Publication Date:
2014-04-11
Description:
Factor V (FV) appears to be pivotal in both procoagulant and anticoagulant mechanisms. A novel homozygote (FV Nara ), 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 FV Nara was resistant to activated protein C (APC). Reduced susceptibility of FVa Nara to APC-catalyzed inactivation and impaired APC cofactor activity of FV Nara 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 FV Nara . APC-catalyzed inactivation of FVa-W1920R was significantly weakened, by ~11- and ~4.5-fold, compared with that of FV–wild-type (WT) and FV Leiden (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 FV Leiden , the more potent APCR of FV Nara 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.
Keywords:
Thrombosis and Hemostasis
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
Permalink