CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S

Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it re-mains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selec-tion bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients ’ relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1 gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95 % confi-dence interval, 1.5-16.8) than those with a normal PROS1 gene and no other recog-nized thrombophilic defect. Although pregnancy/puerperium and immobility/ trauma were important precipitating fac-tors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had signifi-cantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons with PROS1 gene defects and protein S deficiency are at increased risk of throm-bosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency. (Blood. 2000;95:1935-1941