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The interaction of coagulation factors with the perivascular environment affects the development of disease in ways that extend beyond their traditional roles in the acute hemostatic cascade. Key molecular players of the coagulation cascade like tissue factor, thrombin, and fibrinogen are epidemiologically and mechanistically linked with diseases with an inflammatory component. Moreover, the identification of novel molecular mechanisms linking coagulation and inflammation has highlighted factors of the coagulation cascade as new targets for therapeutic intervention in a wide range of inflammatory human diseases. In particular, a proinflammatory role for fibrinogen has been reported in vascular wall disease, stroke, spinal cord injury, brain trauma, multiple sclerosis, Alzheimer’s disease, rheumatoid arthritis, bacterial infection, colitis, lung and kidney fibrosis, Duchenne muscular dystrophy, and several types of cancer. Genetic and pharmacologic studies have unraveled pivotal roles for fibrinogen in determining the extent of local or systemic inflammation. As cellular and molecular mechanisms for fibrinogen functions in tissues are identified, the role of fibrinogen is evolving from a marker of vascular rapture to a multi-faceted signaling molecule with a wide spectrum of functions that can tip the balance between hemostasis and thrombosis, coagulation and fibrosis, protection from infection and extensive inflammation, and eventually life and death. This review will discuss some of the main molecular links between coagulation and inflammation and will focus on the role of fibrinogen in inflammatory disease highlighting its unique structural properties, cellular targets, and signal transduction pathways that make it a potent proinflammatory mediator and a potential therapeutic target.

Atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease, cerebrovascular disease, and peripheral arterial disease, represent a significant cause of premature death worldwide. Biomarkers, the evaluation of which would allow the detection of ASCVD at the earliest stage of development, are intensively sought. Moreover, from a clinical point of view, a valuable biomarker should also enable the assessment of the patient’s prognosis. It has been known for many years that the concentration of fibrinogen in plasma increases, inter alia, in patients with ASCVD. On the one hand, an increased plasma fibrinogen concentration may be the cause of the development of atherosclerotic lesions (increased risk of atherothrombosis); on the other hand, it may be a biomarker of ASCVD, as it is an acute phase protein. In addition, a number of genetic polymorphisms and post-translational modifications of fibrinogen were demonstrated that may contribute to the risk of ASCVD. This review summarizes the current data on the importance of fibrinogen as a biomarker of ASCVD, and also presents the relationship between molecular modifications of this protein in the context of ASCVD.

ObjectivePancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose at resectable stage. Recent studies have suggested that extracellular vesicles (EVs) contain long RNAs. The aim of this study was to develop a diagnostic (d-)signature for the detection of PDAC based on EV long RNA (exLR) profiling.DesignWe conducted a case-control study with 501 participants, including 284 patients with PDAC, 100 patients with chronic pancreatitis (CP) and 117 healthy subjects. The exLR profile of plasma samples was analysed by exLR sequencing. The d-signature was identified using a support vector machine algorithm and a training cohort (n=188) and was validated using an internal validation cohort (n=135) and an external validation cohort (n=178).ResultsWe developed a d-signature that comprised eight exLRs, including FGA, KRT19, HIST1H2BK, ITIH2, MARCH2, CLDN1, MAL2 and TIMP1, for PDAC detection. The d-signature showed high accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.960, 0.950 and 0.936 in the training, internal validation and external validation cohort, respectively. The d-signature was able to identify resectable stage I/II cancer with an AUC of 0.949 in the combined three cohorts. In addition, the d-signature showed superior performance to carbohydrate antigen 19-9 in distinguishing PDAC from CP (AUC 0.931 vs 0.873, p=0.028).ConclusionThis study is the first to characterise the plasma exLR profile in PDAC and to report an exLR signature for the detection of pancreatic cancer. This signature may improve the prognosis of patients who would have otherwise missed the curative treatment window.

Clumping factor A (ClfA), a cell-wall–anchored protein from Staphylococcus aureus, is a virulence factor in various infections and facilitates the colonization of protein-coated biomaterials. ClfA promotes bacterial adhesion to the blood plasma protein fibrinogen (Fg) via molecular forces that have not been studied so far. A unique, yet poorly understood, feature of ClfA is its ability to favor adhesion to Fg at high shear stress. Unraveling the strength and dynamics of the ClfA–Fg interaction would help us better understand how S. aureus colonizes implanted devices and withstands physiological shear stress. By means of single-molecule experiments, we show that ClfA behaves as a force-sensitive molecular switch that potentiates staphylococcal adhesion under mechanical stress. The bond between ClfA and immobilized Fg is weak (∼0.1 nN) at low tensile force, but is dramatically enhanced (∼1.5 nN) by mechanical tension, as observed with catch bonds. Strong bonds, but not weak ones, are inhibited by a peptide mimicking the C-terminal segment of the Fg γ-chain. These results point to a model whereby ClfA interacts with Fg via two distinct binding sites, the adhesive function of which is regulated by mechanical tension. This force-activated mechanism is of biological significance because it explains at the molecular level the ability of ClfA to promote bacterial attachment under high physiological shear stress.

Few studies implicate immunoregulatory gene expression in tumor cells in arbitrating brain tumor progression. Here we show that fibrinogen-like protein 2 (FGL2) is highly expressed in glioma stem cells and primary glioblastoma (GBM) cells. FGL2 knockout in tumor cells did not affect tumor-cell proliferation in vitro or tumor progression in immunodeficient mice but completely impaired GBM progression in immune-competent mice. This impairment was reversed in mice with a defect in dendritic cells (DCs) or CD103 + DC differentiation in the brain and in tumor-draining lymph nodes. The presence of FGL2 in tumor cells inhibited granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced CD103 + DC differentiation by suppressing NF-κB, STAT1/5, and p38 activation. These findings are relevant to GBM patients because a low level of FGL2 expression with concurrent high GM-CSF expression is associated with higher CD8B expression and longer survival. These data provide a rationale for therapeutic inhibition of FGL2 in brain tumors. Fibrinogen-like protein 2 (FGL2) mediates immune suppression in glioblastoma (GBM). Here, the authors show that FGL-2 expressed by GBM cancer cells acts by suppressing the differentiation of CD103+ DC cells required to activate the anti-tumor CD8+ T cell response via blocking GM-CSF signalling at NFKB, STAT1/5 and p38 level.

Fibrinogen is a hexameric plasmatic glycoprotein composed of pairs of three chains (Aα, Bβ, and γ), which play an essential role in hemostasis. Conversion of fibrinogen to insoluble polymer fibrin gives structural stability, strength, and adhesive surfaces for growing blood clots. Equally important, the exposure of its non-substrate thrombin-binding sites after fibrin clot formation promotes antithrombotic properties. Fibrinogen and fibrin have a major role in multiple biological processes in addition to hemostasis and thrombosis, i.e., fibrinolysis (during which the fibrin clot is broken down), matrix physiology (by interacting with factor XIII, plasminogen, vitronectin, and fibronectin), wound healing, inflammation, infection, cell interaction, angiogenesis, tumour growth, and metastasis. Congenital fibrinogen deficiencies are rare bleeding disorders, characterized by extensive genetic heterogeneity in all the three genes: FGA, FGB, and FGG (enconding the Aα, Bβ, and γ chain, respectively). Depending on the type and site of mutations, congenital defects of fibrinogen can result in variable clinical manifestations, which range from asymptomatic conditions to the life-threatening bleeds or even thromboembolic events. In this manuscript, we will briefly review the main pathogenic mechanisms and risk factors leading to thrombosis, and we will specifically focus on molecular mechanisms associated with mutations in the C-terminal end of the beta and gamma chains, which are often responsible for cases of congenital afibrinogenemia and hypofibrinogenemia associated with thrombotic manifestations.

The increasing volume of whole-genome sequence (WGS) and multi-omics data requires new approaches for analysis. As one solution, we have created the cloud-based Analysis Commons, which brings together genotype and phenotype data from multiple studies in a setting that is accessible by multiple investigators. This framework addresses many of the challenges of multicenter WGS analyses, including data-sharing mechanisms, phenotype harmonization, integrated multi-omics analyses, annotation and computational flexibility. In this setting, the computational pipeline facilitates a sequence-to-discovery analysis workflow illustrated here by an analysis of plasma fibrinogen levels in 3,996 individuals from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) WGS program. The Analysis Commons represents a novel model for translating WGS resources from a massive quantity of phenotypic and genomic data into knowledge of the determinants of health and disease risk in diverse human populations.

How cancer cells evade the therapeutic effects of immune checkpoint blockade is largely unknown. Here, we report that fibrinogen-like protein 1 (FGL1), a newly identified immune checkpoint ligand, was modified by acetylation at Lys 98 in hepatocellular carcinoma (HCC), which targeted it for proteasomal degradation. Sirtuin 2 (SIRT2) deacetylated and stabilized FGL1, thus promoting immune evasion. Notably, the SIRT2 inhibitor 2-Cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) enhanced acetylation of FGL1 and reduced FGL1 protein levels in vitro. The combination of AGK2 and programmed death ligand 1 (PD-L1) blockade effectively suppressed tumor growth and improved overall survival of mice. Furthermore, aspirin, an old drug, could directly acetylate FGL1 at Lys 98 and promote its degradation in vitro. Aspirin enhanced the immunotherapeutic efficacy, induced tumor regression, and extended the lifespan of tumor-bearing mice. Furthermore, the SIRT2/FGL1 axis was expressed in HCC specimens. Collectively, these findings unveil an acetylation-mediated regulation of FGL1, identify a potential target for HCC immunotherapy, and provide therapeutic strategies for the clinical treatment of HCC.

Objectives: Thrombosis is rarely reported in cases of afibrinogenemia and is generally associated with thrombophilia or replacement therapy. Often, it is difficult to predict whether the patients will bleed or whether they are exposed to the risk of thrombosis. Methods: We report a patient with afibrinogenemia who presented with complete thrombosis of right hepatic, portal, and splenic veins and who described a lifelong history of bleeding. Direct sequencing of the three fibrinogen genes was performed to identify the mutation. Results: DNA sequencing showed the presence of a homozygous for G8017A substitution in exon 8 of the fibrinogen β-chain gene, resulting in a G434D missense mutation (Fibrinogen Mumbai). Conclusions: Presence of both bleeding and thrombotic manifestations in a patient with afibrinogenemia in the presence of other associated risk factors warrants a very careful individualized approach in the management of patients with afibrinogenemia.

Dysfibrinogenemia is characterized by blood coagulation dysfunction induced by an abnormal molecular structure of fibrinogen. Here, we describe a new case. A 32-year-old female was suspected of having dysfibrinogenemia during routine laboratory screening, based on her decreased functional fibrinogen level, normal fibrinogen antigen level, and prolonged thrombin time. We extracted DNA and performed polymerase chain reaction and DNA sequencing to identify genetic mutation. Fibrin polymerization, the kinetics of the fibrinopeptide release, scanning electron microscopy, mass spectrometric analysis, fibrin cross-linking, sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blot were conducted. DNA sequencing identified a heterozygous point mutation, Gly13Arg in Aα chain. Fibrin polymerization was markedly impaired (prolonged lag phase and decreased final turbidity). The rate and extent of fibrinopeptide A release from the patient were abnormal and reduced. The mass spectrometry analysis revealed the presence of mutant fibrinogen chains in the patient’s circulation. Electron micrographs revealed abnormal fibrin clots. Fibrin cross-linking was normal. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blot showed no difference. We report a new case with a mutation in the fibrinopeptide A region, AαGly13Arg. These results indicated that the functional abnormalities were related to delayed and defective fibrinopeptide A cleavage and likely impaired thrombin binding.