The potential role of synovial thrombomodulin in the pathophysiology of joint bleeds in haemophilia

Haemophilic arthropathy (HA) is one of the main complications of recurrent bleeding episodes in patients with severe haemophilia. However, the precise reasons making joints the predilected site of bleeding in patients with haemophilia are not fully understood. The objective of this project was to study the potential effect of synovium-derived thrombomodulin (TM) on the pathophysiology of haemarthroses. The concentration of TM and tissue factor pathway inhibitor (TFPI) was measured in knee synovial fluid of patients with haemophilia and controls. We used these concentrations of TM and TFPI in a thrombin generation (TG) model to analyse their in vitro effects on coagulation in plasma of six male controls and six severe haemophiliacs. The expression of TM in synovial tissue was also studied in controls and haemophiliacs. Patients with HA had significantly higher synovial fluid TFPI and TM levels, with a mean of 47±27ng/mL (P=0.033) and 56±25ng/mL (P=0.031), respectively, compared to the control group which presented lower levels of synovial fluid TFPI (26±9ng/mL) and TM concentrations (39±21 ng/mL). TG capacity was significantly reduced in the presence of TM 56ng/mL (P=0.02), concentration observed in the synovial fluid of patients with HA. The concomitant addition of TM 56ng/mL and TFPI 47ng/mL induced a highly significant inhibition of TG in the same samples (P=0.008). No significant inhibition of TG capacity was observed in the presence of control synovial concentration of TM (P>0.05). Our results showed increased TM levels in synovial fluid and dramatically impaired expression of TM on synovial cells, suggesting a massive release of TM into the synovial fluid induced by a concerted action of neutrophils and cytokines on synovial cells as previously described in patients with rheumatoid arthritis.