thromboplastin and Chronic-Disease

Venous thromboembolic disease often arises as a complication of another pathological condition and/or triggering event. Infectious diseases result from both the direct action of the pathogens themselves and their effect on the immune system. The resulting inflammatory process and the coagulation and fibrinolysis processes share common pathways, explaining why infection is associated with thrombosis. In this brief overview, besides certain chronic infectious diseases, we also consider some acute infections, as the mechanisms are likely to be similar, particularly in the initial infective stage or the more acute episodes of a chronic infection. The infectious agent can be viral, bacterial, fungal, or parasitic. However, the literature on the link between infections and venous thromboembolism (VTE) is uneven, favoring infections that are found in more developed countries where physicians have access to VTE diagnostic tools. Thus, large epidemiological studies in this field are restricted to a limited number of the common chronic infectious diseases such as tuberculosis, while for other infections, particularly parasitic and fungal infections, the link with VTE is only evoked in a few scattered case reports.

Topics: Cell-Derived Microparticles; Chronic Disease; Developed Countries; Developing Countries; Disease Susceptibility; Endothelium, Vascular; HIV Infections; Humans; Infections; Inflammation; Macrophages; Models, Biological; Risk; Thrombophilia; Thromboplastin; Tuberculosis; Venous Thromboembolism

Chronic urticaria (CU) is a widespread skin disease, characterized by the recurrence of transient wheals and itch for more than 6 weeks. Besides autoimmune mechanisms, coagulation factors, in particular tissue factor and thrombin, might also participate in the disease pathophysiology. Tissue factor expressed by eosinophils can induce activation of blood coagulation generating thrombin which in turn can increase vascular permeability both directly, acting on endothelial cells, and indirectly, inducing degranulation of mast cells with release of histamine, as demonstrated in experimental models. D-dimer, a fibrin degradation product, generated following activation of the coagulation cascade and fibrinolysis, has been found to be increased during urticaria exacerbations; moreover, it has been proposed as a biomarker of severity and resistance to H1-antihistamines in CU patients. The possible role of coagulation in CU is also supported by case reports, case series and a small controlled study showing the efficacy of anticoagulant therapy in this disease. The purpose of this review was to summarize the available data on the possible contribution of coagulation to the pathophysiology of CU focusing on clinical aspects and possible future therapeutic developments.

Topics: Animals; Autoantibodies; Biomarkers; Blood Coagulation; Blood Coagulation Factors; Chronic Disease; Complement System Proteins; Eosinophils; Humans; Thrombin; Thromboplastin; Urticaria

Chronic urticaria (CU) is a skin disorder characterized by the recurrent eruption of short-lived wheals accompanied by redness and itching for at least 6 weeks. The wheals can be associated with angioedema. CU is considered an autoimmune disease in about 50% of cases with the presence of circulating histamine releasing autoantibodies mainly directed against the high affinity IgE receptor FcepsilonRI on mast cells and basophils or against IgE. In several CU cases regarded as idiopathic; the actual pathophysiological mechanisms are still unknown. Some patients with CU do not respond to antihistamines and require the use of systemic steroids or cyclosporin, which are, however, not always effective. In CU, several investigators have demonstrated the activation of coagulation that is due to the involvement of eosinophils and a tissue factor pathway with generation of thrombin potentially contributing to an increased vascular permeability. CU patients often present with elevation of coagulation and fibrinolysis markers, such as prothrombin fragment F1+2 and D: -dimer, which correlate with the disease severity. Preliminary data indicate that anticoagulant treatment with heparin and warfarin may be effective in reducing the symptoms of this disorder. Taken together, all these findings provide the rationale for proposing clinical trials on the use of anticoagulant drugs as adjuvant treatment in CU patients.

Topics: Autoimmunity; Blood Coagulation; Chronic Disease; Eosinophils; Humans; Immunoglobulin E; Mast Cells; Platelet Activation; Thromboplastin; Urticaria

The macrophage is the characteristic cell type in chronic inflammatory reactions, in the rheumatoid synovium, as in other sites. When macrophages are activated, considerable synthesis of enzymes and other proteins occurs. Macrophages can be activated by (i) products of activated lymphocytes, (ii) immune complexes and (iii) the complement cleavage product C3b. Among the many consequences of macrophage activation are (i) secretion of hydrolytic enzymes, (ii) cleavage of C3 into C3a, which is cytolytic, and C3b, (iii) production of tissue thromboplastin, a powerful procoagulant, and (iv) formation of polyamine oxidase, which in the presence of appropriate substrates generates factors that lyse or limit the proliferation of tumour cells, lymphocytes and micro-organisms. The relevance of these observations to the pathogenesis of chronic inflammatory reactions is discussed.

Topics: Animals; Cells, Cultured; Chronic Disease; Colony-Stimulating Factors; Complement System Proteins; Erythrocyte Aggregation; Guinea Pigs; Humans; In Vitro Techniques; Inflammation; Interferons; Macrophages; Mice; Neoplasms; Plasminogen Activators; Prostaglandins; Pyrogens; T-Lymphocytes; Thromboplastin

Chronic heart failure (CHF) is characterised by activation of neuroendocrine and inflammatory pathways, and both are linked to a prothrombotic state. Treatment with omega-3 polyunsaturated fatty acids (n3-PUFA) showed significant benefits including mortality reduction in CHF, but exact mechanisms of action are still unclear. We investigated the effects of n3-PUFA on markers of platelet activation and thrombogenesis in patients with severe CHF. Thirty-six patients with non-ischaemic CHF (LVEF<35%, NYHA class>2) under optimised therapy were randomised to supplementation with 1g/day or 4 g/day n3-PUFA, or placebo for 12 weeks. Using whole-blood flow cytometry, monocyte-platelet aggregates characterised by CD14+/CD42b+ co-expression and monocytic tissue factor (TF) were determined. Plasma levels of P-selectin, sCD40L, fibrinogen, prothrombin fragment F1.2, TF and pro-inflammatory markers (high sensitive[hs] interleukin-6, hsCRP, hsTNF-alpha, monocyte chemotactic protein-1) were measured by immunoassay. Supplementation with 1g/day and 4 g/day n3-PUFA but not placebo significantly reduced monocyte-platelet aggregates in a dose-dependent manner (p for trend = 0.02 across the groups). A dose of 4 g/day but not 1g/day n3-PUFA significantly decreased P-selectin (p = 0.03). Plasma TF decreased dose-dependently upon n3-PUFA supplementation (p for trend = 0.02), paralleled by a significant decrease of TF+-monocytes (p for trend = 0.01). The amount of 4 g/day n3-PUFA exhibited modest anti-inflammatory effects with a significant reduction of hs interleukin-6 (p<0.01) and a trend-wise reduction of hsTNF-alpha (p = 0.09). No changes were seen for sCD40L, fibrinogen, hsCRP and monocyte chemotactic protein-1, while F1.2 was decreased by 4 g/day n3-PUFA (P = 0.03). In patients with severe non-ischaemic CHF, treatment with n3-PUFA leads to a dose-dependent decrease of platelet activation and TF. Higher dosage exhibits also anti-inflammatory effects.

Topics: Adult; Blood Platelets; CD40 Ligand; Cell Separation; Chronic Disease; Disease Progression; Dose-Response Relationship, Drug; Fatty Acids, Omega-3; Female; Flow Cytometry; Heart Failure; Humans; Inflammation Mediators; Lipopolysaccharide Receptors; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Thromboplastin

To determine the relation between plasma tissue factor (TF) and serum angiotensin II(AngII) and the effect of different dosages of fosinopril on chronic heart failure(CHF).. Thirty healthy controls and 35 CHF patients were recruited to observe AngII,TF, left ventricular ejection fractions(LVEF) and left ventricular end-systolic volume index (LVESVI) at baseline and 10 weeks after the treatment. The 35 patients were randomly assigned into 2 groups: A routine dosage fosinopril group received 10 mg once daily and a middle dosage group received 10 mg twice a day for 10 weeks.. Compared with the healthy controls, AngII,TF,and LVESVI significantly increased (P<0.01) and LVEF significantly decreased (P<0.01) in CHF patients. The TF was positively correlated with AngII(r=0.2491, P<0.01) in the patients. After the 10-week treatment with different dosages of fosinopril, AngII,TF,and LVESVI obviously decreased(P<0.05 or P<0.01) and LVEF significantly increased in the 2 groups (P<0.05 or P<0.01). The middle dosage group changed more than the routine dosage group (P<0.01).. TF is positively correlated with AngII in CHF patients. Fosinopril can greatly improve cardiac function and antagonize prethrobotic state,and the therapeutic effect improves with the dosage increase.

Topics: Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Female; Fosinopril; Heart Failure; Humans; Male; Middle Aged; Thromboplastin

Tissue factor (TF; an initiator of coagulation) and vascular endothelial growth factor (VEGF; a marker of angiogenesis) are involved in the hypercoagulable state associated with malignancy. We investigated their roles in chronic atrial fibrillation (AF), a condition also associated with increased risk of stroke and thromboembolism, as well as a prothrombotic or hypercoagulable state.. We studied 25 patients with AF (20 men; mean+/-SD age, 62+/-13 years) who were compared with 2 control groups in sinus rhythm: 30 healthy control subjects (17 men; mean age, 60+/-9 years) and 35 patient control subjects with coronary artery disease (CAD; 27 men; mean age, 60+/-12 years). Plasma levels of TF, VEGF, and the VEGF receptor sFlt-1 were measured by enzyme-linked immunosorbent assay.. VEGF, sFlt-1, and TF were significantly different between the 3 groups, with abnormal levels in AF and CAD patients compared with control subjects (P<0.001, P=0.022, and P=0.008, respectively). Among the AF patients, TF levels were significantly correlated with VEGF (Spearman's r=0.65, P<0.001) and sFlt (r=0.54, P=0.006) levels. Only TF and VEGF levels were significantly correlated in CAD patients (r=0.39, P=0.02). There were no significant correlations among the healthy control subjects.. Patients with chronic AF have high TF levels, in keeping with the prothrombotic state associated with this arrhythmia. The relationships between TF and VEGF and its receptor sFlt-1 in AF suggest a possible role for VEGF in the hypercoagulable state found in AF, as seen in malignancy and atherosclerosis.

Topics: Anticoagulants; Atrial Fibrillation; Blood Pressure; Case-Control Studies; Chronic Disease; Coronary Artery Disease; Cross-Sectional Studies; Demography; Endothelial Growth Factors; Female; Humans; Lymphokines; Male; Middle Aged; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Thrombophilia; Thromboplastin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Warfarin

Changes of hemostatic parameters during percutaneous transluminal coronary angioplasty (PTCA) in 75 patients with chronic coronary artery disease were evaluated. Plasma levels of D-dimer, soluble fibrin monomer, plasmin-alpha2 antiplasmin inhibitor complex, and tissue factor (TF) were significantly increased in all patients with chronic coronary artery disease. The activity of antithrombin and protein C and the levels of protein C antigen were significantly decreased 1 hr after PTCA, but they returned to normal range 1 day after PTCA. There was no significant difference in the level of plasma APC-PCI complex before and 1 hr after PTCA. The plasma levels of D-dimer, soluble fibrin monomer, thrombomodulin, TF and PPIC were significantly decreased 1 hr, and the plasma levels of plasmin-alpha2 antiplasmin inhibitor complex 1 day after PTCA. These findings suggest that the decrease of protein C and antithrombin resulted in activation of the coagulation system. One hour after PTCA, the plasma levels of (total-free) TF pathway inhibitor (TFPI) were significantly decreased, but the plasma levels of total and free-TFPI were significantly increased, suggesting that consumption of (total-free) TFPI occurs during PTCA. Overall, these findings suggest that the hypercoagulable state improves during PTCA and that transient decrease of antithrombin, protein C, (total-free) TFPI or plasmin-alpha2 antiplasmin inhibitor complex may cause restenosis of coronary artery.

Topics: alpha-2-Antiplasmin; Angioplasty, Balloon, Coronary; Biomarkers; Blood Coagulation Factors; Chronic Disease; Coronary Disease; Female; Humans; Lipoproteins; Male; Middle Aged; Protein C; Pyrimidine Dimers; Serine Proteinase Inhibitors; Thromboplastin

Plasma von Willebrand factor antigen, soluble thrombomodulin, and tissue factor were increased in 31 patients with severe chronic renal failure (creatinine clearance <20 ml/min) under conservative treatment, whereas plasminogen activator inhibitor antigen did not differ significantly from healthy controls. No correlation among plasma levels of these proteins was found. Three patterns of relationship between endothelial cell markers and hemostatic defects were identified: 1) Plasma thrombomodulin, a marker of endothelium damage, was found an independent predictor of bleeding time and platelet aggregation, and secretion defects, and was also related to the severity of renal failure; 2) von Willebrand factor antigen, an index of endothelial cell activation and secretion, was significantly correlated with intravascular markers of thrombin and plasmin generation and with platelet adenosine triphosphate content, but not with plasma creatinine levels; and 3) tissue factor and plasminogen activator inhibitor antigen levels were not statistically correlated with the diverse hemostatic defects. Activation of coagulation and fibrinolysis, secondary to endothelial cell activation, appearing early during the evolution of chronic renal failure, is pathogenically related to the platelet dysfunction, and probably to development of atherosclerosis and thrombotic events in this disease. The progression of chronic renal failure, through endothelial cell damage, would lead to aggravation of the platelet functional defect potentiating the hemorrhagic risk.

Topics: Antigens; Biomarkers; Blood Coagulation; Chronic Disease; Disease Progression; Endothelium, Vascular; Fibrinolysis; Hemostasis; Humans; Kidney Failure, Chronic; Plasminogen Activator Inhibitor 1; Thrombomodulin; Thromboplastin; Uremia; von Willebrand Factor

Increased activation of the coagulation cascade and diminished fibrinolysis combine to promote fibrin deposition and polyp formation in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). More information is needed concerning mechanisms of coagulation in CRSwNP.. We investigated the mechanisms as well as the initiation and regulation of coagulation cascade activation in CRS.. Samples were collected from 135 subjects with CRSwNP, 80 subjects with chronic CRS without nasal polyps (NP), and 65 control subjects. The levels of activated factor X (FXa), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex, tissue factor (TF), and TF pathway inhibitor (TFPI) were monitored in CRS by real-time PCR, ELISA, immunohistochemistry, or immunofluorescence. Heteromeric complexes of TF with activated factor VII (FVII) and TF with activated FVII and FXa were assessed by coimmunoprecipitation and Western blotting.. Increased levels of FXa, F1+2, and thrombin-antithrombin complex were detected in NP tissue compared to uncinate tissue from CRS and control subjects. Although free TF protein levels were not increased in NP, immunoprecipitation of TF in NP tissue revealed increased complexes of TF with FVII. Local expression of FVII was detected in sinonasal mucosa, and the ratio of TFPI to FXa was lower in NP tissue.. The coagulation cascade is associated with NP compared to control and uncinate tissue from CRS patients, and TF and FVII are produced locally in sinonasal mucosa in patients. TF and FVII can activate the extrinsic coagulation pathway, suggesting that this pathway may activate fibrin deposition in CRSwNP. Reduced formation of the complex of FXa and TFPI in NP may reduce natural suppression of the extrinsic coagulation pathway in CRSwNP.

Topics: Blood Coagulation; Chronic Disease; Fibrin; Humans; Nasal Polyps; Rhinitis; Sinusitis; Thromboplastin

Tissue factor (TF) signalling has been associated with alterations in Akt activity influencing cellular survival and proliferation. TF is also shown to induce signalling through activation of the protease activated receptor (PAR)2. Seven cell lines were exposed to recombinant-TF (rec-TF), or activated using a PAR2-agonist peptide and the phosphorylation state of PTEN, and the activities of PTEN and Akt measured. Furthermore, by measuring the association of PTEN with MAGI proteins a mechanism for the induction of signalling by TF was proposed. Short term treatment of cells resulted in de-phosphorylation of PTEN, increased lipid-phosphatase activity and reduced Akt kinase activity in most of the cell lines examined. In contrast, continuous exposure to rec-TF up to 14 days, resulted in lower PTEN antigen levels, enhanced Akt activity and increased rate of cell proliferation. To explore the mechanism of activation of PTEN by TF, the association of "membrane-associated guanylate kinase-with inverted configuration" (MAGI)1-3 proteins with PTEN was assessed using the proximity ligation assay and by co-immunoprecipitation. The interaction of PTEN with all three MAGI proteins was transiently reduced following PAR2 activation and explains the changes in PTEN activity. Our data is first to show that PAR2 activation directly, or through exposure of cells to TF releases PTEN from MAGI proteins and is concurrent with increases in PTEN phosphatase activity. However, prolonged exposure to TF results in the reduction in PTEN antigen with concurrent increase in Akt activity which may explain the aberrant cell survival, proliferation and invasion associated with TF during chronic diseases.

Topics: Adaptor Proteins, Signal Transducing; Cell Line, Tumor; Chronic Disease; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Humans; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptor, PAR-2; RNA, Messenger; Signal Transduction; Thromboplastin

Topics: Blood Coagulation; Chronic Disease; Gene Expression Regulation; Histamine; Human Umbilical Vein Endothelial Cells; Humans; Ligands; Lipopolysaccharides; Mast Cells; Thromboplastin; Toll-Like Receptors; Urticaria

Thrombosis is frequently diagnosed as a first symptom in tumor patients and the clinical management of hypercoagulability in cancer patients remains challenging due to concomitant changes in risk factors for severe bleeding. It therefore remains a priority to better understand interactions of the hemostatic system with cancer biology. Specifically, further research is needed to elucidate the details and effects of new anticoagulants on extravascular coagulation and the interplay between cancer progression and chronic inflammation. In addition, it will be important to identify subgroups of cancer patients benefiting from specific modulations of the coagulation system without increasing the bleeding risk. Here, we review recent findings on tissue factor (TF) regulation, its procoagulant activity and TF signaling in the various cell types of the tumor microenvironment.

Topics: Blood Coagulation; Chronic Disease; Humans; Inflammation; Neoplasms; Signal Transduction; Thromboplastin; Tumor Microenvironment

Topics: Anti-Allergic Agents; Chronic Disease; Humans; Immunoglobulin E; Omalizumab; Thromboplastin; Thyroglobulin; Urticaria

In patients with chronic liver diseases, hypercoagulability can contribute to the progression of fibrosis and complications of cirrhosis. Tissue factor (TF) is a transmembrane glycoprotein that initiates the extrinsic pathway of blood coagulation. Recent investigations have established that TF is elevated in patients with pancreatic cancer, blood disorders, diabetes, and cardiovascular disease. Alternatively spliced tissue factor (asTF), a secreted form of TF, induces angiogenesis and exhibits low-level procoagulant activity. The aim of this study was to investigate whether the circulating levels of asTF are elevated in the plasma of patients with liver disease.. In a single-center study, we retrospectively analyzed asTF plasma levels in healthy participants and patients having stage F0-F3 liver fibrosis, liver cirrhosis, as well as hepatocellular carcinoma (HCC). AsTF plasma levels were measured using a sandwich enzyme-linked immunosorbent assay. Values were expressed as median with interquartile range (IQR).. The lowest median plasma asTF concentration (94 pg/ml, IQR: 33-275) was found in the healthy control group. The patients with low-grade liver fibrosis (F0-F1 group) displayed the highest median asTF concentration (404 pg/ml, IQR: 277-789). Significant differences between the asTF levels in the plasma of healthy participants and those in patients with grade F0-F1 fibrosis (P<0.001), patients with grade F2-F3 fibrosis (P=0.019), patients with cirrhosis (P=0.004), and patients with HCC (P<0.001) were found using a Wilcoxon rank-sum test. Treatment-naive patients with HCC had significantly higher asTF levels (P=0.018) than those receiving treatment. AsTF levels were found to increase with worsening Child-Pugh scores and heightened liver disease activity.. AsTF levels are elevated in patients with chronic liver diseases, which increase with worsening Child-Pugh scores and decrease following HCC therapy.

Topics: Adult; Alternative Splicing; Biomarkers; Carcinoma, Hepatocellular; Chronic Disease; Female; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Thromboplastin

Topics: Adult; Aged; Cardiovascular Diseases; Chronic Disease; Female; Humans; Male; Middle Aged; Migraine Disorders; Premenopause; Risk; Risk Factors; Thromboplastin

In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. A better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. We identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression, and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with up-regulated innate immune markers and evidence of robust production of multiple proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, ex vivo and in vitro upon lipopolysaccharide stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with simian immunodeficiency virus (SIV)-related coagulopathy in the progressive [pigtail macaques (PTMs)] but not in the nonpathogenic (African green monkeys) SIV infection model. Last, Ixolaris, an anticoagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to Toll-like receptor stimulation. Strikingly, in vivo treatment of SIV-infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF-expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target.

Topics: Animals; Anti-Retroviral Agents; Antibodies, Viral; Blood Coagulation; Blood Coagulation Disorders; Chlorocebus aethiops; Chronic Disease; Cytokines; HIV Infections; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharide Receptors; Lipopolysaccharides; Monocytes; Receptor, PAR-1; Signal Transduction; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Thromboplastin

Patients with chronic liver disease and cirrhosis have a dysregulated coagulation system and are prone to thrombosis. The basis for this hypercoagulable state is not completely understood. Tissue factor (TF) is the primary initiator of coagulation in vivo. Patients with cirrhosis have increased TF activity in white blood cells and circulating microparticles. The aim of our study was to determine the contribution of TF to the hypercoagulable state in a mouse model of chronic liver injury.. We measured levels of TF activity in the liver, white blood cells and circulating microparticles, and a marker of activation of coagulation (thrombin-antithrombin complexes (TATc)) in the plasma of mice subjected to bile duct ligation for 12days. We used wild-type mice, mice with a global TF deficiency (low TF mice), and mice deficient for TF in either myeloid cells (TF(flox/flox),LysMCre mice) or in hepatocytes (TF(flox/flox),AlbCre).. Wild-type mice with liver injury had increased levels of white blood cell, microparticle TF activity and TATc compared to sham mice. Low TF mice and mice lacking TF in hepatocytes had reduced levels of TF in the liver and in microparticles and exhibited reduced activation of coagulation without a change in liver fibrosis. In contrast, mice lacking TF in myeloid cells had reduced white blood cell TF but no change in microparticle TF activity or TATc.. Hepatocyte TF activates coagulation in a mouse model of chronic liver injury. TF may contribute to the hypercoagulable state associated with chronic liver diseases in patients.

Topics: Animals; Cells, Cultured; Chronic Disease; Disease Models, Animal; Hepatocytes; Humans; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Thrombophilia; Thromboplastin

Thrombosis and inflammation are two major factors underlying chronic thromboembolic pulmonary hypertension (CTEPH). Tissue factor (TF), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) may play critical roles in the process of CTEPH thrombosis and pulmonary vascular remodeling. Ten patients with a confirmed diagnosis of CTEPH, 20 patients with acute pulmonary thromboembolism and 15 patients with other types of pulmonary hypertension were enrolled in this study, along with 20 healthy subjects as the control group. The immunoturbidimetric method was used to determine the plasma content of CRP. The plasma levels of TNF-α, MCP-1, and TF antigen were measured by an enzyme-linked immunosorbent assay, and TF activity was measured by the chromogenic substrate method. Percoll density gradient centrifugation was used to separate peripheral blood mononuclear cells from plasma. The level of monocyte TF mRNA was examined by reverse transcriptase-polymerase chain reaction. The correlations between all indices described above were analyzed. In CTEPH patients, the expression of CRP, TNF-α, and MCP-1 was significantly higher than that in controls (P < 0.05). The levels of TF activity, TF antigen, and TF mRNA in monocyte cells were increased in CTEPH patients when compared with control subjects, but only the TF antigen and TF mRNA levels were significantly different (P < 0.05). In CTEPH patients, levels of CRP, MCP-1, and TNF-α significantly correlated with the level of TF antigen in plasma. TF gene expression was increased in patients with CTEPH, suggesting that blood-borne TF mainly comes from mononuclear cells. TF expression significantly correlated with levels of CRP, TNF-α and MCP-1. These factors may play an important role in the development of CTEPH via the inflammation-coagulation-thrombosis cycle.

Topics: C-Reactive Protein; Case-Control Studies; Chemokine CCL2; Chronic Disease; Cytokines; Humans; Hypertension, Pulmonary; Monocytes; Pulmonary Embolism; RNA, Messenger; Thromboplastin; Tumor Necrosis Factor-alpha

In the presence of a chronically occluded coronary artery, the collateral circulation matures by a process of arteriogenesis; however, there is considerable variation between individuals in the functional capacity of that collateral network. This could be explained by differences in endothelial health and function. We aimed to examine the relationship between the functional extent of collateralization and levels of biomarkers that have been shown to relate to endothelial health.. We measured four potential biomarkers of endothelial health in 34 patients with mature collateral networks who underwent a successful percutaneous coronary intervention (PCI) for a chronic total coronary occlusion (CTO) before PCI and 6-8 weeks after PCI, and examined the relationship of biomarker levels with physiological measures of collateralization.. We did not find a significant change in the systemic levels of sICAM-1, sE-selectin, microparticles or tissue factor 6-8 weeks after PCI. We did find an association between estimated retrograde collateral flow before CTO recanalization and lower levels of sICAM-1 (r=0.39, P=0.026), sE-selectin (r=0.48, P=0.005) and microparticles (r=0.38, P=0.03).. Recanalization of a CTO and resultant regression of a mature collateral circulation do not alter systemic levels of sICAM-1, sE-selectin, microparticles or tissue factor. The identified relationship of retrograde collateral flow with sICAM-1, sE-selectin and microparticles is likely to represent an association with an ability to develop collaterals rather than their presence and extent.

Topics: Aged; Biomarkers; Cardiac Catheterization; Cell-Derived Microparticles; Chronic Disease; Collateral Circulation; Coronary Angiography; Coronary Circulation; Coronary Occlusion; Coronary Vessels; England; Female; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; P-Selectin; Percutaneous Coronary Intervention; Predictive Value of Tests; Thromboplastin; Time Factors; Treatment Outcome; Vascular Resistance

The international normalized ratio (INR) may not be directly applicable to patients with liver disease. We aimed to establish an alternative INR calibration system for patients with liver disease and to evaluate the effect of their use in chronic liver disease patients. Eighty-two patients with liver cirrhosis (LC) were included, and their prothrombin times (PTs) were measured by using 5 commercial thromboplastins. Each of the thromboplastins was also assigned an international sensitivity index (ISIliver) by the plasmas from LC patients. INRvka, INRliver, model for end-stage liver disease (MELD)vka, MELDliver, Child-Pugh (Child)vka, and Childliver scores were calculated. The coefficient of variance of INRvka was significantly larger than that of INRliver (P < 0.01). The mean difference in INRvka between the thromboplastins was also significantly larger than that in INRliver (P < 0.01). The total mean MELDliver score was higher than the total mean MELDvka score. The mean difference between the MELDvka and MELDliver scores (MELD score ≥15) was 3.2 %. We reconfirmed that the use of the alternative calibration system described herein for patients with liver disease may resolve the variability of INR measurement. Our data suggest that we would need to reevaluate the correlation between Child-Pugh class, MELD score, and clinical prognosis by using INRliver for patients with LC.

Topics: Aged; Chronic Disease; Female; Humans; International Normalized Ratio; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Prothrombin Time; Reference Values; Thromboplastin

Atrial fibrillation (AF) is associated with a prothrombotic state. The aim of this study was to analyze platelet activation and tissue factor (TF) induction in mononuclear cells (MNCs) and granulocytes downstream of cell-cell interactions in AF patients.. Blood samples were obtained from patients with paroxysmal AF (n=14) at sinus rhythm and at 15 min after induction of AF during an electrophysiological study, and from control subjects (n=13) and patients with chronic AF (n=14) in the outpatient clinic. The expression of CD41a, CD42b, P-selectin, and P-selectin glycoprotein ligand-1 (PSGL-1) on platelets and microparticles in platelet-rich plasma (PRP), and on MNCs and granulocytes in whole blood were examined by flow cytometry. MNC-platelet interaction was investigated ex vivo.. The expression of CD41a and CD42b on platelets and microparticles was comparable between the control and chronic AF groups, and unchanged after AF induction. Acute induction of AF significantly increased the expression of P-selectin on platelets and microparticles, and to a similar extent, P-selectin-positive MNCs and granulocytes and P-selectin/PSGL-1-double positive MNCs. However, AF induction had no effect on platelet-MNC interactions ex vivo or TF expression on MNCs and granulocytes. Only patients with chronic AF showed platelet-MNC interaction ex vivo and TF overexpression on MNCs.. Acute-onset AF activates platelets within minutes to initiate platelet-MNC interaction. The subsequent platelet binding induced TF expression in patients with chronic AF. These findings support the efficacy of anticoagulant therapeutics in chronic AF and suggest the underlying utility of antiplatelet therapeutics in early phase of AF occurrence.

Topics: Acute Disease; Atrial Fibrillation; Blood Platelets; Case-Control Studies; Cell Communication; Chronic Disease; Female; Flow Cytometry; Granulocytes; Humans; Leukocytes, Mononuclear; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Platelet Membrane Glycoprotein IIb; Thromboplastin

Whereas procoagulation abnormalities in acute stress are well established, little is known about the mechanism of hypercoagulation in chronic stress, such as post-traumatic stress disorder (PTSD). This is crucial, given the fact that chronic coagulation disturbances have been associated with increased morbidity and premature mortality due to thromboembolism and cardiovascular disorders, complications recently described in PTSD patients.. To explore the mechanisms of hypercoagulation in chronic PTSD.. Thirty patients diagnosed with chronic PTSD were enrolled and compared with a control group matched for age, gender and ethnicity. Hypercoagulation state was evaluated by levels of fibrinogen, D-dimer, prothrombin fragment F 1+2, von Willebrand factor (vWF) antigen, factor VIII activity, activated protein C resistance, ProC Global assay, and tissue factor antigen. Psychiatric evaluation was performed using the Mini-International Neuropsychiatric Interview and Clinician Administered PTSD Scale (CAPS).. vWF antigen levels were significantly higher in patients with chronic PTSD compared with the controls (121.3 +/- 42 vs. 99.7 +/- 23, respectively, P = 0.034). Higher levels of vWF antigen and factor VIII activity were found in patients with severe chronic PTSD (CAPS > 80), compared to controls and patients with chronic PTSD and less severe symptoms (CAPS < or = 80). However, no differences were observed in any other studied coagulation parameters between patients and controls.. Increased levels of vWF antigen and factor VIII activity were documented in severe chronic PTSD. These findings suggest that the higher risk of arterial and venous thromboembolic events in PTSD patients could be related to endothelial damage or endothelial activation.

Topics: Activated Protein C Resistance; Adult; Biomarkers; Blood Coagulation Factors; Chronic Disease; Factor VIII; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Israel; Male; Peptide Fragments; Protein Precursors; Prothrombin; Stress Disorders, Post-Traumatic; Surveys and Questionnaires; Thrombophilia; Thromboplastin; von Willebrand Factor

Evidence suggests a role of both innate and adaptive immunity in the development of pulmonary arterial hypertension. The complement system is a key sentry of the innate immune system and bridges innate and adaptive immunity. To date there are no studies addressing a role for the complement system in pulmonary arterial hypertension.. Immunofluorescent staining revealed significant C3d deposition in lung sections from IPAH patients and C57Bl6/J wild-type mice exposed to three weeks of chronic hypoxia to induce pulmonary hypertension. Right ventricular systolic pressure and right ventricular hypertrophy were increased in hypoxic vs. normoxic wild-type mice, which were attenuated in C3-/- hypoxic mice. Likewise, pulmonary vascular remodeling was attenuated in the C3-/- mice compared to wild-type mice as determined by the number of muscularized peripheral arterioles and morphometric analysis of vessel wall thickness. The loss of C3 attenuated the increase in interleukin-6 and intracellular adhesion molecule-1 expression in response to chronic hypoxia, but not endothelin-1 levels. In wild-type mice, but not C3-/- mice, chronic hypoxia led to platelet activation as assessed by bleeding time, and flow cytometry of platelets to determine cell surface P-selectin expression. In addition, tissue factor expression and fibrin deposition were increased in the lungs of WT mice in response to chronic hypoxia. These pro-thrombotic effects of hypoxia were abrogated in C3-/- mice.. Herein, we provide compelling genetic evidence that the complement system plays a pathophysiologic role in the development of PAH in mice, promoting pulmonary vascular remodeling and a pro-thrombotic phenotype. In addition we demonstrate C3d deposition in IPAH patients suggesting that complement activation plays a role in the development of PAH in humans.

Topics: Animals; Arterioles; Biomarkers; Cell Proliferation; Chronic Disease; Complement C3; Complement C3a; Complement C5a; Endothelium, Vascular; Fibrin; Gene Deletion; Humans; Hypertension, Pulmonary; Hypoxia; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Platelet Activation; Pulmonary Artery; Thromboplastin; Up-Regulation

The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors closely linked to inflammation and insulin resistance (IR). Tissue factor (TF) is an initiator of the extrinsic coagulation cascade and is expressed on peripheral blood monocytes and macrophages in atherosclerotic plaques. Monocytes are the principle cells capable of TF synthesis. Therefore, TF plays an important role in both thrombosis and atherosclerosis. Elevated levels of lipopolysaccharide (LPS), a strong stimulator of TF, have been observed in patients with MetS. No study has investigated the relationship between monocyte TF activity and inflammation, and IR in MetS.. Peripheral blood mononuclear cells (PBMCs) were collected from 40 normal subjects and 77 patients with MetS. Mononuclear cell TF procoagulant activity (MPCA) was measured with and without 100 pg/ml LPS stimulation using a 1-stage clotting assay and expressed as the mean +/- SD (mU TF/10(6) PBMCs). MPCA in MetS was significantly greater than in normal subjects (without LPS: 88.0+/-74.8 vs 52.6+/-9.8 mU TF/10(6) PBMCs, P<0.001; with LPS: 269.6+/-165.6 vs 158.6+/-42.8 mU TF/10(6) PBMCs, P<0.001). The LPS-stimulated log MPCA in MetS patients was significantly associated with homeostasis model assessment of IR (r=0.256, P=0.024) and log high-sensitivity C-reactive protein (r=0.332, P=0.003).. Upregulation of monocyte TF is significantly associated with low-grade inflammation and IR in MetS.

Topics: Aged; C-Reactive Protein; Chronic Disease; Disease Progression; Female; Homeostasis; Humans; In Vitro Techniques; Inflammation; Insulin Resistance; Lipopolysaccharides; Male; Metabolic Syndrome; Middle Aged; Monocytes; Risk Factors; Thromboplastin; Up-Regulation

The International Normalised Ratio (INR)/International Sensitivity Index (ISI) system was developed as a way to standardise the prothrombin time during the monitoring of patients undergoing oral anti-coagulant therapy with vitamin K antagonists. The wide acceptance of the INR has led to its use as one of three parameters used in the Model for End stage Liver disease (MELD) scoring system to aid the prioritisation of patients for liver transplant. Literature published recently has highlighted the potential inadequacy of the INR system in this context. Our aim was to investigate the degree of difference between INR values calculated using an ISI derived from warfarinised patients and those calculated using an ISI derived from patients with liver disease. Prothrombin times from 60 patients with liver disease were determined using three working thromboplastin reagents; Innovin, Thromborel S and Thromboplastin C and two reference thromboplastins; rTF/95 and RBT/05. All thromboplastin reagents tested had standard international sensitivity indices (ISIs) assigned following calibration with patients on oral anticoagulant therapy (ISIvka). As a result of the new calibration each of the working thromboplastin reagents was assigned a specific "liver patient" ISI. Two INR values were calculated for each thromboplastin patient involved in the calibration. A comparison of the mean INRliver with INRvka showed a statistically significant difference between the two values (p<0.0001). A similar relationship existed for INRs on a further 20 patients with liver disease whose plasmas were not used to derive the ISIliver. This difference led to a change in the final MELD score and could therefore affect the prioritisation and management of these patients.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Blood Coagulation; Calibration; Chronic Disease; Humans; International Normalized Ratio; Liver; Liver Diseases; Liver Transplantation; Predictive Value of Tests; Prothrombin Time; Recombinant Proteins; Severity of Illness Index; Thromboplastin; Warfarin

Chronic sleep loss, a common feature of human life in industrialized countries, is associated to cardiovascular disorders. Variations in functional parameters of coagulation might contribute to explain this relationship. By exploiting the mouse model and a specifically designed protocol, we demonstrated that seven days of partial sleep deprivation significantly decreases (-30.5%) the thrombin generation potential in plasma evaluated upon extrinsic (TF/FVIIa pathway) but not intrinsic activation of coagulation. This variation was consistent with a decrease (-49.8%) in the plasma activity levels of factor VII (FVII), the crucial physiologicalal trigger of coagulation, which was even more pronounced at the liver mRNA level (-85.7%). The recovery in normal sleep conditions for three days completely restored thrombin generation and FVII activity in plasma. For the first time, we demonstrate that chronic sleep deprivation on its own reduces, in a reversible manner, the FVII expression levels, thus influencing the TF/FVIIa activation pathway efficiency.

Topics: Animals; Chronic Disease; Factor VII; Factor VIIa; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sleep Deprivation; Thrombin; Thromboplastin; Time Factors; Weight Loss

Although several cases of chronic urticaria (CU) are currently regarded as autoimmune in origin, associated with histamine-releasing autoantibodies, an activation of blood coagulation via tissue factor (TF) and a strong expression of TF in lesional skin have been described. Eosinophils, which are involved in CU skin lesions, have recently been demonstrated as the major source of TF in human blood. We assessed whether eosinophils are the cellular source of TF in CU skin lesions.. Twenty patients with severe CU were studied. Skin biopsy specimens were taken from wheals. The control group consisted of specimens of perilesional normal skin from different types of skin tumours (10) and various skin disorders with non-eosinophilic infiltrates, including leukocytoclastic vasculitis (7), lichen planus (8) and mastocytosis (3). TF expression was evaluated by immunohistochemical methods using an anti-TF monoclonal antibody. Co-localization of TF and eosinophil cationic protein, a classic cell marker of eosinophils, was investigated by double-staining studies using 2 specific monoclonal antibodies in the 4 specimens showing the highest TF reactivity scores.. All specimens from patients with CU clearly showed TF expression that was absent in all normal control specimens (p = 0.0001) and in the skin disorders with non-eosinophilic infiltrates (p = 0.001-0.0001). The double-staining experiments for TF and eosinophil cationic protein clearly showed that the TF-positive cells were eosinophils.. Eosinophils are the main source of TF in CU lesional skin. This finding highlights the role of these cells in the pathophysiology of CU and might pave the way for new therapeutic strategies.

Topics: Adolescent; Adult; Aged; Chronic Disease; Eosinophils; Female; Humans; Male; Middle Aged; Thromboplastin; Urticaria; Young Adult

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.

Topics: Adult; Aged; Case-Control Studies; Chronic Disease; Female; Humans; Kidney Diseases; Kynurenine; Lipoproteins; Male; Middle Aged; Thromboplastin; Tryptophan

Postoperative bleeding and adhesion formation remain the two major problems after endoscopic sinus surgery (ESS). This study investigates the effect on adhesion formation and wound healing in a sheep model of chronic sinusitis of three topical agents: recombinant tissue factor (rTF, Dade Innovin, Marburg, Germany), poly-ethylene glycol (SprayGel, Confluent Surgical, Waltham, MA), and a novel chitosan-dextran derivative gel (CD, Department of Chemistry, University of Otago, Dunedin, New Zealand).. Twenty sheep with chronic sinusitis underwent ESS with standardized mucosal injuries created on the lateral nasal wall and the ethmoid region. Injured areas were divided into four groups, and one of the three agents or control (no treatment) was randomly applied. The presence and severity of adhesions were noted and the healing was evaluated by taking brushings for ciliary beat frequency and biopsies of the injured regions at day 28, 56, 84, and 112 post initial surgery. The biopsy specimens were assessed for re-epithelialisation using light microscopy and scanning electron microscopy for reciliation. The cytobrush specimens assessed cilial function by measuring ciliary beat frequency.. CD significantly decreased lateral nasal wall and ethmoidal adhesions compared to tissue factor at all time points (5% vs. 25%, and 0 vs. 50%, respectively). There was a noticeable trend toward decreased adhesions on the lateral nasal wall and ethmoids in the SprayGel group (10% and 14%) and the CD group (10% and 0%) compared to controls (15% and 40%). The CD group had a significantly greater percentage of re-epithelialisation at day 28 and day 84 compared to the rTF group (70% vs. 33%, P < .001; 84.5% vs. 61%, P < 0.05). At day 28, the CD group was significantly more ciliated than control (62% vs. 31%, P < .01) and than rTF (62% vs. 23%, P < .001). This difference between CD and rTF reciliation remained significant at day 56 (67% vs. 40%, P < .05). In addition, the mean cilial grade for CD at day 112 was significantly better than control (1.9 vs. 2.7, P < .05).. In the sheep model of chronic sinusitis, CD significantly improves microscopic wound healing and reduces adhesion formation after ESS.

Topics: Animals; Biocompatible Materials; Chitosan; Chronic Disease; Dextrans; Disease Models, Animal; Endoscopy; Epithelium; Gels; Mucous Membrane; Polyethylene Glycols; Postoperative Complications; Random Allocation; Recombinant Proteins; Sheep; Sinusitis; Thromboplastin; Tissue Adhesions; Wound Healing

In patients with chronic urticaria (CU), plasma shows signs of thrombin generation and autologous plasma skin tests score positive in as many as 95% of cases.. To evaluate the initiators of blood coagulation that lead to thrombin generation and fibrinolysis in CU.. Activated factor VII, activated factor XII, fragment F(1+2), and D-dimer plasma levels were measured in 37 patients with CU and 37 controls. Skin specimens from 10 patients with CU and 10 controls were tested for tissue factor immunohistochemically.. Mean F(1+2) levels were higher in patients than controls (2.54 [SD 2.57] nmol/L vs 0.87 [0.26] nmol/L; P < .001); disease activity was moderate or severe in 9 of 11 (82%) and 9 of 26 (35%) patients showing high or normal F(1+2) levels, respectively (P < .025). Mean D-dimer plasma levels were higher in patients than controls (329 [188] ng/mL vs 236 [81] ng/mL; P < .01); disease activity was moderate or severe in 6 of 8 (75%) and 11 of 29 (38%) showing elevated or normal plasma D-dimer levels (P = NS). Factor VIIa levels were higher in patients than controls (2.86 ng/mL [0.66] vs 1.97 ng/mL [0.65]; P < .001). Activated factor VII and F(1+2) levels were correlated (r = 0.529; P = .008). Tissue factor reactivity was observed only in CU skin specimens.. The extrinsic pathway of clotting cascade is activated in CU. Disease severity is associated with the activation of the coagulation cascade.. The involvement of the coagulation pathway in CU opens new perspectives for a better understanding of the pathogenesis and, possibly, for the treatment of this disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation; Blood Coagulation Factors; Chronic Disease; Factor VIIa; Factor XII; Female; Fibrin Fibrinogen Degradation Products; Humans; Immunohistochemistry; Male; Middle Aged; Peptide Fragments; Prothrombin; Skin; Thromboplastin; Urticaria

Clinically, the vascular pathobiology of human sickle cell disease includes an abnormal state of chronic inflammation and activation of the coagulation system. Since these biologies likely underlie development of vascular disease in sickle subjects, they offer attractive targets for novel therapeutics. Similar findings characterize the sickle transgenic mouse, which therefore provides a clinically relevant inflammation model.. The authors tested two polyhydroxyphenyl hydroxamic acid derivatives, didox and trimidox, in sickle transgenic mice. Animals were examined by intravital microscopy (cremaster muscle and dorsal skin fold preparations) and by histochemistry before and after transient exposure to hypoxia, with versus without preadministration of study drug. Previous studies have validated the application of hypoxia/reoxygenation to sickle transgenic mice as a disease-relevant model.. Animals pretreated with these agents exhibited marked improvements in leukocyte/ endothelial interaction, hemodynamics and vascular stasis, and endothelial tissue factor expression. Thus, these drugs unexpectedly exert powerful inhibition on both the inflammation and coagulation systems.. Each of these changes is expected to be therapeutically beneficial in systemic inflammatory disease in general, and in sickle disease in particular. Thus, these novel compounds offer the advantage of having multiple therapeutic benefits in a single agent.

Topics: Anemia, Sickle Cell; Animals; Benzamidines; Blood Coagulation; Cell Communication; Chronic Disease; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelial Cells; Enzyme Inhibitors; Humans; Hydroxamic Acids; Inflammation; Leukocytes; Mice; Mice, Transgenic; Thromboplastin

Deposition of fibrin in the form of fibrinoid necrosis is a common feature of severe acute renal allograft rejection. The role of the coagulation system and its initiator tissue factor (TF) during this process is, however, still poorly understood. In this study, we analyzed the expression of TF in 88 renal transplants afflicted with different forms of rejection and calcineurin inhibitor-induced nephrotoxicity, to see whether there was differential expression of this protein. TF immunoreactivity was evaluated semiquantitatively in six different renal structures: the podocytes, Bowman epithelium, the endothelium of the glomeruli, the brush border of tubular cells, the thin ascending loop of Henle, and small arteries/arterioles. The TF expression of normal renal tissue (n=6) was restricted to the glomerular podocytes and Bowman epithelium, and to some extent the ascending loop of Henle. Renal allografts undergoing acute rejection (AR) of grades I-III, (n=13, n=17 and n=12, respectively) did not show any altered TF expression in the glomeruli or vascular endothelium. In the ascending loop of Henle, a reduced expression could be seen (ARI, p=0.015; and ARII, p=0.043). TF staining of the brush border of renal transplants undergoing acute cyclosporin A (CsA) nephrotoxicity (n=18) was significantly higher than in normal kidneys (p=0.0003), as well as in transplants undergoing various degrees of acute rejection (ARI, p=0.027; ARII, p=0.0012; and ARIII, p=0.0001). Tubular brush border-expressed TF was also evident in 10 of 15 allografts suffering from chronic CsA nephrotoxicity, compared to 4 out of 13 cases with chronic allograft vasculopathy (CAV), but the increase was not statistically significant relative to normal kidneys. The majority of the grafts afflicted with either of the two chronic conditions displayed a TF-positive arterial endothelium (CAV, p=0.0034; and chronic CsA nephrotoxicity, p=0.0026) relative to controls. In conclusion, these results indicate that vascular TF expression is not altered during acute rejection, but may be of importance in chronic allograft nephropathy. Furthermore, TF immunoreactivity in the tubular brush border may be specific to acute CsA nephrotoxicity and might be used as a biomarker for this condition. Further studies are required to evaluate the possible role of brush border-expressed TF in the pathogenesis of CsA nephrotoxicity.

Topics: Acute Disease; Animals; Biomarkers; Blood Coagulation; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Kidney; Kidney Glomerulus; Kidney Transplantation; Rabbits; Thromboplastin

Most animal models of venous thrombosis involve acute thrombosis with hypercoagulability in small rodents. To better replicate human disease, we developed two models in the pig, a species similar to humans in size and in vascular and coagulation reactivity. One model involves de-endothelialisation with 50% or 80% stenosis and the other replacement of a venous segment by a Gore-Tex vascular prosthesis. Both models were tested with and without acute induced hypercoagulability (thromboplastin infusion). Thrombi obtained without thromboplastin infusion were composed of a multilayered platelet and a fibrin meshwork structure similar to that usually found in humans. With thromboplastin infusion, the thrombi were homogeneous fibrin structures imprisoning red blood cells. The high incidence of thrombosis obtained with the 80% stenosis model would be useful for studying anticoagulant treatments, whereas the low incidence with 50% stenosis would be useful for evaluating procoagulant effects of conditions or treatments. These new models shed further light on the development of venous thrombi under conditions similar to those seen in humans and may prove useful for investigating anticoagulant and procoagulant effects.

Topics: Animals; Blood Vessel Prosthesis; Chronic Disease; Constriction, Pathologic; Disease Progression; Endothelium, Vascular; Fibrin; Hemorheology; Jugular Veins; Models, Animal; Swine; Thrombophilia; Thromboplastin; Venous Thrombosis

Fibrin accumulation in the joint cavity is a common feature of chronic arthritides, such as rheumatoid arthritis (RA). Complex formation between tissue factor (TF) and factor VII (FVII) is the initial step in such a fibrin formation.. To assess the role of the TF/FVII complex in the pathogenesis of joint inflammation, 1) the levels of TF/FVII complex were measured in synovial fluid of RA patients; 2) the complex was injected to healthy mice intra-articularly.. Morphological analysis of the joints 4 days after TF/FVII injection revealed influx of CD4-Mac1+ mononuclear leukocytes into synovial tissue followed by cartilage and bone destruction. Inflammation induced by TF/FVII complex was more profound than that caused by each of the proteins separately, both with respect to frequency, severity and duration of arthritis. Interaction between macrophages and lymphocytes in sustaining joint inflammation was proved by the requirement of the combined lymphocyte/ monocyte depletion to abolish TF/FVII induced arthritis. Induction of monocyte attracting chemokines (MIP-1 alpha and RANTES) was shown to be one of the potential mechanisms for TF/FVII complex triggered inflammatory cell influx. Interestingly, TF/FVII complexes were detected in synovial fluid of 20/40 patients with RA.. Altogether these findings indicate that TF/FVII complexes, frequently found intra-articularly in joints of RA patients, may be an important component in both induction and progression of chronic destructive arthritis.

Topics: Animals; Arthritis; Chemokines; Chronic Disease; Factor VII; Humans; Immune System; Injections, Intra-Articular; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Mice, SCID; Spleen; Synovial Fluid; Thromboplastin

The involvement of coagulation and fibrinolysis in the development of chronic subdural haematoma (CSH) from subdural effusion was investigated. Subdural fluid and venous blood samples were obtained from 34 patients with CSH and 9 patients with subdural effusion, and analyzed using enzyme-linked immunosorbent assays for thrombin-antithrombin III complex (TAT), prothrombin fragment F1 + 2 (F1 + 2), tissue factor, tissue factor pathway inhibitor (TFPI) and D-dimer. CSH was classified into the layering type, believed to be active, and other types according to x-ray computed tomography. All markers in the blood of both patient groups were similar to the values of normal subjects. Levels of TAT and F1 + 2 were much higher in the subdural fluid than in the blood of patients with CSH (P < 0.001, P < 0.001) and with subdural effusion (P < 0.05, P < 0.05). The level of D-dimer in the subdural fluid was significantly higher than in the blood (P < 0.001) in patients with CSH, but not in patients with subdural effusion. All markers in the subdural fluid of layering type CSH, except TFPI, were significantly higher than in the other types (P < 0.05). Local hypercoagulative activity in the subdural space is present in subdural effusion and precedes hyperfibrinolytic activity in CSH. Thrombin generation as indicated by TAT and F1 + 2 might be involved in the development of CSH. Propagation of CSH may be modulated by the coagulation system including the extrinsic pathway and fibrinolysis.

Topics: Adult; Aged; Aged, 80 and over; Antithrombin III; Blood Coagulation Factors; Blood Coagulation Tests; Chronic Disease; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Hematoma, Subdural; Humans; Lipoproteins; Male; Middle Aged; Peptide Fragments; Peptide Hydrolases; Prothrombin; Subdural Effusion; Thrombophilia; Thromboplastin

Topics: Acute Disease; Adult; Aged; Chronic Disease; Female; Humans; Lipoproteins; Male; Middle Aged; Renal Insufficiency; Thromboplastin

Thromboembolic events may complicate clinical course of chronic pancreatitis. It is accepted that trypsin plays a role in the pathogenesis of these abnormalities. However there is a lack of information about local activation of blood coagulation in pancreatic tissue in chronic inflammation and contribution of tissue factor (TF) to this process. Immunohistochemistry was applied to AMeX-fixed sections of tissues of ten cases of chronic pancreatitis to explore the presence and distribution of components of the coagulation system in situ. TF antigen was present in cells of ductules. Fibrinogen and fibrin were detected in the inflammatory infiltrates of the pancreatic tissue. The data suggest that there is local activation of blood coagulation in pancreatic tissue in chronic inflammation that depends on tissue factor.

Topics: Antibodies, Monoclonal; Blood Coagulation; Chronic Disease; Fibrinogen; Humans; Immunohistochemistry; Pancreatitis; Thromboplastin; Whole Blood Coagulation Time

Topics: Animals; Blood Coagulation Disorders; Chronic Disease; Graft Rejection; Kidney Glomerulus; Kidney Transplantation; Rats; Rats, Inbred BN; Rats, Inbred Lew; Thromboplastin; Tissue Plasminogen Activator; Transplantation, Homologous

A case is reported of a 60 year-old patient with chronic disseminated intravascular coagulation (DIC) which was increased by the therapeutic embolization of a renal tumour. The patient had 2 primary carcinomas (renal and prostatic) with vertebral metastases, severe chronic anaemia (due to haematuria), and chronic DIC, with thrombocytopaenia, soluble complexes, and fibrinogen and fibrin degradation products. Therapeutic embolization of the renal artery was carried out with fragments of dura mater. Although the result was anatomically very satisfactory, the patient's condition worsened, with continuing haematuria, and development of an haematoma in the lumbar fossa. Coagulation factors and antithrombin III (AT III) concentrations decreased, whereas the activated partial thromboplastin, thrombin and reptilase times increased. The patient also suffered from acute renal failure (creatinine: 690 mumol.l-1). Treatment consisted in fluid replacement, red blood cell and platelet transfusions, 150 IU.kg-1.d-1 heparin and 20 IU.kg-1.d-1 AT III. Haematological tests returned to pre-embolization values on the ninth day. The sudden worsening in the patient's condition was probably due to the sudden massive release of tissue thromboplastins related to the renal necrosis induced by the therapeutic embolization. The use of heparin AT III in the management of this patient is discussed.

Topics: Antithrombin III; Blood Coagulation Factors; Blood Platelets; Blood Transfusion; Chronic Disease; Disseminated Intravascular Coagulation; Embolization, Therapeutic; Hematuria; Heparin; Humans; Kidney Neoplasms; Male; Middle Aged; Renal Artery; Thromboplastin

Plasma or serum extrinsic pathway inhibitor (EPI) activity was measured in 24 patients with disseminated intravascular coagulation (DIC) and in 23 patients with severe hepatocellular disease. EPI was measured as activity in a test sample that inhibited factor VIIa/tissue factor (TF)-catalyzed activation of 3H-factor IX (activation peptide release) in the presence of factor X. Of the 24 patients with DIC, 13 had sepsis and five had metastatic carcinoma, disorders in which tissue factor is believed to initiate DIC. EPI activity ranged from 68% to 300% (mean 134% +/- 50%). Serial measurements in nine patients failed to show depletion of EPI activity coincident with worsening DIC. DIC induced by tissue factor or other activating materials may progress despite normal EPI levels. In the patients with liver disease, of whom 15 had decompensated chronic hepatocellular disease (two fatal cases) and eight had acute fulminant liver failure (seven fatal cases), plasma or serum EPI activity varied from less than 20% to 194%. Values were distributed in a bimodal fashion. EPI activity could not be correlated with either the etiology of the liver disease or the degree of prolongation of the prothrombin time. Patients with chronic hepatocellular disease who survived had normal or elevated EPI activity. Patients with fatal hepatic dysfunction had low, normal, or high values for EPI activity. This must mean that secretion of EPI from cells other than hepatocytes can maintain normal plasma EPI levels.

Topics: Acinetobacter Infections; Adult; Chronic Disease; Disseminated Intravascular Coagulation; Factor VII; Factor VIIa; Female; Humans; Liver Diseases; Male; Mediastinitis; Middle Aged; Stomach Neoplasms; Thromboplastin

Inhibition of Factor VIIa-tissue factor activity by a plasma component(s) that requires factor Xa has been described recently. In this communication, we have developed a specific radiometric assay (which utilizes 3H-Factor IX and is sensitive to less than 1% of plasma level) for this inhibitor and have measured its activity in various disease states. Strikingly, the levels of this inhibitor were found to be normal in patients with advanced chronic hepatocellular disease but low in patients with disseminated intravascular coagulation (DIC). When endotoxin was used to induce DIC in rabbits, the levels of this inhibitor fell by 25-90%. Human umbilical vein endothelial cells (HUVE), bovine pulmonary artery endothelial cells, and a human hepatoma cell line (HepG2) all synthesized and secreted this inhibitor, whereas a promyelocytic cell line (HL-60) did not and a monocytic cell line (U937) appears to synthesize only small amounts. When ammonium sulfate-fractionated human plasma and serum-free conditioned media from both HUVE and HepG2 cells were electrophoresed on sodium dodecyl sulfate acrylamide gels, two activity peaks corresponding to Mr approximately 45,000 and Mr approximately 33,000 were eluted in each case. These observations suggest that (a) the inhibitor is consumed in DIC and that (b) endothelial cells (or other cells) synthesize sufficient amounts of this inhibitor in vivo to compensate for any decreased production by liver cells.

Topics: Animals; Carcinoma, Hepatocellular; Cattle; Cells, Cultured; Chronic Disease; Disseminated Intravascular Coagulation; Factor VII; Factor VIIa; Humans; Infant, Newborn; Leukemia, Myeloid, Acute; Liver Diseases; Liver Neoplasms; Lymphoma, Large B-Cell, Diffuse; Pulmonary Artery; Rabbits; Thromboplastin; Umbilical Veins

A patient undergoing subtotal pancreatectomy and intraportal islet tissue autotransplantation for chronic pancreatitis developed severe portal hypertension (49 cm of H(2)O) and acute disseminated intravascular coagulation (DIC). In an attempt to identify the cause of these problems, portal pressure and the activities of the coagulation and fibrinolytic systems were studied in dogs undergoing intraportal autotransplantation of islet tissue. Following intraportal injection of the pancreatic tissue in five control dogs, the portal pressure rose to a maximum of 43.2 cm of H(2)O +/- 2.4 and major coagulation abnormalities occurred. The mean hematocrit value fell to 18% +/- 8.6, the mean platelet count to 218,000 +/- 31,000, the mean plasma fibrinogen to 40 mg/dl +/- 18, and the mean euglobulin clot lysis time (ECLT) to 25 min +/- 4. Partial thromboplastin time (PTT) became prolonged (233 secs +/- 30) and significant quantities of fibrinogen-fibrin degradation products (FDP-fdp) (1:128 +/- 32) appeared. These changes indicate the development of DIC probably secondary to significant amounts of tissue thromboplastin detected in the tissue homogenate infused at time of autotransplantation. In a group of seven dogs in whom heparin and Trasylol (aprotinin) were added to the pancreatic tissue at the time of transplantation, portal pressure rose only to a peak of 28.3 cm of H(2)O +/- 3.6 and no significant abnormalities occurred in mean hematocrit value, plasma fibrinogen, platelet count or ECLT. Minor prolongation of PTT occurred secondary to the activity of heparin. FDP-fdp (1:16) were present transiently during tissue injection. Four patients in whom heparin and Trasylol were added to the pancreatic tissue at the time of autotransplantation developed only minor elevations of portal pressure (mean 15.5 cm of H(2)O) without intravascular coagulopathy.

Topics: Animals; Blood Coagulation Tests; Blood Pressure; Chronic Disease; Disseminated Intravascular Coagulation; Dogs; Female; Humans; Hypertension, Portal; Islets of Langerhans Transplantation; Liver; Male; Pancreas; Pancreatectomy; Pancreatitis; Postoperative Complications; Thromboplastin; Transplantation, Autologous

Three techniques have been employed for the in vitro detection of circulating platelet antibodies in thrombocytopenic patients affected by 'idiopathic' form or by lupus erythematosus (SLE), the complement fixation test, the platelet factor 3 availability test and the serotonin release test. 29 of the 35 sera tested (82.8%) gave positive results for antiplatelet activity. In particular the serotonin release test allows to distinguish 4 groups of patients: a first group affected by idiopathic form; two groups with autoimmune thrombocytopenia and various degrees of serotonin release, and finally a fourth group which comprises subjects affected by SLE, with circulating immunocomplexes.

Topics: Autoimmune Diseases; Blood Platelets; Chronic Disease; Complement Fixation Tests; Humans; Isoantibodies; Lupus Erythematosus, Systemic; Serotonin; Thrombocytopenia; Thromboplastin

When an emulsion of dog brain thromboplastin was infused continuously into dogs for 1--4 weeks only platelets and factor XI were consistently depressed. The remaining clotting factors fell in a dose-dependent fashion but there was a tendency toward recovery despite continued infusion of thromboplastin. Fibrinogen and factor V were unique in that with weaker emulsions of thromboplastin, they often rose without a preliminary fall.

Topics: Animals; Chronic Disease; Disseminated Intravascular Coagulation; Dogs; Factor VIII; Fibrinogen; Heparin; Platelet Factor 4; Prothrombin; Thromboplastin

Topics: Acute Disease; Adaptation, Physiological; Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Cardiovascular Diseases; Chronic Disease; Convalescence; Coronary Disease; Fibrinolysin; Fibrinolysis; Humans; Myocardial Infarction; Rheumatic Diseases; Thrombelastography; Thromboplastin; Time Factors

Topics: Aged; Autopsy; Chronic Disease; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrosarcoma; Hematoma; Hematuria; Humans; Leiomyosarcoma; Pulmonary Artery; Sarcoma; Thromboplastin

Topics: Adult; Blood Coagulation; Chronic Disease; Factor XIII; Female; Fibrinogen; Fibrinolysis; Hemoptysis; Humans; Male; Middle Aged; Plasminogen; Thromboplastin; Tuberculosis, Pulmonary

Topics: Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Blood Coagulation; Chronic Disease; Disseminated Intravascular Coagulation; Fibrinogen; Humans; Male; Prothrombin; Thrombelastography; Thrombophlebitis; Thromboplastin

Topics: Adult; Aged; Blood Coagulation; Chronic Disease; Female; Fibrinogen; Humans; Male; Middle Aged; Pneumonia; Thrombelastography; Thromboplastin

Topics: Acute Disease; Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Blood Coagulation Tests; Cholangitis; Chronic Disease; Diagnosis, Differential; Female; Hepatitis A; Humans; Indicators and Reagents; Male; Methods; Middle Aged; Prothrombin Time; Thromboplastin

Topics: Aged; Blood Coagulation Tests; Blood Platelet Disorders; Chronic Disease; Disseminated Intravascular Coagulation; Fibrin; Gastrointestinal Hemorrhage; Heparin; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Prothrombin Time; Thromboplastin

Topics: Blood Cell Count; Blood Platelets; Chronic Disease; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Fibrinolysis; Heparin; Humans; Liver Cirrhosis; Pregnancy; Pregnancy Complications, Hematologic; Prothrombin Time; Thrombin; Thromboplastin

Topics: Acute Disease; Aspartate Aminotransferases; Blood Coagulation Factors; Blood Coagulation Tests; Chronic Disease; Hepatitis A; Humans; Indicators and Reagents; Thromboplastin

Topics: Antithrombins; Blood Coagulation; Chronic Disease; Fibrinolysis; Heparin Antagonists; Humans; Leukocytes; Lymphadenitis; Primary Myelofibrosis; Prothrombin; Thromboplastin; Tissue Extracts

Topics: Animals; Chronic Disease; Disseminated Intravascular Coagulation; Dogs; Thromboplastin

Topics: Blood Coagulation Tests; Chronic Disease; Factor VII; Hemorrhage; Hepatic Encephalopathy; Humans; Methods; Prothrombin Time; Thromboplastin

Coagulation studies were carried out on 30 patients with chronic liver disease. The clotting defect was complex and involved factors V, VII, IX (Christmas factor), and prothrombin. Some patients showed a significant depression of factor IX in the presence of a normal one-stage prothrombin time. Thrombotest was found to be a good indicator of factor IX deficiency in this group of patients and may be of use as an additional liver function test. The screening of patients with liver disease for surgery or liver biopsy should assess the coagulation factors involved in both intrinsic and extrinsic thromboplastin generation.

Topics: Adult; Aged; Blood Coagulation Disorders; Chronic Disease; Factor IX; Factor V; Factor VII; Female; Humans; Liver Diseases; Liver Function Tests; Male; Middle Aged; Prothrombin; Prothrombin Time; Thromboplastin

Topics: Adolescent; Adult; Aged; Blood Coagulation Factors; Blood Coagulation Tests; Chronic Disease; Colitis, Ulcerative; Factor IX; Factor VII; Factor VIII; Factor X; Factor XII; Female; Fibrinogen; Humans; Male; Middle Aged; Thromboembolism; Thromboplastin

Topics: Adolescent; Adult; Age Factors; Aged; Aminohippuric Acids; Biopsy; Blood Glucose; Blood Pressure; Cell Nucleus; Child; Child, Preschool; Cholesterol; Chronic Disease; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Glomerulonephritis; Humans; Kidney Glomerulus; Lipids; Middle Aged; Nitrogen; Thromboplastin

Topics: Arteriosclerosis; Chronic Disease; Erythrocytes; Fibrinogen; Glomerulonephritis; Humans; Kidney Diseases; Lipid Metabolism; Thromboplastin

Topics: Aged; Amputation, Surgical; Arteriosclerosis Obliterans; Blood Coagulation Disorders; Chronic Disease; Coumarins; Diabetes Mellitus; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Middle Aged; Myocardial Infarction; Thromboplastin