thromboplastin and Osteoarthritis

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

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

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