Pathogenesis of thrombophilia in the Japanese population.

By using a screening program to clarify the etiology of thrombophilia, we found protein S deficiency, either congenital or acquired, to be an important pathogenesis of thrombosis in the Japanese population. A gene analysis revealed that about one third of the patients with a low protein S activity are associated with varied mutations in the PROS 1 gene. Protein S (PS) is a nonenzymatic cofactor for activated protein C (APC) and plays an integral role as a regulator of APC that inhibits coagulation by enzymatically cleaving the activated forms of factor V and factor VIII. Approximately 60% of plasma PS circulates as a complex with C4b binding protein (C4BP), while the remainder circulates as free PS. Since only free PS has APC cofactor activity, a reduction in free PS is considered to be a cause of plasma PS deficiency. Factor V Leiden (R506Q) is resistant to the protein C/protein S anticoagulant pathway and is found in 20% to 60% of Caucasian patients with venous thrombosis. In Japan, no thrombotic patient having the factor V Leiden gene has been observed, instead, the decreased PS activity was found with a high incidence in thrombotic patients.