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Sub-cellular Biochemistry 2017Fibrinogen and fibrin are essential for hemostasis and are major factors in thrombosis, wound healing, and several other biological functions and pathological... (Review)
Review
Fibrinogen and fibrin are essential for hemostasis and are major factors in thrombosis, wound healing, and several other biological functions and pathological conditions. The X-ray crystallographic structure of major parts of fibrin(ogen), together with computational reconstructions of missing portions and numerous biochemical and biophysical studies, have provided a wealth of data to interpret molecular mechanisms of fibrin formation, its organization, and properties. On cleavage of fibrinopeptides by thrombin, fibrinogen is converted to fibrin monomers, which interact via knobs exposed by fibrinopeptide removal in the central region, with holes always exposed at the ends of the molecules. The resulting half-staggered, double-stranded oligomers lengthen into protofibrils, which aggregate laterally to make fibers, which then branch to yield a three-dimensional network. Much is now known about the structural origins of clot mechanical properties, including changes in fiber orientation, stretching and buckling, and forced unfolding of molecular domains. Studies of congenital fibrinogen variants and post-translational modifications have increased our understanding of the structure and functions of fibrin(ogen). The fibrinolytic system, with the zymogen plasminogen binding to fibrin together with tissue-type plasminogen activator to promote activation to the active proteolytic enzyme, plasmin, results in digestion of fibrin at specific lysine residues. In spite of a great increase in our knowledge of all these interconnected processes, much about the molecular mechanisms of the biological functions of fibrin(ogen) remains unknown, including some basic aspects of clotting, fibrinolysis, and molecular origins of fibrin mechanical properties. Even less is known concerning more complex (patho)physiological implications of fibrinogen and fibrin.
Topics: Animals; Fibrin; Fibrinogen; Humans; Protein Conformation
PubMed: 28101869
DOI: 10.1007/978-3-319-49674-0_13 -
Journal of Thrombosis and Haemostasis :... Aug 2005Fibrinogen molecules are comprised of two sets of disulfide-bridged Aalpha-, Bbeta-, and gamma-chains. Each molecule contains two outer D domains connected to a central... (Review)
Review
Fibrinogen molecules are comprised of two sets of disulfide-bridged Aalpha-, Bbeta-, and gamma-chains. Each molecule contains two outer D domains connected to a central E domain by a coiled-coil segment. Fibrin is formed after thrombin cleavage of fibrinopeptide A (FPA) from fibrinogen Aalpha-chains, thus initiating fibrin polymerization. Double-stranded fibrils form through end-to-middle domain (D:E) associations, and concomitant lateral fibril associations and branching create a clot network. Fibrin assembly facilitates intermolecular antiparallel C-terminal alignment of gamma-chain pairs, which are then covalently 'cross-linked' by factor XIII ('plasma protransglutaminase') or XIIIa to form 'gamma-dimers'. In addition to its primary role of providing scaffolding for the intravascular thrombus and also accounting for important clot viscoelastic properties, fibrin(ogen) participates in other biologic functions involving unique binding sites, some of which become exposed as a consequence of fibrin formation. This review provides details about fibrinogen and fibrin structure, and correlates this information with biological functions that include: (i) suppression of plasma factor XIII-mediated cross-linking activity in blood by binding the factor XIII A2B2 complex. (ii) Non-substrate thrombin binding to fibrin, termed antithrombin I (AT-I), which down-regulates thrombin generation in clotting blood. (iii) Tissue-type plasminogen activator (tPA)-stimulated plasminogen activation by fibrin that results from formation of a ternary tPA-plasminogen-fibrin complex. Binding of inhibitors such as alpha2-antiplasmin, plasminogen activator inhibitor-2, lipoprotein(a), or histidine-rich glycoprotein, impairs plasminogen activation. (iv) Enhanced interactions with the extracellular matrix by binding of fibronectin to fibrin(ogen). (v) Molecular and cellular interactions of fibrin beta15-42. This sequence binds to heparin and mediates platelet and endothelial cell spreading, fibroblast proliferation, and capillary tube formation. Interactions between beta15-42 and vascular endothelial (VE)-cadherin, an endothelial cell receptor, also promote capillary tube formation and angiogenesis. These activities are enhanced by binding of growth factors like fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF), and cytokines like interleukin (IL)-1. (vi) Fibrinogen binding to the platelet alpha(IIb)beta3 receptor, which is important for incorporating platelets into a developing thrombus. (vii) Leukocyte binding to fibrin(ogen) via integrin alpha(M)beta2 (Mac-1), which is a high affinity receptor on stimulated monocytes and neutrophils.
Topics: Amino Acid Sequence; Animals; Cross-Linking Reagents; Cytokines; Endothelial Cells; Factor XIII; Fibrin; Fibrinogen; Fibrinolysis; Growth Substances; Humans; Leukocytes; Models, Biological; Models, Molecular; Molecular Sequence Data; Protein Conformation; Time Factors
PubMed: 16102057
DOI: 10.1111/j.1538-7836.2005.01365.x -
Current Drug Targets 2022Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the highly pathogenic and highly transmissible human coronavirus that is the causative agent for the... (Review)
Review
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the highly pathogenic and highly transmissible human coronavirus that is the causative agent for the worldwide COVID-19 pandemic. COVID-19 manifests predominantly as a respiratory illness with symptoms consistent with viral pneumonia, but other organ systems (e.g., kidney, heart, brain) can also become perturbed in COVID-19 patients. Accumulating data suggest that significant activation of the hemostatic system is a common pathological manifestation of SARS-CoV-2 infection. The clotting protein fibrinogen is one of the most abundant plasma proteins. Following activation of coagulation, the central coagulation protease thrombin converts fibrinogen to fibrin monomers, which selfassemble to form a matrix, the primary structural component of the blood clot. Severe COVID-19 is associated with a profound perturbation of circulating fibrinogen, intra- and extravascular fibrin deposition and persistence, and fibrin degradation. Current findings suggest high levels of fibrinogen and the fibrin degradation product D-dimer are biomarkers of poor prognosis in COVID-19. Moreover, emerging studies with in vitro and animal models indicate fibrin(ogen) as an active player in COVID-19 pathogenesis. Here, we review the current literature regarding fibrin(ogen) and COVID-19, including possible pathogenic mechanisms and treatment strategies centered on clotting and fibrin(ogen) function.
Topics: Humans; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrin; Pandemics; COVID-19; SARS-CoV-2
PubMed: 36029073
DOI: 10.2174/1389450123666220826162900 -
Journal of Thrombosis and Haemostasis :... Jan 2022Polymeric fibrin displays unique structural and biomechanical properties that contribute to its essential role of generating blood clots that stem bleeds. The aim of... (Review)
Review
Polymeric fibrin displays unique structural and biomechanical properties that contribute to its essential role of generating blood clots that stem bleeds. The aim of this review is to discuss how the fibrin clot is formed, how protofibrils make up individual fibrin fibers, what the relationship is between the molecular structure and fibrin biomechanical properties, and how fibrin biomechanical properties relate to the risk of thromboembolic disease. Fibrin polymerization is driven by different types of bonds, including knob-hole interactions displaying catch-slip characteristics, and covalent crosslinking of fibrin polypeptides by activated factor XIII. Key biophysical properties of fibrin polymer are its visco-elasticity, extensibility and resistance to rupture. The internal packing of protofibrils within fibers changes fibrin biomechanical behavior. There are several methods to analyze fibrin biomechanical properties at different scales, including AFM force spectroscopy, magnetic or optical tweezers and rheometry, amongst others. Clinically, fibrin biomechanical characteristics are key for the prevention of thromboembolic disorders such as pulmonary embolism. Future studies are needed to address unanswered questions regarding internal molecular structure of the fibrin polymer, the structural and molecular basis of its remarkable mechanical properties and the relationship of fibrin biomechanical characteristics with thromboembolism in patients with deep vein thrombosis and ischemic stroke.
Topics: Elasticity; Factor XIIIa; Fibrin; Hemostasis; Humans; Thromboembolism; Thrombosis
PubMed: 34528378
DOI: 10.1111/jth.15531 -
Arteriosclerosis, Thrombosis, and... Mar 2017
Review
Topics: Animals; Fibrin; Fibrinogen; Fibrinolytic Agents; Hemostasis; Hemostatics; Humans; Protein Conformation; Protein Processing, Post-Translational; Protein Stability; Structure-Activity Relationship; Thrombin; Thrombosis
PubMed: 28228446
DOI: 10.1161/ATVBAHA.117.308564 -
Methods in Molecular Biology (Clifton,... 2012The study of clot retraction in vitro has been adopted as a simple and reproducible approach to assess platelet function. Plasma clots should retract away from the sides...
The study of clot retraction in vitro has been adopted as a simple and reproducible approach to assess platelet function. Plasma clots should retract away from the sides of a glass tube within a few hours allowing the rapid characterization of outside-in signaling through platelet integrin α(IIb)β(3). In this chapter, we describe the role of platelets in fibrin clot retraction and provide a detailed description of the methods used to assess this process.
Topics: Animals; Biological Assay; Blood Platelets; Clot Retraction; Fibrin; Humans; Mice
PubMed: 22130703
DOI: 10.1007/978-1-61779-307-3_8 -
European Journal of Vascular and... Mar 2018The physical properties of a venous thrombus are derived from molecular characteristics, including fibrin polymer diameter, density, branching, and cross-linking. Dense... (Review)
Review
BACKGROUND
The physical properties of a venous thrombus are derived from molecular characteristics, including fibrin polymer diameter, density, branching, and cross-linking. Dense thrombi with thin, highly branched fibrin fibres and small pores in the meshwork have been observed to be more rigid, less permeable, and more resistant to lysis. The three dimensional fibrin meshwork acts as the main structure to entrap and capture erythrocytes, platelets and plasma components. Attached factors become integrated into the developing thrombus, co-localise with fibrin deposition and act in either a pro- or anticoagulant capacity. Similarly, factors including blood flow, osmolarity and pH, oxidative stress, platelet and leukocyte recruitment, and thrombin concentration alter thrombus composition, architecture, and its mechanical properties.
CONCLUSIONS
Over time, an increase in thrombus cellular composition and a linear decrease in fibrin content as a function of thrombus age is observed. However, little else is known regarding the evolution of fibrin based clots. The role of fibrin in mediating cellular coordination, thrombus maturation, and changes of the venous wall also requires further research. This review discusses the current impact of fibrin on thrombus remodeling and addresses the limitations of the work done in this area.
Topics: Animals; Blood Coagulation; Elasticity; Fibrin; Fibrinolysis; Humans; Protein Conformation; Structure-Activity Relationship; Time Factors; Vascular Remodeling; Veins; Venous Thrombosis; Viscosity
PubMed: 29336975
DOI: 10.1016/j.ejvs.2017.12.002 -
International Journal of Nanomedicine 2017Tissue engineering has emerged as a new treatment approach for bone repair and regeneration seeking to address limitations associated with current therapies, such as... (Review)
Review
Tissue engineering has emerged as a new treatment approach for bone repair and regeneration seeking to address limitations associated with current therapies, such as autologous bone grafting. While many bone tissue engineering approaches have traditionally focused on synthetic materials (such as polymers or hydrogels), there has been a lot of excitement surrounding the use of natural materials due to their biologically inspired properties. Fibrin is a natural scaffold formed following tissue injury that initiates hemostasis and provides the initial matrix useful for cell adhesion, migration, proliferation, and differentiation. Fibrin has captured the interest of bone tissue engineers due to its excellent biocompatibility, controllable biodegradability, and ability to deliver cells and biomolecules. Fibrin is particularly appealing because its precursors, fibrinogen, and thrombin, which can be derived from the patient's own blood, enable the fabrication of completely autologous scaffolds. In this article, we highlight the unique properties of fibrin as a scaffolding material to treat bone defects. Moreover, we emphasize its role in bone tissue engineering nanocomposites where approaches further emulate the natural nanostructured features of bone when using fibrin and other nanomaterials. We also review the preparation methods of fibrin glue and then discuss a wide range of fibrin applications in bone tissue engineering. These include the delivery of cells and/or biomolecules to a defect site, distributing cells, and/or growth factors throughout other pre-formed scaffolds and enhancing the physical as well as biological properties of other biomaterials. Thoughts on the future direction of fibrin research for bone tissue engineering are also presented. In the future, the development of fibrin precursors as recombinant proteins will solve problems associated with using multiple or single-donor fibrin glue, and the combination of nanomaterials that allow for the incorporation of biomolecules with fibrin will significantly improve the efficacy of fibrin for numerous bone tissue engineering applications.
Topics: Biocompatible Materials; Bone Regeneration; Bone and Bones; Cell Adhesion; Cell Differentiation; Fibrin; Fibrin Tissue Adhesive; Fibrinogen; Humans; Hydrogels; Nanocomposites; Nanomedicine; Tissue Engineering; Tissue Scaffolds
PubMed: 28761338
DOI: 10.2147/IJN.S124671 -
Journal of Thrombosis and Haemostasis :... Jun 2013Fibrinogen is an abundant plasma protein that, when converted to fibrin by thrombin, provides the main building blocks for the clot. Dys-, a-, and hypo-fibrinogenemias... (Review)
Review
Fibrinogen is an abundant plasma protein that, when converted to fibrin by thrombin, provides the main building blocks for the clot. Dys-, a-, and hypo-fibrinogenemias have been variably linked to a normal phenotype, bleeding or even thrombosis. Meanwhile, increased fibrinogen concentrations in the blood have been associated with risk for thrombosis. More recently, studies have focussed on abnormal fibrin structure as a cause for thrombosis. Fibrin clots that have high fiber density and increased resistance to fibrinolysis have been consistently associated with risk for thrombosis. Fibrin structure measurements can (i) provide an overall assessment of hemostatic capacity of a sample, (ii) include effects of thrombin generation and fibrinogen concentrations, (iii) include effects of fibrinogen mutations, polymorphisms, and modifications, and (iv) give an indication of clot mechanical strength and resistance to fibrinolysis. A fibrinogen splice variation of the γ-chain (γ') is discussed as a model for changes in fibrin structure in relation to thrombosis. Results from prospective studies on fibrin structure are awaited. Studies of fibrin formation under flow, interactions of fibrin with blood cells, the mechanical properties of the fibrin clot, and nanoscale/molecular characterization of fibrin formation are likely to expose new causal mechanisms for the role of fibrin in thrombotic disease. Future studies into the causality and mechanisms may lead to new opportunities using fibrin structure in the diagnosis or treatment of thrombosis.
Topics: Causality; Fibrin; Fibrinogen; Humans; Thrombosis
PubMed: 23809133
DOI: 10.1111/jth.12229 -
Matrix Biology : Journal of the... Jul 2017Fibrin is a protein polymer that is essential for hemostasis and thrombosis, wound healing, and several other biological functions and pathological conditions that... (Review)
Review
Fibrin is a protein polymer that is essential for hemostasis and thrombosis, wound healing, and several other biological functions and pathological conditions that involve extracellular matrix. In addition to molecular and cellular interactions, fibrin mechanics has been recently shown to underlie clot behavior in the highly dynamic intra- and extravascular environments. Fibrin has both elastic and viscous properties. Perhaps the most remarkable rheological feature of the fibrin network is an extremely high elasticity and stability despite very low protein content. Another important mechanical property that is common to many filamentous protein polymers but not other polymers is stiffening occurring in response to shear, tension, or compression. New data has begun to provide a structural basis for the unique mechanical behavior of fibrin that originates from its complex multi-scale hierarchical structure. The mechanical behavior of the whole fibrin gel is governed largely by the properties of single fibers and their ensembles, including changes in fiber orientation, stretching, bending, and buckling. The properties of individual fibrin fibers are determined by the number and packing arrangements of double-stranded half-staggered protofibrils, which still remain poorly understood. It has also been proposed that forced unfolding of sub-molecular structures, including elongation of flexible and relatively unstructured portions of fibrin molecules, can contribute to fibrin deformations. In spite of a great increase in our knowledge of the structural mechanics of fibrin, much about the mechanisms of fibrin's biological functions remains unknown. Fibrin deformability is not only an essential part of the biomechanics of hemostasis and thrombosis, but also a rapidly developing field of bioengineering that uses fibrin as a versatile biomaterial with exceptional and tunable biochemical and mechanical properties.
Topics: Biomechanical Phenomena; Blood Coagulation; Elasticity; Extracellular Matrix; Fibrin; Humans; Protein Stability; Rheology; Stress, Mechanical; Tissue Engineering; Viscosity; Wound Healing
PubMed: 27553509
DOI: 10.1016/j.matbio.2016.08.003