamaguchi ◽  
Norio Iriguchi ◽  
Shoogo Ueno
Keyword(s):  
Spin Relaxation ◽  
Proton Spin ◽  
Fibrin Gels ◽  
Fibrin Fiber

scholarly journals Nanomechanics of Blood Clot and Thrombus Formation

2022 ◽  
Vol 51 (1) ◽  
Author(s):  
Marco M. Domingues ◽  
Filomena A. Carvalho ◽  
Nuno C. Santos
Keyword(s):  
Mechanical Properties ◽  
Thrombus Formation ◽  
Blood Clot ◽  
Fibrin Clot ◽  
Annual Review ◽  
Publication Date ◽  
New Methods ◽  
Fibrin Network ◽  
Protein Cell

Mechanical properties have been extensively studied in pure elastic or viscous materials; however, most biomaterials possess both physical properties in a viscoelastic component. How the biomechanics of a fibrin clot is related to its composition and the microenvironment where it is formed is not yet fully understood. This review gives an outline of the building mechanisms for blood clot mechanical properties and how they relate to clot function. The formation of a blood clot in health conditions or the formation of a dangerous thrombus go beyond the mere polymerization of fibrinogen into a fibrin network. The complex composition and localization of in vivo fibrin clots demonstrate the interplay between fibrin and/or fibrinogen and blood cells. Studying these protein–cell interactions and clot mechanical properties may represent new methods for the evaluation of cardiovascular diseases (the leading cause of death worldwide), creating new possibilities for clinical diagnosis, prognosis, and therapy. Expected final online publication date for the Annual Review of Biophysics, Volume 51 is May 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals von Willebrand factor competes with fibrin for occupancy of GPIIb:IIIa on thrombin-stimulated platelets

Blood ◽  
1990 ◽  
Vol 75 (4) ◽  
pp. 889-894 ◽  
Author(s):  
RR Hantgan ◽  
WL Nichols ◽  
ZM Ruggeri
Keyword(s):  
Von Willebrand Factor ◽  
Three Dimensional ◽  
Fibrin Clot ◽  
Human Platelets ◽  
Terminal Region ◽  
Platelet Surface ◽  
Fibrin Network ◽  
Dependent Inhibition ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract We have investigated two major questions related to the molecular basis of interactions between the three-dimensional fibrin network and thrombin-stimulated human platelets. First, what are the roles played by glycoproteins (GP) Ib and IIb:IIIa in linking the fibrin clot tightly to the platelet surface? Second, does von Willebrand factor (vWF) modulate the extent of platelet-fibrin interactions? Quantitative fluorescence microscopy (microfluorimetry) has been used to determine the quantity of fluorescein-labeled fibrin bound to the surface of thrombin-stimulated, gel-filtered platelets (the supernatants of which contained small quantities of vWF) in the presence/absence of receptor- specific and vWF-specific monoclonal antibodies (MoAbs), as well as exogenous vWF. A MoAb specific for the GPIIb:IIIa complex exhibited a concentration-dependent inhibition of fibrin binding, whereas a MoAb specific for GPIb was ineffective in this regard. Similarly, a MoAb that recognizes the N-terminal region of vWF involved in GPIb binding did not influence fibrin binding. In contrast, a MoAb that binds to a C- terminal region of vWF involved in GPIIb:IIIa recognition caused a specific, concentration-dependent increase in the quantity of platelet- bound fibrin. We also found that exogenous vWF caused a concentration- dependent decrease in fibrin binding. These results support the hypothesis that vWF and fibrin, both of which are multimeric adhesive ligands, compete for occupancy of the GPIIb:IIIa complex on thrombin- stimulated platelets.

scholarly journals Glycaemic control improves fibrin network characteristics in type 2 diabetes – A purified fibrinogen model

2008 ◽  
Vol 99 (04) ◽  
pp. 691-700 ◽  
Author(s):  
Namukolo Covic ◽  
Francois van der Westhuizen ◽  
Chandrasekaran Nagaswami ◽  
Yelena Baras ◽  
Du Loots ◽  
...  
Keyword(s):  
Glycaemic Control ◽  
Network Formation ◽  
Reference Group ◽  
Factor Xiiia ◽  
Network Structures ◽  
High Blood Glucose ◽  
Fibrin Network ◽  
Lysis Rate ◽  
Fibrin Clots

SummaryDiabetic subjects have been shown to have altered fibrin network structures. One proposed mechanism for this is non-enzymatic glycation of fibrinogen due to high blood glucose. We investigated whether glycaemic control would result in altered fibrin network structures due to decreased fibrinogen glycation. Twenty uncontrolled type 2 diabetic subjects were treated with insulin in order to achieve glycaemic control. Twenty age- and body mass index (BMI)-matched non-diabetic subjects were included as a reference group. Purified fibrinogen, isolated from plasma samples was used for analysis. There was a significant decrease in fibrinogen glycation (6.81 to 5.02 mol glucose/mol fibrinogen) with a corresponding decrease in rate of lateral aggregation (5.86 to 4.62) and increased permeability (2.45 to 2.85 × 10−8 cm2) and lysis rate (3.08 to 3.27 μm/min) in the diabetic subjects after glycaemic control. These variables correlated with markers of glycaemic control. Fibrin clots of non-diabetic subjects had a significantly higher ratio of inelastic to elastic deformation than the diabetic subjects (0.10 vs. 0.09). Although there was no difference in median fiber diameter between diabetic and non-diabetic subjects, there was a small increase in the proportion of thicker fibers in the diabetic samples after glycaemic control. Results from SDS-PAGE indicated no detectable difference in factor XIIIa-crosslinking of fibrin clots between uncontrolled and controlled diabetic samples. Diabetic subjects may have altered fibrin network formation kinetics which contributes to decreased pore size and lysis rate of fibrin clots. Achievement of glycaemic control and decreased fibrinogen glycation level improves permeability and lysis rates in a purified fibrinogen model

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