Hereditary protein C deficiency and thrombosis risk: genotype and phenotype relation in a large Italian family

Protein C (PC) deficiency is an autosomal dominant inherited disorder associated with spontaneous and recurrent thrombotic events. Factor V Leiden (FVL) increases the risk of thrombosis in PC‐deficient type I families. We have investigated the relationship between PC deficiency genotype and clinical phenotype in a large four‐degree Italian family followed since 1988. Methods: PC activity and antigen levels were quantified; sequencing of PC DNA was performed to identify polymorphism. FVL and factor II (G20210A) polymorphism were screened. Results: PC activity ranged from 5% to 9%, and PC antigen levels were 5,3% in two homozygous for PROC missense mutation Arg32Cys; PC activity ranged from 18% to 60% and antigen levels from 21% to 64%, respectively, in 11 heterozygous for Arg32Cys; PC activity was 99% and 120% in two wild type. Of 15, eight were heterozygous for FVL. The two subjects with PC < 6%, homozygous for Arg32Cys and heterozygous for FVL, suffered from thrombosis during childhood. Of 11, six subjects with PC deficiency and heterozygous for FVL showed the first thrombosis at an age between 21 and 54. None of the five PC‐deficient subjects, who were wild type for FVL, showed thrombosis. Two subjects with PC > 70%, both heterozygous for FVL developed thrombosis in the presence of another risk factor. This study suggests that FVL and PROC mutations increase the risk of thrombosis in subjects with PC deficiency, which could be considered as a ‘variable’ risk factor. The thrombosis‐prone PC‐deficient families carry additional risk factors for thrombosis.

[1]  J. Griffin,et al.  Deficiency of protein C in congenital thrombotic disease. , 1981, The Journal of clinical investigation.

[2]  E. Davie,et al.  The nucleotide sequence of the gene for human protein C. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Berkner,et al.  Propeptide of human protein C is necessary for gamma-carboxylation. , 1987, Biochemistry.

[4]  P. Reitsma,et al.  Citations from the Literature , 2003 .

[5]  P. Reitsma,et al.  Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect , 1993 .

[6]  P. Reitsma,et al.  Protein C Deficiency: A Database of Mutations, 1995 Update , 1995, Thrombosis and Haemostasis.

[7]  G. Leone,et al.  Two novel (R(-11)C; T394D) and two repeat missense mutations in the protein C gene associated with venous thrombosis in six kindreds. , 1996, Human mutation.

[8]  G. S. Begley,et al.  Hydrophobic amino acids define the carboxylation recognition site in the precursor of the gamma-carboxyglutamic-acid-containing conotoxin epsilon-TxIX from the marine cone snail Conus textile. , 1999, Biochemistry.

[9]  F. Rosendaal.  Venous thrombosis: a multicausal disease , 1999, The Lancet.

[10]  R. Bertina.  Protein C Deficiency and Venous Thrombosis – the Search for the Second Genetic Defect , 2000, Thrombosis and Haemostasis.

[11]  M. Prins,et al.  An association between atherosclerosis and venous thrombosis. , 2003, The New England journal of medicine.

[12]  B. Mahmoodi,et al.  Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age: Results From a Large Family Cohort Study , 2008, Circulation.

[13]  B. Dahlbäck.  Advances in understanding pathogenic mechanisms of thrombophilic disorders. , 2008, Blood.

[14]  C. Carty,et al.  PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study , 2008, Journal of thrombosis and haemostasis : JTH.

[15]  P. Reitsma,et al.  Polymorphisms in the protein C gene as risk factor for venous thrombosis , 2008, Thrombosis and Haemostasis.

[16]  S. Pal,et al.  Protein C deficiency , 2014, Indian Journal of Hematology and Blood Transfusion.