1. A novel factor V compound heterozygous mutation associated with thrombosis (Y1961C; FV-Kanazawa, together with 1982_1983del).
- Author
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Shimonishi N, Morishita E, Ogiwara K, Maruyama K, Yoshida J, Horie K, and Nogami K
- Subjects
- Humans, HEK293 Cells, Male, Protein C metabolism, Protein C genetics, Factor V Deficiency genetics, Factor V Deficiency blood, Genetic Predisposition to Disease, Partial Thromboplastin Time, Female, Phenotype, Blood Coagulation Tests, DNA Mutational Analysis, Middle Aged, Factor V genetics, Factor V metabolism, Heterozygote, Venous Thrombosis genetics, Venous Thrombosis blood, Mutation, Activated Protein C Resistance genetics, Activated Protein C Resistance blood, Blood Coagulation genetics
- Abstract
Background: Factor (F)V is pivotal in both procoagulant and anticoagulant mechanisms. The present report describes a novel F5 mutation in a FV-deficient patient (FV activity, 6 IU/dL; FV antigen, 32 IU/dL) complicated by recurrent deep vein thrombosis. The patient demonstrated activated protein C resistance (APCR) with compound heterozygous mutations consisting of FV-Y1961C (FV
Kanazawa ) and FV-1982_1983del., Objectives: To clarify thrombotic mechanisms associated with this FV abnormality., Methods and Results: Levels of FV-1982_1983del were below the detection sensitivity in our expression experiments using human embryonic kidney 293T cells, and analyses were targeted, therefore, on the FV-Y1961C mutation. Activated partial thromboplastin time-based clotting assays demonstrated that FV-Y1961C exhibited APCR and that the reduced activated protein C (APC) susceptibility in FVa-Y1961C resulted in a marked depression of APC-catalyzed inactivation with delayed cleavage at Arg506 and little cleavage at Arg306 with or without protein S. The APC cofactor activity of FV-Y1961C in APC-catalyzed FVIIIa inactivation promoted by Arg336 cleavage in FVIII was impaired. The binding affinity of FVa-Y1961C to phospholipid membranes was reduced in reactions involving APC/protein S-catalyzed inactivation and in prothrombinase activity. Furthermore, the addition of FVa-Y1961C to plasma failed to inhibit tissue factor-induced procoagulant function. These characteristics were similar to those of FV-W1920R (FVNara ) and FV-A2086D (FVBesançon )., Conclusion: We identified a compound heterozygous FV-Y1961C mutation in the C1 domain representing a novel FV mutation (FVKanazawa ) resulting in not only APCR due to impaired FVa susceptibility and FV cofactor activity for APC function but also impaired inhibition of tissue factor-induced procoagulant function. These defects in anticoagulant function associated with FV in FV-Y1961C contributed to a prothrombotic state., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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