Molecular diversity and thrombotic risk in protein S deficiency: the PROSIT study.
The Protein S Italian Team (PROSIT) enrolled 79 protein S (PS) deficient families and found 38 PROS1 variations (19 novel) in 53 probands. Of these, 23 variants were selected for expression in'vitro, to evaluate their role as possible causative variants. Transient expression showed high secretion levels (>75%) for three variants, which were considered neutral. Seven missense and five nonsense variants showed low (<or=11%) expression levels and were classified as severe defects. Intermediate expression was observed for eight variants, which were evaluated by factor Va inactivation assay in order to be globally classified as severe or intermediate. Based on the cumulative data, the hazard ratio associated with causative variants was 4.9 (95% CI: 1.4-17.7) for deep vein thrombosis and/or pulmonary embolism, 5.1 (95% CI: 1.1-23.9) for superficial thrombophlebitis, and 4.8 (95% CI: 1.8-13.0) for any venous thrombosis. The hazard ratio for deep vein thrombosis and/or pulmonary embolism in carriers of severe defects only was 7.4 (95% CI: 1.6-24.1). PROSIT showed that dysfunctional variants causing PS deficiency are more common than expected and confirmed that PS deficiency is associated with increased thrombotic risk, although risk assessment is complicated by molecular heterogeneity.
Biguzzi
Eugenia
E
Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Department of Internal Medicine and Dermatology, IRCCS Maggiore Hospital and University of Milan, Milan, Italy. eugeniabiguzzi@yahoo.it
Razzari
Cristina
C
Lane
David A
DA
Castaman
Giancarlo
G
Cappellari
Antonio
A
Bucciarelli
Paolo
P
Fontana
Gessica
G
Margaglione
Maurizio
M
D'Andrea
Giovanna
G
Simmonds
Rachel E
RE
Rezende
Suely M
SM
Preston
Roger
R
Prisco
Domenico
D
Faioni
Elena M
EM
D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D015943:Factor Va / Q000032:analysis; D018740:Genetic Heterogeneity; D006801:Humans; D007558:Italy / Q000453:epidemiology; D020125:Mutation, Missense; D016016:Proportional Hazards Models; D017293:Protein S / Q000235:genetics*; D018455:Protein S Deficiency / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D011655:Pulmonary Embolism / Q000453:epidemiology / Q000209:etiology; D022821:RNA Splice Sites / Q000235:genetics; D018570:Risk Assessment; D019851:Thrombophilia / Q000209:etiology / Q000235:genetics*; D013924:Thrombophlebitis / Q000453:epidemiology / Q000209:etiology; D020246:Venous Thrombosis / Q000453:epidemiology / Q000209:etiology
D018389:Codon, Nonsense; D017293:Protein S; D022821:RNA Splice Sites; D015943:Factor Va