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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 -
British Journal of Anaesthesia Dec 2014Cryoprecipitate, originally developed as a therapy for patients with antihaemophilic factor deficiency, or haemophilia A, has been in use for almost 50 yr. However,... (Review)
Review
Cryoprecipitate, originally developed as a therapy for patients with antihaemophilic factor deficiency, or haemophilia A, has been in use for almost 50 yr. However, cryoprecipitate is no longer administered according to its original purpose, and is now most commonly used to replenish fibrinogen levels in patients with acquired coagulopathy, such as in clinical settings with haemorrhage including cardiac surgery, trauma, liver transplantation (LT), or obstetric haemorrhage. Cryoprecipitate is a pooled product that does not undergo pathogen inactivation, and its administration has been associated with a number of adverse events, particularly transmission of blood-borne pathogens and transfusion-related acute lung injury. As a result of these safety concerns, along with emerging availability of alternative fibrinogen preparations, cryoprecipitate has been withdrawn from use in a number of European countries. Compared with the plasma from which it is prepared, cryoprecipitate contains a high concentration of coagulation factor VIII, coagulation factor XIII, and fibrinogen. Cryoprecipitate is usually licensed by regulatory authorities for the treatment of hypofibrinogenaemia, and recommended for supplementation when plasma fibrinogen levels decrease below 1 g litre(-1); however, this threshold is empiric and is not based on solid clinical evidence. Consequently, there is uncertainty over the appropriate dosing and optimal administration of cryoprecipitate, with some guidelines from professional societies to guide clinical practice. Randomized, controlled trials are needed to determine the clinical efficacy of cryoprecipitate, compared with the efficacy of alternative preparations. These trials will allow the development of evidence-based guidelines in order to inform physicians and guide clinical practice.
Topics: Blood Coagulation Disorders; Coagulants; Drug Administration Schedule; Drug Approval; Drug Costs; Drug Monitoring; Factor VIII; Fibrinogen; Humans; Practice Guidelines as Topic
PubMed: 24972790
DOI: 10.1093/bja/aeu158 -
Arquivos Brasileiros de Cardiologia Feb 2017
Topics: Atherosclerosis; Fibrinogen; Humans; Risk Factors
PubMed: 28327873
DOI: 10.5935/abc.20170017 -
Seminars in Thrombosis and Hemostasis Mar 2016Fibrinogen has a central role in coagulation. Following trauma and perioperatively, low fibrinogen levels have been found to be risk factors for exaggerated bleeding,... (Review)
Review
Fibrinogen has a central role in coagulation. Following trauma and perioperatively, low fibrinogen levels have been found to be risk factors for exaggerated bleeding, transfusion needs, and adverse outcome. Conversely, treatment with exogenous fibrinogen in critically bleeding patients with low fibrinogen levels has been shown to decrease transfusion needs. Because following trauma and in many perioperative situations fibrinogen is the first coagulation "element" to become critically low, it appears reasonable to target fibrinogen in clinical coagulation algorithms aiming at early specific and goal-directed treatment. A low fibrinogen can be a low plasma concentration or a low functional fibrinogen as assessed by point-of-care techniques such as thromboelastography (TEG) or thromboelastometry (ROTEM). This review summarizes the evidence base for perioperative algorithm-based fibrinogen administration, including the exact thresholds for fibrinogen administration used in the different algorithms. Algorithm-based individualized goal-directed use of fibrinogen resulted in highly significant reduction in transfusion needs, adverse outcomes, in certain studies even mortality, and where investigated reduced costs, with high safety levels at the same time. Best evidence exists in cardiac surgery, followed by trauma, postpartum hemorrhage, and liver transplantation. The introduction of these concepts is highly demanding and requires a tremendous educational effort to familiarize all health care workers with the necessary knowledge and the skills of how to run TEG/ROTEM tests. Future research is needed to compare the efficacy, safety, and costs of different algorithms. This, however, should not prevent us from introducing these expedient point-of-care-based algorithms clinically today.
Topics: Algorithms; Blood Coagulation; Cardiac Surgical Procedures; Female; Fibrinogen; Humans; Male; Perioperative Care; Postpartum Hemorrhage; Wounds and Injuries
PubMed: 26716503
DOI: 10.1055/s-0035-1564841 -
Acta Haematologica 2021Congenital fibrinogen deficiency is an inherited disorder due to genetic mutations with diverse presentations arising from reduced fibrinogen levels... (Review)
Review
Congenital fibrinogen deficiency is an inherited disorder due to genetic mutations with diverse presentations arising from reduced fibrinogen levels (hypofibrinogenemia), absence of fibrinogen in circulation (afibrinogenemia), abnormal functioning (dysfibrinogenemia) or both reduced levels and abnormal functioning (hypodysfibrinogenemia) of fibrinogen. The decreased fibrinogen concentration in congenital fibrinogen deficiency necessitates fibrinogen replacement therapy with fresh frozen plasma, cryoprecipitate, or human fibrinogen concentrate. However, the use of fresh frozen plasma and cryoprecipitate is limited owing to their longer transfusion time, requirement of high doses, volume overload, risk of viral transmission, and other safety concerns. The availability of human fibrinogen concentrate has made it the preferred replacement alternative due to its reduced risk of viral transmission, smaller infusion volume, and accurate dosing. The hemostatic efficacy and safety of human fibrinogen concentrate in congenital fibrinogen deficiency is well established in the literature. We review the prevalence of congenital fibrinogen deficiency in India and the current role of human fibrinogen concentrate in its management.
Topics: Afibrinogenemia; Blood Transfusion; Fibrinogen; Guidelines as Topic; Humans; India; Plasma
PubMed: 34091452
DOI: 10.1159/000516339 -
Annales de Biologie Clinique Aug 2016Congenital fibrinogen disorders comprise quantitative disorders defined by a complete absence (afibrinogenemia) or by a decreased level (hypofibrinogenemia) of... (Review)
Review
Congenital fibrinogen disorders comprise quantitative disorders defined by a complete absence (afibrinogenemia) or by a decreased level (hypofibrinogenemia) of circulating fibrinogen and qualitative disorders characterized by a discrepancy between the activity and the antigenic levels of fibrinogen (dysfibrinogenemia and hypodysfibrinogenemia). The biological diagnosis is based on a standard haemostasis assessment. All the coagulation tests that depend on the formation of fibrin as the end point are affected; although in dysfibrinogenemia the specificity and sensitivity of routine test depend on reagent and techniques. A genetic exploration permits to confirm the diagnosis and may enhance the prediction of the patient's phenotype. Homozygous or composite heterozygous null mutations are most often responsible for afibrinogenemia while hypofibrinogenemic patients are mainly heterozygous carrier of an afibrinogenemic allele. Heterozygous missense mutations are prevalent in dysfibrinogenemia, with two hot spot localized in exon 2 of the FGA and in the exon 8 of the FGG. The correlation between phenotype and genotype has been identified in some fibrinogen variants, including six mutations clustered in exons 8 and 9 of the FGG leading to hypofibrinogenemia with hepatic inclusions of abnormal fibrinogen aggregates as well as a few mutations associated with an increase risk of thrombotic events. A familial screening and additional functional assays should be carried out when possible.
Topics: Afibrinogenemia; Blood Coagulation; Blood Coagulation Disorders, Inherited; Clinical Laboratory Techniques; Diagnosis, Differential; Fibrinogen; Fibrinogens, Abnormal; Humans; Molecular Diagnostic Techniques
PubMed: 27492693
DOI: 10.1684/abc.2016.1167 -
International Journal of Molecular... Dec 2021Atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease, cerebrovascular disease, and peripheral arterial disease, represent a significant... (Review)
Review
Atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease, cerebrovascular disease, and peripheral arterial disease, represent a significant cause of premature death worldwide. Biomarkers, the evaluation of which would allow the detection of ASCVD at the earliest stage of development, are intensively sought. Moreover, from a clinical point of view, a valuable biomarker should also enable the assessment of the patient's prognosis. It has been known for many years that the concentration of fibrinogen in plasma increases, inter alia, in patients with ASCVD. On the one hand, an increased plasma fibrinogen concentration may be the cause of the development of atherosclerotic lesions (increased risk of atherothrombosis); on the other hand, it may be a biomarker of ASCVD, as it is an acute phase protein. In addition, a number of genetic polymorphisms and post-translational modifications of fibrinogen were demonstrated that may contribute to the risk of ASCVD. This review summarizes the current data on the importance of fibrinogen as a biomarker of ASCVD, and also presents the relationship between molecular modifications of this protein in the context of ASCVD.
Topics: Animals; Atherosclerosis; Blood Coagulation; Fibrinogen; Humans; Prognosis; RNA Processing, Post-Transcriptional; Risk Factors
PubMed: 35008616
DOI: 10.3390/ijms23010193 -
International Journal of Molecular... Jan 2018The study of inherited fibrinogen disorders, characterized by extensive allelic heterogeneity, allows the association of defined mutations with specific defects... (Review)
Review
The study of inherited fibrinogen disorders, characterized by extensive allelic heterogeneity, allows the association of defined mutations with specific defects providing significant insight into the location of functionally important sites in fibrinogen and fibrin. Since the identification of the first causative mutation for congenital afibrinogenemia, studies have elucidated the underlying molecular pathophysiology of numerous causative mutations leading to fibrinogen deficiency, developed cell-based and animal models to study human fibrinogen disorders, and further explored the clinical consequences of absent, low, or dysfunctional fibrinogen. Since qualitative disorders are addressed by another review in this special issue, this review will focus on quantitative disorders and will discuss their diagnosis, clinical features, molecular bases, and introduce new models to study the phenotypic consequences of fibrinogen deficiency.
Topics: Afibrinogenemia; Animals; Disease Models, Animal; Fibrinogen; Humans; Phenotype
PubMed: 29316703
DOI: 10.3390/ijms19010192 -
International Journal of Molecular... May 2018Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been... (Review)
Review
Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been identified in individuals with fibrinogen disorders. The complexity of the fibrinogen molecules, formed by three non-identical chains and with a trinodal organization, renders the identification of molecular causes and of clinical and biochemical phenotypes very challenging. However, the acknowledgement of the type of molecular defect is crucial for a safer therapy, which is going to improve the clinical management of these patients. In this review, some aspects concerning molecular and clinical findings available on congenital fibrinogen disorders will be discussed.
Topics: Afibrinogenemia; Fibrinogen; Humans
PubMed: 29844251
DOI: 10.3390/ijms19061597 -
Journal of Biomedical Materials... Oct 2018Fibrinogen (Fg) adsorption is an important mechanism underlying cell adhesion to biomaterials and was the major focus of the author's research career. This article... (Review)
Review
Fibrinogen (Fg) adsorption is an important mechanism underlying cell adhesion to biomaterials and was the major focus of the author's research career. This article summarizes our work on Fg adsorption, with citations of related work as appropriate. The molecular properties of Fg that promote adsorption and cell adhesion will be described. In addition, the adsorption behavior of Fg from buffer, binary solutions with other proteins, and blood plasma will be discussed, including the Vroman effect. Studies of platelet adhesion to surfaces preadsorbed with blood plasmas selectively deficient in Fg, vitronectin (Vn), fibronectin (Fn), or von Willebrand's factor (vWf) will be reviewed. These studies clearly showed a major role for Fg in platelet adhesion under static conditions and both Fg and vWf for adhesion from flowing suspensions, but no significant role for Vn or Fn. However, it was also shown that platelet adhesion was poorly correlated with the total amount of adsorbed Fg, but very well correlated with the binding of antibodies specific to the cell binding domains of Fg. A brief overview of nonfouling surfaces for prevention of Fg adsorption will be given. A more extensive discussion of structural changes in Fg after its adsorption is included, including changes detected with both physicochemical and biological methods. A short discussion of the state of the art of structural determination of adsorbed proteins with computational methods is also given. A final section identifies Fg adsorption as the single most important event determining the biocompatibility of implants in soft tissue and in blood. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2777-2788, 2018.
Topics: Adsorption; Animals; Biocompatible Materials; Biofouling; Fibrinogen; Humans; Monocytes; Platelet Adhesiveness
PubMed: 29896846
DOI: 10.1002/jbm.a.36460