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Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains 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 selection 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 PROS1gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1.5-16.8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors 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 significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons withPROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency.

Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains 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 PROS1gene defect were studied, together with 109 first-degree relatives. To avoid selection 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 PROS1gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1.5-16.8) than those with a normal PROS1gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons withPROS1gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency.

Hampton: Novo Nordisk: Honoraria. Chowdary:CSL Behring: Consultancy, Research Funding; Bayer: Consultancy; SOBI: Consultancy; Biogen Idec: Consultancy; Baxter: Consultancy; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Dunkley:Baxter: Consultancy; Novo Nordisk: Honoraria; Bayer: Honoraria; Pfizer: Honoraria. Ehrenforth:Novo Nordisk: Employment. Jacobsen:Novo Nordisk: Employment. Neff:Alexion: Speakers Bureau; Baxter: Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau. Santagostino:Bayer: Speakers Bureau; Octapharma: Speakers Bureau; Roche: Speakers Bureau; Biogen/Sobi: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Novo Nordisk: Speakers Bureau; CSL Behring: Speakers Bureau; Kedrion: Speakers Bureau. Takedani:Novo Nordisk: Speakers Bureau; Baxter: Speakers Bureau; Bayer: Speakers Bureau; Kaketsuken: Speakers Bureau; Pfizer: Speakers Bureau. Takemoto:Novo Nordisk: Research Funding; Mast Therapeutics: Speakers Bureau. Négrier:Biogen/Sobi: Consultancy; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; LFB: Consultancy; Bayer: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding.

Introduction

The data indicate that Human-cl rh FVIII is safe and efficacious in preventing and treating bleeds in PTPs with severe haemophlia A.Knaub: Octapharma AG: Employment. Lissitchkov:Octapharma AG: PI Other. Tuddenham:College London: Consultancy, Employment, Gene therapy for hemophilia A, Gene therapy for hemophilia A Patents & Royalties, Research Funding. Collins:Octapharma AG: Consultancy. Oldenburg:d and e: Baxter, Bayer, Biotest, CSL-Behring, Grifols, Inspiration, NovoNordisk, Octapharma, Pfizer e: Biogen IDec, Swedish Orphan Biovitrum: Honoraria, Research Funding. Bichler:Octapharma AG: Employment.

Abstract 1132