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In severely injured patients, fibrinogen supplementation is recommended when fibrinogenemia is < 1.5 g L-1, but some teams have suggested to use higher thresholds (fibrinogenemia < 2.0 g L-1 or FIBTEM clot amplitude at 5 min (A5) values < 11 mm). The goal of this study was to specify in patients with a moderate fibrinogen deficit (MFD) whether some admission characteristics would be associated with fibrinogen administration at 24 h.
Hepatic fibrinogen storage disease is a rare autosomal dominant genetic disorder characterized by hypofibrinogenemia, as well as the retention of variant fibrinogen within the hepatocellular endoplasmic reticulum. Here, we describe an asymptomatic 4-year-old boy with abnormal liver function test results and unexpected hypofibrinogenemia. Liver biopsy showed circular eosinophil inclusion bodies in the hepato-cytoplasm. Immunostaining results of eosinophil inclusion bodies were positive for fibrinogen. Following pretreatment with diastase, the inclusion bodies failed to stain with the periodic acid–Schiff technique; moreover, immunostaining results were positive for fibrinogen, but negative for alpha-1-antitrypsin. Genetic analysis identified a heterozygous missense mutation c.1201C > T (p. Arg401Trp) within the fibrinogen γ-chain (FGG) gene and an additional single nucleotide polymorphism c.-58 A > G within the 5′-untranslated region of the fibrinogen Aα-chain (FGA) gene. Thus, the patient was diagnosed with hepatic fibrinogen storage disease. Our results indicate that, for patients who exhibit chronic liver disease with unexpected hypofibrinogenemia, hepatic fibrinogen storage disease should be considered in the differential diagnosis. Moreover, our findings emphasize the importance of molecular diagnosis in patients with cryptogenic liver disease.
Congenital fibrinogen disorders are caused by mutations in one of the three fibrinogen genes that affect the synthesis, assembly, intracellular processing, stability or secretion of fibrinogen. Functional studies of mutant Bβ-chains revealed the importance of individual residues as well as three-dimensional structures for fibrinogen assembly and secretion. This study describes two novel homozygous fibrinogen Bβ chain mutations in two Slovak families with afibrinogenemia and hypofibrinogenemia. Peripheral blood samples were collected from all subjects with the aim of identifying the causative mutation. Coagulation-related tests and rotational thromboelastometry were performed. All exons and exon-intron boundaries of the fibrinogen genes (FGA, FGB and FGG) were amplified by PCR followed by direct sequencing. Sequence analysis of the three fibrinogen genes allowed us to identify two novel homozygous mutations in the FGB gene. A novel Bβ chain truncation (BβGln180Stop) was detected in a 28-year-old afibrinogenemic man with bleeding episodes including repeated haemorrhaging into muscles, joints, and soft tissues, and mucocutaneous bleeding and a novel Bβ missense mutation (BβTyr368His) was found in a 62-year-old hypofibrinogenemic man with recurrent deep and superficial venous thromboses of the lower extremities. The novel missense mutation was confirmed by molecular modelling. Both studying the molecular anomalies and the modelling of fibrinogenic mutants help us to understand the extremely complex machinery of fibrinogen biosynthesis and finally better assess its correlation with the patient's clinical course.
Interleukin-6 (IL-6) induces the expression of fibrinogen, and polymorphic variation within the fibrinogen genes is believed to alter the magnitude of this expression. The identification of the functional relevance of individual fibrinogen single nucleotide polymorphisms (SNPs) has been hindered by the high linkage disequilibrium (LD) reported in the European fibrinogen gene locus. This study investigated two novel and 12 known fibrinogen SNPs of potential functional relevance, in 2010 Tswana individuals known to have low LD. We aimed to identify functional polymorphisms that contribute to clot-related phenotypes and total and γ' fibrinogen concentrations independently and through their interaction with IL-6, by taking advantage of the high fibrinogen and IL-6 concentrations and the low LD reported in black South Africans. Fibrinogen was significantly associated with IL-6, thereby mediating associations of IL-6 with clot formation and structure, although attenuating the association of IL-6 with clot lysis time. None of the common European fibrinogen haplotypes was present in this study population. Putative functional fibrinogen SNPs FGB-rs7439150, rs1800789 (-1420G/A) and rs1800787 (-148C/T) were significantly associated with fibrinogen concentration and altered clot properties, with several associations significantly influenced by IL-6 concentrations. The impact of harbouring several minor fibrinogen SNP alleles on the association of IL-6 and fibrinogen concentration was cumulative, with possession of each additional minor allele showing a stronger relationship of IL-6 with fibrinogen. This was also reflected in differences in clot properties, suggesting potential clinical relevance. Therefore, when investigating the effect of fibrinogen genetics on fibrinogen concentrations and CVD outcome, the possible interactions with modulating factors and the fact that SNP effects seem to be additive should be taken into account.
Primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are common types of primary glomerular disease; they share numerous clinical and pathological similarities but have different treatment regimens and prognoses. It is therefore necessary to distinguish between them and to explore the mechanism underlying their differences. Fibrinogen is reportedly involved in podocyte damage and in renal fibrosis in vitro and in animal models of kidney disease. We thus tested urinary fibrinogen, serum fibrinogen, and renal fibrinogen deposition levels in a cohort comprising 50 patients with FSGS and 40 patients with MCD. Our results suggested that urinary fibrinogen and renal interstitial fibrinogen deposition levels were significantly higher in the FSGS patients than in the MCD patients, while serum fibrinogen levels did not differ between the groups. Receiver operating characteristic (ROC) curve analysis showed an excellent diagnostic ability for urinary fibrinogen and a fair diagnostic ability for tubulointerstitial fibrinogen deposition in differentiating FSGS from MCD. Additionally, we found that urinary fibrinogen levels were positively correlated with the 24-h urine protein levels in patients with FSGS but not in patients with MCD. In conclusion, urinary fibrinogen and renal interstitial fibrinogen deposition is elevated in primary FSGS compared to MCD, which may be relevant to both diagnosis and pathogenesis.
The high resolution crystal structures of a recombinant fragment of the C-terminal fibrinogen-like recognition domain of FIBCD1, a vertebrate receptor that binds chitin, have been determined. The overall tetrameric structure shows similarity in structure and aggregation to the horseshoe crab innate immune protein tachylectin 5A. The high affinity ligand N-acetylmannosamine (ManNAc) binds in the S1 site, predominantly via the acetyl group with the oxygen and acetamide nitrogen hydrogen-bonded to the protein and the methyl group inserted into a hydrophobic pocket. The binding of the ManNAc pyranose ring differs markedly between the two independent subunits, but in all structures the binding of the N-acetyl group is conserved. In the native structure, a crystal contact results in one of the independent protomers binding the first GlcNAc of the Asn(340) N-linked glycan on the other independent protomer. In the ligand-bound structure this GlcNAc is replaced by the higher affinity ligand ManNAc. In addition, a sulfate ion has been modeled into the electron density at a location similar to the S3 binding site in L-ficolin, whereas in the native structure an acetate ion has been placed in the S1 N-acetyl binding site, and a sulfate ion has been placed adjacent to this site. These ion binding sites are ideally placed to receive the N-acetyl and sulfate groups of sulfated GalNAc residues of glycosaminoglycans such as chondroitin and dermatan sulfate. Together, these structures give insight into important determinants of ligand selectivity, demonstrating versatility in recognition and binding while maintaining conservation in N-acetyl and calcium binding.
We identified a novel heterozygous variant, Bβp.Pro234Leu (fibrinogen Tokorozawa), which was suspected to be associated with hypofibrinogenemia. Therefore, we analyzed the assembly and secretion of this fibrinogen using Chinese hamster ovary (CHO) cells. To determine the impact on the synthesis and secretion of fibrinogen of the Bβp.P234L and γp.G242E substitutions, we established recombinant variant fibrinogen-producing CHO cell lines. Synthesis and secretion analyses were performed using an enzyme-linked immunosorbent assay (ELISA) and immunoblotting analysis with the established cell lines. In addition, we performed fibrin polymerization using purified plasma fibrinogen and in-silico analysis. Both Bβp.P234L and γp.G242E impaired the secretion and synthesis of fibrinogen. Moreover, immunoblotting analysis elucidated the mobility migration of the Bβγ complex in Bβp.P234L. On the other hand, the fibrin polymerization of fibrinogen Tokorozawa was similar to that of normal fibrinogen. In-silico analysis revealed that the Bβp.P234 residue is located in the contact region between the Bβ and γ chains and contacts γp.G242 residue. The present study demonstrated that the Bβp.P234L substitution resulted in hypofibrinogenemia by decreasing the assembly and secretion of fibrinogen. Therefore, there is a possibility that substitutions in the contact region between the Bβ and γ chains impact the assembly and secretion of fibrinogen.
Fibrinogen-related proteins with lectin activity are believed to be part of the tick innate immune system. Several fibrinogen-related proteins have been described and characterised mainly on the basis of their cDNA sequences while direct biochemical evidence is missing. One of them, the haemolymph lectin Dorin M from the tick Ornithodoros moubata was isolated and characterised in more depth.
We observed fine fibrin deposition along the paravascular spaces in naive animals, which increased dramatically following subarachnoid hemorrhage (SAH). Following SAH, fibrin deposits in the areas remote from the hemorrhage. Traditionally it is thought that fibrinogen enters subarachnoid space through damaged blood brain barrier. However, deposition of fibrin remotely from hemorrhage suggests that fibrinogen chains Aα, Bβ, and γ can originate in the brain. Here we demonstrate in vivo and in vitro that astroglia and neurons are capable of expression of fibrinogen chains. SAH in mice was induced by the filament perforation of the circle of Willis. Four days after SAH animals were anesthetized, transcardially perfused and fixed. Whole brain was processed for immunofluorescent (IF) analysis of fibrin deposition on the brain surface or in brains slices processed for fibrinogen chains Aα, Bβ, γ immunohistochemical detection. Normal human astrocytes were grown media to confluency and stimulated with NOC-18 (100 μM), TNF-α (100 nM), ATP-γ-S (100 μM) for 24 h. Culture was fixed and washed/permeabilized with 0.1% Triton and processed for IF. Four days following SAH fibrinogen chains Aα IF associated with glia limitans and superficial brain layers increased 3.2 and 2.5 times (p < 0.05 and p < 0.01) on the ventral and dorsal brain surfaces respectively; fibrinogen chains Bβ increased by 3 times (p < 0.01) on the dorsal surface and fibrinogen chain γ increased by 3 times (p < 0.01) on the ventral surface compared to sham animals. Human cultured astrocytes and neurons constitutively expressed all three fibrinogen chains. Their expression changed differentially when exposed for 24 h to biologically significant stimuli: TNFα, NO or ATP. Western blot and RT-qPCR confirmed presence of the products of the appropriate molecular weight and respective mRNA. We demonstrate for the first time that mouse and human astrocytes and neurons express fibrinogen chains suggesting potential presence of endogenous to the brain fibrinogen chains differentially changing to biologically significant stimuli. SAH is followed by increased expression of fibrinogen chains associated with glia limitans remote from the hemorrhage. We conclude that brain astrocytes and neurons are capable of production of fibrinogen chains, which may be involved in various normal and pathological processes.
Disulfide bonds link pairs of cysteine amino acids and their formation is assumed to be complete in the mature, functional protein. Here, we test this assumption by quantifying the redox state of disulfide bonds in the blood clotting protein fibrinogen. The disulfide status of fibrinogen from healthy human donor plasma and cultured human hepatocytes are measured using differential cysteine alkylation and mass spectrometry. This analysis identifies 13 disulfide bonds that are 10-50% reduced, indicating that fibrinogen is produced in multiple disulfide-bonded or covalent states. We further show that disulfides form upon fibrin polymerization and are required for a robust fibrin matrix that withstands the mechanical forces of flowing blood and resists premature fibrinolysis. The covalent states of fibrinogen are changed by fluid shear forces ex vivo and in vivo, indicating that the different states are dynamic. These findings demonstrate that fibrinogen exists and functions as multiple covalent forms.
Fibrinogen is one of the key proteins that participate in the protein corona composition of many types of nanoparticles (NPs), and its conformational changes are crucial for activation of immune systems. Recently, we demonstrated that the fibrinogen highly contributed in the protein corona composition at the surface of zeolite nanoparticles. Therefore, understanding the interaction of fibrinogen with zeolite nanoparticles in more details could shed light of their safe applications in medicine. Thus, we probed the molecular interactions between fibrinogen and zeolite nanoparticles using both experimental and simulation approaches. The results indicated that fibrinogen has a strong and thermodynamically favorable interaction with zeolite nanoparticles in a non-cooperative manner. Additionally, fibrinogen experienced a substantial conformational change in the presence of zeolite nanoparticles through a concentration-dependent manner. Simulation results showed that both E- and D-domain of fibrinogen are bound to the EMT zeolite NPs via strong electrostatic interactions, and undergo structural changes leading to exposing normally buried sequences. D-domain has more contribution in this interaction and the C-terminus of γ chain (γ377-394), located in D-domain, showed the highest level of exposure compared to other sequences/residues.
Fibrinogen is an abundant plasma protein with an essential role in blood coagulation and haemostasis thus receiving significant research interest. However, protein purification is time consuming and commercial preparations often have protein contaminants. The aim of this study was to develop a new method to purify high quality and functional fibrinogen.
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