Thrombin in inflammation and healing: relevance to rheumatoid arthritis.

Accepted for publication 15 September 1993 Thrombin is classically recognised as factor IIa of the coagulation cascade, where it catalyses the conversion of fibrinogen into fibrin and so aids in the formation of a blood clot. Active thrombin is generated from prothrombin at the cell surface of platelets, lymphocytes, monocytes, neutrophils and endothelial cells.' It belongs to the serine protease enzyme group, members of which share a common catalytic mechanism and also the triad of amino acids at their active site (aspartate-serine-histidine) from which their name derives. Thrombin has several forms, the largest and most active of which is 39 kD ct-thrombin. It is able to catalyse the cleavage of a wide range ofproteins including itself. Recently it has been found that thrombin causes a number of pro-inflammatory and mitogenic effects, many of which appear to take place after thrombin cleavage of a G-protein coupled transmembrane receptor. These in vitro observations suggest that thrombin may be important in the healing process, acting as a mediator of inflammation and initiating repair through the stimulation of cell growth. It has also been linked with the development of vascular disease, notably atherosclerosis.2 However, the multiple actions of thrombin implicate this enzyme in the pathogenesis of any disorder where there is sustained vascular injury and cellular infiltration. In particular thrombin may be important during the progression of rheumatoid arthritis (RA), a chronic inflammatory disease marked by increased vascular permeability, synovial proliferation, and an abnormal angiogenic response. Extravascular coagulation is also seen in RA, with fibrin deposition being a well documented feature of inflamed synovial tissue. Advances in immunohistochemical techniques have made it possible to demonstrate the existence of intact coagulation pathways within the rheumatoid synovium.34 This review describes current knowledge about how thrombin works to promote successful healing, and outlines the pathological relevance of prolonged and inappropriate thrombin activity in RA.