What Is the Biological and Clinical Relevance of Fibrin?

Litvinov, Rustem I.; Weisel, John W.

doi:10.1055/s-0036-1571342

Cited by 111 publications

(76 citation statements)

References 107 publications

(106 reference statements)

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“…Non-muscle myosin IIa inside the platelet interacts with actin filaments attached to the cell membrane integrin αIIbβ3 via talin and kindlin. Fibrin or fibrinogen binds to αIIbβ3 outside the platelet to link other platelets [82, 83]. …”

Section: Rbcs In Clot Contractionmentioning

confidence: 99%

Role of red blood cells in haemostasis and thrombosis

Litvinov

Weisel

2016

ISBT Science Series

169

154

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In contrast to an obsolete notion that erythrocytes, or red blood cells (RBCs), play a passive and minor role in hemostasis and thrombosis, over the past decades there has been increasing evidence that RBCs have biologically and clinically important functions in blood clotting and its disorders. This review summarizes the main mechanisms that underlie the involvement of RBCs in hemostasis and thrombosis in vivo, such as rheological effects on blood viscosity and platelet margination, aggregation and deformability of RBCs; direct adhesion and indirect biochemical interactions with endothelial cells and platelets, etc. The ability of stored and pathologically altered RBCs to generate thrombin through exposure of phosphatidylserine has been emphasized. The procoagulant and prothrombotic potential of RBC-derived microparticles transfused with stored RBCs or formed in various pathological conditions associated with hemolysis has been described along with prothrombotic effects of free hemoglobin and heme. Binding of fibrinogen or fibrin to RBCs may influence their effects on fibrin network structure, clot mechanical properties, and fibrinolytic resistance. Recent data on platelet-driven clot contraction show that RBCs compressed by platelets pulling on fibrin form a tightly packed array of polyhedral erythrocytes, or polyhedrocytes, which comprises a nearly impermeable barrier important for hemostasis and wound healing. RBCs may perform dual roles, both helping to stem bleeding but at the same time contributing to thrombosis in a variety of ways.

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Section: Rbcs In Clot Contractionmentioning

confidence: 99%

Role of red blood cells in haemostasis and thrombosis

Litvinov

Weisel

2016

ISBT Science Series

169

154

View full text Add to dashboard Cite

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“…Key intermediaries of this manifestation are the structural components of formed thrombi. Soluble fibrinogen is cleaved by thrombin in order to form dense matrices of thin fibrous protein known as fibrin (24). Polymerized fibrin networks are essential for wound healing and other occlusive physiological processes (24).…”

Section: Introductionmentioning

confidence: 99%

The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis

Bezuidenhout

Venter

Roberts

et al. 2020

Preprint

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Objective. The risk of cardiovascular events in patients with RA is disproportionately heightened as a result of systemic inflammation. The relative effect of autoimmuneassociated citrullination on the structure and thrombotic potential of fibrin(ogen) remains unknown. We therefore compared indices of vascular function, inflammation, coagulation and fibrin clot composition in RA patients with healthy controls and evaluated inter-parameter relationships. Methods. Blood samples were collected from 30 RA patients and 25 age-and gender-matched healthy volunteers.Levels of SAA, CRP, ICAM-1 and VCAM-1 was measured using a sandwich immunoassay. Whole blood coagulation was assessed using Thromboelastography. Fibrin clot networks and fiber structure was investigated using Scanning Electron Microscopy. The detection and quantification of citrullination in formed fibrin clots were performed using a fluorescently labeled Citrulline monoclonal antibody with Confocal Microscopy. Results. Concentrations of SAA, CRP and ICAM-1 were significantly elevated in RA patients compared to controls. TEG parameters relating to coagulation initiation (R and K), rate of fibrin cross-linking (α-Angle), and time to reach maximum thrombus generation (TMRTG) were attenuated in RA patients. Parameters relating to clot strength (MA, MRTG, TGG) did not statistically differ between RA and controls. Logistic regression modelling revealed stronger association between acute phase reactants (CRP, SAA) with TEG parameters than endothelial function markers. Microscopic analysis revealed denser networks of thicker fibrin fibers in RA patients compared to controls [median (interquartile range) 214 (170-285) vs 120 (100-144) nm respectively, p<0.0001, Odds ratio=22.7). Detection of multiple citrullinated regions within fibrin clot structures in RA patients, which was less prevalent in control samples (p<0.05, OR=2.2). Conclusion.Patients with active RA display a coagulation profile that is dissimilar to general findings associated with other inflammatory conditions. The alteration of protein structures by autoimmune linked citrullination could play a role in determining the structure of fibrin and the potential of conferring a heightened thrombotic risk in RA patients.

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“…Formation of fibrin is essential for hemostasis, thrombosis, and antimicrobal host defense; fibrin is also widely used as a biomaterial. 1 Fibrin is formed from a blood plasma protein, fibrinogen, which converts to monomeric fibrin that polymerizes to form soluble fibrin protofibrils. These further elongate and aggregate laterally into insoluble thick fibers that branch to form the space-filling network ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Transition from Catch to Slip Bonds in Fibrin

Litvinov

Kononova

Zhmurov

et al. 2019

Biophysical Journal

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The lifetimes of non-covalent A:a knob-hole bonds in fibrin probed with the optical trap-based force-clamp first increases ("catch bonds") and then decreases ("slip bonds") with increasing tensile force. Molecular modeling of "catch-to-slip" transition using the atomic structure of the A:a complex reveals that the movable flap serves as tension-dependent molecular switch. Flap dissociation from the regulatory B-domain in γ-nodule and translocation from the periphery to knob 'A' triggers the hole 'a' closure and interface remodeling, which results in the increased binding affinity and prolonged bond lifetimes. Fluctuating bottleneck theory is developed to understand the "catch-to-slip" transition in terms of the interface stiffness κ = 15.7 pN nm −1 , interface size fluctuations 0.7-2.7 nm, knob 'A' escape rate constant k 0 = 0.11 nm 2 s −1 , and transition distance for dissociation σ y = 0.25 nm. Strengthening of the A:a knob-hole bonds under small tension might favor formation and reinforcement of nascent fibrin clots under hydrodynamic shear. arXiv:1709.05727v1 [physics.bio-ph] 17 Sep 2017 unusual strengthening with the increasing pulling force applied to disrupt the bond, but the nature of this finding remained unclear. Such counterintuitive behavior has been described in the literature for a number of receptor-ligand pairs as the "catch" bond 9, 10 in contrast to the commonly known "slip" bond that dissociates faster with the increasing force. Interestingly, a non-covalent bond can behave as a catch bond at low forces (typically <30-40 pN) and as a slip bond at higher forces, thus displaying the dual "catch-slip" character. Several receptor-ligand complexes showing the catch-slip transition have been characterized including coupled cell adhesion molecules and glycoprotein ligand-1, 10 E-cadherin dimer, 11 integrin α5β 1 and fibronectin, 12 bacterial adhesin FimH, 13, 14 von Willebrand factor and receptor GP1b, 15, 16 actomyosin, 17 microtubulekinetochore, 18 and microtubule-dynein 19, 20 complexes. The catch-slip phenomenon was studied experimentally 14, 15, 21-24 and computationally. 14, 25-30 Theoretical models have been purposed including the two-state model, 31, 32 two-pathway model, 33 sliding-rebinding model, 34 hydrogen bond network model, 35 and other models. 36, 37 Yet, the atomic-level structural basis underlying the catch-slip transition in receptor-ligand complexes has eluded detailed characterization 9 .Here, we combined the single-molecule forced unbinding experiments in vitro and in silico using nanomechanical measurements and Molecular Dynamics (MD) simulations to resolve the structural mechanism underlying the dual catch-slip response of fibrin polymers to tension. We show that the strength of A:a knob-hole bonds first increases with tensile force up to f ≈ 30-35 pN (catch bond) and then decreases with force at f > 35 pN (slip bonds). Forced dissociation assays in silico revealed dynamic remodeling of the A:a association interface, which results in a manifold of bound states with tension-de...

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What Is the Biological and Clinical Relevance of Fibrin?

Cited by 111 publications

References 107 publications

Role of red blood cells in haemostasis and thrombosis

Role of red blood cells in haemostasis and thrombosis

The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis

Molecular Mechanisms of Transition from Catch to Slip Bonds in Fibrin

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