scholarly journals Extracellular vesicles from human saliva promote hemostasis by delivering coagulant tissue factor to activated platelets

2018 ◽  
Vol 16 (6) ◽  
pp. 1153-1163 ◽  
Author(s):  
Y. Yu ◽  
E. Gool ◽  
R.J. Berckmans ◽  
F.A.W. Coumans ◽  
A.D. Barendrecht ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Extracellular Vesicles ◽  
Human Saliva ◽  
Activated Platelets

Elevated blood plasma levels of tissue factor-bearing extracellular vesicles in patients with atrial fibrillation

2019 ◽  
Vol 173 ◽  
pp. 141-150 ◽  
Author(s):  
Morten Mørk ◽  
Jan J. Andreasen ◽  
Lars H. Rasmussen ◽  
Gregory Y.H. Lip ◽  
Shona Pedersen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Blood Plasma ◽  
Tissue Factor ◽  
Extracellular Vesicles ◽  
Plasma Levels ◽  
Elevated Blood

scholarly journals Glioblastoma cell populations with distinct oncogenic programs release podoplanin as procoagulant extracellular vesicles

2021 ◽  
Vol 5 (6) ◽  
pp. 1682-1694
Author(s):  
Nadim Tawil ◽  
Rayhaan Bassawon ◽  
Brian Meehan ◽  
Ali Nehme ◽  
Laura Montermini ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tissue Factor ◽  
Extracellular Vesicles ◽  
Coagulation System ◽  
Platelet Factor ◽  
Increased Risk ◽  
Cell Subpopulations ◽  
Cancer Associated Thrombosis

Abstract Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and epigenome. Although the molecular effectors of these changes are poorly understood, the upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk for venous thromboembolism (VTE) in GBM patients. Therefore, regulation of this platelet-activating protein by transforming events in cancer cells is of considerable interest. We used single-cell and bulk transcriptome data mining, as well as cellular and xenograft models in mice, to analyze the nature of cells expressing PDPN, as well as their impact on the activation of the coagulation system and platelets. We report that PDPN is expressed by distinct (mesenchymal) GBM cell subpopulations and downregulated by oncogenic mutations of EGFR and IDH1 genes, along with changes in chromatin modifications (enhancer of zeste homolog 2) and DNA methylation. Glioma cells exteriorize their PDPN and/or tissue factor (TF) as cargo of exosome-like extracellular vesicles (EVs) shed from cells in vitro and in vivo. Injection of glioma-derived podoplanin carrying extracelluar vesicles (PDPN-EVs) activates platelets, whereas tissue factor carrying extracellular vesicles (TF-EVs) activate the clotting cascade. Similarly, an increase in platelet activation (platelet factor 4) or coagulation (D-dimer) markers occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Coexpression of PDPN and TF by GBM cells cooperatively affects tumor microthrombosis. Thus, in GBM, distinct cellular subsets drive multiple facets of cancer-associated thrombosis and may represent targets for phenotype- and cell type–based diagnosis and antithrombotic intervention.

scholarly journals Dissemination of extreme levels of extracellular vesicles: tissue factor activity in patients with severe COVID-19

2021 ◽  
Vol 5 (3) ◽  
pp. 628-634
Author(s):  
Christophe Guervilly ◽  
Amandine Bonifay ◽  
Stephane Burtey ◽  
Florence Sabatier ◽  
Raphaël Cauchois ◽  
...  
Keyword(s):  
Septic Shock ◽  
Tissue Factor ◽  
Extracellular Vesicles ◽  
Severe Disease ◽  
Plasminogen Activator Inhibitor ◽  
Hospitalized Patients ◽  
Plasminogen Activator Inhibitor 1 ◽  
Thrombotic Risk ◽  
Public Health Challenges ◽  
Inflammatory State

Abstract Coronavirus disease 2019 (COVID-19) has become one of the biggest public health challenges of this century. Severe forms of the disease are associated with a thrombo-inflammatory state that can turn into thrombosis. Because tissue factor (TF) conveyed by extracellular vesicles (EVs) has been implicated in thrombosis, we quantified the EV-TF activity in a cohort of hospitalized patients with COVID-19 (n = 111) and evaluated its link with inflammation, disease severity, and thrombotic events. Patients with severe disease were compared with those who had moderate disease and with patients who had septic shock not related to COVID-19 (n = 218). The EV-TF activity was notably increased in patients with severe COVID-19 compared with that observed in patients with moderate COVID-19 (median, 231 [25th to 75th percentile, 39-761] vs median, 25 [25th to 75th percentile, 12-59] fM; P < .0001); EV-TF was correlated with leukocytes, D-dimer, and inflammation parameters. High EV-TF values were associated with an increased thrombotic risk in multivariable models. Compared with patients who had septic shock, those with COVID-19 were characterized by a distinct coagulopathy profile with significantly higher EV-TF and EV-fibrinolytic activities that were not counterbalanced by an increase in plasminogen activator inhibitor-1 (PAI-1). Thus, this article is the first to describe the dissemination of extreme levels of EV-TF in patients with severe COVID-19, which supports the international recommendations of systematic preventive anticoagulation in hospitalized patients and potential intensification of anticoagulation in patients with severe disease.

scholarly journals Accumulation of Tissue Factor into Developing Thrombi In Vivo Is Dependent upon Microparticle P-Selectin Glycoprotein Ligand 1 and Platelet P-Selectin

2003 ◽  
Vol 197 (11) ◽  
pp. 1585-1598 ◽  
Author(s):  
Shahrokh Falati ◽  
Qingde Liu ◽  
Peter Gross ◽  
Glenn Merrill-Skoloff ◽  
Janet Chou ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Blood Coagulation ◽  
Thrombus Formation ◽  
Recipient Mouse ◽  
Wild Type ◽  
Activated Platelets ◽  
Injury Model ◽  
Platelet Thrombus ◽  
Flowing Blood

Using a laser-induced endothelial injury model, we examined thrombus formation in the microcirculation of wild-type and genetically altered mice by real-time in vivo microscopy to analyze this complex physiologic process in a system that includes the vessel wall, the presence of flowing blood, and the absence of anticoagulants. We observe P-selectin expression, tissue factor accumulation, and fibrin generation after platelet localization in the developing thrombus in arterioles of wild-type mice. However, mice lacking P-selectin glycoprotein ligand 1 (PSGL-1) or P-selectin, or wild-type mice infused with blocking P-selectin antibodies, developed platelet thrombi containing minimal tissue factor and fibrin. To explore the delivery of tissue factor into a developing thrombus, we identified monocyte-derived microparticles in human platelet–poor plasma that express tissue factor, PSGL-1, and CD14. Fluorescently labeled mouse microparticles infused into a recipient mouse localized within the developing thrombus, indicating that one pathway for the initiation of blood coagulation in vivo involves the accumulation of tissue factor– and PSGL-1–containing microparticles in the platelet thrombus expressing P-selectin. These monocyte-derived microparticles bind to activated platelets in an interaction mediated by platelet P-selectin and microparticle PSGL-1. We propose that PSGL-1 plays a role in blood coagulation in addition to its known role in leukocyte trafficking.

SAT-077-Intraperitoneal activation of blood coagulation via tissue factor-exposing extracellular vesicles in patients with advanced chronic liver disease

2019 ◽  
Vol 70 (1) ◽  
pp. e661
Author(s):  
Mattias Mandorfer ◽  
Johannes Thaler ◽  
Lena Hell ◽  
Philipp Schwabl ◽  
Lukas Wisgrill ◽  
...  
Keyword(s):  
Liver Disease ◽  
Chronic Liver Disease ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Extracellular Vesicles ◽  
Chronic Liver

scholarly journals Alternative activation of human macrophages enhances tissue factor expression and production of extracellular vesicles

Haematologica ◽  
2020 ◽  
pp. haematol.2019.220210 ◽  
Author(s):  
Philipp J. Hohensinner ◽  
Julia Mayer ◽  
Julia Kichbacher ◽  
Julia Kral-Pointner ◽  
Barbara Thaler ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Extracellular Vesicles ◽  
Alternative Activation ◽  
Tissue Factor Expression ◽  
Human Macrophages ◽  
Factor Expression

scholarly journals Reduction of salivary tissue factor (thromboplastin) activity by warfarin therapy

Blood ◽  
1979 ◽  
Vol 53 (3) ◽  
pp. 366-374 ◽  
Author(s):  
LR Zacharski ◽  
R Rosenstein
Keyword(s):  
Tissue Factor ◽  
Vitamin K ◽  
Coagulation Factors ◽  
Human Saliva ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Total Protein Content ◽  
Factor X ◽  
Clotting Factors

Abstract The coagulant of normal human saliva has been identified as tissue factor (thromboplastin, TF) by virtue of its ability to cause rapid coagulation in plasmas deficient in first-stage coagulation factors and to activate factor x in the presence of factor VII and by virtue of the fact that its activity is expressed only in the presence of factor VII and is inhibited by an antibody to TF. The TF is related to cells and cell fragments in saliva. Salivary TF activity has been found to be significantly reduced in patients taking warfarin. The decline in TF activity during induction of warfarin anticoagulation occurs during the warfarin-induced decline in vitamin-K-dependent clotting factor activity, as judged by the prothrombin time. The decrease in TF activity is not related to a reduction in salivary cell count or total protein content or to a direct effect of warfarin on the assay. It is hypothesized that the mechanism by which warfarin inhibits TF activity may be related to the mechanism by which it inhibits expression of the activity of the vitamin-K-dependent clotting factors. Inhibition of the TF activity may be involved in the antithrombotic effect of warfarin.

Factor VIII activation by factor VIIa analog (V158D/E296V/M298Q) in tissue factor-independent mechanisms

2011 ◽  
Vol 106 (10) ◽  
pp. 665-674 ◽  
Author(s):  
Kenichi Ogiwara ◽  
Midori Shima ◽  
Keiji Nogami
Keyword(s):  
Tissue Factor ◽  
Catalytic Domain ◽  
Factor Viia ◽  
Peak Level ◽  
Activated Platelets ◽  
Fviii Activity ◽  
Rapid Inactivation ◽  
Von Willebrand ◽  
A2 Domain ◽  
Willebrand Factor

SummaryFactor (F)VIIa with tissue factor (TF) is a primary trigger of blood coagulation. The recombinant (r)FVIIa analog, NN1731 (V158D/E296V/ M298Q) containing a thrombin/FIXa-mimicking catalytic domain, is ~30-fold more effective on activated platelets without TF, but ~1.2-fold with TF, than rFVIIa for FX activation. We have recently demonstrated the FVIIa/TF-dependent FVIII activation in the early coagulation phase. We assessed the action of NN1731 on FVIII activation. NN1731/TF increased FVIII activity ~2.9-fold within 30 seconds, followed by rapid inactivation, and was slightly more active than rFVIIa/TF. NN1731-catalysed activation, however, was enhanced ~6-fold at 5 minutes (min), and its peak level persisted for ~30 min. NN1731/TF proteolysed FVIII at Arg740, Arg372, and Arg336, similar to rFVIIa/TF, but cleavage by NN1731 alone was much slower at Arg336 than at Arg740 and Arg372. The Km and Vmax for NN1731/TF-catalysed activation were ~1.8-fold lower and ~2.3-fold greater than rFVIIa/TF. The Km for NN1731 alone was ~1.3-fold lower than rFVIIa, whilst the Vmax was ~7.9-fold greater, indicating that the efficiency of FVIII activation by NN1731 and NN1731/TF was ~11- and ~4-fold greater, respectively, than equivalent reactions with rFVIIa. In SPR-based assays, NN1731 bound to FVIII and the heavy chain (Kd; 0.62 and 1.9 nM) with ~1.4- and ~3.1-fold higher affinity than rFVIIa, and the A2 domain contributed to this increase. Von Willebrand factor moderated NN1731-catalysed activation more significantly than NN1731/TF. In conclusion, NN1731 was a greater potential than rFVIIa in up-regulating FVIII activity, and the TF-independent FVIII activation might represent a potential extra mode of its enhanced haemostatic effect.

scholarly journals The procoagulant activity of tissue factor expressed on fibroblasts is increased by tissue factor-negative extracellular vesicles

PLoS ONE ◽  
2020 ◽  
Vol 15 (10) ◽  
pp. e0240189
Author(s):  
Marcela Rosas ◽  
David A. Slatter ◽  
Samya G. Obaji ◽  
Jason P. Webber ◽  
Jorge Alvarez-Jarreta ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Extracellular Vesicles ◽  
Procoagulant Activity
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