Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways

Abstract

Summary. Background: Activation of coagulation and ®brino-lysis play a role in the pathophysiology of experimental arthritis. Objective: To determine the extent of activation of the coagulation and ®brinolytic pathways in different joint diseases in humans and to ascertain the factors that may in¯uence ®brin deposition within the joint. Methods: Plasma from normal subjects (controls, n 21) and plasma and synovial¯uid samples from patients with rheumatoid arthritis (RA; n 64), osteoarthritis (OA; n 29), spondyloarthropathy (SpA; n 22) and crystal arthritis (CA; n 25) were analyzed for the levels of TF (tissue factor) and tissue factor pathway inhibitor (TFPI) activities, thrombin±antithrombin III (TAT) complexes, and F1 2 (thrombin fragment), ®brin D-dimer and thrombin-activated ®brinolysis inhibitor (TAFI) antigenic levels. The measurements were analyzed by pairwise correlation with each other as well as with standard parameters of in¯ammation [C-reactive protein (CRP), joint leukocyte count]. Inter-group comparisons were performed to look for diseasespeci®c differences. Results: Compared with healthy controls, patients with joint diseases had higher levels of TAT, F1 2 and D-dimers in their plasma. In the synovial¯uid, TF activity, TAT, D-dimers, and TAFI were signi®cantly higher in in¯ammatory arthritides than in OA. The levels were highest in RA patients. In the plasma, TF activity was correlated with TAT and D-dimer levels with CRP, TFPI, and TAT. In the synovial¯uid, TF activity correlated with plasma CRP levels, synovial¯uid leukocyte count, and synovial TAT and TAFI levels. In addition, synovial D-dimers correlated with CRP, and synovial TAFI levels were correlated with synovial F1 2 and TAT. Conclusions: Activation of the coagulation and ®brinolytic cascades in the joint and in the circulation is evident in both in¯ammatory and degenerative joint diseases. Within the joint, in¯ammatory mechanisms leading to TF-mediated activation of the coagulation pathway and subsequent ®brin deposition is the most likely explanation for the observed ®ndings. In the plasma, the link between in¯ammation (CRP increase) and TF activation is weak, and a non-TF-mediated mechanism of coagulation activation could explain these ®ndings. RA is characterized by signi®cantly higher levels of TAT in the synovial¯uid and plasma than other arthritides. Although ®brinolytic activity is linked to in¯ammation, the increased amounts of TAFI in the joint, particularly in RA, may explain why ®brin formation is so prominent in this condition compared with other joint diseases.

Citrullinated fibrinogen shows defects in FPA and FPB release and fibrin polymerization catalyzed by thrombin

“…As the expression of PAD2 and PAD4 has been demonstrated in the synovial tissue of RA patients [19], the fibrinogen in the extravasated plasma that passes into the synovium might be deiminated at residues Aα16Arg and Bβ14Arg, resulting in citrullinated fibrinogen. In addition, elevated levels of thrombin in the RA synovial fluid were demonstrated by measurement of thrombin-antithrombin III complexes [20]; therefore, some fibrinogen (non-citrullinated fibrinogen at residues Aα16Arg and Bβ14Arg) might be converted into fibrin by thrombin and deposited on synovial tissue, before finally being deiminated by PAD2 and PAD4. The roles of synovium-based citrullinated fibrinogen and fibrin in the pathogenesis of RA disease are controversial; however, there is the possibility that both are associated with the onset and/or pathophysiology of RA.…”

Emerging roles of serine proteinases in tissue turnover in arthritis

“…Furthermore, blockade of this cascade using the thrombin inhibitor hirudin or inhibition of tissue factor reduces the severity of murine arthritis (10)(11)(12). Fibrin accumulation in the joint, a characteristic of arthritis (especially RA), is a consequence of this cascade (9,13) and may be detrimental due to impaired nutrition for the synovium and cartilage, leading to hypoxia and acidosis. In addition, fibrin can enhance inflammation and provides a matrix for cell adhesion and migration (9).…”

Innate Mechanisms of Synovitis – Fibrin Deposits Contribute to Invasion

“…The beta chain of C4BP has also been found in omen fibroblasts participating in the invasion and resorption of the corpus luteum, therefore indicating that besides its prothrombotic role, the molecule is important in fibroblast-dependent remodelling processes. In the light of these experimental data, a potential participation of fibrin in synovitis has been argued by different groups including ourselves (Busso & Hamilton, 2002;So et al, 2003;Sánchez-Pernaute et al, 2003b), and several antithrombotic strategies have been tried, proving useful in attenuating the inflammatory process in experimental models of rheumatoid arthritis (Busso et al, 1998;Varisco et al, 2000).…”