Imbalance in Coagulation/Fibrinolysis Inhibitors Resulting in Extravascular Thrombin Generation in Gliomas of Varying Levels of Malignancy

Neoplastic processes are integrally related to disturbances in the mechanisms regulating hemostatic processes. Brain tumors, including gliomas, are neoplasms associated with a significantly increased risk of thromboembolic complications, affecting 20–30% of patients. As gliomas proliferate, they cause damage to the brain tissue and vascular structures, which leads to the release of procoagulant factors into the systemic circulation, and hence systemic activation of the blood coagulation system. Hypercoagulability in cancer patients may be, at least in part, a result of the inadequate activity of coagulation inhibitors. The aim of the study was to evaluate the expression of the inhibitors of the coagulation and fibrinolysis systems (tissue factor pathway inhibitor, TFPI; tissue factor pathway inhibitor-2 TFPI-2; protein C, PC; protein S, PS, thrombomodulin, TM; plasminogen activators inhibitor, PAI-1) in gliomas of varying degrees of malignancy. Immunohistochemical studies were performed on 40 gliomas, namely on 13 lower-grade (G2) gliomas (8 astrocytomas, 5 oligodendrogliomas) and 27 high-grade gliomas (G3–12 anaplastic astrocytomas, 4 anaplastic oligodendrogliomas; G4–11 glioblastomas). A strong expression of TFPI-2, PS, TM, PAI-1 was observed in lower-grade gliomas, while an intensive color immunohistochemical (IHC) reaction for the presence of TFPI antigens was detected in higher-grade gliomas. The presence of PC antigens was found in all gliomas. Prothrombin fragment 1+2 was observed in lower- and higher-grade gliomas reflecting local activation of blood coagulation. Differences in the expression of coagulation/fibrinolysis inhibitors in the tissues of gliomas with varying degrees of malignancy may be indicative of their altered role in gliomas, going beyond that of their functions in the hemostatic system.

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Upregulation of anticoagulant proteins, protein S and tissue factor pathway inhibitor, in the mouse myocardium with cardio-specific TNF-α overexpression

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01026.2011 ◽

2012 ◽

Vol 302 (11) ◽

pp. H2352-H2362 ◽

Cited By ~ 11

Author(s):

Yoshihiro Higuchi ◽

Toru Kubota ◽

Masamichi Koyanagi ◽

Toyoki Maeda ◽

Arthur M. Feldman ◽

...

Keyword(s):

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Plasminogen Activator Inhibitor ◽

Protein S ◽

Wild Type ◽

Failing Heart ◽

Tnf Α ◽

In The Wild ◽

Tissue Factor Pathway ◽

Pai 1

Heart failure (HF) has been recognized as a hypercoagulable state. However, the natural anticoagulation systems in the failing heart have not been studied. Recent experimental and clinical data have indicated that not only the thrombomodulin (TM)/protein C (PC) pathway but also the protein S (PS)/tissue factor pathway inhibitor (TFPI) system function as potent natural anticoagulants. To investigate the balance between procoagulant and anticoagulant activities in the failing heart, we measured the cardiac expression of tissue factor (TF), type 1 plasminogen activator inhibitor (PAI-1), TM, PC, PS, and TFPI by RT-PCR and/or Western blot analysis in male transgenic (TG) mice with heart-specific overexpression of TNF-α. Both procoagulant (TF and PAI-1) and anticoagulant (PS and TFPI) factors were upregulated in the myocardium of 24-wk-old TG (end-stage HF) but not in that of 4-wk-old TG (early decompensated HF) compared with the wild-type mice. Both factors were also upregulated in the infarcted myocardium at 3 days after coronary ligation in the wild-type mice. The expression of TM was downregulated in the TG heart, and PC was not detected in the hearts. The transcript levels of PS orphan receptors, Mer and Tyro3, but not Axl, were significantly upregulated in the TG heart. Double immunohistochemical staining revealed that myocardial infiltrating CD3-positive T cells may produce PS in the TG myocardium. In conclusion, the PS/TFPI was upregulated in the myocardium of a different etiological model of HF, thus suggesting a role for the PS/TFPI system in the protection of the failing heart under both inflammatory and hypercoagulable states.

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Effect of Heparanase and Heparan Sulfate Chains in Hemostasis

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0041-1725065 ◽

2021 ◽

Vol 47 (03) ◽

pp. 254-260

Author(s):

Yona Nadir

Keyword(s):

Cell Surface ◽

Heparan Sulfate ◽

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Contraceptive Use ◽

Coagulation System ◽

Endothelial Cell Surface ◽

Oral Contraceptive Use ◽

Increased Risk ◽

Tissue Factor Pathway

AbstractHeparanase, the only mammalian enzyme known to degrade heparan sulfate chains, affects the hemostatic system through several mechanisms. Along with the degrading effect, heparanase engenders release of syndecan-1 from the cell surface and directly enhances the activity of the blood coagulation initiator, tissue factor, in the coagulation system. Upregulation of tissue factor and release of tissue factor pathway inhibitor from the cell surface contribute to the prothrombotic effect. Tissue factor pathway inhibitor and the strongest physiological anticoagulant antithrombin are attached to the endothelial cell surface by heparan sulfate. Hence, degradation of heparan sulfate induces further release of these two natural anticoagulants from endothelial cells. Elevated heparanase procoagulant activity and heparan sulfate chain levels in plasma, demonstrated in cancer, pregnancy, oral contraceptive use, and aging, could suggest a potential mechanism for increased risk of thrombosis in these clinical settings. In contrast to the blood circulation, accumulation of heparan sulfate chains in transudate and exudate pleural effusions induces a local anticoagulant milieu. The anticoagulant effect of heparan sulfate chains in other closed spaces such as peritoneal or subdural cavities should be further investigated.

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Antibodies to β2-Glycoprotein I Associated with Antiphospholipid Syndrome Suppress the Inhibitory Activity of Tissue Factor Pathway Inhibitor

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614082 ◽

2000 ◽

Vol 84 (10) ◽

pp. 653-656 ◽

Cited By ~ 34

Author(s):

Irene Salemink ◽

Ron Blezer ◽

George Willems ◽

Monica Galli ◽

Edouard Bevers ◽

...

Keyword(s):

Tissue Factor ◽

Blood Coagulation ◽

Tissue Factor Pathway Inhibitor ◽

Factor Xa ◽

Anionic Phospholipid ◽

Normal Plasma ◽

Increased Risk ◽

Tissue Factor Pathway

SummaryAnionic phospholipid membranes have a dual role in blood coagulation: they are essential for the initiation and propagation as well as for the limitation and termination of the blood coagulation process. Patients with the anti-phospholipid syndrome (APS) carrying antibodies against complexes of anionic phospholipids and plasma proteins, show in vitro inhibited phospholipid dependent coagulation reactions, whereas in vivo the presence of these antibodies is associated with an increased risk of thrombosis. In this study we focussed on the effects of these anti-phospholipid antibodies on the regulation of TF-mediated factor Xa (FXa) generation in plasma. We hypothesized that anti-phospholipid antibodies interfere with the phospholipiddependent inhibition by tissue factor pathway inhibitor (TFPI) of TFinduced coagulation. Indeed, total-IgG, anti-cardiolipin-IgG (aCL) and anti-β2GPI-IgG, isolated from patient plasmas, all stimulated TF-induced FXa generation in normal plasma. This enhanced FXa generation was not observed when the patient’s IgG was depleted of anti-β2GPI-IgG or when normal plasma was depleted of β2GPI or TFPI. Taken together, these data indicate that antibodies to β2GPI, circulating in patients with APS, suppress TFPI-dependent inhibition of TF-induced coagulation, which results in an increased FXa generation.

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Zn2+-containing protein S inhibits extrinsic factor X-activating complex independently of tissue factor pathway inhibitor

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2010.03919.x ◽

2010 ◽

Vol 8 (9) ◽

pp. 1976-1985 ◽

Cited By ~ 12

Author(s):

N. FERNANDES ◽

L. O. MOSNIER ◽

L. TONNU ◽

M. J. HEEB

Keyword(s):

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Protein S ◽

Factor X ◽

Extrinsic Factor ◽

Tissue Factor Pathway ◽

Factor X Activating Complex

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Association of Tissue Factor Pathway Inhibitor With Human Umbilical Vein Endothelial Cells

Blood ◽

10.1182/blood.v90.9.3568 ◽

1997 ◽

Vol 90 (9) ◽

pp. 3568-3578 ◽

Cited By ~ 20

Author(s):

John-Bjarne Hansen ◽

Randi Olsen ◽

Paul Webster

Keyword(s):

Endothelial Cells ◽

Cell Surface ◽

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Umbilical Vein ◽

Coagulation Factors ◽

Coagulation System ◽

Human Umbilical Vein ◽

Tissue Factor Pathway ◽

Umbilical Vein Endothelial Cells

AbstractTissue factor pathway inhibitor (TFPI) is a serine protease inhibitor of the extrinsic coagulation system, synthesized in endothelial cells, which has recently been shown to play an important role in the regulation of activated coagulation factors at the endothelial cell surface. In the present study we investigated the subcellular localization and metabolism of TFPI in human umbilical vein endothelial cells (HUVEC). Immunocytochemical labeling of HUVEC with anti-TFPI showed specific labeling associated with the cell surface and with many intracellular organelles including the Golgi complex. Further characterization of these organelles was performed by colocalizing the anti-TFPI with 3-(2,4-dinitroanilino)′-amino-N-methyldipropylamine (DAMP; to demonstrate low pH), mannose phosphate receptor (endosomes), and LAMP 1 (late endocytic compartments). TFPI also colocalized with antibodies to the human transferrin receptor, a marker for early endocytic, recycling compartment. Endogenous TFPI colocalized with biotin in intracellular vesicles during endocytosis after biotinylation of the cell surface, which indicated that TFPI was being co-internalized with the surface biotin. The binding of exogenously added 125I-TFPI increased linearly to HUVEC over the concentration range of 0 to 32 nmol/L without saturation, the binding was not affected by up to a thousand-fold molar excess of unlabeled TFPI, and heparin inhibited the binding dose dependently. An intact C-terminal domain was important for the interaction between TFPI and the cell surface of HUVEC, because less than 10% of a C-terminal truncated form of TFPI (TFPI1-161 ) was bound after addition of equimolar concentrations of full-length TFPI. Exogenously added 125I-TFPI was not degraded in HUVEC during 4 hours at 37°C. The presence of TFPI in endocytic and recycling compartments support the hypothesis that endogenous, membrane-anchored TFPI could be internalized for subsequent recycling back to the cell surface.

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