Summary
Protein S is a vitamin K-dependent plasma protein that functions as an APC-cofactor,
but also exhibits anticoagulant activity in the absence of APC. The Heerlen polymorphism
of protein S is characterized by a Ser460Pro substitution and lacks glycosylation
at Asn458. It is associated with decreased protein S levels due to selective deficiency
of free protein S Heerlen.To understand the lack of thrombotic complications associated
with the protein S Heerlen mutation, we compared recombinant protein S Heerlen, wild
type (wt) protein S and plasmaderived protein S. wt-Protein S and protein S Heerlen
each bound 1:1 to C4BP with dissociation constants of 0.27 and 0.33 nM, respectively.
Both wt-protein S and protein S Heerlen, either free or in complex with C4BP, were
equally active as prothrombinase inhibitors in the absence of APC. All three protein
S preparations stimulated APC-catalyzed inactivation of normal FVa, FVa Leiden and
FVIIIa to the same extent. If extrapolated to plasma, it is not likely that the decreased
free protein S levels in carriers of the protein S Heerlen mutation are compensated
by an increased anticoagulant activity of protein S Heerlen-C4BP complexes. It is
possible that an unrecognized plasma factor selectively enhances the anticoagulant
activity of protein S Heerlen. If not, the reduction of free protein S levels in heterozygous
protein S Heerlen-carriers combined with (low) normal total protein S levels apparently
minimally affects the total anticoagulant activity of protein S (APC-cofactor and
APC-independent activity) and hence is not associated with increased risk of venous
thrombosis.
Keywords
Factor VIII - factor V - factor V Leiden - protein C/S pathway - protein function/activity
