Reduction of Collagen-Induced Arthritis By Anti-Coagulation
Previous work has suggested that activation of the coagulation cascade may contribute to the amplification of joint inflammation by non-immune mechanisms. Thrombin, a coagulation casecade enzyme that activates a cell-surface receptor, converts fibrinogen into fibrin, the end product of the coagulation cascade. Intrarticular fibrin deposition is associated with inflammatory arthritis. In this study Marty et al (J Clin Invest 107:631, 2001) investigated the effect of thrombin inhibition on the course of collagen-induced arthritis in the mouse.
Collagen-induced arthritis was induced in male DBA/1J mice with native chicken type II collagen. Substantial fibrin deposits were found in the knees and paw joint of the arthritic mice, indicating activation of the coagulation cascade. When compared to mioce without collagen-induced arthritis (naive mice), the arthritic mice exhibited increased expression of the thrombin receptor PAR-1 as well as increased levels of thrombin-antithrombin (TAT) complexes. TAT complexes occur during the formation of thrombin and thrombin itself increases expression of PAR-1 levels. These data are also indicative of the activation of the coagulation cascade.
Mice were then treated with PEG-hirudin, a thrombin inhibitor, either just before onset of the arthritis or after the establishment of the arthritis. Mice with collagen-induced arthritis treated with PEG-hirudin exhibited prolonged clotting times, including thrombin time (TT), PT and aPTT, as well as a marked decrease in plasma TAT levels as compared to levels in untreated mice with collagen-induced arthritis.
Preventive treatment with PEG-hirudin led to a significant decrease in disease incidence and severity. Treatment with PEG-hirudin beginning at the onset of clinical symptoms also demonstrated a significant reduction in arthritis symptoms.
Histologically, the PEG-hirudin treated group had a significantly thinner synovial membrane that the placebo treated group. Also statistically significant was the finding that treated mice had reduced fibrin deposits in their arthritic joints. The mRNA of two synovial cytokines, IL-1band IL-12p35, were found to be downregulated after PEG-hirudin treatment. Thrombin receptor PAR- mRNA levels were significantly downregulated, comparable to the levels found in naive mice.
The results of this study have shown that there are substantial fibrin deposits in the arthritic joints of mice with collagen-induced arthritis. Ongoing coagulation activity was evidenced by increased TAT levels, indicating an increase in thrombin formation. Both fibrin deposits and increased TAT levels are observed in human rheumatoid arthritis. Results from PEG-hirudin treatments suggest that the coagulation pathway, in specific thrombin-mediated coagulation, may be a therapeutic target in joint inflammation.
Editorial Comment: Enhanced coagulation is an interesting non-immune mechanism for propagating joint inflammation. (Bradykinin is another by-product of the coagulation pathway that is highly inflammatory.) In practical terms, chronic anticoagulation, as a therapeutic strategy, would increase the risk of serious bleeding. Nonetheless, the approach is interesting and worth further investigation.
