thromboplastin and Arthritis--Rheumatoid

The interaction of coagulation factors with the perivascular environment affects the development of disease in ways that extend beyond their traditional roles in the acute hemostatic cascade. Key molecular players of the coagulation cascade like tissue factor, thrombin, and fibrinogen are epidemiologically and mechanistically linked with diseases with an inflammatory component. Moreover, the identification of novel molecular mechanisms linking coagulation and inflammation has highlighted factors of the coagulation cascade as new targets for therapeutic intervention in a wide range of inflammatory human diseases. In particular, a proinflammatory role for fibrinogen has been reported in vascular wall disease, stroke, spinal cord injury, brain trauma, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, bacterial infection, colitis, lung and kidney fibrosis, Duchenne muscular dystrophy, and several types of cancer. Genetic and pharmacologic studies have unraveled pivotal roles for fibrinogen in determining the extent of local or systemic inflammation. As cellular and molecular mechanisms for fibrinogen functions in tissues are identified, the role of fibrinogen is evolving from a marker of vascular rapture to a multi-faceted signaling molecule with a wide spectrum of functions that can tip the balance between hemostasis and thrombosis, coagulation and fibrosis, protection from infection and extensive inflammation, and eventually life and death. This review will discuss some of the main molecular links between coagulation and inflammation and will focus on the role of fibrinogen in inflammatory disease highlighting its unique structural properties, cellular targets, and signal transduction pathways that make it a potent proinflammatory mediator and a potential therapeutic target.

Topics: Alzheimer Disease; Animals; Arthritis, Rheumatoid; Bacterial Infections; Blood Coagulation; Brain Injuries; Colitis; Fibrinogen; Humans; Inflammation; Kidney Diseases; Multiple Sclerosis; Muscular Dystrophy, Duchenne; Neoplasms; Pulmonary Fibrosis; Spinal Cord Injuries; Stroke; Thrombin; Thromboplastin; Vascular Diseases

Glucose-regulated protein 78 (GRP78) is a potential receptor for targeting therapy in cancer and chronic vascular disease due to its overexpression at the cell surface in tumor cells and in atherosclerotic lesions. Presence of the GRP78 autoantibody in cancer patient sera is generally associated with poor prognosis since it signals a prosurvival mechanism in response to cellular stress. Association of GRP78 with various binding partners involves coordination of multiple signaling pathways that result in either cell survival or cell death. Binding of activated alpha2-macroglobulin to cell-surface GRP78 activates Akt to suppress apoptotic pathways through multiple downstream effectors, and concomitantly upregulates NF-kappaBeta and induces the unfolded protein response (UPR) so that cell proliferation prevails. Interaction of GRP78 with cell-surface T-cadherin promotes endothelial cell survival. Association of oncogenic Cripto with GRP78 nullifies TGF-beta superfamily-dependent signaling through Smad2/3 to promote cell proliferation. In contrast, association of GRP78 with the plasminogen kringle 5 domain or extracellular Par-4 promotes apoptosis. Interaction of GRP78 with microplasminogen induces the UPR while association with tissue factor inhibits procoagulant activity. The diverse and multiple binding proteins of GRP78 and their equally diverse functional outcomes reflect the regulatory cellular functions that GRP78 orchestrates. Several GRP78 targeting peptides have been isolated from different tumors and they show remarkable tumor specificity. Conjugation of GRP78-targeting peptides to an apoptosis-inducing peptide suppresses tumor growth in tumor xenografts, thereby demonstrating that GRP78 is a viable target by which clinical cancer therapies can be successfully developed as well as its potential utility in treating vascular disease.

Topics: alpha-Macroglobulins; Apoptosis; Arthritis, Rheumatoid; Autoantibodies; Cadherins; Cell Proliferation; Cell Survival; Endoplasmic Reticulum Chaperone BiP; Heat-Shock Proteins; Humans; Neoplasms; Peptide Fragments; Plasminogen; Receptors, Thrombin; Signal Transduction; Thromboplastin; Unfolded Protein Response; Vascular Diseases

The importance of the blood coagulation sequence as an integral part in the pathogenesis of diseases inside as well as outside the blood vessels is becoming increasingly apparent. Mononuclear phagocytes have important functions in initiation of coagulation by producing several procoagulant substances, including thromboplastin, the potent trigger of the extrinsic pathway. Increasing evidence demonstrates the clinical importance of monocyte and macrophage thromboplastin synthesis in the pathogenesis of a variety of diseases. This review surveys the role of monocyte/macrophage thromboplastin in relation to inflammatory diseases, cancer, disseminated intravascular coagulation and diseases of the blood vessels, thrombosis and atherosclerosis.

Topics: Arteriosclerosis; Arthritis, Rheumatoid; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Endopeptidases; Glomerulonephritis; Graft Rejection; Humans; Hypersensitivity, Delayed; Kidney Transplantation; Membrane Proteins; Monocytes; Neoplasm Proteins; Pulmonary Embolism; Thromboplastin

Fibroblast-like synoviocytes (FLSs) play a key role in the progression of rheumatoid arthritis (RA) as a primary component of invasive hypertrophied pannus. FLSs of RA patients (RA-FLSs) exhibit cancer-like features, including promigratory and proinvasive activities that largely contribute to joint cartilage and bone destruction. In this study, we hypothesized that the NF of activated T cell 5 (NFAT5), a transcription factor involving tumor invasiveness, would control the migration and invasion of RA-FLSs. Analyses of transcriptomes demonstrated the significant involvement of NFAT5 in locomotion of RA-FLSs and that tissue factor (TF; also known as coagulation factor III) and CCL2 were the major downstream target genes of NFAT5 involving FLS migration and invasion. In cultured RA-FLSs, IL-1β and TGF-β increased TF and CCL2 expression by upregulating NFAT5 expression via p38 MAPK. Functional assays demonstrated that NFAT5- or TF-deficient RA-FLSs displayed decreased lamellipodia formation, cell migration, and invasion under IL-1β- or TGF-β-stimulated conditions. Conversely, factor VIIa, a specific activator of TF, increased migration of RA-FLSs, which was blocked by NFAT5 knockdown. Recombinant CCL2 partially restored the decrease in migration and invasion of NFAT5-deficient RA-FLSs stimulated with IL-1β. NFAT5-knockout mouse FLSs also showed decreased expressions of TF and CCL2 and reduced cell migration. Moreover, KRN2, a specific inhibitor of NFAT5, suppressed migration of FLSs stimulated with TGF-β. Conclusively, to our knowledge, this is the first study to provide evidence of a functional link between osmoprotective NFAT5 and TF in the migration and invasion of RA-FLSs and supports a role for NFAT5 blockade in the treatment of RA.

Topics: Aged; Animals; Arthritis, Rheumatoid; Cell Movement; Cells, Cultured; Chemokine CCL2; Female; Humans; Interleukin-1beta; Male; Mice; Mice, Knockout; Middle Aged; Neoplasm Invasiveness; Signal Transduction; Synovial Membrane; Synoviocytes; Thromboplastin; Transcription Factors; Transcriptome; Transforming Growth Factor beta; Up-Regulation

Angiogenesis, as well as pannus formation within the joint, plays an important role in the erosion of articular cartilage and bone in the pathological process of rheumatoid arthritis (RA). Tissue factor (TF), an essential initiator of the extrinsic pathway of blood coagulation, is also involved in the angiogenesis and the pannus formation of RA progression. In the present study, we used immunofluorescence and confocal scanning methods to characterize TF immunolocalization in RA synovium. We showed that positive staining of TF could be immunolocalized in synoviocytes, CD19(+) B cells and CD68(+) macrophages, whereas weak or negative staining of tissue factor could be found in CD34(+) endothelial cells of neo-vessels, CD3(+) T cells and CD14(+) monocytes in RA synovium tissues. Our study demonstrates a detailed local expression of TF in the rheumatoid synovium, and supports the notion that TF, expressed not only by the synoviocytes themselves, but also the infiltrating CD19(+) B cells and CD68(+) macrophages, is involved in the pannus invasion in the progression of rheumatoid arthritis.

Topics: Antigens, CD; Arthritis, Rheumatoid; B-Lymphocytes; Cartilage, Articular; Endothelial Cells; Endothelium, Vascular; Fluorescent Antibody Technique; Gene Expression; Humans; Macrophages; Microscopy, Confocal; Monocytes; Neovascularization, Pathologic; Synovial Membrane; Thromboplastin

Accelerated atherosclerosis represents a major problem in both systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients, and endothelial damage is a key feature of atherogenesis. We aimed to assess early endothelial changes in SLE and RA female patients (127 SLE and 107 RA) without previous CV events. Biomarkers of endothelial cell activation (intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), thrombomodulin (TM), and tissue factor (TF)) were measured and endothelial function was assessed using peripheral artery tonometry. Reactive hyperemia index (RHI), an indicator of microvascular reactivity, and augmentation index (AIx), a measure of arterial stiffness, were obtained. In addition, traditional CV risk factors, disease activity and medication were determined. Women with SLE displayed higher sICAM-1 and TM and lower TF levels than women with RA (p = 0.001, p<0.001 and p<0.001, respectively). These differences remained significant after controlling for CV risk factors and medication. Serum levels of vascular biomarkers were increased in active disease and a moderate correlation was observed between sVCAM-1 levels and lupus disease activity (rho = 0.246) and between TF levels and RA disease activity (rho = 0.301). Although RHI was similar across the groups, AIx was higher in lupus as compared to RA (p = 0.04). Also in active SLE, a trend towards poorer vasodilation was observed (p = 0.06). In conclusion, women with SLE and RA present with distinct patterns of endothelial cell activation biomarkers not explained by differences in traditional CV risk factors. Early vascular alterations are more pronounced in SLE which is in line with the higher CV risk of these patients.

Topics: Adult; Arthritis, Rheumatoid; Atherosclerosis; Biomarkers; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Lupus Erythematosus, Systemic; Manometry; Middle Aged; Risk Factors; Thrombomodulin; Thromboplastin; Vascular Cell Adhesion Molecule-1; Vascular Stiffness

Topics: Adult; Aged; Alleles; Arthritis, Rheumatoid; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Thromboplastin

LIGHT (TNFSF 14) belongs to the tumor necrosis factor superfamily and is expressed by activated T cells as well as various types of antigen presenting cells. LIGHT binds to its cellular receptors TR2 and LTbetaR and has a co-stimulatory role in T cell activation. Here, we compared the relative expression of LIGHT in different immune cells and the biological activity of immune cell-derived LIGHT on endothelial cells.. Surface expression of LIGHT and mRNA production by PBMC and isolated T cells (CD4+ or CD8+) significantly increased after stimulation with PMA (Phorbolester-12- Myristat-13-Acetat)+ionomycin. No LIGHT expression on PMA stimulated monocytes or monocytic-like THP-1 cells could be detected; differentiation of monocytes and THP-1 cells into macrophages, however, resulted in up-regulation of LIGHT. Supernatants of stimulated T cells contained higher concentrations of soluble LIGHT than macrophage supernatants normalized to cell numbers; release of soluble LIGHT was found to be dependent on metalloproteinase activity. Size determination of released soluble LIGHT by size exclusion chromatography revealed a molecular mass of approximately 60 kDa, suggesting a trimeric form. Released soluble LIGHT induced expression of proinflammatory antigens ICAM-1, tissue factor and IL-8 in human endothelial cells and caused apoptosis of IFN-g pretreated endothelial cells. Soluble LIGHT was detected at low levels in sera of healthy controls and was significantly enhanced in sera of patients with chronic hepatitis C and rheumatoid arthritis (24.93+/-9.41 vs. 129.53+/-49.14 and 172.13+/-77.64; p<0.0005).. These findings suggest that among immune cells activated T lymphocytes are the main source of soluble LIGHT with released amounts of soluble LIGHT markedly higher compared to platelets. Immune cell-derived membrane-bound and soluble trimeric LIGHT is biologically active, inducing proinflammatory changes in endothelial cells. Enhanced plasma levels of soluble LIGHT in patients with chronic infections suggest a role of LIGHT in systemic inflammatory activation.

Topics: Adolescent; Adult; Aged; Arthritis, Rheumatoid; Cell Differentiation; Cells, Cultured; Drug Combinations; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Hepatitis C, Chronic; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Ionomycin; Leukocytes, Mononuclear; Macrophages; Middle Aged; Molecular Weight; RNA, Messenger; T-Lymphocytes; Tetradecanoylphorbol Acetate; Thromboplastin; Tumor Necrosis Factor Ligand Superfamily Member 14; Umbilical Veins; Up-Regulation; Young Adult

C-reactive protein (CRP) and serum amyloid A (SAA) increase in the blood of patients with inflammatory conditions and CRP-induced monocyte tissue factor (TF) may contribute to inflammation-associated thrombosis. This study demonstrates that SAA is a potent and rapid inducer of human monocyte TF. SAA induced TF mRNA in PBMC within 30 min and optimal procoagulant activity within 4 h, whereas CRP (25 mug/ml)-induced activity was minimal at this time. Unlike CRP, SAA did not synergize with LPS. Procoagulant activity was inhibited by anti-TF and was dependent on factors VII and X, and TF Ag levels were elevated on CD14(+) monocytes. Responses were optimal with lymphocytes, although these were not obligatory. Inhibitor studies indicate activation of NF-kappaB through the ERK1/2 and p38 MAPK pathways; the cyclo-oxygenase pathway was not involved. SAA-induced TF was partially inhibited by high-density lipoprotein, but not by low-density lipoprotein or by apolipoprotein A-I. SAA is a ligand for the receptor for advanced glycation end products (RAGE), and TF generation was suppressed by approximately 50% by a RAGE competitor, soluble RAGE, and by approximately 85% by anti-RAGE IgG. However, another RAGE ligand, high mobility group box-1 protein, capable of inducing monocyte chemotactic protein-1 mRNA in 2 h, did not induce TF within 24 h. Cross-linking studies confirmed SAA binding to soluble RAGE. Elevated SAA is a marker of disease activity in patients with rheumatoid arthritis, and PBMC from patients with rheumatoid arthritis were more sensitive to SAA than normals, suggesting a new link between inflammation and thrombosis.

Topics: Aged; Arthritis, Rheumatoid; C-Reactive Protein; Cells, Cultured; Female; Gene Expression Regulation; Humans; Lipoproteins; Male; Middle Aged; Monocytes; NF-kappa B; Receptor for Advanced Glycation End Products; Receptors, Immunologic; RNA, Messenger; Serum Amyloid A Protein; Signal Transduction; Thrombophilia; Thromboplastin

To determine the relationship between plasma C-reactive protein (CRP) concentrations and monocyte tissue factor (TF) expression induced in vitro by combinations of CRP, ss2-glycoprotein I (ss2-GPI), and lipopolysaccharide (LPS).. Peripheral blood mononuclear cells (PBMC) from 26 healthy individuals and 31 patients with inflammatory rheumatic diseases (IRD) were cultured with combinations of CRP, purified or recombinant ss2-GPI, and LPS and monocyte TF procoagulant activity, TF antigen, and TF mRNA were measured. Results were examined against plasma CRP levels.. Monocytes from patients with IRD expressed significantly more TF when stimulated with CRP compared to normal monocytes (p = 0.002). An incremental positive correlation was observed between plasma CRP levels and TF induced by CRP or ss2-GPI. Significantly more TF was induced with CRP combined with ss2-GPI, compared to ss2-GPI alone, either with costimulation or CRP priming. Conversely, when combined with LPS, ss2-GPI suppressed TF induction in a dose-dependent manner on normal PBMC but not on PBMC from patients with IRD. The loss of suppression correlated strongly with plasma CRP levels.. This study shows a remarkably consistent effect of CRP on monocyte TF expression. Systemic inflammation associated with elevated plasma CRP conferred a phenotype on PBMC, whereby incremental priming with respect to TF expression (induced by CRP itself or ss2-GPI) was apparent, and ss2-GPI-mediated inhibition of TF expression induced by LPS was incrementally lost. CRP regulation of monocyte TF could contribute to the higher than expected atherosclerotic vascular disease seen in patients with IRD.

Topics: Adult; Arteriosclerosis; Arthritis, Rheumatoid; beta 2-Glycoprotein I; C-Reactive Protein; Cells, Cultured; Female; Glycoproteins; Humans; Lipopolysaccharides; Male; Middle Aged; Monocytes; Thromboplastin; Up-Regulation

Clinical and experimental evidence suggests that extravascular fibrin deposition in arthritic joints is prominent and deleterious. The aim of this study was to investigate the contributions of tissue factor (TF) and its inhibitor, TF pathway inhibitor (TFPI), in arthritis.. Synovial tissue specimens obtained from 10 patients with rheumatoid arthritis (RA) and 12 patients with osteoarthritis (OA) were scored histologically for inflammation and fibrin content. TF and TFPI levels were assayed at antigenic and functional levels. TF messenger RNA (mRNA) levels were determined using RNase protection assays. The effect of TF inhibition in murine antigen-induced arthritis (AIA) was assessed by administering systemically active site-blocked activated factor VIIa (FVIIai).. Functional TF activity was significantly increased in synovial membranes from RA patients compared with those from OA patients. In contrast, no difference in TF mRNA and TF antigenic levels was observed between these 2 groups. This discrepancy can be accounted for by TFPI, because we observed a negative correlation between TF activity and TFPI activity. There was a significant difference between the RA and OA groups in terms of synovial inflammation, with more inflammation observed in the RA group. Most importantly, TF activity was associated with fibrin (P = 0.024) and with histologic inflammation (P = 0.03) scores. In AIA, inhibition of TF-induced coagulation by FVIIai led, on day 9 of arthritis, to decreased synovial thickness and decreased articular cartilage damage, although only the latter difference between controls and treated mice reached significance (P < 0.04). Finally, in FVIIai-treated mice, there was a strong negative association between the prothrombin time and intraarticular fibrin deposition.. Our results show that TF expression in arthritic synovial tissue favors extravascular coagulation and may play a role in inflammation in RA. In this context, TF inhibitors may be of therapeutic value.

Topics: Aged; Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Dansyl Compounds; Disease Models, Animal; Factor VIIa; Female; Fibrin; Fibrinolytic Agents; Hindlimb; Humans; Immunohistochemistry; Lipoproteins; Male; Mice; Mice, Inbred C57BL; Middle Aged; Osteoarthritis; Radionuclide Imaging; RNA, Messenger; Synovitis; Thromboplastin

STATEMENT OF FINDINGS: We have analyzed the pattern of procoagulant and fibrinolytic gene expression in affected joints during the course of arthritis in two murine models. In both models, we found an increased expression of tissue factor, tissue factor pathway inhibitor, urokinase plasminogen activator, and plasminogen activator inhibitor 1, as well as thrombin receptor. The observed pattern of gene expression tended to favor procoagulant activity, and this pattern was confirmed by functional assays. These alterations would account for persistence of fibrin within the inflamed joint, as is seen in rheumatoid arthritis.

Topics: Animals; Antithrombin III; Arthritis, Rheumatoid; Blood Coagulation; Collagen; Fibrinolysis; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; RNA, Messenger; Synovial Membrane; Thrombin; Thromboplastin

Macrophages are normal constituents of synovial tissue, and in inflammatory synovitis the number of synovial macrophages increases. Synovial macrophages and their secretory products are important in initiating, propagating, and maintaining the synovial inflammation in rheumatoid arthritis (RA). The purpose of this study was to determine the absolute numbers of macrophages in synovia resected from patients with RA and osteoarthritis (OA) and to determine their abilities to produce and/or functionally express tumor necrosis factor (TNF), interleukin-1 (IL-1), and tissue factor (thromboplastin). Results demonstrate that synovial tissue from RA patients (as compared to that from OA patients) weighed more, contained more cells, more macrophages, and more multinucleated giant cells (macrophage polykaryons). Also, isolated cells from both OA and RA patients had tissue factor activity and could produce TNF and IL-1 with in vitro culture, but these parameters were not different in cells from OA and RA patients. RA patients receiving glucocorticoid treatment for their arthritis had fewer total synovial cells than did patients not on glucocorticoids, but treatment with nonsteroidal anti-inflammatory agents did not alter cell numbers. Patient treatment with glucocorticoids or non-steroidal anti-inflammatory drugs did not influence the ability of their isolated cells to produce TNF or IL-1.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cells, Cultured; Glucocorticoids; Humans; Interleukin-1; Leukocyte Count; Macrophages; Osteoarthritis; Phagocytes; Synovitis; Thromboplastin; Tumor Necrosis Factor-alpha

Immunohistochemical techniques were applied to rheumatoid synovium in order to detect components of coagulation and fibrinolysis pathways within these tissues. These techniques revealed an intact coagulation pathway and plasminogen activator inhibitor-2 associated with macrophage-like cells that were present throughout these tissues, especially in subsurface areas. Cell-associated thrombin generation appeared to account for conversion of abundant fibrinogen to fibrin. Occasional macrophage-like cells also stained for urokinase but tissue-type plasminogen activator and plasminogen activator inhibitor-1 were restricted to vascular endothelium. Intense synovial fibrin deposition (with the limited evidence for associated fibrinolysis) may contribute to local inflammation and explain certain clinical features of rheumatoid arthritis. These findings suggest novel treatment hypotheses for this disease.

Topics: Arthritis, Rheumatoid; Blood Coagulation Disorders; Factor V; Factor VII; Factor X; Factor XIII; Fibrin; Fibrinogen; Humans; Immunohistochemistry; Macrophages; Plasminogen Inactivators; Synovial Membrane; Thromboplastin

Fibrin deposition is a prominent finding in the synovium of patients with rheumatoid arthritis (RA). Macrophages are found in increased numbers in RA synovium, and these cells are known to produce a variety of procoagulant and anticoagulant molecules. Using immunohistologic techniques, the content and distribution of several important components of the coagulation system in the synovium of patients with RA, osteoarthritis (OA), or traumatic joint abnormalities requiring surgery were investigated. Samples from 3 patients from each category were examined in detail. RA synovium (compared with that of patients with OA or joint trauma) had increased numbers of macrophages and increased expression/content of fibrinogen, tissue factor, factor XIII, tissue transglutaminase, cross-linked fibrin (fibrin D dimer), urokinase-type plasminogen activator, and alpha 2-plasmin inhibitor. Macrophage content in RA synovium was increased in both the lining cell areas and the interstitial cell areas. Fibrinogen was distributed throughout the tissue in all samples and was greater in RA synovium. In trauma and OA synovia, tissue factor was seen only in association with vessels (endothelial cells), but in RA synovium, it was markedly increased throughout the tissues. While fibrin D dimer was seen in small amounts in synovial lining cell areas of trauma and OA synovia, it was present in increased amounts in the lining cell and interstitial cell areas of RA synovium. Factor XIII and tissue transglutaminase were present in scant amounts in trauma and OA synovia, but there were increased amounts of both (especially tissue transglutaminase) in RA synovium in the vessel, lining cell, and interstitial cell areas. Urokinase and alpha 2-plasmin inhibitor were also markedly increased in RA synovium. These results suggest that in inflamed synovium, there is ongoing extravascular tissue fibrin formation and dissolution that correlates with the degree of inflammation and macrophage content. Extravascular coagulation/fibrinolysis in RA represents a potential target for therapeutic intervention in this disease.

Topics: alpha-2-Antiplasmin; Arthritis, Rheumatoid; Factor XIII; Fibrin; Fibrinogen; Fibrinolytic Agents; Humans; Immunohistochemistry; Macrophages; Osteoarthritis; Plasminogen Activators; Synovial Membrane; Thromboplastin; Transglutaminases; Urokinase-Type Plasminogen Activator

We examined thromboplastin activity (TA) of monocytes and release of oxygen-derived free radicals (ODRFs) from monocytes and granulocytes before and after implantation of a hip or a knee prosthesis in 7 patients with rheumatoid arthritis and in 8 patients with arthrosis. Monocyte TA rose threefold on the first postoperative day in the rheumatoid patients, but was unaltered postoperatively in the arthrosis patients. Granulocyte chemiluminescence doubled in the arthrosis group on the second postoperative day, but was unaltered in the rheumatoid patients. Monocyte chemiluminescence was not influenced by the operation. Thus, leukocytes from the rheumatoid patients responded differently from surgical trauma when compared with leukocytes from the arthrosis patients. This difference may have an impact postoperatively.

Topics: Arthritis, Rheumatoid; Granulocytes; Hip Prosthesis; Humans; Joint Diseases; Knee Prosthesis; Monocytes; Thrombophlebitis; Thromboplastin

Procoagulant activity (PCA) in normal urine has been recognized for over 50 years. Although tissue factor (TF) is produced by certain tumours, and is increased in both tumour-associated macrophages and blood monocytes, the possibility that it might also be increased in urine has not been studied in patients with cancer. We have measured urinary PCA in hospital controls without inflammatory or neoplastic disease (n = 79), in patients with rheumatoid arthritis (n = 8), inflammatory bowel disease (n = 19), colorectal cancer (n = 70) and in patients undergoing colonoscopy (n = 50). Urinary PCA was higher (P less than 0.001) in patients with colorectal cancer and inflammatory bowel disease than controls or patients with rheumatoid arthritis. Fourteen (88 per cent) out of 16 colonoscopy patients subsequently found to have carcinoma or inflammatory bowel disease had levels above the control upper quartile, compared with 8 (24 per cent) out of 34 with normal colonoscopy (P less than 0.001). TF inhibitors confirmed the nature of the PCA and Western blotting studies indicated a urinary TF molecular weight of approximately 38,000. These studies provide further evidence of abnormal haemostasis in malignancy and suggest that determination of urinary TF may provide a useful screening test in patients undergoing colonoscopy.

Topics: Arthritis, Rheumatoid; Blotting, Western; Colonic Diseases; Colonoscopy; Colorectal Neoplasms; Humans; Molecular Weight; Proctocolitis; Rectal Diseases; Thromboplastin

Topics: Arthritis, Rheumatoid; Female; Fibrocystic Breast Disease; Humans; Inflammatory Bowel Diseases; Male; Neoplasms; Thromboplastin

Extravascular, primarily, alveolar fibrin deposition is commonly associated with the alveolitis of many interstitial lung diseases including the interstitial lung disease associated with rheumatoid arthritis (RA). We therefore hypothesized that coagulation pathways, which promote fibrin formation, would be activated in the alveolar lining fluids of patients with rheumatoid interstitial lung disease. To test this hypothesis, we studied the bronchoalveolar lavage (BAL) fluids from patients with rheumatoid interstitial lung disease (n = 7) and patients with RA unassociated with interstitial lung disease (n = 10) to characterize and quantitatively compare the BAL procoagulant material and levels of fibrinopeptide A (FPA), which is cleaved from fibrinogen by thrombin. FPA reactive peptide concentrations were significantly greater in rheumatoid interstitial lung disease than RA when normalized per ml of concentrated BAL fluid (p = 0.02), per mg BAL total protein (p = 0.01) or BAL albumin content (p = 0.03) and correlated with BAL antigenic neutrophil elastase concentrations (r = 0.87). Procoagulant activity was present in similar concentration of BAL of patients with RA and rheumatoid interstitial lung disease and was mainly attributable to tissue factor associated with factor VII (or VIIa). Our results demonstrate that tissue factor and factor VII are endogenous in the alveoli of subjects with RA and interstitial lung disease and could interact with distal coagulation substrates which may enter the alveoli in interstitial lung disease to locally promote fibrin deposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Arthritis, Rheumatoid; Blood Coagulation Factors; Bronchoalveolar Lavage Fluid; Factor VII; Factor X; Fibrinogen; Fibrinopeptide A; Humans; Middle Aged; Neutrophils; Peptide Hydrolases; Pulmonary Fibrosis; Thromboplastin

Monocytes isolated from peripheral blood of patients with various rheumatic diseases and circulating immune complexes (IC) developed a significantly higher thromboplastin (tissue factor) activity than normal cells when cultured in vitro without inducers, but normal cells responded more strongly with thromboplastin production upon stimulation with IC or phytohaemagglutinin (PHA). Sera from patients with rheumatic diseases and circulating IC induced a significant increase in the thromboplastin activity of normal monocytes. Lysozyme release from patient monocytes was significantly lower than the release from control cells when stimulated with IC. Patient sera contained higher amounts of lysozyme than normal sera, indicating lysozyme release in vivo. These data suggest that activation of monocytes in vivo by IC may take place. The increased expression of thromboplastin in monocytes/tissue macrophages may be important for the development of microvascular thrombosis and fibrin deposition seen in chronic inflammatory lesions.

Topics: Adolescent; Adult; Aged; Antigen-Antibody Complex; Arthritis, Rheumatoid; Female; Glucuronidase; Humans; Male; Middle Aged; Monocytes; Muramidase; Rheumatic Diseases; Thromboplastin

Topics: Adult; Aged; Antibody Formation; Arthritis, Rheumatoid; Aurothioglucose; Blood Coagulation Factors; Blood Platelets; Bone Marrow; Bone Marrow Cells; Dimercaprol; Drug Hypersensitivity; Drug Therapy, Combination; Female; Gold; Humans; Immunity, Cellular; Lipoproteins; Lymphocyte Activation; Male; Middle Aged; Prednisone; Thrombocytopenia; Thromboplastin

Topics: Arthritis, Rheumatoid; Blood Coagulation Factors; Blood Coagulation Tests; Epitopes; Factor V; Factor VIII; Factor X; Factor XII; Phosphatidylethanolamines; Prothrombin; Synovial Fluid; Thromboplastin

Topics: Anticoagulants; Arthritis; Arthritis, Rheumatoid; Hemorrhagic Disorders; Medical Records; Thromboplastin

Topics: Anticoagulants; Arthritis; Arthritis, Rheumatoid; Blood Coagulation; Hemorrhagic Disorders; Humans; Thromboplastin