Thromb Haemost 2020; 120(09): 1270-1281
DOI: 10.1055/s-0040-1714100
Coagulation and Fibrinolysis

Genotype–Phenotype Relationships in a Large French Cohort of Subjects with Inherited Protein C Deficiency

Martine Alhenc-Gelas
1  Hématologie Biologique, AP-HP Hôpital Européen G Pompidou, QUP Centre Université de Paris, Paris, France
,
Geneviève Plu-Bureau
2  Unité d'hémostase, Unité de Gynécologie Endocrinienne, AP-HP, Hôpital Cochin, QUP Centre Université de Paris, Paris, France
,
Laetitia Mauge
1  Hématologie Biologique, AP-HP Hôpital Européen G Pompidou, QUP Centre Université de Paris, Paris, France
,
Sophie Gandrille
1  Hématologie Biologique, AP-HP Hôpital Européen G Pompidou, QUP Centre Université de Paris, Paris, France
3  Innovative Therapies in Haemostasis, Université de Paris, Paris, France
,
Isabelle Présot
1  Hématologie Biologique, AP-HP Hôpital Européen G Pompidou, QUP Centre Université de Paris, Paris, France
,
GFHT Study Group on Genetic Thrombophilia› Author Affiliations
Funding This study was supported in part by a DHOS program “Soutien financier en faveur des laboratoires pratiquant le diagnostic par génétique moléculaire des maladies rares.”

Abstract

Inherited protein C (PC) deficiency caused by mutations in the PROC gene is a well-known risk factor for venous thromboembolism. Few studies have investigated the relationship between PROC genotype and plasma or clinical phenotypes. We addressed this issue in a large retrospective cohort of 1,115 heterozygous carriers of 226 PROC pathogenic or likely pathogenic mutations. Mutations were classified in three categories according to their observed or presumed association with type I, type IIa, or type IIb PC deficiency. The study population comprised 876 carriers of type I category mutations, 55 carriers of type IIa category mutations, and 184 carriers of type IIb category mutations. PC anticoagulant activity significantly influenced risk of first venous thrombosis (p trend < 10−4). No influence of mutation category on risk of whole or unprovoked thrombotic events was observed. Both PC anticoagulant activity and genotype significantly influenced risk of venous thrombosis. Effect of detrimental mutations on plasma phenotype was ambiguous in several carriers, whatever the mutation category. Altogether, our findings confirm that diagnosing PC inherited deficiency based on plasma measurement may be difficult but show that diagnosis can be improved by PROC genotyping.

Supplementary Material



Publication History

Received: 20 January 2020

Accepted: 30 May 2020

Publication Date:
27 July 2020 (online)

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York