Page 50 - 2020_02-Haematologica-web

Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):284-296
Fibrin(ogen) in human disease: both friend and foe
Rui Vilar,1 Richard J. Fish,1 Alessandro Casini2 and Marguerite Neerman-Arbez1,3
1Department of Genetic Medicine and Development, University of Geneva Faculty of Medicine, 2Division of Angiology and Hemostasis, University Hospitals and University of Geneva Faculty of Medicine and 3iGE3, Institute of Genetics and Genomics in Geneva, Geneva, Switzerland
ABSTRACT
Fibrinogen is an abundant protein synthesized in the liver, present in human blood plasma at concentrations ranging from 1.5-4 g/L in healthy individuals with a normal half-life of 3-5 days. With fibrin, pro- duced by thrombin-mediated cleavage, fibrinogen plays important roles in many physiological processes. Indeed, the formation of a stable blood clot, containing polymerized and cross-linked fibrin, is crucial to prevent blood loss and drive wound healing upon vascular injury. A balance between clot- ting, notably the conversion of fibrinogen to fibrin, and fibrinolysis, the pro- teolytic degradation of the fibrin mesh, is essential. Disruption of this equi- librium can cause disease in distinct manners. While some pathological con- ditions are the consequence of altered levels of fibrinogen, others are related to structural properties of the molecule. The source of fibrinogen expression and the localization of fibrin(ogen) protein also have clinical implications. Low levels of fibrinogen expression have been detected in extra-hepatic tis- sues, including carcinomas, potentially contributing to disease. Fibrin(ogen) deposits at aberrant sites including the central nervous system or kidney, can also be pathological. In this review, we discuss disorders in which fib- rinogen and fibrin are implicated, highlighting mechanisms that may con- tribute to disease.
Introduction
Fibrinogen biosynthesis takes place in hepatocytes, starting with expression of three genes, FGA, FGB and FGG, clustered in a 50 kb region of human chromo- some 4. The genes encode fibrinogen Aα, Bβ and γ chains, respectively. Both FGA and FGG are transcribed to produce two transcripts. The major transcript encoding Aα is transcribed from five exons, but a minor transcript, resulting from splicing of a sixth exon, encodes the AαE chain which is present in 1-3% of circulating fibrino- gen molecules. For FGG, a major γ chain mRNA is transcribed from ten exons while in the minor γ’ chain intron 9 is retained, substituting the four amino acids encoded by exon 10 with 20 γ’ COOH-terminal residues. γ/γ’ and γ’/γ’ represent approxi- mately 8 to 15% of a healthy person’s total fibrinogen.1,2
The fibrinogen genes are co-regulated both for basal expression and when upreg- ulated upon an inflammation-driven acute phase response.3 The latter leads to a prompt increase in plasma fibrinogen after bleeding or clotting events, or to support wound healing.3 Each fibrinogen gene is thought to be regulated by a proximal pro- moter and local enhancer elements. These appear to act together with tissue- restricted transcription factors, regulatory chromatin marks and a looped architec- ture to co-regulate expression of the three-gene cluster.4,5 CpG DNA methylation of the fibrinogen regulatory regions,6 and microRNA7,8 can also contribute to cell- and state-specific fibrinogen expression.
Fibrinogen mRNA are translated into nascent polypeptides with signal peptides that are cleaved in the lumen of the endoplasmic reticulum. Here the chains assem- ble, with the assistance of chaperones, first as Aα-γ or Bβ-γ dimers and then as trimeric molecules, by addition of the missing chain. NH2-terminal disulfide bridges connect two trimers producing hexameric molecules. These transit to the Golgi apparatus, where the final Bβ and γ chain N-glycosylation steps take place.9 While
Correspondence:
MARGUERITE NEERMAN-ARBEZ
marguerite.neerman-arbez@unige.ch
Received: September 19, 2019. Accepted: November 21, 2019. Pre-published: January 16, 2020.
doi:10.3324/haematol.2019.236901
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/284
©2020 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
284
haematologica | 2020; 105(2)
REVIEW ARTICLE