Thrombin in the synovial fluid of patients with rheumatoid arthritis mediates proliferation of synovial fibroblast-like cells by induction of platelet derived growth factor

J Rheumatol. 1996 Sep;23(9):1505-11.


Objective: To investigate the clotting and fibrinolytic activities in synovial fluid (SF) from patients with rheumatoid arthritis (RA) and to examine the role of thrombin in synovial hyperplasia.

Methods: We measured the amounts of thrombin-antithrombin-III complex (TAT), antithrombin-III (AT-III), thrombin, plasminogen, alpha 2-plasmin inhibitor (alpha 2-PI), and plasmin-alpha 2-antiplasmin complex (PAP) in SF of 20 patients with RA and 16 patients with osteoarthritis (OA). The proliferative response of synovial fibroblast-like cells to thrombin was measured using [3H] thymidine incorporation. Expression of platelet derived growth factors (PDGF) in conditioned medium was analyzed using a Western blot method, and expression of the mRNA of PDGF and their receptors was analyzed by reverse transcription polymerase chain reaction.

Results: The amounts of clotting factors (TAT, AT-III) and fibrinolytic factors (plasminogen, alpha 2-PI, and PAP) were significantly higher in the patients with RA than in patients with OA (p < 0.01). Moreover, SF thrombin concentrations of patients with RA correlated significantly with erythrocyte sedimentation rates (rs = 0.751, p < 0.01) and serum C-reactive protein concentrations (rs = 0.531, p < 0.05). Thrombin exhibits mitogenic activity toward synovial fibroblast-like cells in vitro, and this mitogenic activity is associated with an increase in the expression of mRNA of both PDGF-alpha receptor and PDGF-beta-receptor.

Conclusion: The high levels of thrombin activity in the SF of patients with RA and strong mitogenic activity of thrombin toward the synovial fibroblast-like cells suggest that thrombin plays an important role in the pathogenesis of RA.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology*
  • Becaplermin
  • Blood Coagulation Factors / metabolism
  • Blood Sedimentation
  • C-Reactive Protein / metabolism
  • Cell Division / drug effects
  • Cell Division / physiology
  • Fibrinolysis
  • Fibroblasts / pathology
  • Humans
  • Middle Aged
  • Osmolar Concentration
  • Platelet-Derived Growth Factor / genetics
  • Platelet-Derived Growth Factor / metabolism*
  • Platelet-Derived Growth Factor / pharmacology
  • Proto-Oncogene Proteins c-sis
  • RNA, Messenger / metabolism
  • Receptors, Platelet-Derived Growth Factor / genetics
  • Synovial Fluid / metabolism*
  • Synovial Membrane / pathology*
  • Thrombin / pharmacology
  • Thrombin / physiology*


  • Blood Coagulation Factors
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • RNA, Messenger
  • platelet-derived growth factor A
  • Becaplermin
  • C-Reactive Protein
  • Receptors, Platelet-Derived Growth Factor
  • Thrombin