The ability of thrombin to alter the growth of human skin fibroblasts was studied under a variety of experimental conditions. In agreement with previous reports, we obtained a moderate level of cell growth in confluent cultures using 0.5-8.0 U/ml of thrombin. In subconfluent cultures, the effect was strikingly different and was found to be dependent upon the time in culture when the enzyme was added. Cultures exposed to thrombin 24 h after subculturing showed growth stimulation several days later. In contrast, thrombin added at the time of cell plating produced a complete block of DNA synthesis and cell growth that lasted for at least 3 d. Cells exposed to thrombin under these conditions were morphologically altered and smaller. These thrombin-induced effects were reversible and could be completely prevented by pretreatment of the enzyme with hirudin before it was added to the culture medium. Growth inhibition and altered morphology were found to be the result of changes generated in the growth medium by thrombin and could be blocked by higher serum concentrations. The results of this study indicate that thrombin's influence on cell growth can be stimulatory or inhibitory and suggest that the state of the cell surface determines the response.

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