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Thromb Haemost 2016; 115(03): 570-579
DOI: 10.1160/th15-05-0391
Coagulation and Fibrinolysis
Schattauer GmbH

PROS1 genotype phenotype relationships in a large cohort of adults with suspicion of inherited quantitative protein S deficiency

Martine Alhenc-Gelas
1   Hématologie biologique, AP-HP, Hôpital Européen G Pompidou, Hôpitaux Universitaires Paris Ouest, Paris, France
,
Genevieve Plu-Bureau
2   Unité d’hémostase et Unité de Gynécologie endocrinienne, AP-HP, Hôpital Cochin, Hôpitaux universitaires Paris Centre, Faculté de Médecine Paris Descartes, Paris, France
,
Marie Héléne Horellou
3   Laboratoire d’Hématologie, AP-HP Hôpital Cochin, Hôpitaux universitaires Paris Centre Faculté de Médecine Paris Descartes, Paris, France
,
Antoine Rauch
4   Pôle Biologie Pathologie Génétique, Institut d’Hématologie-Transfusion, CHRU, Lille, France
,
Pierre Suchon
5   Laboratoire d’hématologie, CHU La Timone, INSERM UMR S1062, Université Aix Marseille, Marseille, France
,
for the GEHT genetic thrombophilia group › Author Affiliations Financial support: This study was in part supported by a DHOS program „Soutien financier en faveur des laboratoires pratiquant le diagnostic par génétique moléculaire des maladies rares”.
Further Information

Publication History

Received: 11 May 2015

Accepted after major revision: 08 October 2015

Publication Date:
20 March 2018 (online)

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Summary

Inherited protein S deficiency (PSD) is an established risk factor for venous thromboembolism (VTE). However, data are conflicting concerning risk of VTE associated with decreased free PS level (FPS) and information on PROS1 genotype-phenotype relationship is sparse. In a retrospective cohort of 579 patients with inherited type I/III deficiency suspicion, PROS1 genotyping was performed and the effect of genotype on FPS and on VTE risk was investigated. We found 116 (including 65 novel) detrimental mutations (DM) in 222 (type I/III in 194, type II in 28), PS Heerlen in 74, possibly non DM in 38 and no mutation in 245 subjects. Among DMs, type I/IIIDMs only were found in subjects with FPS<30 %. Prevalence of type I/III DM decreased with increasing FPS level. Risk of VT associated with FPS level and genotype was studied in the 467 subjects with personal or family history of thrombosis. Only type I/IIIDM carriers presented with an increased risk of VTE [1.41 (95%CI (1.05–1.89)] compared to subjects with no mutation. Among the group of type I/IIIDM heterozygotes and subjects with no mutation, the optimal FPS cut-off point for identifying subjects at increased VTE risk was searched for. We found that only subjects with FPS<30% and type I/IIIDM presented with an increased risk [1.48 (95%CI 1.08–2.04)]. Our findings confirm the value of a cut-off FPS level for identifying subjects at increased VTE risk far below the lower limit of the normal range and suggest a place for PROS1 genotyping in PSD diagnosis strategy.

Keywords

Coagulation inhibitor - protein S - PROS1 - thrombophilia - venous thrombosis
 

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