Figure 1 .

Pathogenesis of RA as a fibrin induced disease. (A) The figure shows two sequential panels; the numbers indicate the pathogenic steps leading to established RA. 1. Exudation of fibrinogen and clotting factors to the joint space follows joint swelling. 2. Haemostasis activation within the cavity leads to fibrin formation. 3. Fibrin clots are partially removed by the plasminogen system (unfilled circle), but most of them get stuck to the synovial intima (black circle). 4. Cells at the fibrin-synovium interface migrate into and around the deposits (arrows). 5. Clot components induce multiple activating pathways in synoviocytes by the coupling of specific receptors. These include proliferation, secretion of proteinases, and synthesis of proinflammatory mediators. 6. A fibroproliferative tissue appears underneath the front of migrating cells, as a result of remodelling of the invaded clots by activated cells. In this area, macrophages and blood vessels are increased owing to the release of growth factors and chemokines. 7. Remodelling induces modifications in the structure of fibrin chains, which become immunogenic. Epitopes from these transformed autologous peptides are presented to T lymphocytes, which in turn initiate a specific immune reactivity against them. As illustrated in the right panel, continuous deposition of fibrin clots and the advance of the front of migration account for tissue hypertrophic growth at the areas of attachment. (B) Left upper panel: photomicrograph of a rheumatoid synovial membrane stained with haematoxylin-eosin (x40). The image shows a large eosinophilic deposit of fibrin adhering to the synovial tissue. Areas indicated with the letters a to e are magnified in the following panels. (a) A detail of cell migration into the deposit (x200). (b) The deposit shows a partial epithelisation at the margin of attachment with the tissue (x400). (c) The interface area is magnified (x100) to see the sharp differences of microarchitecture and cellularity at both sides. (d) Over the interface shown in (c), cells are scattered and have various shapes and sizes. Some of them are undergoing mitosis. The interstitium is predominantly amorphous (x1000). (e) At the base of the clot, the tissue looks fibrotic, hypercellular with fibroblasts and mononuclear cells, and rich in microvasculature. Some fibroblasts are undergoing mitosis. FDPs, fibrin(ogen) degradation peptides.