title: Hereditary protein C deficiency and thrombosis risk: genotype and phenotype relation in a large Italian family.
abstract: 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.
authors.affiliation: Dipartimento di Ematologia 'Sapienza' University Rome, Rome, Italy. cafolla@bce.uniroma1.it
authors.forename: Arturo
authors.initials: A
authors.lastname: Cafolla
authors.forename: Giovanna
authors.initials: G
authors.lastname: D'Andrea
authors.forename: Erminia
authors.initials: E
authors.lastname: Baldacci
authors.forename: Maurizio
authors.initials: M
authors.lastname: Margaglione
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Mazzucconi
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D005165:Factor V / Q000235:genetics*; D005192:Family Health; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020151:Protein C Deficiency / Q000235:genetics*; D012306:Risk; D013927:Thrombosis / Q000175:diagnosis / Q000235:genetics*
chemical_list: C095381:factor V Leiden; D005165:Factor V