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Factor Pathway Inhibitor (factor + pathway_inhibitor)
Kinds of Factor Pathway Inhibitor Selected AbstractsAtorvastatin or transgenic expression of TFPI inhibits coagulation initiated by anti-nonGal IgG binding to porcine aortic endothelial cellsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2010C. C. LIN Summary.,Background:,Intravascular thrombosis remains a barrier to successful xenotransplantation. Tissue factor (TF) expression on porcine aortic endothelial cells (PAECs), which results from their activation by xenoreactive antibodies (Abs) to Gal,1,3Gal (Gal) and subsequent complement activation, plays an important role. Objectives:,The present study aimed to clarify the role of Abs directed against nonGal antigens in the activation of PAECs to express functional TF and to investigate selected methods of inhibiting TF activity. Methods:,PAECs from wild-type (WT), ,1,3-galactosyltransferase gene-knockout (GT-KO) pigs, or pigs transgenic for CD46 or tissue factor pathway inhibitor (TFPI), were incubated with naïve baboon serum (BS) or sensitized BS (with high anti-nonGal Ab levels). TF activity of PAECs was assessed. Results:,Only fresh, but not heat-inactivated (HI), naïve BS activated WT PAECs to express functional TF. Similarly, PAECs from CD46 pigs were resistant to activation by naïve BS, but not to activation by fresh or HI sensitized BS. HI sensitized BS also activated GT-KO PAECs to induce TF activity. TF expression on PAECs induced by anti-nonGal Abs was inhibited if serum was pretreated with (i) an anti-IgG Fab Ab or (ii) atorvastatin, or (iii) when PAECs were transgenic for TFPI. Conclusions:,Anti-nonGal IgG Abs activated PAECs to induce TF activity through a complement-independent pathway. This implies that GT-KO pigs expressing a complement-regulatory protein may be insufficient to prevent the activation of PAECs. Genetic modification with an ,anticoagulant' gene (e.g. TFPI) or a therapeutic approach (e.g. atorvastatin) will be required to prevent coagulation dysregulation after pig-to-primate organ transplantation. [source] Interaction between tissue factor pathway inhibitor and factor V levels on the risk of venous thrombosisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2010A. E. A. DAHM No abstract is available for this article. [source] Regulation of TFPI function by protein SJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2009T. M. HACKENG Summary., Protein S is an anticoagulant cofactor of full-length tissue factor pathway inhibitor (TFPI) that facilitates optimal factor Xa-inhibition and efficient down-regulation of thrombin generation in plasma. Protein S and TFPI are constitutively active in plasma and therefore provide an effective anticoagulant barrier against unwanted procoagulant activity in the circulation. In this review, we describe the current status on how TFPI-activity depends on protein S, and show that TFPI and protein S are major regulators of thrombin generation both in the absence and presence of activated protein C (APC). As there is covariation of plasma TFPI and protein S levels both in health and in disease, these findings suggest that the risk of venous thrombosis associated with protein S deficiency states might be in part explained by the accompanying low plasma TFPI levels. [source] Activity and regulation of glycoPEGylated factor VIIa analogsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2008S. GHOSH Summary.,Background:,Recombinant coagulation factor VIIa (rFVIIa) has proven to be a safe and effective drug for treatment of bleeding episodes in hemophilic patients with inhibitors. However, rFVIIa is cleared from the circulation relatively quickly. Protein modification with poly(ethylene glycol) (PEG) can prolong the circulatory lifetime of proteins but it could also impair protein function by molecular shielding of the protein surface. Objectives:, To characterize the interaction of glycoPEGylated rFVIIa , rFVIIa-10K PEG and rFVIIa-40K PEG , with tissue factor (TF), factor X (FX) and plasma inhibitors, tissue factor pathway inhibitor (TFPI) and antithrombin (AT). Methods:, The amidolytic and FX activation assays were employed to investigate the interaction of glycoPEGylated rFVIIa with its macromolecular substrate and inhibitors. Results:, Both the glycoPEGylated rFVIIa analogs exhibited similar amidolytic activity as that of rFVIIa in the absence or the presence of relipidated TF. The analogs were as effective as rFVIIa in activating FX in the absence of TF. In the presence of TF, the glycoPEGylated rFVIIa variants, relative to rFVIIa, were slightly less effective at lower concentrations, but no significant differences were found among them in activating FX at saturating concentrations. Both AT/heparin and TFPI effectively inhibited the glycoPEGylated rFVIIa bound to relipidated TF or TF on stimulated endothelial cells. In contrast to their normal interaction with TF, the glycoPEGylated rFVIIa variants appeared to interact poorly with phospholipids. Conclusions:, The glycoPEGylated rFVIIa variants retained their catalytic activity and interacted efficiently with TF, FX and the plasma inhibitors. Further work with appropriate in vitro and in vivo model systems is needed to determine the feasibility of using glycoPEGylated rFVIIa to improve therapeutic options for bleeding disorders. [source] Combined tissue factor pathway inhibitor and thrombomodulin deficiency produces an augmented hypercoagulable state with tissue-specific fibrin depositionJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2008S. A. MARONEY Summary.,Background and Objective:,Tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) are endothelial-associated anticoagulant proteins thought to control hemostasis in specific vascular beds. Here, we have examined the consequences of TFPI deficiency in the presence of a compounding procoagulant state caused by reduced TM function. Methods and results:,TFPI+/,/TMpro/pro mice are born at less than expected frequency in either TFPI+/,/TMpro/+ or TMpro/pro mothers but are born at near the expected frequency in TMpro/+ mothers. Adult TFPI+/,/TMpro/pro mice have elevated thrombin,antithrombin complex and increased thrombus volume in an electrical injury model of venous thrombosis. In striking contrast to mice with single deficiency of TFPI or TM, TFPI+/,/TMpro/pro mice exhibit augmented fibrin deposition not only in the liver, but also in the cerebral microvasculature. Conclusions:,TFPI+/,/TMpro/pro mice exhibit partial intrauterine lethality when carried by mothers with an underlying prothrombotic state, providing the first experimental evidence in an animal model that TFPI-dependent control of hemostasis in the vascular bed of the placenta fulfills a critical role for successful pregnancy outcome. In addition to the placenta, partial TFPI deficiency interacts with decreased TM function in an organ selective manner to produce fibrin deposition in other specific vascular beds, the liver and brain. [source] Fibronectin-adherent monocytes express tissue factor and tissue factor pathway inhibitor whereas endotoxin-stimulated monocytes primarily express tissue factor: physiologic and pathologic implicationsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 7 2007M. S. BAJAJ Summary Background:,Monocytes are critical cells in initiating physiologic and/or pathologic tissue factor (TF)-induced intravascular and extravascular coagulation. Monocytes constitutively express small amounts of TF and tissue factor pathway inhibitor (TFPI). Non-adherent lipopolysaccharide (LPS)-stimulated monocytes express significant amounts of TF; however, increased expression of TFPI by these cells is controversial. Further, whether fibronectin-adherent monocytes (mimicking conditions in the extravascular space) express sufficient TFPI to inhibit TF-procoagulant activity (PCA) is unknown.Objective:,To compare TF and TFPI expression by fibronectin-adherent and LPS-stimulated non-adherent monocytes.Methods:,Monocytes were isolated from normal peripheral blood, adhered to fibronectin or stimulated with lipopolysaccharide (LPS) under non-adherent conditions and examined for expression of TF and TFPI using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), ELISA and factor X (FX) activation.Results:,Under LPS-free conditions, the fibronectin-adherent monocyte TF mRNA, antigen and activity were markedly upregulated. Notably, cell and microparticle (MP)-associated TF and alternatively spliced TF (asTF) were all upregulated. TFPI mRNA and antigen were also upregulated in the fibronectin-adherent monocytes, which significantly inhibited TF-PCA. TFPI mRNAs for both alpha and beta forms were detected. The peak in TFPI activity occurred in tandem with the peak in TF-PCA. In contrast, LPS-stimulated monocytes, which expressed cell and MP-associated TF and asTF, demonstrated only minimal expression of TFPI as determined by mRNA, antigen or inhibition of TF activity.Conclusion:,Both LPS-stimulated and fibronectin-adherent monocytes demonstrate a procoagulant phenotype by expressing TF but only fibronectin-adherent monocytes express significant amounts of TFPI to control thrombin generation and fibrin formation in the context of extravascular space. [source] Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trialJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2007H. SAITO Summary.,Background: Soluble thrombomodulin is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. Objectives: We conducted a multicenter, double-blind, randomized, parallel-group trial to compare the efficacy and safety of recombinant human soluble thrombomodulin (ART-123) to those of low-dose heparin for the treatment of disseminated intravascular coagulation (DIC) associated with hematologic malignancy or infection. Methods: DIC patients (n = 234) were assigned to receive ART-123 (0.06 mg kg,1 for 30 min, once daily) or heparin sodium (8 U kg,1 h,1 for 24 h) for 6 days, using a double-dummy method. The primary efficacy endpoint was DIC resolution rate. The secondary endpoints included clinical course of bleeding symptoms and mortality rate at 28 days. Results: DIC was resolved in 66.1% of the ART-123 group, as compared with 49.9% of the heparin group [difference 16.2%; 95% confidence interval (CI) 3.3,29.1]. Patients in the ART-123 group also showed more marked improvement in clinical course of bleeding symptoms (P = 0.0271). The incidence of bleeding-related adverse events up to 7 days after the start of infusion was lower in the ART-123 group than in the heparin group (43.1% vs. 56.5%, P = 0.0487). Conclusions: When compared with heparin therapy, ART-123 therapy more significantly improves DIC and alleviates bleeding symptoms in DIC patients. [source] Postinjury vascular intimal hyperplasia in mice is completely inhibited by CD34+ bone marrow-derived progenitor cells expressing membrane-tethered anticoagulant fusion proteinsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2006D. CHEN Summary.,Background:,Coagulation proteins promote neointimal hyperplasia and vascular remodelling after vessel injury, but the precise mechanisms by which they act in vivo remain undetermined. Objectives:,This study, using an injury model in which the neointima is derived from bone marrow (BM)-derived cells, compared inhibition of tissue factor or thrombin on either BM-derived or existing vascular smooth muscle cells. Methods:,Two transgenic (Tg) mouse strains expressing membrane-tethered tissue factor pathway inhibitor (TFPI) or hirudin (Hir) fusion proteins driven by an , smooth muscle actin (SMA) promoter were generated (, -TFPI-Tg and , -Hir-Tg) and the phenotype after wire-induced endovascular injury was compared with that in wild-type (WT) controls. Results:,WT mice developed progressive neointimal expansion, whereas injury in either Tg was followed by repair back to a preinjured state. This was also seen when WT mice were reconstituted with BM from Tg mice but not when Tgs were reconstituted with WT BM, in which injury was followed by slowly progressive neointimal expansion. Injection of CD34+ cells from Tg mice into injured WT mice resulted in the accumulation of fusion protein-expressing cells from day 3 onwards and an absence of neointimal hyperplasia in those areas. Conclusions:,Neointimal development after wire-induced endovascular injury in mice was completely inhibited when BM-derived cells infiltrating the damaged artery expressed membrane tethered anticoagulant fusion proteins under an , -SMA promoter. These findings enhance our understanding of the pathological role that coagulation proteins play in vascular inflammation. [source] Tissue factor pathway inhibitor revisitedJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2004L. VIJAYA MOHNA RAO [source] Tissue factor pathway inhibitor revisitedJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2004A. MAST [source] Antibodies to tissue factor pathway inhibitor are uncommonly detected in patients with infection-related antiphospholipid antibodiesJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2003R. R. Forastiero No abstract is available for this article. [source] The rediscovery and isolation of TFPIJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 8 2003G. J. Broze Jr Summary., Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type proteinase inhibitor that produces factor (F)Xa-dependent feedback inhibition of the factor VIIa/tissue factor (FVIIa/TF) catalytic complex that is responsible for the initiation of coagulation. Since 1985, when Rapaport and colleagues reported that the lipoprotein fraction of plasma contained a FXa-dependent inhibitor of FVIIa/TF, myriad articles have established its biochemical structure, its mechanism of action, and its physiological importance. This brief personal account reviews historical studies that established the existence of the inhibitor and the events that led to its initial isolation. [source] Poor anticoagulant response to tissue factor pathway inhibitor in patients with venous thrombosisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2003B. Tardy-Poncet Summary., Tissue factor pathway inhibitor (TFPI) is of major importance in regulating the coagulation triggering effects of tissue factor. An association between TFPI deficiency and thrombosis has still not been clearly demonstrated. We evaluated the anticoagulant activity of exogenous TFPI added either to the plasma of patients with venous thrombosis (n = 118) or to the plasma of healthy controls similar in terms of mean age and sex ratio (n = 107). A poor anticoagulant response to TFPI, defined as TFPI resistance, was observed in 4.7% of controls and in 11.0% of patients. TFPI resistance was associated with an almost threefold increase in the risk of thrombosis and could therefore represent a novel hemostatic risk factor for venous thrombosis. [source] Modulation of endothelial cell inflammatory integrins and stress markers with rh-factor VIIa in patients with advanced chronic hepatitis CJOURNAL OF VIRAL HEPATITIS, Issue 4 2003D. H. Van Thiel Summary. Individuals with chronic hepatitis C (CHC) progress to cirrhosis and hepatic cancer. Individuals with advanced CHC are coagulopathic and can manifest fibrinolysis. The coagulopathy is a consequence of hepatocytic dysfunction. The fibrinolysis represents a response to local endothelial cell injury, and is of a low-grade. Based upon this hypothesis, the effect of the infusion of recombinant human factor VIIa (rh-FVIIa) on endothelial cell inflammatory integrins and measures of endothelial stress were determined in 17 individuals with advanced CHC. Immediately prior to the infusion of rh-FVIIa, the plasma levels of tissue factor (TF), Thrombomodulin (TM), human soluble ICAM-1 (hs-ICAM-1), human soluble VCAM-1 (hs-VCAM-1), human soluble L-Selectin (hs-L-Selectin), the prothrombin time and the activated partial thromboplastin time were determined. The same parameters were assayed at 5, 10, 30, 120, 240 and 360 min after infusion. TF and TM levels were very high at baseline consistent with a vascular endothelial stress response. Similarly hs-ICAM-1, hs-VCAM-1 as well as L-Selectin levels were increased. Thirty minutes after the infusion, a marked reduction in ICAM-1 and VCAM-1 and to a lesser degree L-Selectin levels was observed. This reduction persisted for 360 min. No change in measures of fibrinolysis [plasminogen activator inhibitor-1 (PAI-1), total tissue factor pathway inhibitor (t-TFPI), activated tissue factor pathway inhibitor (TFPIa), d-dimers (DD), FSP and fibrinogen levels] occurred. In addition, no change in plasma Annexin-V was observed. Based upon these data it can be concluded that: (1) rh-FVIIa corrects the coagulopathy seen in advanced CHC; (2) reduces endothelial cell injury and/or stress as evidenced by the TF, TM, hs-ICAM-1 and hs-VCAM-1 levels in plasma; (3) these changes in coagulation occurred without inducing a propagated vascular thrombosis. [source] Venous thrombosis associated with gene deletion of tissue factor pathway inhibitor,AMERICAN JOURNAL OF HEMATOLOGY, Issue 11 2009Alex Kentsis No abstract is available for this article. [source] Absence of hypercoagulability in acute Kawasaki diseasePEDIATRICS INTERNATIONAL, Issue 2 2005Ming-Tsan Lin AbstractBackground:,Kawasaki disease (KD) is a systemic vasculitis syndrome with the striking feature of cardiovascular involvement. Endothelial cell (EC) damage has been suggested to predispose individuals to the development of coronary vascular disorders. When EC are perturbed, prethrombotic complications ensue. The purpose of this study was to examine the clinical relevance of EC activation and hypercoagulability in the pathogenesis of KD and to determine if plasma levels of these markers are correlated with the development of coronary aneurysms. Methods:,EC function and coagulation status were assessed in 52 patients with acute KD, 20 febrile control subjects, and 20 healthy control subjects. Biological markers of EC and hypercoagulability were measured and included thrombomodulin, tissue factor, tissue factor pathway inhibitor, von Willebrand factor (vWF), coagulation factor VII (FVII), activated factor VII, prothrombin fragment 1 + 2 (F1 + 2), and D-dimer. Results:,Transient dilatation of coronary arteries was the most common complication (55.8%), and coronary aneurysm was noted in five patients (9.6%). Levels of vWF, FVII, F1 + 2 and D-dimer were higher in acute KD patients compared with healthy controls but not febrile controls. Markers of EC and hypercoagulability were not different between patients with cardiac complications and those without cardiac complications. Biological and immunological assays did not demonstrate the prethrombotic state in acute KD. Conclusions:,Our results suggest that hypercoagulability does not occur during the acute stage of KD. Markers of EC damage and hypercoagulability are not predictive of coronary aneurysms in KD. [source] Tissue factor and tissue factor pathway inhibitorANAESTHESIA, Issue 5 2004G. C. Price Summary The classical ,cascade/waterfall' hypothesis formulated to explain in vitro coagulation organised the amplification processes into the intrinsic and extrinsic pathways. Recent molecular biology and clinical data indicate that tissue factor/factor-VII interaction is the primary cellular initiator of coagulation in vivo. The process of blood coagulation is divided into an initiation phase followed by a propagation phase. The discovery of tissue factor pathway inhibitor further supports the revised theory of coagulation. Tissue factor is also a signalling receptor. Recent evidence has shown that blood-borne tissue factor has an important procoagulant function in sepsis, atherosclerosis and cancer, and other functions beyond haemostasis such as immune function and metastases. [source] Quantification of heparin-induced TFPI release: a maximum release at low heparin doseBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2002Michiel J. B. Kemme Aims Heparin releases tissue factor pathway inhibitor (TFPI) from the endothelium and this release may decrease after repeated high dose heparin administration. The primary aim was to investigate and quantify this phenomenon during a short low dose heparin infusion. Also, the effects of heparin on tissue plasminogen activator (t-PA) were studied. Methods Nine healthy, nonsmoking, male volunteers (range 19,23 years) received a continuous heparin infusion (2000 IU) over 40 min. The endothelial TFPI release rate was estimated from the total TFPI concentration profile using a pharmacokinetic model. Results , Mean ,±,s.d. ,total ,and ,free ,TFPI ,increased ,from ,62.9 ± 9.4/8.3 ± 2.1 ng ml,1 at baseline to 237.2 ± 40.9/111.0 ± 19.9 ng ml,1 after 40 min infusion. The relationship between heparin concentration (anti-IIa activity) and TFPI concentration followed a maximum effect model and a clockwise loop (proteresis) was observed. The TFPI release rate rapidly increased to maximum of 200 ± 45 µg min,1 after 17.5 min heparin infusion but did not increase further although heparin concentrations further doubled. In contrast to TFPI, t-PA antigen decreased from 5.6 ± 1.0 at baseline to 4.5 ± 1.0 ng ml,1 at the end of infusion (t = 40 min) (difference of 1.1 ng ml,1 (95% confidence interval; 0.9, 1.3). Conclusions Our application of concentration-effect models and pharmacokinetic principles to these haemostatic variables showed that endothelial TFPI release has a maximum that is already reached at low heparin dose, corresponding with an anti-IIa activity of 0.08 IU ml,1. The relationship between anti-IIa activity and TFPI release rate showed signs of acute tolerance (clockwise loop) indicating exhaustion of endothelial TFPI pools. These findings may be of importance for the heparin dose used in conditions such as unstable angina, in which the favourable effects of heparin have been ascribed to its ability to release TFPI. [source] | ||||||||||