Tissue factor expressed by circulating cancer cell-derived microparticles drastically increases the incidence of deep vein thrombosis in mice

Background: Circulating Tissue Factor (TF) is associated with inflammation and may contribute to thrombotic events. Aim of this study was to analyze circulating TF activity and proinflammatory cytokines in patients with deep venous thrombosis. Patients and methods: Forty-eight patients with deep vein thrombosis and 45 control subjects were included. Venous blood samples were obtained at diagnosis for analysis of TF activity, TF antigen, prothrombin fragment F1 + 2, microparticles (expressing phosphatidylserine and supporting FXa generation), Interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12 and Tumor-Necrosis-Factor-alpha (TNF). Results: TF antigen, activity and microparticles were similar in both groups: In contrast, a significant increase in plasma IL-6, IL-8 and F1 + 2 levels was found in thrombosis. This increase in IL-6 and IL-8 as well as F1 + 2 was not correlated with the extent of thrombosis, predisposing factors or onset of symptoms. Conclusions: Circulating TF and microparticles are not elevated in deep venous thrombosis. The increase in IL-6, IL-8 and F1 + 2 during thrombosis was not proportional to the extent or predisposing risk factors.

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Regulation of Tissue Factor by NF-kB Transcription Factor p50 Is Essential for the Pathogeneses of Deep Vein Thrombosis and Arterial Restenosis.

Blood ◽

10.1182/blood.v108.11.1458.1458 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1458-1458

Author(s):

Jian-Guo Geng ◽

Jian-Guo Wang ◽

Nigel Mackman ◽

Arne Slungaard ◽

Yuqing Huo ◽

...

Keyword(s):

Endothelial Cells ◽

Transcription Factor ◽

Transcription Factors ◽

Deep Vein Thrombosis ◽

Venous Thrombosis ◽

Tissue Factor ◽

Coagulation Cascade ◽

Vein Thrombosis ◽

Arterial Restenosis ◽

Deep Vein

Abstract NF-kB transcription factors regulate the expression of tissue factor (TF), a principal initiator for the coagulation cascade. Dominant among the five cellular members of NF-kB transcription factors is the p50/p65 heterodimer. Here we report that Andrographolide (Andro; a 350-dalton antagonist that targets reduced cysteine62 of p50 for inhibition of NF-kB activation) and genetic deletion of p50 potently attenuated TF activity in stimulated endothelial cells and monocytes/macrophages. The direct binding of p50/p65 heterodimer to the TF-kB site in human TF promoter was demonstrated by p50 and p65 antibody ‘supershift’ using electrophoretic mobility shift assay and immunoprecipitation of the promoter of the human TF gene from chromatins of TNF-a-stimulated human umbilical vein endothelial cells. Andro-treated and p50 null mice both exhibited suppressed TF expression, blunted fibrin deposition, reduced venous thrombosis, and decreased neointimal hyperplasia. Blockade of TF activity by an anti-murine TF antibody also attenuated venous thrombosis and neointimal proliferation in vivo. Our findings thus indicate that NF-kB transcription factor p50 critically regulates TF activity in the pathogeneses of deep vein thrombosis and arterial restenosis, and suggest that specific inhibitors of p50, such as Andro, have the potential to be therapeutically valuable for preventing and perhaps treating arterial and venous thrombosis.

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Trauma magnitude of the meta-epyphyseal cancellous affects the incidence of deep vein thrombosis. A prospective cohort study on the dynamic of Collagen I, Collagen IV, Tissue factor, P-Selectin and Nitric Oxide in the thrombus formation following hip and knee surgeries

Annals of Medicine and Surgery ◽

10.1016/j.amsu.2021.102190 ◽

2021 ◽

Vol 63 ◽

pp. 102190

Author(s):

Franky Hartono ◽

Irawan Yusuf ◽

Budhianto Suhadi ◽

Andi Fachruddin ◽

Yohanes Augustinus

Keyword(s):

Nitric Oxide ◽

Cohort Study ◽

Deep Vein Thrombosis ◽

Tissue Factor ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Thrombus Formation ◽

Collagen Iv ◽

Vein Thrombosis ◽

Deep Vein

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Cell-based laboratory evaluation of coagulation activation by antineoplastic drugs for the treatment of lymphoid tumors

SAGE Open Medicine ◽

10.1177/2050312116660936 ◽

2016 ◽

Vol 4 ◽

pp. 205031211666093

Author(s):

Misae Tsunaka ◽

Reina Arai ◽

Ayaka Ohashi ◽

Takatoshi Koyama

Keyword(s):

Deep Vein Thrombosis ◽

Tissue Factor ◽

Tumor Cells ◽

Procoagulant Activity ◽

Laboratory Evaluation ◽

Antineoplastic Drugs ◽

Vascular Endothelial ◽

Vein Thrombosis ◽

Phosphatidylserine Exposure ◽

Deep Vein

Objectives: Combining vorinostat, L-asparaginase, and doxorubicin (Dox) led to improved response rates in the treatment of lymphoid tumors. However, deep-vein thrombosis has been noted as one of the most serious side effects with these drugs, and how these regimens cause deep-vein thrombosis is unclear. Methods: We investigated the procoagulant effects of vorinostat, L-asparaginase, and doxorubicin in lymphoid tumors, focusing on tissue factor, phosphatidylserine, and antithrombin. The human vascular endothelial cell line EAhy926 as well as the lymphoid neoplastic cell lines HUT78 (cutaneous T-cell lymphoma), Molt4 (acute T-lymphoblastic leukemia), and Ramos (Burkitt lymphoma) were employed to investigate these procoagulant effects. Results: Vorinostat, L-asparaginase, and doxorubicin induced exposure of phosphatidylserine and procoagulant activity on the surface of lymphoid tumor cells. Vorinostat and doxorubicin also induced phosphatidylserine exposure and increased procoagulant activity on EAhy926 cells. Expression of tissue factor antigen was induced by doxorubicin on the surface of each type of cells, whereas expression of tissue factor mRNA was unchanged. Secretion of antithrombin from HepG2 cells was reduced only by L-asparaginase. Conclusion: These data suggest that vorinostat and doxorubicin may induce procoagulant activity in vessels through apoptosis of tumor cells and through phosphatidylserine exposure and/or tissue factor expression on vascular endothelial cells. L-asparaginase may induce a thrombophilic state by reducing the secretion of anticoagulant proteins such as antithrombin. The laboratory methods described here could be useful to evaluate the procoagulant effects of antineoplastic drugs.

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Influence of tissue factor polymorphisms (603A>G and 5466A>G) on plasma tissue factor levels and their impact on deep vein thrombosis risk in young Indian population

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-018-1666-6 ◽

2018 ◽

Vol 46 (1) ◽

pp. 88-94

Author(s):

Kamal Kishor ◽

Amit Sharma ◽

Kanwaljeet Singh ◽

Ravi Ranjan ◽

Hareram Pandey ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Tissue Factor ◽

Indian Population ◽

Vein Thrombosis ◽

Thrombosis Risk ◽

Deep Vein

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Inflammasome Activation Promotes Deep Vein Thrombosis through Pyroptosis

Blood ◽

10.1182/blood-2019-130439 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3644-3644

Author(s):

Yan Zhang ◽

Guoying Zhang ◽

Cui Jian ◽

Congqing Wu ◽

Nigel Mackman ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Tissue Factor ◽

Critical Role ◽

Inflammasome Activation ◽

Vein Thrombosis ◽

Flow Restriction ◽

Caspase 1 ◽

Deep Vein ◽

Deficient Mice

Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), is one of the most common causes of cardiovascular death worldwide. Monocytic cells (including monocytes/macrophages) and their derived tissue factor have been reported to play important roles in the development of DVT. However, the mechanism by which monocytes contribute to the development DVT is not well elucidated. In this study, we reported a critical role of inflammasome activation and pyroptosis in the development of DVT. Using a flow restriction-induced mouse DVT model in the inferior vena cava, we show that deficiency of caspase-1 protected against flow restriction-induced DVT. Inflammasome activation leads to interleukin (IL)-1b and IL-18 maturation/release and pyroptosis. Recent studies show that caspases-1 cleaves Gasdermin D (GSDMD) and triggers pyroptosis-a form of programmed cell death with similar morphology to necrosis. We tested the hypothesis that GSDMD-dependent pyroptosis drives inflammasome-induced coagulation and DVT using Gsdmd-/- mice. Indeed, flow restriction-induced DVT was inhibited by GSDMD deficiency. After induction of DVT, fibrin was deposited in the vein as detected by Western blot with a monoclonal antibody that specifically recognizes mouse fibrin, which were inhibited in the caspase-1 deficient mice and GSDMD deficient mice. IL-1b was also increased in tissue of vein following induction of DVT, which was inhibited by caspase-1 or GSDMD deficiency. Following inflammasome activation, pyroptotic macrophages release tissue factor (TF), an essential initiator of coagulation cascades. Consistently, flow restriction-induced DVT was flow restriction-induced DVT inhibited in inducible TF deficient mice. Our data reveal a critical role of inflammasome activation and pyroptosis in the development of DVT. Disclosures No relevant conflicts of interest to declare.

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