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Activated protein C resistance: molecular mechanisms based on studies using
purified Gln506-factor V
MJ Heeb, Y Kojima, JS Greengard and JH Griffin
Department of Molecular and Experimental Medicine, Scripps Research
Institute, La Jolla, CA 92037, USA.
Gln506-factor V (FV) was purified from plasma of an individual homozygous
for an Arg506Gln mutation in FV that is associated with activated protein C
(APC) resistance. Purified Gln506-FV, as well as Gln506-FVa generated by
either thrombin or FXa, conveyed APC resistance to FV-deficient plasma in
coagulation assays. Clotting assay studies also suggested that APC
resistance does not involve any abnormality in FV-APC-cofactor activity. In
purified reaction mixtures, Gln506-FVa in comparison to normal FVa showed
reduced susceptibility to APC, because it was inactivated approximately
10-fold slower than normal Arg506-FVa. It was previously reported that
inactivation of normal FVa by APC involves an initial cleavage at Arg506
followed by phospholipid- dependent cleavage at Arg306. Immunoblot and
amino acid sequence analyses showed that the 102-kD heavy chain of
Gln506-FVa was cleaved at Arg306 during inactivation by APC in a
phospholipid-dependent reaction. This reduced but measurable susceptibility
of Gln506-FVa to APC inactivation may help explain why APC resistance is a
mild risk factor for thrombosis because APC can inactivate both normal FVa
and variant Gln506-FVa. In summary, this study shows that purified Gln506-
FV can account for APC resistance of plasma because Gln506-FVa, whether
generated by thrombin or FXa, is relatively resistant to APC.
Volume 85,
Issue 12,
pp. 3405-3411,
06/15/1995
Copyright © 1995 by The American Society of Hematology
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