Regulation of fibrinogen synthesis
Dre’Von A. Dobson a), Richard J. Fish b), Paul S. de Vries c), Alanna C. Morrison c), Marguerite Neerman-Arbez b), Alisa S. Wolberg a)
a – Department of Pathology and Laboratory Medicine and UNC Blood Research Center, The University of North Carolina at Chapel Hill, NC, USA
b – Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
c – Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
Abstract
The plasma protein fibrinogen is encoded by 3 structural genes (FGA, FGB, and FGG) that are transcribed to mRNA, spliced, and translated to 3 polypeptide chains (Aα, Bβ, and γ, respectively). These chains are targeted for secretion, decorated with post-translational modifications, and assembled into a hexameric “dimer of trimers” (AαBβγ)2. Fully assembled fibrinogen is secreted into the blood as a 340 kDa glycoprotein. Fibrinogen is one of the most prevalent coagulation proteins in blood, and its expression is induced by inflammatory cytokines, wherein circulating fibrinogen levels may increase up to 3-fold during acute inflammatory events. Abnormal levels of circulating fibrinogen are associated with bleeding and thrombotic disorders, as well as several inflammatory diseases. Notably, therapeutic strategies to modulate fibrinogen levels have shown promise in experimental models of disease. Herein, we review pathways mediating fibrinogen synthesis, from gene expression to secretion. Knowledge of these mechanisms may lead to the identification of biomarkers and new therapeutic targets to modulate fibrinogen in health and disease.
Introduction
Fibrinogen is a 340 kDa glycoprotein that circulates in blood. Following activation of coagulation, thrombin proteolytically cleaves fibrinogen to form fibrin. Fibrin entraps blood cells within the consolidated clot, and increases the clot’s mechanical strength and stability. There is wide variation in circulating fibrinogen levels among healthy individuals (2–4 mg/mL). Fibrinogen is essential for hemostasis, but abnormal fibrinogen levels are associated with hemostatic and thrombotic disorders [1]. Partial or complete loss of circulating fibrinogen and/or the presence of abnormal fibrinogen can cause bleeding and/or thrombosis [[2], [3], [4]]. Elevated fibrinogen (hyperfibrinogenemia) has been implicated in cardiovascular disease and thrombosis risk [[5], [6], [7], [8], [9], [10], [11], [12], [13]], as well as inflammatory diseases including obesity [14,15], neurological disorders [[16], [17], [18]], cancer metastasis [19], and bacterial and viral infections [20,21]. Accordingly, therapeutic strategies to modulate fibrinogen levels have shown promise in clinical studies, as well as experimental models of these pathologies [[22], [23], [24], [25], [26], [27], [28]]. Collectively, these observations underscore the importance of defining mechanisms that determine circulating fibrinogen levels. Here, we present a narrative review of the published literature on pathways mediating fibrinogen synthesis, from gene expression to secretion.