Fibrin Degradation in the Synovial Fluid of Rheumatoid Arthritis Patients: A Model for Extravascular Fibrinolysis

Abstract

The patterns of degradation and the influence of factor XIII polymerization on fibrin stability were examined in vitro following incubation with leukocyte elastase. In vivo experiments, various factor XIII-polymerized fibrin clots were implanted subcutaneously in mice to evaluate the stability of clots in the extravascular space. Both in vitro and in vivo lysis proceeded faster with nonpolymerized fibrin and was not influenced by the presence of cross-linked alpha 2-plasmin inhibitor. In vivo lysis of implanted clots was prevented by elastatinal, powerful elastase inhibitor, suggesting that granulocyte elastase is chiefly responsible for clot lysis in the extravascular space. To further extend investigations on the mechanisms of fibrinolysis in tissues, we evaluated fibrin and its degradation products in the synovial space. Expression of factor XIII in synovial cells and activities of coagulation factors, fibrinolytic enzymes, and inhibitors were investigated in the synovial fluid of rheumatoid arthritis patients. Immunohistochemical analysis showed deposits of insoluble fibrin on synovial membranes and pannus to an extent related to the progression of the disease. Factor XIII was expressed by fibroblasts and macrophages in the early stages of the disease, whereas in advanced stages factor XIII staining was associated with fibrin. The reduction of certain coagulation factors and high level of thrombin-antithrombin complexes in synovial fluid show a steady activation of the coagulation cascade. The evaluation of fibrinogen degradation products and the pattern of degradation of synovial fibrin(ogen) suggest the participation of leukocyte elastase in fibrin(ogen) lysis in synovial tissue of rheumatoid arthritis.

Fibrin(ogen)-Induced Expression of ICAM-1 and Chemokines in Human Synovial Fibroblasts

“…28, 38 -41). Quantitative studies of fibrinogen antigenic proteins in synovial fluid have correlated higher levels of these substances with higher inflammatory indices (38,39,42). A suspected role for fibrin in the pathogenesis of the disease is supported by many studies beginning with the early demonstration that chronic arthritis could be induced in rabbits by intra-articular fibrin injection (43).…”

Fibrin Stabilization (Factor XIII), Fibrin Structure and Thrombosis

“…Extravascular cross-linked fibrin deposits have been detected in guinea pig carcinomas, in lymph nodes with Hodgkin's disease [51][52][53] and in rheumatoid synovial tissue [54,55]. Both plasma FXIII leaked out through the capillary wall and cellular FXIII derived from tumor associated and inflammatory macrophages [51,52,56] could contribute to the cross-linking process.…”

Reduction in Arthritis Severity and Modulation of Immune Function in Tissue Factor Cytoplasmic Domain Mutant Mice

“…[13][14][15][16] Moreover, reduced levels of coagulation factors, with increased thrombin activity and thrombin-anti-thrombin complexes, have been found in RA synovial fluids. 17,18 More recently, it has been shown that intra-articular injection of either recombinant TF or TF/FVIIa complex in mice induces remarkable cellular infiltration of synovium, and cartilage and bone destruction, indicating direct proinflammatory properties of TF. 19,20 The function of the cytoplasmic domain of TF, which consists of only 21 residues in humans and 20 residues in mice, is primarily unknown.…”