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Fibrin(ogen): friend and foe
properly assembled fibrinogen is secreted as a 340 kDa glycoprotein, misfolded proteins are retained intracellular- ly and degraded by quality control mechanisms.10
During human development, hemostatic proteins, including fibrinogen, are present in plasma around the time of the termination of hepatic histogenesis and spleen vascularization (~10-11 weeks of gestation), reaching lev- els at term similar to those in the adult.11 Fetal fibrinogen has qualitative differences, notably delayed fibrin forma- tion, which persist for approximately 1 year after birth. Neonatal clots are less dense than those of an adult and have a different three-dimensional structure.12 However, this does not have a significant impact on coagulation parameters such as bleeding time.
Circulating fibrinogen promotes hemostasis as the solu- ble fibrin precursor, but also by bridging activated platelets, and enabling a correct disposition of erythro- cytes, macrophages and fibroblasts around a wound.13 The development and control of these processes is important to stop bleeding, enhance wound healing and promote tis- sue regeneration. In addition, fibrin(ogen) is implicated in preventing microbial invasion and proliferation upon trau- ma,14 enhancing host defenses through the assembly of matrices that entrap invaders and recruit and activate host immune cells.15
The association of fibrin(ogen) with disease results from different mechanisms. These include triggering signaling pathways within given physiological contexts, and alter- ations in the normal range of fibrinogen levels or in its structure. The latter can contribute to altered fibrin clot properties which can impair thrombin and plasminogen binding. In this review, we focus on the involvement of fibrin(ogen) in the development of a range of human dis- orders, describing its role in different pathological mecha- nisms.
Bleeding disorders
Bleeding or hemorrhage is the escape of blood from the closed cardiovascular system due to damaged blood ves- sels.16 The natural control of bleeding is known as hemo- stasis.17 Many defects in hemostatic proteins, including fibrinogen, can cause pathological hemorrhage.
Quantitative and qualitative variations in fibrinogen plasma levels can be inherited or acquired. Inherited disor- ders are divided into type I and II.18 Type I, comprising afibrinogenemia and hypofibrinogenemia, affect the con- centration of plasma fibrinogen (<1.5 g/L). Type II, includ- ing dysfibrinogenemia and hypodysfibrinogenemia, affect the quality of circulating fibrinogen, the latter also affect- ing plasma levels.19
Afibrinogenemia, which has an estimated prevalence of one to two cases per 106 people,20 is an inherited disease characterized by the absence of circulating fibrinogen due to homozygous or compound heterozygous mutations in one of the fibrinogen genes. These may affect mRNA pro- duction, splicing or stability, protein production or stabili- ty, or hexamer assembly, storage, or secretion.21 An initial case of afibrinogenemia in a 9-year old boy was described in 1920,22 but the first causative mutation was identified many years later.23,24 Since then, dozens of other causative mutations have been reported for afibrinogenemia. The majority of these are null mutations, i.e., large deletions, frameshift, early-truncating nonsense, or splice-site muta-
tions. Missense mutations are mostly grouped in the con- served COOH-terminal globular domains of the Bβ and γ chains which has given insights into structural determi- nants of fibrinogen hexamer assembly and secretion.10
Bleeding is the main symptom of afibrinogenemia, often occurring in the neonatal period at the umbilical cord. The natural course of afibrinogenemia is usually characterized by spontaneous and severe bleeding, involving all tissues, such as the skin, the oral cavity, the genitourinary tract, the gastrointestinal tract and the central nervous system (CNS). Intracranial hemorrhage is potentially fatal.25 In addition, bone kysts, prolonged wound healing and spon- taneous spleen rupture are typically observed through the life of afibrinogenemic patients.19 Hemarthroses are also frequent but less invalidating than in patients with hemo- philia. Women are particularly at risk of bleeding during the child-bearing period. Even in women with no known fibrinogen disorder, in a prospective study aimed at deter- mining hemostatic markers predictive of the severity of postpartum hemorrhage, only fibrinogen concentration was independently associated after multivariate analysis.26 In particular, a fibrinogen concentration lower than 2 g/L was found to have positive predictive value for bleeding events.
Paradoxically, afibrinogenemic patients are at risk of thrombosis, a finding replicated in fibrinogen-deficient mice, since primary hemostasis enables thrombus forma- tion, but clots lacking fibrin are unstable and tend to embolize.27 The reasons for increased thrombotic risk are not entirely understood, but could be related to the absence of thrombin sequestration by the fibrin clot, lead- ing to excessive platelet activation.28
Fibrinogen infusions are efficient to treat acute bleeding and prevent bleeding in the case of surgery. Plasma- derived fibrinogen concentrate is the treatment of choice, providing the safest and most efficient profile among the sources of fibrinogen. Modalities of long-term fibrinogen supplementation (on-demand versus prophylactic), as well as the optimal trough fibrinogen level to target, are still unresolved issues. Some concerns have been raised regarding a potential link between fibrinogen infusion and the occurrence of thrombotic events, although available clinical and biological data are controversial.29
While the role of fibrinogen in hereditary bleeding dis- orders is well-documented,30,31 similar afibrinogenemia phenotypes have been reported in mice and zebrafish models. The Fga knock-out mouse (Fga-/-)32 shows sponta- neous bleeding, loss of platelet aggregation and clotting function and reduced survival. Serious injuries, overcome by wildtype mice, were lethal for the Fga-/- animals. Females could not maintain gestation and fatal uterine bleeding was observed. Many of the latter effects were corrected by a transgene for the Aα chain, or the AαE iso- form, in Fga-/- mice.33 Fibrinogen-deficient zebrafish have an adult bleeding phenotype with cephalic and ventral hemorrhaging and reduced survival compared with that of control fish.34 In addition, venous thrombosis could not be induced by laser in embryonic zebrafish, clearly demon- strating a hemostatic deficiency.35
Congenital hypofibrinogenemia is much more frequent than afibrinogenemia and is often caused by heterozygous fibrinogen gene mutations. Recently, a systematic analysis of exome/genome data from about 140,000 individuals belonging to the genome Aggregation Database showed that the worldwide prevalence of recessive fibrinogen dis-
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