Protein S deficiency in sickle cell anemia.

Abstract To investigate the status of the protein C-protein S anticoagulant pathway in sickle cell disease, we measured protein C, total and free protein S, and C4b-binding protein levels in 20 subjects with sickle cell disease (Hb SS or SC). Mean total and free protein S levels were both significantly lower in subjects with sickle cell disease than in normal individuals, but greater reductions were observed for free S. The free protein S level was below the mean — 2 SD for normal subjects in 12 subjects with sickle cell disease; the total protein S level was below this level in three subjects. Mean C4b-binding protein levels were normal in subjects with sickle cell disease, both during painful crisis and in the steady state, and no correlation was observed between the levels of C4b-binding protein and free protein S, suggesting that the low free protein S level was not caused by increased levels of C4b-binding protein. Crossed immunoelectrophoresis of plasma samples from eight subjects with sickle cell disease showed marked reductions in free protein S, with normal levels of protein S bound to C4b-binding protein. In contrast to the protein S level, mean protein C activity was normal in subjects with sickle cell disease, both during painful crisis and in the steady state. However, the protein C level was below the mean -2 SD for normal subjects on at least one occasion in four subjects with sickle cell disease. We conclude that a disproportionate reduction of the free protein S level not caused by increased levels of C4b-binding protein is present in many patients with sickle cell anemia and could contribute to the increased fibrin formation observed in this disorder.