International Journal of Molecular Sciences Review Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders Giovanni Luca Tiscia 1 and Maurizio Margaglione 2,* ID 1 Atherosclerosis and Thrombosis Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; [email protected] 2 Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy * Correspondence: [email protected]; Tel.: +39-0881-733-842 Received: 15 April 2018; Accepted: 25 May 2018; Published: 29 May 2018 Abstract: 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. Keywords: afibrinogenemia; hypofibrinogenemia; dysfibrinogenemia 1. Introduction Fibrinogen is a 45 nm-long plasma glycoprotein with a molecular weight of 340 KDa. It is synthetized in the liver [1] and has a plasma concentration of 1.5–3.5 g/L. Structurally, it consists of 2 identical monomers, each constituted by 3 non-identical polypeptide chains, namely alpha, beta and gamma chains [2–4], which interact through 17 crucial inter-chains disulfide bridges, to ensure structural stabilization of the fibrinogen molecules [5,6]. Fibrinogen has a typical trinodal organization, presenting one central (node E) and two distal nodes (nodes D) [7]. The central one is characterized by N-terminal ends of the six polypeptide chains, while the distal ones are made by C-terminal ends of beta and gamma chains, whereas the C-terminal of the alpha chain folds to further form the central node [8–10]. The central and distal nodes are connected through coiled-coil regions, built by three α-helices of the three fibrinogen chains, wound around each other. The fibrinogen has a well-established role in the clotting enzymatic cascade, representing the fibrin polymer precursor. The impaired mechanism of fibrinogen formation and fibrin polymerization can have a clinical impact on the occurrence and outcome of various diseases, such as coagulopathies, or ischemic stroke and also obstetrical complications [11]. Fibrinogen disorders may also have a clinical impact on afore-mentioned diseases. Fibrinogen is an acute phase protein that is part of the coagulation cascade and is converted into the insoluble protein fibrin during the clotting process. The activated thrombin or Factor II (FIIa) converts fibrinogen to fibrin in response to bleeding. FIIa rapidly proteolyses fibrinogen, releasing two peptides, fibrinopeptide A and fibrinopeptide B, from fibrin and, in turn, forms fibrin monomers, which spontaneously polymerize to form an insoluble gel. Then, fibrin molecules, the major component of the blood clot, combine to form long fibrin threads that entangle platelets, building up a spongy mass that gradually hardens and contracts to form the blood clot, blocking the damaged blood vessel and preventing further bleeding (Figure1). The polymerized Int. J. Mol. Sci. 2018, 19, 1597; doi:10.3390/ijms19061597 www.mdpi.com/journal/ijms Int.Int. J. J. Mol. Mol. Sci.Sci. 20182018,, 1919,, 1597x FOR PEER REVIEW 2 2of of 12 12 bleeding (Figure 1). The polymerized fibrin molecules are held together by non-covalent and fibrinelectrostatic molecules forces are and held stabilized together by bythe non-covalenttransamidating and enzyme, electrostatic factor XIIIa, forces that and is stabilizedproduced by by the the transamidatingaction of FIIa on enzyme, FXIII. 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Because congenital fibrinogen disorders are rare, to not duplicate available articles reviewing and colleagues [17]. Because congenital fibrinogen disorders are rare, to not duplicate available the literature, we attempt to provide an update, focusing on molecular aspects and articles reviewing the literature, we attempt to provide an update, focusing on molecular aspects genotype-phenotype correlations in quantitative (afibrinogenemia, hypofibrinogenemia) and and genotype-phenotype correlations in quantitative (afibrinogenemia, hypofibrinogenemia) and functional disorders (dysfibrinogenemia). functional disorders (dysfibrinogenemia). Figure 1. A sketch representing the physiologic role of fibrinogen in the clot formation. The fibrinogen Figure 1. A sketch representing the physiologic role of fibrinogen in the clot formation. The molecule links activated platelets together (white clot) through the alphaIIb–beta3integrin that serves fibrinogen molecule links activated platelets together