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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 523-531
Deficient APC-cofactor activity of protein S Heerlen in
degradation of factor Va Leiden: a possible mechanism of synergism
between thrombophilic risk factors
Tusar Kanti Giri,
Tomio Yamazaki,
Núria Sala,
Björn Dahlbäck, and
Pablo
García de Frutos
From the Department of Laboratory Medicine, Division of
Clinical Chemistry, Lund University, University Hospital,
Malmö, Sweden, and Centre de Genètica
Mèdica i Molecular, Institut de Recerca Oncològica,
Barcelona, Spain.
In protein S Heerlen, an S-to-P (single-letter amino acid codes)
mutation at position 460 results in the loss of glycosylation of N458.
This polymorphism has been found to be slightly more prevalent in
thrombophilic populations than in normal controls, particularly in
cohorts of patients having free protein S deficiency. This suggests
that carriers of the Heerlen allele may have an increased risk of
thrombosis. We have now characterized the expression in cell cultures
of recombinant protein S Heerlen and investigated the anticoagulant
functions of the purified recombinant protein in vitro. Protein S
Heerlen was synthesized and secreted equally well as wild-type protein
S by transiently transfected COS-1 cells. The recombinant protein S
Heerlen interacted with conformation-dependent monoclonal antibodies
and bound C4b-binding protein to the same extent as wild-type protein
S. Protein S Heerlen displayed reduced anticoagulant activity as
cofactor to activated protein C (APC) in plasma-based assays, as well
as in a factor VIIIa-degradation system. In contrast, protein S
Heerlen functioned equally well as an APC cofactor in the degradation
of factor Va as wild-type protein S did. However, when
recombinant activated factor V Leiden (FVa:Q506) was used as APC
substrate, protein S Heerlen was found to be a poor APC cofactor as
compared with wild-type protein S. These in vitro results suggest a
possible mechanism of synergy between protein S Heerlen and factor V
Leiden that might be involved in the pathogenesis of thrombosis in
individuals carrying both genetic traits.
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