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Activated protein C resistance: molecular mechanisms based on studies using purified Gln506-factor V.

Abstract
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.
AuthorsM J Heeb, Y Kojima, J S Greengard, J H Griffin
JournalBlood (Blood) Vol. 85 Issue 12 Pg. 3405-11 (Jun 15 1995) ISSN: 0006-4971 [Print] United States
PMID7780127 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Protein C
  • Factor V
  • Glycine
Topics
  • Adult
  • Factor V (genetics, isolation & purification, metabolism)
  • Family
  • Glycine (genetics)
  • Homozygote
  • Humans
  • Male
  • Point Mutation
  • Protein C (metabolism)

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