The inhibition of pancreatic cancer invasion-metastasis cascade in both cellular signal and blood coagulation cascade of tissue factor by its neutralisation antibody

2011 ◽  
Vol 47 (14) ◽  
pp. 2230-2239 ◽  
Author(s):  
Yohei Saito ◽  
Yuki Hashimoto ◽  
Jun-ichiro Kuroda ◽  
Masahiro Yasunaga ◽  
Yoshikatsu Koga ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Cancer Invasion ◽  
Coagulation Cascade ◽  
Cellular Signal

Microfluidic Tools To Probe the Spatial Dynamics of Coagulation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3934-3934
Author(s):  
Christian J. Kastrup ◽  
Matthew K. Runyon ◽  
Feng Shen ◽  
Rustem F. Ismagilov
Keyword(s):  
Surface Chemistry ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Microfluidic Device ◽  
Spatial Dynamics ◽  
Vascular Damage ◽  
Coagulation Cascade ◽  
Clotting Factors ◽  
Micrometer Scale

Abstract To investigate the biophysical mechanisms that regulate the spatial dynamics of blood coagulation, we have developed a set of microfluidic tools that allow analysis and perturbation of blood coagulation on the micrometer scale with precise control of fluid flow, geometry, and surface chemistry. Physiological coagulation occurs in a localized manner; specifically, coagulation is believed to occur exclusively at regions of substantial vascular damage and does not spread throughout the entire vascular system. In vitro analysis and characterization of these spatial dynamics requires the ability to reproduce and perturb this system, an ability that is not provided by the mixed reactor systems commonly used for in vitro studies of blood coagulation. We developed microfluidic devices with micrometer-scale channels and methods to coat these channels with various phospholipids, including components of the blood coagulation network such as thrombomodulin and tissue factor, to reproduce in vitro the geometry and surface chemistry of blood vessels in vitro. In a microfluidic device with channels coated with phospholipids and thrombomodulin, we demonstrated that clots propagate in a wave-like fashion with a constant velocity in the absence of flow. We also showed that propagation of coagulation from an occluded channel to a channel with flowing blood plasma can be regulated by the geometry of the junction and the shear rate in the channel with flowing plasma. We also developed microfluidic tools to probe the spatial dynamics of initiation of clotting by patterning surfaces with tissue factor reconstituted into phospholipids bilayers. When human plasma or whole blood was exposed to these surfaces in a microfluidic device, clotting occurred only on patches of tissue factor larger than a threshold size. This threshold patch size is controlled by the rate of activation of clotting factors at the patch and the rate of transport of activated factors off the patch. These results suggest a mechanism for how tissue factor can circulate in blood without causing clotting, and how small regions of vascular damage can exist without causing clotting. These results also suggest new biophysical mechanisms that may control interactions between the coagulation cascade and bacterial surfaces.

scholarly journals Tissue factor–positive neutrophils bind to injured endothelial wall and initiate thrombus formation

Blood ◽  
2012 ◽  
Vol 120 (10) ◽  
pp. 2133-2143 ◽  
Author(s):  
Roxane Darbousset ◽  
Grace M. Thomas ◽  
Soraya Mezouar ◽  
Corinne Frère ◽  
Rénaté Bonier ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Thrombus Formation ◽  
Coagulation Cascade ◽  
Factor Xii ◽  
Long Time ◽  
Platelet Accumulation

AbstractFor a long time, blood coagulation and innate immunity have been viewed as interrelated responses. Recently, the presence of leukocytes at the sites of vessel injury has been described. Here we analyzed interaction of neutrophils, monocytes, and platelets in thrombus formation after a laser-induced injury in vivo. Neutrophils immediately adhered to injured vessels, preceding platelets, by binding to the activated endothelium via leukocyte function antigen-1–ICAM-1 interactions. Monocytes rolled on a thrombus 3 to 5 minutes postinjury. The kinetics of thrombus formation and fibrin generation were drastically reduced in low tissue factor (TF) mice whereas the absence of factor XII had no effect. In vitro, TF was detected in neutrophils. In vivo, the inhibition of neutrophil binding to the vessel wall reduced the presence of TF and diminished the generation of fibrin and platelet accumulation. Injection of wild-type neutrophils into low TF mice partially restored the activation of the blood coagulation cascade and accumulation of platelets. Our results show that the interaction of neutrophils with endothelial cells is a critical step preceding platelet accumulation for initiating arterial thrombosis in injured vessels. Targeting neutrophils interacting with endothelial cells may constitute an efficient strategy to reduce thrombosis.

Recombinant Thrombomodulin and Activated Protein C in the Treatment of Disseminated Intravascular Coagulation

1999 ◽  
Vol 82 (08) ◽  
pp. 718-721 ◽  
Author(s):  
Ikuro Maruyama
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
Activated Protein C ◽  
Coagulation Cascade ◽  
Regulation System ◽  
Luminal Surface ◽  
Intravascular Coagulation

IntroductionThe blood coagulation cascade is regulated by the luminal surface of the endothelial cell lining.1 Endothelial cells synthesize tissue factor pathway inhibitor (TFPI), which, in part, binds to the cell surface glycosaminoglycans and inhibits factors Xa, VIIa, and tissue factor.2 Endothelial cells also produce and exhibit thrombomodulin (TM) on their luminal surface.3 TM is a kind of thrombin receptor that forms a 1:1 complex with thrombin. In this complex, thrombin activates protein C (PC) more than 1,000-fold more than thrombin alone. TM then loses its procoagulant activities, which include fibrinogen clotting, activation of factors V and VIII, and platelet activation. Thus, TM converts thrombin from a procoagulant protease to an anticoagulant. Pathologic states, such as an endothelial injury or perturbation or continuous rapid coagulation cascade activation, overcomes the endothelial regulating activity, resulting in the development of intravascular coagulation and the induction of disseminated intravascular coagulation (DIC). Theoretically, then, supplementing soluble TM or activated PC (APC) to reconstitute the endothelial coagulation regulation system in the circulation and regulate pathologically-activated blood coagulation could be beneficial. In this chapter, application of soluble TM and APC in the treatment of DIC is reviewed.

scholarly journals Targeted disruption of the murine tissue factor gene results in embryonic lethality

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1583-1587 ◽  
Author(s):  
JR Toomey ◽  
KE Kratzer ◽  
NM Lasky ◽  
JJ Stanton ◽  
GJ Jr Broze
Keyword(s):  
Tissue Factor ◽  
Blood Coagulation ◽  
Embryonic Lethality ◽  
Coagulation Cascade ◽  
Mouse Tissue ◽  
Bleeding Complications ◽  
Membrane Glycoprotein ◽  
Targeted Disruption ◽  
Factor Gene ◽  
Murine Tissue

Tissue factor (TF) is an integral membrane glycoprotein that is believed to be the physiologic initiator of the blood coagulation cascade. Disruption of the mouse tissue factor gene leads to embryonic lethality between days E9.5-E11.5 of gestation. On E9.5, TF(-/-) embryos appear indistinguishable from their TF(+/+) and TF(+/-) littermates. By E10.5, TF(-/-) embryos are severely growth retarded, appear nearly bloodless, and are in most cases dead. Initial observations suggest that TF(-/-) embryos are dying of circulatory failure. Approximately 15% of the TF(-/-) embryos survive beyond E10.5, but none complete gestation. Heterozygotes appear normal and free of bleeding complications.

Critical Role of the Blood Coagulation in Malaria: Plasmodium falciparum-Infected Red Blood Cells Induce Tissue Factor Expression by Endothelial Cells and Support the Assembly of Coagulation Complexes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4044-4044
Author(s):  
Ivo M.B. Francischetti ◽  
Karl B. Seydel ◽  
Robson Q. Monteiro
Keyword(s):  
Endothelial Cells ◽  
Plasmodium Falciparum ◽  
Red Blood Cells ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Falciparum Malaria ◽  
Late Stage ◽  
Blood Cells ◽  
Coagulation Cascade ◽  
Prothrombinase Complex

Abstract Malaria is still the world’s most important parasitic disease and is responsible for the death of more people than any other communicable disease except tuberculosis. According to WHO estimates, 300–500 million people are infected with malaria every year. Deaths occur mostly among young children in Africa. Cerebral malaria (CM) is the most severe complication and accounts for up to 80% of fatal cases of Plasmodium falciparum malaria. The mechanisms of malaria and CM pathogenesis remain the subject of continuing debate. It is believed that hemostatic alterations could be of importance in the disease since P. falciparum malaria has been associated with thrombocytopenia and hemostatic alterations (pro-coagulant state), by an unknown mechanism. Here we demonstrate that P. falciparum-infected red blood cells (IRBC) induce Tissue Factor (TF) expression by endothelial cells in culture, in a parasitemia- and time-dependent manner. Tissue Factor was consistently detected by functional (Factor Xa formation), antigen (ELISA), and RT-PCR. Remarkably, only mid-late but not early trophozoites and ring stage parasites were capable of inducing TF expression. These findings are compatible with post-mortem brain biopsies where sequestration is composed mostly by late-stage trophozoites. Our experiments also demonstrate that late-stage IRBC support the assembly of the prothrombinase complex in the presence of FVa, FXa, prothrombin and Ca2+ with thrombin formation. IRBC also support the intrinsic Xnase assembly in the presence of FIXa, FVIIIa, FX and Ca2+ with generation of FXa. It is concluded that IRBC manipulates the hemostatic system by initiating the blood coagulation cascade through induction of TF expression by endothelial cells, leading to FXa production. FXa and other components of the prothrombinase complex assemble in the IRBC allowing the coagulation cascade to propagate, with thrombin formation. Thrombin, FXa and FVIIa may also activate the pro-inflammatory PAR receptors in endothelial cells creating a unique inflammatory environment in the vessels where sequestration has occurred. These finding introduces the concept that malaria is an inflammatory syndrome triggered by expression of TF and activation of the coagulation cascade. Identification of TF as a critical mediator of malaria may allow investigators to test other therapeutic alternatives targeting TF in the treatment of malaria.

Thrombin selectively induces transcription of genes in human monocytes involved in inflammation and wound healing

2014 ◽  
Vol 112 (11) ◽  
pp. 992-1001 ◽  
Author(s):  
Gustavo Bruges ◽  
Gustavo Crespo ◽  
Victor Salazar ◽  
Pierre-Antoine Deglesne ◽  
Heike Schneider ◽  
...  
Keyword(s):  
Wound Healing ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Coagulation Cascade ◽  
Main Role ◽  
Human Monocytes ◽  
Gene Encoding ◽  
Blocking Antibody ◽  
Microarray Experiments

SummaryThrombin is essential for blood coagulation but functions also as a mediator of cellular signalling. Gene expression microarray experiments in human monocytes revealed thrombin-induced upregulation of a limited subset of genes, which are almost exclusively involved in inflammation and wound healing. Among these, the expression of F3 gene encoding for tissue factor (TF) was enhanced indicating that this physiological initiator of coagulation cascade may create a feed-forward loop to enhance blood coagulation. Activation of protease-activated receptor type 1 (PAR1) was shown to play a main role in promoting TF expression. Moreover, thrombin induced phosphorylation of ERK1/2, an event that is required for expression of thrombin-regulated genes. Thrombin also increased the expression of TF at the protein level in monocytes as evidenced by Western blot and immunostaining. Furthermore, FXa generation induced by thrombin-stimulated monocytes was abolished by a TF blocking antibody and therefore it is entirely attributable to the expression of tissue factor. This cellular activity of thrombin provides a new molecular link between coagulation, inflammation and wound healing.

scholarly journals Targeted disruption of the murine tissue factor gene results in embryonic lethality

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1583-1587 ◽  
Author(s):  
JR Toomey ◽  
KE Kratzer ◽  
NM Lasky ◽  
JJ Stanton ◽  
GJ Jr Broze
Keyword(s):  
Tissue Factor ◽  
Blood Coagulation ◽  
Embryonic Lethality ◽  
Coagulation Cascade ◽  
Mouse Tissue ◽  
Bleeding Complications ◽  
Membrane Glycoprotein ◽  
Targeted Disruption ◽  
Factor Gene ◽  
Murine Tissue

Abstract Tissue factor (TF) is an integral membrane glycoprotein that is believed to be the physiologic initiator of the blood coagulation cascade. Disruption of the mouse tissue factor gene leads to embryonic lethality between days E9.5-E11.5 of gestation. On E9.5, TF(-/-) embryos appear indistinguishable from their TF(+/+) and TF(+/-) littermates. By E10.5, TF(-/-) embryos are severely growth retarded, appear nearly bloodless, and are in most cases dead. Initial observations suggest that TF(-/-) embryos are dying of circulatory failure. Approximately 15% of the TF(-/-) embryos survive beyond E10.5, but none complete gestation. Heterozygotes appear normal and free of bleeding complications.

Self-Damping Mechanism in Blood Coagulation

1974 ◽  
Vol 32 (01) ◽  
pp. 057-064 ◽  
Author(s):  
Y Nemerson ◽  
S.A Silverberg ◽  
J Jesty
Keyword(s):  
Tissue Factor ◽  
Blood Coagulation ◽  
Calcium Ions ◽  
Control Mechanism ◽  
Factor Vii ◽  
Damping Factor ◽  
Factor V ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Two Systems

SummaryTwo reactions of the extrinsic pathway of coagulation, the activations of Factor X and prothrombin, have been studied in purified systems and shown to be self-damping. Factor X was activated by the tissue factor - Factor VII complex, and prothrombin by two systems: the coagulant protein of Taipan venom, and the physiological complex of activated Factor X, Factor V, lipid, and calcium ions. In each case the yield of enzyme, activated Factor X or thrombin, is a function of the concentration of activator. These and other observations are considered as a basis for a control mechanism in coagulation.

Differential Drug Target Selection in Blood Coagulation: What can we get from Computational Systems Biology Models?

2020 ◽  
Vol 26 (18) ◽  
pp. 2109-2115 ◽  
Author(s):  
Mikhail A. Panteleev ◽  
Anna A. Andreeva ◽  
Alexey I. Lobanov
Keyword(s):  
Blood Coagulation ◽  
Biological Network ◽  
Target Selection ◽  
Anticoagulation Therapy ◽  
Differential Regulation ◽  
Coagulation Cascade ◽  
Computational Systems Biology ◽  
Analysis Strategies ◽  
Optimal Target ◽  
Computational Systems

Discovery and selection of the potential targets are some of the important issues in pharmacology. Even when all the reactions and the proteins in a biological network are known, how does one choose the optimal target? Here, we review and discuss the application of the computational methods to address this problem using the blood coagulation cascade as an example. The problem of correct antithrombotic targeting is critical for this system because, although several anticoagulants are currently available, all of them are associated with bleeding risks. The advantages and the drawbacks of different sensitivity analysis strategies are considered, focusing on the approaches that emphasize: 1) the functional modularity and the multi-tasking nature of this biological network; and 2) the need to normalize hemostasis during the anticoagulation therapy rather than completely suppress it. To illustrate this effect, we show the possibility of the differential regulation of lag time and endogenous thrombin potential in the thrombin generation. These methods allow to identify the elements in the blood coagulation cascade that may serve as the targets for the differential regulation of this system.

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