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The layers above the lumen show an intact blood vessel, while those below the lumen show a blood vessel after injury. The blood vessel is divided into four major sections: 1) tunica adventitia, 2) tunica media, 3) tunica intima and 4) lumen. The tunica adventitia is composed of fibroblasts, connective tissue and collagen and is separated from the tunica media by the external elastic lamina. The tunica media contains fibroblasts, smooth muscle cells (SMCs), connective tissue and collagen and is isolated from the tunica intima by the internal elastic lamina. The tunica intima, which is bordered on one side by the tunica media and on the other side by the lumen, contains endothelial cells, and in the case of new intima, the internal elastic lamina is damaged and therefore their contents leaks into the tunica media. In a normal vascular system, blood cells circulate in a regulated way (including monocytes, platelets, and others). After a vascular injury, the wound healing and repair process will be immediately activated. However, OX-LDL particles are one of the major causes of chronic vascular injury. After a vascular injury, TF is released by the wound and forms a complex with the activated FVII (FVIIa) present in circulation, as shown by the black arrow at the site of injury (indicated in the middle of the lumen). At the same time, monocytes and platelets arrive quickly to the site of the injury to stop bleeding and repair the injury via the direct activation of coagulation cascade components (FV/FVIII). These two cofactors are involved in the optimal activation of FXa. Both platelets and monocytes ensure the stability of the fibrin network via cross-linking with FXIIIA, which is delivered by these two cell types. Thrombomodulin (TM) is also expressed by monocytes, macrophages, endothelial cells, and fibroblasts. When monocytes enter the tissue at the site of injury, they are converted to macrophages (Mφ). Macrophages do not express FV or FX, while fibroblasts express FX but not FV.
Source publication
The coagulation/fibrinolysis system is essential for wound healing after vascular injury. According to the standard paradigm, the synthesis of most coagulation factors is restricted to liver, platelets and endothelium. We challenged this interpretation by measuring coagulation factors in nine human primary cell types. FX mRNA was expressed by fibro...
Citations
... 1q24.2 Hepatocytes [20] Monocytes [18,20] Neutrophils [21] T cells [21] Platelets [20] F8 Xq28 ...
... 1q24.2 Hepatocytes [20] Monocytes [18,20] Neutrophils [21] T cells [21] Platelets [20] F8 Xq28 ...
... 1q24.2 Hepatocytes [20] Monocytes [18,20] Neutrophils [21] T cells [21] Platelets [20] F8 Xq28 ...
Ovarian cancer (OC) is the deadliest gynaecological malignancy. Identifying new prognostic biomarkers is an important research field. Haemostatic components together with leukocytes can drive cancer progression while increasing the susceptibility to venous thromboembolism (VTE) through immunothrombosis. Unravelling the underlying complex interactions offers the prospect of uncovering relevant OC prognostic biomarkers, predictors of cancer-associated thrombosis (CAT), and even potential targets for cancer therapy. Thus, this study evaluated the expression of F3, F5, F8, F13A1, TFPI1, and THBD in peripheral blood cells (PBCs) of OC patients.
... FV is a cofactor for the prothrombinase complex, which converts prothrombin to thrombin in the final common pathway of the coagulation cascade. [32] FV deficiency has been reported in 8.3% of all inherited bleeding disorders. Its bleeding manifestations include mucosal and soft tissue bleeds, including life-threatening hemorrhages. ...
BACKGROUND: Rare bleeding disorder (RBDs) encompasses a deficiency of one or more of FXIII, FXI, FX, FVII, FV, FII, and FI clotting factors, leading to bleeding disorders with variable presentations and outcomes ranging from none or minimal to life-threatening events. RBDs are still underdiagnosed and underreported, especially in Saudi population with a high prevalence of consanguinity.
... One possible explanation could be the impaired blood flow/vasculopathy deriving from the inflammatory state triggered by HBV and HCV chronic infections, specifically the immune-mediated hepatic inflammation associated with the unstable cytokine secretion by hepatic cells [72]. As it is well-known, chronic liver disease is frequently associated with complex alterations in the haemostatic system, most likely due to the pivotal role liver has in the synthesis and clearance of activated coagulation factors and platelet production through thrombopoietin (TPO) synthesis [73]. Specifically, the haemostatic disturbance can be triggered by changes in platelet counts with the onset of thrombocytopenia (low platelet count) during the stage of chronic liver disease, as well as a decreased synthesis of anti-coagulant proteins (protein C, protein S and antithrombin III) and increased synthesis of pro-coagulant ones (for instance, von Willebrand factor (cWF)) by liver cells [70,72,[74][75][76][77]. Thrombocytopenia is a complex and multifactorial pathology that, among other underlying causes, can result from impaired TPO production due to hepatic damage during chronic liver disease [77]. ...
Viruses are pathogenic agents responsible for approximately 10% of all human cancers and significantly contribute to the global cancer burden. Until now, eight viruses have been associated with the development of a broad range of malignancies, including solid and haematological tumours. Besides triggering and promoting oncogenesis, viral infections often go hand-in-hand with haemostatic changes, representing a potential risk factor for venous thromboembolism (VTE). Conversely, VTE is a cardiovascular condition that is particularly common among oncological patients, with a detrimental impact on patient prognosis. Despite an association between viral infections and coagulopathies, it is unclear whether viral-driven tumours have a different incidence and prognosis pattern of thromboembolism compared to non-viral-induced tumours. Thus, this review aims to analyse the existing evidence concerning the association of viruses and viral tumours with the occurrence of VTE. Except for hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection, which are associated with a high risk of VTE, little evidence exists concerning the thrombogenic potential associated with oncoviruses. As for tumours that can be induced by oncoviruses, four levels of VTE risk are observed, with hepatocellular carcinoma (HCC) and gastric carcinoma (GC) associated with the highest risk and nasopharyngeal carcinoma (NPC) associated with the lowest risk. Unfortunately, the incidence of cancer-related VTE according to tumour aetiology is unknown. Given the negative impact of VTE in oncological patients, research is required to better understand the mechanisms underlying blood hypercoagulability in viral-driven tumours to improve VTE management and prognosis assessment in patients diagnosed with these tumours.
... Production of FV by T cells (Shen et al., 1993) and monocytes (Dashty et al., 2012) has been previously reported. We were interested to learn whether leukocyte derived FV may increase in and if so what the functional consequences of this may be. ...
Clotting Factor V (FV) is primarily synthesised in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes and T regulatory cells as sources of increased FV in hospitalised patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease. Increased leukocyte FV expression in severe disease correlates with T cell lymphopenia. Both plasma-derived and a cleavage resistant recombinant FV, but not thrombin cleaved FVa, suppress T cell proliferation in vitro. Anticoagulants that reduce FV conversion to FVa, including heparin, may have the unintended consequence of suppressing the adaptive immune system.
... On the other hand, it must be said that a 4-fold increase was observed in factor IX gene expression under hepatic differentiation. To our knowledge, this is the first report showing DMSC expression of factor IX. By contrast, factor VIII gene expression is not specific to the liver and can be observed in both undifferentiated DMSC and in cells differentiated to hepatospheres, as has been reported by other authors [29,30]. ...
Deficiency of factor V is a congenital autosomal recessive coagulopathy associated with mutations in the F5 gene that results in mild-to-severe bleeding episodes. Factor V is a component of the prothrombinase complex responsible for accelerating conversion of prothrombin to thrombin. At the present time there are no therapeutic factor V concentrates available. This study was designed to lay the preliminary foundations for future cell-based therapy for patients with severe factor V deficiency. The study showed that hepatospheres, which produce coagulation factors VIII, IX, and V, synthetize and store intracellular glycogen and express albumin levels up to 8 times higher than those of undifferentiated cells. Factor IX and factor V gene expression increased significantly in hepatospheres as compared to undifferentiated cells, whereas factor VIII gene expression remained constant. The factor V protein was detected in the hepatospheres´ secretome. Considering the enormous potential of mesenchymal stem cells as therapeutic agents, this study proposes a highly reproducible method to induce differentiation of mesenchymal stem cells from human placenta to factor V-producing hepatospheres. This strategy constitutes a preliminary step towards a curative treatment of factor V deficiency through advanced therapies such as cell therapy.
... Recent evidence indicates that the mutation of this gene is likely associated with atherogenesis, and the mutations lead to gene expression deficiency or severe biological function impairment of the protein product. It was also reported that when monocytes extravasate by crossing the vascular endothelium, they differentiate into macrophages and gradually lose F5 expression [43]. However, there has been little research on the function of F5 in atherosclerosis, and it is unclear whether the simple change of F5 expression has a direct effect on promoting internal progression, thrombosis, or rupture of atherosclerotic plaque. ...
Background
In an atherosclerotic artery wall, monocyte-derived macrophages are the principal mediators that respond to pathogens and inflammation. The present study aimed to investigate potential genetic changes in gene expression between normal tissue-resident macrophages and atherosclerotic macrophages in the human body.
Material/Methods
The expression profile data of GSE7074 acquired from the Gene Expression Omnibus (GEO) database, which includes the transcriptome of 4 types of macrophages, was downloaded. Differentially expressed genes (DEGs) were identified using R software, then we performed functional enrichment, protein-protein interaction (PPI) network construction, key node and module analysis, and prediction of microRNAs (miRNAs)/transcription factors (TFs) targeting genes.
Results
After data processing, 236 DEGs were identified, including 21 upregulated genes and 215 downregulated genes. The DEG set was enriched in 22 significant Gene Ontology (GO) terms and 25 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the PPI network constructed with these DEGs comprised 6 key nodes with degrees ≥8. Key nodes in the PPI network and simultaneously involved in the prime modules, including rhodopsin (RHO), coagulation factor V (F5), and bestrophin-1 (BEST1), are promising for the prediction of atherosclerotic plaque formation. Furthermore, in the miRNA/TF-target network, hsa-miR-3177-5p might be involved in the pathogenesis of atherosclerosis via regulating BEST1, and the transcription factor early growth response-1 (EGR1) was found to be a potential promoter in atherogenesis.
Conclusions
The identified key hub genes, predicted miRNAs/TFs, and underlying molecular mechanisms may be involved in atherogenesis, thus potentially contributing to the treatment and diagnosis of patients with atherosclerotic disease.
... Extravascular clotting factors have indeed been often detected in selected body districts, e.g. in the lungs, or under pathological conditions, e.g. in the atheroma [56][57][58][59][60]. Surprisingly, albeit devoid of a nucleus, also platelets were reported to produce significant amounts of clotting factors [61]. Extravascular expression of clotting factors was systematically analyzed by Dashty and co-workers in eight human primary cell types (Table 2) [62]. To complete the picture, a recent investigation demonstrated the presence of ectopic FIX in mouse small intestine, where expression was upregulated by stimulation with Toll-like receptor (TLR) agonists, such as lipopolysaccharide (LPS) from Escherichia coli [63]. ...
Protease‐activated receptors (PARs) are a unique class of G‐protein‐coupled transmembrane receptors, which revolutionized the perception of proteases from degradative enzymes to context‐specific signaling factors. Although PARs are traditionally known to affect several vascular responses, recent investigations have started to pinpoint the functional role of PAR signaling in the gastrointestinal (GI) tract. This organ is exposed to the highest number of proteases, either from the gut lumen or from the mucosa. Luminal proteases include the host's digestive enzymes and the proteases released by the commensal microbiota, while mucosal proteases entail extravascular clotting factors and the enzymes released from resident and infiltrating immune cells. Active proteases and, in case of a disrupted gut barrier, even entire microorganisms are capable to translocate the intestinal epithelium, particularly under inflammatory conditions. Especially PAR‐1 and PAR‐2, expressed throughout the GI tract, impact gut permeability regulation, a major factor affecting intestinal physiology and metabolic inflammation. In addition, PARs are critically involved in the onset of inflammatory bowel diseases, irritable bowel syndrome, and tumor progression. Due to the number of proteases involved and the multiple cell types affected, selective regulation of intestinal PARs represents an interesting therapeutic strategy. The analysis of tissue/cell‐specific knockout animal models will be of crucial importance to unravel the intrinsic complexity of this signaling network. Here, we provide an overview on the implication of PARs in intestinal permeability regulation under physiologic and disease conditions.
... On the other hand, we observed more TUNEL immunoreactivity in segment IV, suggesting more hepatocellular apoptosis. We sought to assess factor V, which is specifically produced by hepatocytes [24]; we observed that immunoreactivity was more intense in segment II than in segment IV. These results corroborated the finding that elevated portal perfusion pressures are detrimental to SFSG with progressive loss of SEC integrity, reduction of hepatocellular proliferative capacity, and increase in hepatocellular apoptosis. ...
... We further assessed the hepatocellular regenerative capacity with RNAscope for in situ mRNA expression levels of the upstream regulators of CDKN1A/p21 [8]. As factor V has a short half-life among all proteins that are synthesized by hepatocytes [24], future assaying with quantitative RT-PCR and RNAscope will facilitate detecting early changes in factor V mRNA gene expression. Additionally, EdU assays will be useful for detecting early changes in DNA synthesis [28]. ...
Small-for-size-liver grafts (SFSG) in adult transplant recipients have elevated risk of graft failure, limiting its application in clinical liver transplantation. Relevant preclinical model of SFSG is lacking. Relevant to deceased-donor split liver transplant and living-donor liver transplant in adult recipients, in this study, we present our initial characterization of SFSG model using monosegments of a discarded human donor liver.
... According to the standard paradigm, synthesis of coagulation FX is primarily restricted to the liver 18,19 . However, the expression of coagulation FX is much more complex than previously thought, as our in situ hybridization data showed that FX was also locally produced in VSMCs, ECs, and inflammatory cells (Fig. 1A-F). ...
Our previous study demonstrated that coagulation factor Xa (FXa) induced endothelial cell senescence, resulting in inflammation and impaired angiogenesis. This mechanism is dictated through protease-activated receptors, PARs, insulin-like growth factor-binding protein 5 (IGFBP-5), and p53. Activation of PARs contributes to the pathophysiology of several chronic inflammatory diseases, including atherosclerosis. Thus, we speculated that similar mechanism might participate in the progression of atherosclerotic plaques. In the present study, we successfully identified the cells that produced FX/Xa in atherosclerosis using human atherosclerotic plaques obtained from carotid endarterectomy. In situ hybridization for FX revealed that FX was generated in vascular smooth muscle cells (VSMC), inflammatory cells, and endothelial cells. Then, we examined the effects of FXa on the growth of VSMC in vitro. The present study revealed that chronic FXa stimulation significantly induced the senescence of VSMC with concomitant upregulation of IGFBP-5 and p53. Inhibition of FXa signaling with rivaroxaban or knock down of IGFBP-5 significantly reduced FXa-induced VSMC senescence and inflammatory cytokine production. Finally, we confirmed that FXa and IGFBP-5 are co-distributed in atherosclerotic plaques. In conclusion, induction of senescence of VSMC induced by locally produced FX/Xa may contribute to the progression of atherosclerosis.
... IU/ml). Interestingly, because monocytes are known to secrete clotting factor VII [13,14], its activity was observed when monocytes were transplanted in a partially hepatectomized mouse, which is a confirmation. No human clotting factor VII activity was detected when RM were transplanted. ...
Significance:
This is the first report in which normal hepatocyte-like cells have been generated from blood monocytes of hepatitis B virus-infected patients without the introduction of any exogenous genetic material. These monocyte-derived hepatocyte-like cells possess cytochrome P450 enzyme cascade, suggesting their potential application in a drug-screening system. Most important, it opens up possibilities for the autologous hepatocyte-like cell transplantation to support liver functions during the acute conditions of viral hepatitis.
