Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency.
BACKGROUND
Protein S, which circulates in plasma in both free and bound forms, is an anticoagulant protein that stimulates activated protein C and tissue factor pathway inhibitor. Hereditary type I protein S deficiency (low total and low free protein S) is a well-established risk factor for venous thrombosis, whereas the thrombosis risk associated with type III deficiency (normal total and low free protein S) has been questioned.


METHODS
Kaplan-Meier analysis was performed on 242 individuals from 30 families with protein S deficiency. Subjects were classified as normal, or having type I or type III deficiency according to their total and free protein S levels. Genetic and functional studies were performed in 23 families (132 individuals).


RESULTS
Thrombosis-free survival was not different between type I and type III protein S-deficient individuals. Type III deficient individuals were older and had higher protein S, tissue factor pathway inhibitor and prothrombin levels than type I deficient individuals. Thrombin generation assays sensitive to the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S revealed similar hypercoagulable states in type I and type III protein S-deficient plasma. Twelve PROS1 mutations and two large deletions were identified in the genetically characterized families.


CONCLUSIONS
Not only type I, but also type III protein S deficiency is associated with a hypercoagulable state and increased risk of thrombosis. These findings may, however, be restricted to type III deficient individuals from families with mixed type I/III protein S deficiency, as these represented 80% of type III deficient individuals in our cohort.
Castoldi
Elisabetta
E
Department of Biochemistry, Maastricht University P.O. Box 616, 6200 Maastricht, The Netherlands. e.castoldi@bioch.unimaas.nl
Maurissen
Lisbeth F A
LF
Tormene
Daniela
D
Spiezia
Luca
L
Gavasso
Sabrina
S
Radu
Claudia
C
Hackeng
Tilman M
TM
Rosing
Jan
J
Simioni
Paolo
P
D000293:Adolescent; D000328:Adult; D018572:Disease-Free Survival; D005190:Family; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018455:Protein S Deficiency / Q000097:blood* / Q000145:classification / Q000235:genetics; D019851:Thrombophilia / Q000209:etiology*; D013927:Thrombosis / Q000209:etiology*; D055815:Young Adult