Novel FV mutation (W1920R, FVNara) associated with serious deep vein thrombosis and more potent APC resistance relative to FVLeiden

Blood. 2014 Apr 10;123(15):2420-8. doi: 10.1182/blood-2013-10-530089. Epub 2014 Feb 12.

Abstract

Factor V (FV) appears to be pivotal in both procoagulant and anticoagulant mechanisms. A novel homozygote (FVNara), a novel mechanism of thrombosis associated with Trp1920→Arg (W1920R), was found in a Japanese boy and was associated with serious deep vein thrombosis despite a low level of plasma FV activity (10 IU/dL). Activated partial thromboplastin time-based clotting assays and thrombin generation assays showed that FVNara was resistant to activated protein C (APC). Reduced susceptibility of FVaNara to APC-catalyzed inactivation and impaired APC cofactor activity of FVNara on APC-catalyzed FVIIIa inactivation contributed to the APC resistance (APCR). Mixtures of FV-deficient plasma and recombinant FV-W1920R confirmed that the mutation governed the APCR of FVNara. APC-catalyzed inactivation of FVa-W1920R was significantly weakened, by ~11- and ~4.5-fold, compared with that of FV-wild-type (WT) and FVLeiden (R506Q), respectively, through markedly delayed cleavage at Arg506 and little cleavage at Arg306, consistent with the significantly impaired APC-catalyzed inactivation. The rate of APC-catalyzed FVIIIa inactivation with FV-W1920R was similar to that without FV, suggesting a loss of APC cofactor activity. FV-W1920R bound to phospholipids, similar to FV-WT. In conclusion, relative to FVLeiden, the more potent APCR of FVNara resulted from significant loss of FVa susceptibility to APC and APC cofactor activity, mediated by possible failure of interaction with APC and/or protein S.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activated Protein C Resistance / genetics*
  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Adolescent
  • Blood Coagulation / genetics
  • Blood Coagulation Tests
  • Blotting, Western
  • Factor V / genetics*
  • Humans
  • Male
  • Point Mutation*
  • Venous Thrombosis / genetics*

Substances

  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • factor V Leiden
  • Factor V