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 remains the most difficult t o diagnose because of phenotypic variability, which can lead to inconclusiv e results. We have overcome this problem by studying a cohort of patients f rom a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene def ect were studied, together with 109 first-degree relatives. To avoid select ion bias, we confined analysis of total and free protein S levels and throm botic risk to the patients' relatives. In this group of relatives, a low fr ee protein S level was the most reliable predictor of a PROS1 gene defect ( sensitivity 97.7%, specificity 100%), First-degree relatives with a PROS1 g ene defect had a 5.0-fold higher risk of thrombosis (95% confidence interva l, 1.5-16.8) than those with a normal PROS1 gene and no other recognized th rombophilic defect. Although pregnancy/puerperium and immobility/trauma wer e important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects i n the PROS1 gene were more likely to have had a thrombotic event and had si gnificantly lower total and free protein S levels than those relatives havi ng missense mutations. We conclude that persons with PROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free pro tein S estimation offers the most reliable way of diagnosing the deficiency . (C) 2000 by The American Society of Hematology.