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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2002-02-0343.
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Blood, 15 July 2002, Vol. 100, No. 2, pp. 524-530
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Functional characterization of recombinant FV Hong Kong and
FV Cambridge
Eva Norstrøm,
Elisabeth Thorelli, and
Björn Dahlbäck
From the Department of Clinical Chemistry, Division of
Laboratory Medicine, Lund University, University Hospital Malmö,
Sweden.
In factor V (FV) Cambridge (Arg306Thr) and Hong Kong (Arg306Gly), a
cleavage site for anticoagulant activated protein C (APC), which is
crucial for the inactivation of FVa, is lost. Although patients
carrying FV Hong Kong have a normal APC response, those with FV
Cambridge were reported to be APC resistant. To elucidate the molecular
characteristics of the 2 FV mutants, we recreated them in a recombinant
system and evaluated their functional properties. The 2 FV variants
yielded identical APC resistance patterns, with APC responses being
intermediate to those of wild-type FV and FV Leiden (Arg506Gln), which
is known to be associated with the APC resistance phenotype. In the
absence of protein S, APC mediated FVa inactivation curves obtained
with the 2 variants were identical, resulting in partial FVa
inactivation. In the presence of protein S, both FVa variants were
almost completely inactivated because of protein S stimulation of the
cleavage at Arg679. In a FVIIIa degradation system, both FV variants
demonstrated slightly impaired APC cofactor activity. The ability of
APC to cleave at Arg506 and at Arg679 in FVa Cambridge and Hong Kong
and the slight decrease in APC cofactor activity of the 2 FV variants
may explain the low thrombotic risk associated with these Arg306
mutations. In conclusion, we demonstrate that recombinant FV Cambridge
and Hong Kong behave identically in in vitro assays and provide a
mechanism for the low thrombotic risk associated with these FV mutations.
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