Plasma protein S activity correlates with protein S genotype but is not sensitive to identify K196E mutant carriers

Abstract

Background: Protein S (PS) is an anticoagulant protein that functions as a cofactor for activated protein C (APC), and congenital PS deficiency is a well-known risk factor for the development of deep vein thrombosis (DVT). Recently, we and others identified the K196E missense mutation in the second epidermal growth factor-like domain of PS as a genetic risk factor for DVT in the Japanese population. The incidence of this mutation is high in the Japanese population. Objectives: In the present study, we investigated the relationship between plasma PS activity and the presence of the K196E mutation. Patients and methods: We measured PS activity as a cofactor activity for APC in 1862 Japanese individuals and determined the PS K196E genotype in this population. Results: Individuals heterozygous for the mutant E-allele had lower plasma PS activity than wildtype subjects (mean ± SD, 71.9 ± 17.6%, n = 34 vs. 87.9 ± 19.8%, n = 1828, P < 0.0001). However, the PS activity of several heterozygous individuals (n = 8) was greater than the population average. In contrast, multiple wildtype subjects (n = 26) had PS activity less than 2 SD below the population mean, indicating that other genetic or environmental factors affect PS activity. Conclusions: Plasma PS activity itself is not suitable for identifying PS 196E carriers and other methods are required for carrier detection. © 2006 International Society on Thrombosis and Haemostasis.