Plasma Concentrations Of Tissue Factor Research Articles

Inflammasome Activation: A Keystone of Proinflammatory Response in Obstructive Sleep Apnea

Introduction: As the mechanism that links obstructive sleep apnea (OSA) with the regulation of inflammatory response is not well known, it is important to understand the inflammasome activation, mainly of NLRP3 (nucleotide-binding oligomerization domain-like receptor 3).To assess the NLRP3 activity in patients with severe OSA and to identify its role in the systemic inflammatory response of patients with OSA. Materials and Methods: We analyzed the NLRP3 activity as well as key components of the inflammasome cascade, such as adaptor molecule apoptosis-associated speck-like protein, caspase-1, Gasdermin D, IL-1b, IL-18, and tissue factor, in monocytes and plasma from patients with severe OSA and control subjects without sleep apnea. We explored the association of the different key markers with inflammatory comorbidities. Results: Monocytes from patients with severe OSA presented higher NLRP3 activity than those from control subjects, which directly correlated with the apnea–hypopnea index and hypoxemic indices. NLRP3 overactivity triggered inflammatory cytokines (Il-1b and IL-18) via caspase-1 and increased Gasdermin D, allowing for tissue factor to be released. In vitro models confirmed that monocytes increase NLRP3 signaling under intermittent hypoxia in a hypoxia- inducible factor-1a–dependent manner, and/or in combination with plasma from patients with OSA. Plasma concentrations of tissue factor were higher in patients with OSA with systemic inflammatory comorbidities than in those without them. Conclusions: In patients with severe OSA, NLRP3 activation might be a linking mechanism between intermittent hypoxia and other OSA-induced immediate changes with the development of systemic inflammatory response.

Inflammasome Activation: A Keystone of Proinflammatory Response in Obstructive Sleep Apnea.

Rationale: As the mechanism that links obstructive sleep apnea (OSA) with the regulation of inflammatory response is not well known, it is important to understand the inflammasome activation, mainly of NLRP3 (nucleotide-binding oligomerization domain-like receptor 3). Objectives: To assess the NLRP3 activity in patients with severe OSA and to identify its role in the systemic inflammatory response of patients with OSA. Methods: We analyzed the NLRP3 activity as well as key components of the inflammasome cascade, such as adaptor molecule apoptosis-associated speck-like protein, caspase-1, Gasdermin D, IL-1β, IL-18, and tissue factor, in monocytes and plasma from patients with severe OSA and control subjects without sleep apnea. We explored the association of the different key markers with inflammatory comorbidities. Measurements and Main Results: Monocytes from patients with severe OSA presented higher NLRP3 activity than those from control subjects, which directly correlated with the apnea-hypopnea index and hypoxemic indices. NLRP3 overactivity triggered inflammatory cytokines (IL-1β and IL-18) via caspase-1 and increased Gasdermin D, allowing for tissue factor to be released. In vitro models confirmed that monocytes increase NLRP3 signaling under intermittent hypoxia in a hypoxia-inducible factor-1α-dependent manner, and/or in combination with plasma from patients with OSA. Plasma concentrations of tissue factor were higher in patients with OSA with systemic inflammatory comorbidities than in those without them. Conclusions: In patients with severe OSA, NLRP3 activation might be a linking mechanism between intermittent hypoxia and other OSA-induced immediate changes with the development of systemic inflammatory response.

Comparative Study on the Chronic Vascular Responses Induced by Regular Versus Occasional Waterpipe Smoke Inhalation in Mice.

Waterpipe smoke (WPS) is the second most prevalent form of smoking in the world. There are ample evidences about the vascular alterations caused by regular WPS (Reg-WPS). Nonetheless, comparison of the chronic vascular response induced by regular versus occasional WPS (Occ-WPS) exposure is very scarce. We investigated, in BALB/c mice, the effects of Occ-WPS (30 minutes/day, 1 day/week) versus Reg-WPS (30 minutes/day, 5 days/week) for 6 months on thrombogenicity and platelet aggregation in vivo and in vitro. Moreover, various markers of endothelial integrity, inflammation and oxidative stress were assessed by enzyme-linked immunosorbent assay and colorimetric assay. Control mice were exposed to air. Our results showed that either Occ-WPS or Reg-WPS exposure shortened the thrombotic time in pial microvessels in vivo. Moreover, in pial venules, this effect was more marked in Reg-WPS group (-47%) compared with Occ-WPS (-34%). Similarly, exposure to either Occ-WPS or Reg-WPS reduced the prothrombin time and activated partial thromboplastin time. Platelet count was increased only in Reg-WPS exposure. Exposure to either Occ-WPS or Reg-WPS induced platelet aggregation in vitro. In addition, there was a statistically significant difference between Occ-WPS and Reg-WPS groups in platelet count and aggregation. Plasma concentration of tissue factor (+98%), P-selectin (+14%) and E-selectin (+16%) were significantly increased in Occ-WPS group compared with air exposed group. Likewise, compared with air group Reg-WPS caused an increase in concentration of tissue factor (+193%), P-selectin (+21%) and E-selectin (+42%). Nevertheless, only Reg-WPS induced a decrease (-38%) in the plasma concentration of tissue plasminogen activator. Notably, our results showed a statistically significant difference between Occ-WPS and Reg-WPS groups in the concentration of tissue factor. Erythrocyte numbers, hemoglobin concentration, hematocrit and lactate dehydrogenase activity were augmented only in Reg-WPS group compared with either control or Occ-WPS groups. Likewise, only Reg-WPS induced an increase in proinflammatory cytokines, tumor necrosis factor-α and interleukin-1β compared with either control or Occ-WPS groups. However, markers of oxidative stress including 8-isoprostane and total antioxidants were enhanced in both Occ-WPS and Reg-WPS compared with control group. Our data confirm the vascular toxicity of the chronic Reg-WPS exposure and shows that even occasional chronic exposure to WPS caused thrombosis, platelet aggregation, endothelial alterations and oxidative stress. The latter findings are an additional cause of concern about the long-term toxicity of occasional waterpipe smoking.

Waterpipe smoke-induced hypercoagulability and cardiac injury in mice: Influence of cessation of exposure

Waterpipe tobacco smoking has gained worldwide popularity, particularly among youths. Several clinical and experimental studies have reported that waterpipe smoking (WPS) injures the cardiovascular system. However, the impact of smoking cessation (CS) on the cardiovascular toxicity induced by WPS received scant attention. Hence, we assessed, in C57BL/6 mice, the cardiovascular effects of WPS exposure for 3 months followed by 3 months of SC, as compared with mice exposed for either 3 months to WPS or air (control). WPS exposure induced hypertension, prothrombotic events both in vivo and in vitro and increased the plasma concentrations of tissue factor, fibrinogen and plasminogen activator inhibitor-1. These effects were significantly alleviated by SC. In heart tissue, the levels of troponin I, creatine kinase, lipid peroxidation, 8-isoprostane, tumor necrosis factor α, inteleukin 6, DNA damage and cleaved caspase-3 were significantly increased by WPS exposure. These actions were significantly reduced in the group of mice exposed to WPS followed by SC. Similarly, the increase in the level of nuclear factor κ-β induced by WPS exposure was significantly mitigated by SC. Immunohistochemical analysis of the hearts showed that WPS exposure increased the expression of nuclear factor erythroid-derived 2-like 2 by cardiomyocytes. The latter effect was significantly reduced by SC. Taken together, our data show that SC is associated with amelioration of WPS induced hypertension, prothrombotic events and cardiac oxidative stress, inflammation, DNA damage and apoptosis.

Association between hemostatic markers, serum lipid fractions and progression of cerebral small vessel disease: A 2-year follow-up study

IntroductionLittle is known if hemostatic markers and serum lipid fractions can predict further radiological progression beyond vascular risk factors in cerebral small vessel disease (SVD). We investigated whether they are associated with SVD radiological progression and if they are related to different SVD clinical manifestations. MethodsA single-center, prospective, cohort study with 2 years of radiological follow-up was performed in consecutive patients with different SVD manifestations. The study group consisted of 123 patients: 49 with lacunar stroke (LS), 48 with vascular dementia (VaD) and 26 with vascular parkinsonism (VaP). We assessed SVD progression by a visual SVD scale. We determined the relationship between serum or plasma concentrations of tissue factor (TF), thrombomodulin, beta-thromboglobulin (BTG), fibrinogen, D-dimer and total cholesterol, HDL-C, LDL-C, triglycerides and SVD progression by logistic regression analysis. Results34.9% patients had SVD radiological progression: 43% had isolated WMLs progression, 23.2% had new lacunes, 34.8% had both WMLs progression and new lacunes. Fibrinogen [OR 1.02 (95% CI 1.006–1.011] was significantly associated with risk of new lacunes or WMLs progression regardless of the clinical SVD manifestation. While low HDL [OR 0.96 (0.93–1)] and TF [OR 1.07 (0.99–1.1)] were marginally associated with new lacunes, BTG [OR 1.005 (0.99–1.01)] was associated with WMLs progression. ConclusionWe found a relationship between fibrinogen and risk of radiological progression of SVD regardless of the clinical SVD manifestation. In addition, lower HDL and increased TF predicted development of new lacunes, and higher BTG was associated with risk of WMLs progression.

Significant inhibition of the triggering mechanism of the extrinsic system of blood coagulation in rats by thymus peptides thymulin, thymosin alpha 1 and thymosin beta 4

INTRODUCTION : The role of the thymus gland and the effects of thymic peptides on the coagulation status are relatively insufficiently studied. Recent data indicate controversial and not persuasive results due to in­vestigation of single hemostasis parameters and application of various pathological models. AIM : The present study aimed to elucidate the influence of thymus peptides thymulin, thymosin alpha 1 and thymosin beta 4 applied s.c. on intact rats, on key triggering factors of blood coagulation via the extrin­sic pathway: plasma concentration of tissue factor (TF); concentration and activity of free TFPI; and the ac­tivity of plasma clotting factor VII, as well as on prothrombin time (PT) - an integral clinical parameter of the intrinsic pathway. MATERIALS AND METHODS : The study was performed on 52 male Wistar strain rats, weighing 200-220 g and bred under standard conditions at dark/light cycle 12/12 h. The rats were divided into four equal groups (n=13) and injected s.c. once daily in the time interval 08.00-09.00 h in the course of three consecutive days as follows: 1st group (controls) - with saline (the solvent of the peptides); 2nd group - with thymulin (Sigma Aldrich, 0.4 mg/kg b.m.); 3rd group - with thymosin alpha 1 (Sigma Aldrich, 0.3 mg/kg b.m.); and the 4th group - with thymosin beta 4 (Sigma Aldrich, 0.3 mg/kg b.m.). RESULTS : Results indicate that thymulin and thymosin alpha 1 expressively decrease TF and increase TFPI concentrations. All three thymic peptides reduce FVIIa activity, increase TFPI activity, and significantly elongate PT. CONCLUSIONS : Thymus peptides thymulin, thymosin alpha 1 and thymosin beta 4 significantly suppress blood coagulation through the extrinsic pathway and generate a distinct tendency for hypocoagulability.

Activation of Coagulation and Fibrinolysis in Acute Respiratory Distress Syndrome: A Prospective Pilot Study.

Coagulation and fibrinolysis remain sparsely addressed with regards to acute respiratory distress syndrome (ARDS). We hypothesized that ARDS development might be associated with changes in plasma coagulation and fibrinolysis. Our aim was to investigate the relationships between ARDS diagnosis and plasma concentrations of tissue factor (TF), tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) in mechanically ventilated patients at increased risk of developing ARDS. We performed an ethically approved prospective observational pilot study. Inclusion criteria were patients with PaO2/FiO2 < 300 mmHg admitted to the intensive care unit (ICU) for mechanical ventilation for 24 h, or more, because of one or more disease conditions associated with increased risk of developing ARDS. Exclusion criteria were age below 18 years; cardiac disease. We sampled plasma prospectively and compared patients who developed ARDS with those who did not using descriptive statistics and chi-square analysis of baseline demographical and clinical data. We also analyzed plasma concentrations of TF, t-PA, and PAI-1 at inclusion (T0) and on third (T3) and seventh day (T7) of the ICU stay with non-parametric statistics inclusive their sensitivity and specificity associated with the development of ARDS using receiver operating characteristic curve analysis. Statistical significance: p < 0.05. Of 24 patients at risk, 6 developed mild ARDS and 4 of each moderate or severe ARDS, respectively, 3 ± 2 (mean ± SD) days after inclusion. Median plasma concentrations of TF and PAI-1 were significantly higher at T7 in patients with ARDS, as compared to non-ARDS. Simultaneously, we found moderate correlations between plasma concentrations of TF and PAI-1, TF and PaO2/FiO2, and positive end-expiratory pressure and TF. TF plasma concentration was associated with ARDS with 71% sensitivity and 100% specificity, a cut off level of 145 pg/ml and AUC 0.78, p = 0.02. PAI-1 displayed 64% sensitivity and 100% specificity with a cut off concentration of 117.5 pg/ml and AUC 0.77, p = 0.02. t-PA did not change significantly during the observation time. This pilot study showed that increased plasma concentrations of TF and PAI-1 might support ARDS diagnoses in mechanically ventilated patients after 7 days in ICU.

Plasma concentrations of tissue factor and its inhibitor in chronic thromboembolic pulmonary hypertension: a step closer to explanation of the disease aetiology?

The aetiology of chronic thromboembolic pulmonary hypertension (CTEPH) is not clearly understood. In some patients, the disease is preceded by acute pulmonary embolism (APE), and is characterised by intravascular thrombosis, vasoconstriction, inflammation and remodelling of pulmonary arteries. Ensuing pulmonary hypertension leads to potentially fatal chronic right ventricle failure. Both inborn and acquired risk factors were identified. Pathogenesis of haemostatic disorders is not completely explained, and extrinsic coagulation pathway disorders may play a role in CTEPH aetiology. To evaluate levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in CETPH, and to delineate their role in the disease pathogenesis. Plasma concentrations of TF and TFPI were evaluated in 21 CTEPH patients, in 12 patients with pulmonary arterial hypertension (PAH), in 55 APE survivors without persistent pulmonary hypertension after at least 6 months from the acute episode, and in 53 healthy volunteers (control group C). Most patients were treated with vitamin K antagonists (VKA), and some with unfractionated or low molecular weight heparin. Exclusion criteria included malignancy, inflammation, and recent operation. Tissue factor concentration was lower in CTEPH and in post-APE patients, not stratified by anticoagulation modality, as compared to control group (p = 0.042; p = 0.011) and PAH group (p = 0.024, p = 0.014). Patients with CTEPH and post-APE on adequate VKA-anticoagulation had similar TF concentration to group C. TFPI concentration was similar in CETPH and post-APE patients irrespective of anticoagulation, and higher as compared to group C (respectively, p = 0.012; p = 0.024; p = 0.004). TFPI concentration was similar in patients with CETPH and in post-APE group, both on adequate VKA-anticoagulation when compared to group C. In the post-APE group, there was no significant difference in TFPI concentration between patients receiving adequate and subjects without anticoagulation. Group C was significantly (p = 0.000) younger than any other group, and showed correlation (r = 0.31) between age and TFPI concentration. In CTEPH there is a high consumption of TF, leading to reduction in plasma concentration of TF and increase in TFPI. Adequate VKA-anticoagulation normalises TF and TFPI plasma concentrations, as is the case of APE survivors.

Tissue Factor in Dermatitis Herpetiformis and Bullous Pemphigoid: Link between Immune and Coagulation System in Subepidermal Autoimmune Bullous Diseases.

Dermatitis herpetiformis (DH) and bullous pemphigoid (BP) are skin diseases associated with eosinophilic and neutrophilic infiltrations. Although chemokines are critical for the selective accumulation and activation of various leukocyte subsets in the inflammatory process, there are few findings concerning inflammatory cells and production of coagulation factors in blistering diseases. Skin biopsies were taken from 14 patients with DH, 27 with BP, and 20 control subjects. The localization and expression of tissue factor (TF) in skin lesions and perilesional skin were studied by immunohistochemistry and confirmed by Western Blot. Moreover the plasma concentrations of TF were measured by immunoassays. D dimers, fibrinogen, and selected coagulation parameters were measured by routine methods. Expression of TF in the epidermis and in inflammatory influxed cells in dermis was detected in skin biopsies from BP patients. Examined TF expression was detected in perilesional skin of all BP patients too. The expression of TF was not observed in biopsies from healthy people and DH patients. The findings of the study show an increased expression of tissue factor in the lesional and perilesional skin of patients with bullous pemphigoid. The difference in chemokine pattern expression and variations in the cellular infiltration in BP and DH cause variable expression of TF.

Abstract 350: Influence of HIV-1 Infection and Antiretroviral Therapy on the Coagulation System

HIV-1-infected individuals have a two- to four-fold greater incidence of cardiovascular disease and atherothrombotic events compared with the general population. The mechanisms responsible for this heightened cardiovascular risk are not fully understood. We have previously reported that the capacity of the endothelium to release tissue-type plasminogen activator (t-PA), the primary activator of fibrinolysis and a key endogenous defense mechanism against intravascular fibrin deposition and thrombosis, is impaired in HIV-1-seropositive adults. Whether diminished fibrinolytic activity is coupled with a hypercoagulative state in this population is unknown. Elevations in specific coagulation markers such as tissue factor and Factor VII are associated with increased thrombotic risk. The experimental aim of this study was to determine the influence of HIV-1 infection and antiretroviral therapy (ART) on markers of coagulation. To address this aim we studied 33 men: 16 HIV-1-seronegative (age: 41±3 yr); 7 HIV-1-seropositive treatment-naïve (34±2 yr); and 10 HIV-1-seropositive receiving ART (42±3 yr; efavirenz-based regimen). All subjects were non-obese, normotensive and free of overt cardiometabolic disease. Circulating concentrations of tissue factor, Factor VII, Factor VIII and Factor X were determined by immunoassay. There were no significant differences in plasma concentrations of tissue factor (32+3 vs 40+3 pg/mL), Factor VII (103+9 vs 100+5 %), Factor VIII (111+13 vs 117+8 %) and Factor X (89+5 vs 91+2 %) between HIV-1-seropositive treatment-naïve and healthy men. Moreover, there was no influence of ART on these circulating markers. Plasma tissue factor (41+5 pg/mL), Factor VII (107+6 %), Factor VIII (103+7 %) and Factor X (90+3%) were similar in the HIV-1-seropositive receiving ART compared with HIV-1-seropositive treatment-naïve and seronegative groups. These data suggest that neither HIV-1 infection per se nor ART are associated with unfavorable changes in specific coagulation markers. Thus, changes in the coagulation system that have been linked to increased thrombotic burden are not apparent in HIV-1-seropositive adults.

Risk of venous thromboembolic disease in postmenopausal women taking oral or transdermal hormone replacement therapy

The influence of hormone replacement therapy (HRT) on hemostasis processes depends on the type of hormone, the combination of doses, the time of taking HRT, and the route of administration (oral, transdermal, implanted). The aim of the current study was to assess some parameters of coagulation, especially tissue factor pathway inhibitor (TFPI) and tissue factor (TF) in postmenopausal women using oral or transdermal HRT. The study was conducted on 76 healthy women, including 46 women aged 44-58 years who were taking oral (26) or transdermal (20) HRT, and 30 women aged 44-54 years who did not take HRT as the control group. Plasma concentrations of TF, TFPI, thrombin-antithrombin complex (TAT), and D-dimer were performed by enzyme-linked immunosorbent assay (ELISA). Moreover, the concentration of fibrinogen and activity of protein C were measured by chromogenic and chronometric methods. We observed a significantly higher concentration of TF and a significantly lower concentration of TFPI in women taking oral and transdermal HRT in comparison with the control group. We also found a significantly lower concentration of fibrinogen in women taking oral HRT vs. the control group. Moreover, no statistically significant changes in concentrations of TAT and D-dimer, or activity of protein C were noted. In this study, the occurrence of an increased TF concentration simultaneously with a decreased concentration of TFPI in women taking HRT indicates hypercoagulability. No significant modification of TAT or D-dimer occurred, and thus there may not be increased risk of thrombosis.

Alternations of Maternal and Cord Plasma Hemostasis in Preeclampsia Before and After Delivery

Objective: The aim of this study was to investigate the role of hemostatic factors in the pathogenesis of preeclampsia. Materials and Methods: Maternal and cord plasma concentrations of tissue factor (TF), tissue factor pathway inhibitor (TFPI), von willebrand factor (vWF), soluble P-selectin (sP-selectin), fibrinopeptide A (FPA), D-dimer, and antithrombin III (AT-III) were measured by enzyme-linked immunosorbent assay (ELISA) in 46 women with preeclampsia and 40 normotensive pregnant women before and after delivery. Results: The maternal plasma concentrations of TF, vWF, and sP‐selectin were higher, but lower concentrations of TFPI, AT-III, and D-dimer were observed in women with preeclampsia compared to normotensive pregnant women before and after delivery. Compared with maternal plasma, fetal plasma concentrations of TF concentrations were increased significantly in both groups, whereas vWF, FPA, TFPI, AT-III, and D-dimer were decreased. Compared with normotensive pregnancy, fetal plasma concentrations of TF were markedly increased in preeclampsia, accompanied with a higher vWF and a lower sP-selectin and D-dimer levels. Furthermore, fetal plasma TF concentrations were more significantly increased in women with high blood pressure and severe proteinuria. Conclusions: Imbalance in the coagulation/fibrinolysis equilibrium, especially alterations in the extrinsic pathway of coagulation and anticoagulation, may play an important role in the pathogenesis of preeclampsia. In addition, fetal alteration of TF may be involved in the pathogenesis of fetal complications of preeclampsia.

High tissue factor activity and low tissue factor pathway inhibitor concentrations in patients with preterm labor

Objective. Preterm labor (PTL) has been associated with an increased thrombin generation in the maternal circulation and amniotic fluid. Tissue factor (TF) is a potent initiator of the coagulation cascade, which can trigger the hemostatic system to generate thrombin. The aims of this study were to determine whether spontaneous PTL with intact membranes is associated with changes in the maternal plasma concentrations and activity of TF as well as tissue factor pathway inhibitor (TFPI).Methods. This cross-sectional study included women in the following groups: (1) normal pregnancies (n = 86); (2) term pregnancies in spontaneous labor (TIL) (n = 67) and not in labor (TNL) (n = 88); and (3) patients with spontaneous PTL and intact membranes (n = 136) that were classified into three sub-groups: (a) PTL without intra-amniotic infection and/or inflammation (IAI) who delivered at term (n = 49); (b) PTL without IAI who delivered preterm (n = 54); and (c) PTL with IAI who delivered preterm (n = 33). Plasma concentrations of TF and TFPI were measured by ELISA, and their activity was measured by chromogenic assays. Non-parametric statistics were used for analysis.Results. (1) Among women at term, those with spontaneous labor had a higher median maternal plasma TF and a lower median TFPI concentration than those without labor. (2) Patients with PTL had a significantly lower median maternal plasma TFPI concentration than that of normal pregnant women, regardless of the presence of IAI. (3) There was no significant difference in the median maternal plasma TF concentration between patients with a normal pregnancy and those with PTL. (4) In contrast, the median maternal plasma TF activity was higher among patients with PTL than in women with normal pregnancies, regardless of the presence of IAI or preterm delivery. (5) However, maternal plasma TFPI activity did not differ among the study groups.Conclusion. Women with preterm parturition, in contrast to those in labor at term, have a higher TF activity and a lower TFPI concentration, without a significant change in the median maternal plasma TF concentration. These observations suggest that the increased thrombin generation reported in patients with PTL may be the result of activation of the extrinsic pathway of the coagulation cascade. In addition, the increased thrombin generation reported in patients with PTL could be due to insufficient anti-coagulation, as reflected by the low maternal plasma TFPI concentration.

Tissue factor/its pathway inhibitor system and kynurenines in chronic kidney disease patients on conservative treatment

The abnormalities of tissue factor (TF) and its inhibitor (TFPI) system could potentially contribute to high incidence of thrombotic complications and atherosclerosis in patients with chronic kidney disease (CKD). Recently, the role of the kynurenine (KYN) pathway of tryptophan (TRP) degradation has been postulated in the progression of cardiovascular complications. We compared the plasma TF, TFPI and the metabolites of TRP degradation: KYN and 3-hydroxykynurenine (3-HKYN) levels in 55 CKD patients on conservative treatment and 19 healthy controls; and we tried to establish whether or not there is an association between TF/TFPI system and above-mentioned metabolites in these patients. Compared with the controls, the patients with CKD showed a significant increase in plasma concentrations of TF (P < 0.01), KYN, 3-HKYN (both P < 0.0001), KYN-to-TRP (kyn/trp) ratio (P < 0.001) and 3-HKYN-to-KYN (3-hkyn/kyn) ratio (P < 0.05). In contrast, TRP concentrations were significantly decreased in the CKD group compared with controls (P < 0.001). The difference in TFPI levels between CKD patients and controls was not statistically significant. TF/TFPI system was inversely correlated with TRP, whereas it was positively related to the 3-HKYN, kyn/trp and 3-hkyn/kyn ratios. Moreover, both the TF/TFPI system and KYNs were associated with the markers of kidney function. These data suggested for the first time a significant relationship between TF/TFPI system and KYN pathway in CKD patients on conservative treatment.

Erythropoietin Therapy Decreased Tissue Factor, Its Pathway Inhibitor, and Oxidative Stress in Peritoneal Dialysis Patients with Diabetes

Aims: We designed a study to evaluate whether erythropoietin (EPO), given to patients on continuousambulatory peritoneal dialysis (CAPD) both with and without diabetes mellitus (DM), influences tissue factor (TF), tissue factor pathway inhibitor (TFPI) and oxidative stress (SOX). Methods: We assessed TF, TFPI and a marker of SOX, Cu/Zn superoxide dismutase (Cu/Zn SOD) in 16 diabetic CAPD patients (8 with EPO therapy), 39 non-diabetic CAPD patients (23 with EPO therapy) and 18 healthy controls. Results: Patients on CAPD showed a significant increase in plasma concentrations of TF, TFPI and Cu/Zn SOD as compared to controls. EPO therapy was related to a decrease in these parameters in diabetic patients, whereas in non-diabetic patients EPO did not affect their levels. In diabetics, TF was positively correlated with TFPI and Cu/Zn SOD levels. There was a positive relationship between TFPI and Cu/Zn SOD, whereas inverse relationships existed between TFPI and haemoglobin, haematocrit (Ht), EPO dose and triglycerides. Multivariate analysis showed that independent variables linked to TFPI levels in diabetic patients were Cu/Zn SOD, Ht and EPO dose. Conclusion: Our data suggest that correction of anaemia with EPO therapy is associated with a significant decrease in TF, TFPI and SOX in diabetic CAPD patients.

Plasma tissue factor and tissue factor pathway inhibitor in patients with primary glomerulonephritis

Nephrotic syndrome (NS) is associated with numerous blood coagulation abnormalities and a marked predisposition to thromboembolism. Fibrin formation within the glomeruli occurs in various forms of human and experimental glomerulonephritis and may play an important role in progressive glomerular injury. The aim of this study was to measure the plasma concentrations of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) and intravascular thrombin generation markers and to analyze their relationships in patients with primary glomerulonephritis. The study population comprised 57 patients (mean age 35.2 years; range 18-63 years) with primary glomerulonephritis: 36 with NS (NS group) and 21 without (non-NS group). The control group consisted of 24 sex- and age-matched healthy volunteers. TF and TFPI antigen, prothrombin fragment F 1+2 (PF 1+2) and thrombin-antithrombin III complex (TAT) concentrations in plasma were estimated using commercially available kits. Serum TF and TFPI concentrations in both the NS and non-NS groups were higher than those observed in the control group. Moreover, there were significant differences in TF and TFPI concentrations between the NS and non-NS groups. TF:TFPI ratios in both the examined groups were constant and significantly higher than those in the control group. Positive correlations between TF and both PF 1+2 and TAT concentrations in the total cohort of patients were shown. Furthermore, a positive correlation between TF and TFPI concentrations was observed. Our data support the hypothesis concerning activation of coagulation pathways in patients with primary glomerulonephritis. An inadequate TFPI concentration as a result of an elevated TF:TFPI ratio characterizes not only patients with clinical manifestations of NS but also patients with mild proteinuria.

Tissue factor and tissue pathway inhibitor: A link between a hemostatic disorder and preterm PROM?

STATIC DISORDER AND PRETERM PROM? OFFER EREZ, JIMMY ESPINOZA, TINNAKORN CHAIWORAPONGSA, FRANCESCA GOTSCH, JUAN PEDRO KUSANOVIC, NANDOR GABOR THAN, SHALI MAZAKI-TOVI, ZOLTAN PAPP, BO HYUN YOON, DEBRA HOPPENSTEADT, JAWED FAREED, SONIA HASSAN, ROBERTO ROMERO, PerinatologyResearch Branch, NICHD,NIH, DHHS, Detroit, Michigan, Wayne StateUniversity School ofMedicine,Department ofObstetrics andGynecology, Detroit, Michigan, Semmelweis University, 1st Department of Obstetrics and Gynecology, Budapest, Hungary, Seoul National University College of Medicine, Department of Obstetrics and Gynecology, Seoul, South Korea, Loyola University Medical Center, Department of Pathology, Maywood, Illinois OBJECTIVE: Vaginal bleeding is a risk factor for preterm PROM (PPROM). A disorder of decidual hemostasis has been implicated in the genesis of PROM. Indeed, excessive thrombin generation has been demonstrated in PPROM before as well as at the time of diagnosis. Decidua is a potent source of tissue factor, the most powerful natural pro-coagulant. A decidual hemostatic disorder may link vaginal bleeding, PPROM, and abruptio placenta. This study was conducted to determine the behavior of maternal plasma tissue factor (TF), the tissue factor pathway inhibitor (TFPI), its natural inhibitor, as well as the thrombin activatable fibrinolysis inhibitor (TAFI) in PPROM. STUDY DESIGN: This cross-sectional study included women with PPROM (n = 123) and women with normal pregnancies (n = 71). Plasma concentrations of TF, TFPI and TAFI were measured by a sensitive immunoassay. Nonparametric statistics were used for analysis. RESULTS: 1) Maternal TF plasma concentrations were significantly higher in patients with PPROM than in women with a normal pregnancy (median: 369.5 pg/ml; range: 3.27-2551 pg/ml vs. median: 345.7 pg/ml; range: 21.72660.2 pg/ml; p = 0.016, respectively); 2) TFPI plasma concentrations were significantly lower in patients with PPROM than in women with a normal pregnancy (median: 58.7 ng/ml; range: 26.3-116 ng/ml vs. median: 66.7 ng/ml; range: 37.4-86.5 ng/ml; p!0.001, respectively); 3) In contrast, there was no significant difference in the median plasma concentrations of TAFI between patients with PPROM and women with normal pregnancy. CONCLUSION: 1) Patients with PPROM have a higher median plasma concentration of TF and a lower median plasma concentration of TFPI than women with normal pregnancies; 2) However, there were no differences in the concentrations of TAFI; 3) These findings suggest that PPROM is associated with specific changes in the hemostatic/coagulation system.

Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations.

We have recently demonstrated that an infusion of a low dose of insulin reduces the intranuclear NF-kappa B (a pro-inflammatory transcription factor) content in MNC while also reducing the plasma concentration of NF-kappa B dependent pro-inflammatory cytokines and adhesion molecules. We have now tested the effect of insulin on the pro-inflammatory transcription factor, early growth response-1 (Egr-1) and plasma concentration of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), two major proteins whose expression is modulated by Egr-1. Insulin was infused at the rate of 2 IU/h in 5% dextrose (100 mL/h) and KCI (8 mmol/h) for 4 h in the fasting state in ten obese subjects. Blood samples were obtained at 0, 2, 4 and 6 h. MNC were isolated and their total homogenates and nuclear fractions were prepared and Egr-1 was measured by electrophoretic mobility shift assay (EMSA). Plasma TF and PAI-1 were assayed by ELISA. There was a significant fall in Egr-1 at 2 (66 +/- 14% of basal level) and 4 h (47 +/- 17% of the basal level; P<0.01). PAI-1 levels (basal = 100%) decreased significantly after insulin infusion at 2 h (57 +/- 6.7% of the basal level) and at 4 h (58 +/- 8.3% of the basal level; P<0.001). Plasma TF levels (basal = 100%) decreased to 76 +/- 7.7% of the basal level at 2 h and to 85 +/- 10.4% of the basal level at 4 h (P<0.05). Thus, insulin reduces intranuclear Egr-1 and the expression of TF and PAI-1. These data provide further evidence that insulin has an anti-inflammatory effect including the inhibition of TF and PAI-1 expression. These effects suggest a potential beneficial effect of insulin in thrombin formation and fibrinolysis in atherothrombosis.

Insulin Inhibits the Pro-Inflammatory Transcription Factor Early Growth Response Gene-1 (Egr)-1 Expression in Mononuclear Cells (MNC) and Reduces Plasma Tissue Factor (TF) and Plasminogen Activator Inhibitor-1 (PAI-1) Concentrations

We have recently demonstrated that an infusion of a low dose of insulin reduces the intranuclear NF-κB (a pro-inflammatory transcription factor) content in MNC while also reducing the p;asma concentration of NF-κB dependent pro-inflammatory cytokines and adhesion molecules. We have now tested the effect of insulin on the pro-inflammatory transcription factor, early growth response-1 (Egr-1) and plasma concentration of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), two major proteins whose expression is modulated by Egr-1. Insulin was infused at the rate of 2 IU/h in 5% dextrose (100 mL/h) and KCI (8 mmol/h) for 4 h in the fasting state in ten obese subjects. Blood samples were obtained at 0, 2, 4 and 6 h. MNC were isolated and their total homogenates and nuclear fractions were prepared and Egr-1 was measured by electrophoretic mobility shift assay (EMSA). Plasma TF and PAI-1 were assayed by ELISA. There was a significant fall in Egr-1 at 2 (66 ± 14% of basal level) and 4 h (47± 17% of the basal level; P<0.01). PAI-1 levels (basal = 100%) decreased significantly after insulin infusion at 2 h (57 ± 6.7% of the basal level) and at 4 h (58 ± 8.3% of the basal level; P<0.001). Plasma TF levels (basal = 100%) decreased to 76 ± 7.7% of the basal level at 2 h and to 85 ± 10.4% of the basal level at 4 h (P<0.05). Thus, insulin reduces intranuclear Egr-1 and the expression of TF and PAI-1. These data provide further evidence that insulin has an anti-inflammatory effect including the inhibition of TF and PAI-1 expression. These effects suggest a potential beneficial effect of insulin in thrombin formation and fibrinolysis in atherothrombosis.

Plasma concentration of tissue factor and factor VII in patients after abdominal surgery

Tissue injury following trauma and surgery may induce alterations in blood coagulation and fibrinolysis. Hypercoagulable state after surgery can be associated with the risk of postoperative thromboembolic complications. The contact of coagulation factors with TF after injury of vessel wall and organ tissues may contribute to the development of thrombosis after surgery (1). TF, the cell surface receptor and cofactor of factor VII/VIIa is normally not expressed by cells within the vasculature. Only monocytes and endothelial cells can be stimulated to express TF transiently by a variety of inflammatory and immunological reactions (for review see 2,3). Also surgical treatment was reported to induce TF synthesis in monocytes (4,5,6). TF is present in many extravascular tissues as vascular adventitia, organ capsules, epidermis, colonic mucosal epithelium, liver stroma, pancreas stroma and also on tumor cells (7-12). In this study, we investigated, whether we can detect the release of TF from the traumatized tissues and from activated monocytes into the circulation following abdominal surgery. To test the dependence of the extension of tissue injury during surgery we segregated the patients into group A with major abdominal operations and group B consisting of patients with appendectomy and cholecystectomy. No relationship could be established between changes of TF and postoperative thromboembolic complications.