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Fibrinogen and a Triad of Thrombosis, Inflammation, and the Renin-Angiotensin System in Premature Coronary Artery Disease in Women: A New Insight into Sex-Related Differences in the Pathogenesis of the Disease.
Kryczka, KE, Kruk, M, Demkow, M, Lubiszewska, B
Biomolecules. 2021;(7)
Abstract
Coronary artery disease (CAD) is the leading cause of morbidity and mortality in women worldwide. Its social impact in the case of premature CAD is particularly devastating. Many differences in the presentation of the disease in women as compared to men, including atypical symptoms, microvascular involvement, and differences in pathology of plaque formation or progression, make CAD diagnosis in women a challenge. The contribution of different risk factors, such as smoking, diabetes, hyperlipidemia, or obesity, may vary between women and men. Certain pathological pathways may have different sex-related magnitudes on CAD formation and progression. In spite of the already known differences, we lack sufficiently powered studies, both clinical and experimental, that assess the multipathogenic differences in CAD formation and progression related to sex in different age periods. A growing quantity of data that are presented in this article suggest that thrombosis with fibrinogen is of more concern in the case of premature CAD in women than are other coagulation factors, such as factors VII and VIII, tissue-type plasminogen activator, and plasminogen inhibitor-1. The rise in fibrinogen levels in inflammation is mainly affected by interleukin-6 (IL-6). The renin-angiotensin (RA) system affects the inflammatory process by increasing the IL-6 level. Unlike in men, in young women, the hypertensive arm of the RA system is naturally downregulated by estrogens. At the same time, estrogens promote the fibrinolytic path of the RA system. In young women, the promoted fibrinolytic process upregulates IL-6 release from leukocytes via fibrin degradation products. Moreover, fibrinogen, whose higher levels are observed in women, increases IL-6 synthesis and exacerbates inflammation, contributing to CAD. Therefore, the synergistic interplay between thrombosis, inflammation, and the RA system appears to have a more significant influence on the underlying CAD atherosclerotic plaque formation in young women than in men. This issue is further discussed in this review. Fibrinogen is the biomolecule that is central to these three pathways. In this review, fibrinogen is shown as the biomolecule that possesses a different impact on CAD formation, progression, and destabilization in women to that observed in men, being more pathogenic in women at the early stages of the disease than in men. Fibrinogen is a three-chain glycoprotein involved in thrombosis. Although the role of thrombosis is of great magnitude in acute coronary events, fibrinogen also induces atherosclerosis formation by accumulating in the arterial wall and enabling low-density lipoprotein cholesterol aggregation. Its level rises during inflammation and is associated with most cardiovascular risk factors, particularly smoking and diabetes. It was noted that fibrinogen levels were higher in women than in men as well as in the case of premature CAD in women. The causes of this phenomenon are not well understood. The higher fibrinogen levels were found to be associated with a greater extent of coronary atherosclerosis in women with CAD but not in men. Moreover, the lysability of a fibrin clot, which is dependent on fibrinogen properties, was reduced in women with subclinical CAD compared to men at the same stage of the disease, as well as in comparison to women without coronary artery atherosclerosis. These findings suggest that the magnitude of the pathological pathways contributing to premature CAD differs in women and men, and they are discussed in this review. While many gaps in both experimental and clinical studies on sex-related differences in premature CAD exist, further studies on pathological pathways are needed.
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Extension of the Human Fibrinogen Database with Detailed Clinical Information-The αC-Connector Segment.
Sovova, Z, Pecankova, K, Majek, P, Suttnar, J
International journal of molecular sciences. 2021;(1)
Abstract
Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are manifested mainly in bleeding and thrombotic disorders. Clinically relevant mutations of fibrinogen are listed in the Human Fibrinogen Database. For the αC-connector (amino acids Aα240-410, nascent chain numbering), we have extended this database, with detailed descriptions of the clinical manifestations among members of reported families. This includes the specification of bleeding and thrombotic events and results of coagulation assays. Where available, the impact of a mutation on clotting and fibrinolysis is reported. The collected data show that the Human Fibrinogen Database reports considerably fewer missense and synonymous mutations than the general COSMIC and dbSNP databases. Homozygous nonsense or frameshift mutations in the αC-connector are responsible for most clinically relevant symptoms, while heterozygous mutations are often asymptomatic. Symptomatic subjects suffer from bleeding and, less frequently, from thrombotic events. Miscarriages within the first trimester and prolonged wound healing were reported in a few subjects. All mutations inducing thrombotic phenotypes are located at the identical positions within the consensus sequence of the tandem repeats.
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Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation.
Casini, A, Brungs, T, Lavenu-Bombled, C, Vilar, R, Neerman-Arbez, M, de Moerloose, P
Journal of thrombosis and haemostasis : JTH. 2017;(5):876-888
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Abstract
UNLABELLED Essentials Hypodysfibrinogenemia is rarely reported among the congenital fibrinogen disorders. This first systematic literature review led to identification of 51 hypodysfibrinogenemic cases. Diagnosis based only on functional/antigenic fibrinogen ratio may be insufficient. Family studies show an incomplete segregation of mutation with the clinical phenotypes. SUMMARY Background Hypodysfibrinogenemia is a rare disease characterized by decreased levels of a dysfunctional fibrinogen. It shares features with both hypo- and dysfibrinogenemia, although with specific molecular patterns and clinical phenotypes. Objectives To better define the genetics, the diagnosis and the clinical features of hypodysfibrinogenemia. Patients/Methods A systematic literature search led to 167 records. After removal of duplicates, abstract screening and full-text reviewing, 56 molecular and/or clinical studies were analyzed, including a novel FGB missense mutation in a woman with a mild bleeding phenotype. Results A total of 32 single causative mutations were reported, mainly in the COOH-terminal region of the γ or Aα chains at heterozygous or homozygous state. Seven additional hypodysfibrinogenemias were due to compound heterozygosity. The hypofibrinogenemic phenotypes were a result of an impaired assembly or secretion or an increased clearance of the fibrinogen variant, whereas the dysfibrinogenemic phenotype was mainly a result of a defective fibrin polymerization and an abnormal calcium or tPA binding. Among 51 identified index cases, a functional/antigenic fibrinogen ratio < 0.7 had a sensitivity of 86% for the diagnosis of hypodysfibrinogenemia. Eleven patients (22%) were asymptomatic at time of diagnosis, 23 (45%) had a mild bleeding phenotype with mainly obstetrical or gynecologic-related hemorrhage and 22 (43%) had experienced at least one thrombotic event, including 23 venous and eight arterial thromboses. Conclusions This first systematic review on hypodysfibrinogenemia shows the heterogeneity of causative mutations and that misdiagnosis could occur in relation to the functional and antigenic fibrinogen levels. Family studies reveal an incomplete segregation of the mutation with the clinical phenotype.
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Treatment of rare factor deficiencies in 2016.
Peyvandi, F, Menegatti, M
Hematology. American Society of Hematology. Education Program. 2016;(1):663-669
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Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation disorders characterized by fibrinogen, prothrombin, factors V, VII, X, XI, or XIII (FV, FVII, FX, FXI, or FXIII, respectively), and the combined factor V + VIII and vitamin K-dependent proteins deficiencies, representing roughly 5% of all bleeding disorders. They are usually transmitted as autosomal, recessive disorders, and the prevalence of the severe forms could range from 1 case in 500 000 for FVII up to 1 in 2-3 million for FXIII in the general population. Patients affected with RBDs may present a wide range of clinical symptoms, varying from mucocutaneous bleeding, common to all types of RBDs to the most life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Treatment of these disorders is mainly based on the replacement of the deficient factor, using specific plasma-derived or recombinant products. In countries where these facilities are not available, bleedings could be managed using cryoprecipitate, fresh frozen plasma (FFP), or virus-inactivated plasma. Minor bleedings could be managed using antifibrinolytic agents. Recently, 2 novel drugs, recombinant FXIIIA and a plasma-derived FX, have been added to the list of available specific hemostatic factors; only prothrombin and FV deficiencies still remain without a specific product. Novel no-replacement therapies, such as monoclonal antibody anti-tissue factor pathway inhibitor, RNA interference, and a bispecific antibody that is an FVIIIa mimetic, enhancing thrombin generation through different mechanisms, were developed for patients with hemophilia and may in the future be a good therapeutic option also in RBDs.
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A review of the effect of the psychosocial working environment on physiological changes in blood and urine.
Hansen, AM, Larsen, AD, Rugulies, R, Garde, AH, Knudsen, LE
Basic & clinical pharmacology & toxicology. 2009;(2):73-83
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The aim of the present survey was to provide a literary review of current knowledge of the possible association between the psychosocial working environment and relevant physiological parameters measured in blood and urine. Literature databases (PubMed, Toxline, Biosis and Embase) were screened using the key words job, work-related and stress in combination with selected physiological parameters. In total, 51 work place studies investigated the associations between the psychosocial working environment and physiological changes, of which 20 were longitudinal studies and 12 population-based studies. The studied exposures in work place/population-based studies included: job demands (26/8 studies), job control (24/10 studies), social support and/or leadership behaviour (12/3 studies), effort-reward imbalance (three/one studies), occupational changes (four studies), shift work (eight studies), traumatic events (one study) and other (five studies). The physiological responses were catecholamines (adrenaline, noradrenaline) (14 studies), cortisol (28 studies), cholesterol (23 studies), glycated haemoglobinA(1c) (six studies), testosterone (nine studies), oestrogens (three studies), dehydroepiandrosterone (six studies), prolactin (14 studies), melatonin (one study), thyroxin (one study), immunoglobulin (Ig) A (five studies), IgG (four studies), IgM (one study) and fibrinogen (eight studies). In general, fibrinogen and catabolic indicators, defined as energy releasing, were increased, whereas the anabolic indicators defined as constructive building up energy resources were decreased when the psychosocial working environment was perceived as poor. In conclusion, in this review the association between an adverse psychosocial working environment and HbA(1c), testosterone and fibrinogen in serum was found to be a robust and potential candidate for a physiological effect of the psychosocial working environment. Further, urinary catecholamines appear to reflect the effects of shift work and monotonous work.