Phenotype and genotype expression in pseudohomozygous R2 factor V

Kalafatis, Michael; Simioni, Paolo; Bernardi, Francesco

doi:10.1182/blood.v98.6.1988

Cited by 6 publications

(14 citation statements)

References 8 publications

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“…Our findings are consistent with those from a recent meta‐analysis of available studies exploring the thrombotic risk in carriers of factor V Leiden alone or associated with HR2 haplotype [18]. Of interest, recent data suggest a possible role of the HR2 haplotype in determining thrombosis in patients with factor V deficiency [19,20]. In our cohort, all carriers of HR2 haplotype (alone or in association with clotting inhibitors deficiency) had normal levels of factor V.…”

Section: Discussionsupporting

confidence: 91%

The incidence of venous thromboembolism in carriers of antithrombin, protein C or protein S deficiency associated with the HR2 haplotype of factor V: a family cohort study

Tormene

Fortuna

Tognin

et al. 2005

Journal of Thrombosis and Haemostasis

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Summary. In order to assess whether the HR2 haplotype of the factor V gene (HR2) increases the risk of venous thromboembolism (VTE) in carriers of antithrombin (AT), protein C (PC) or S (PS) defects, we performed this determination in 336 subjects, who were family members of 66 symptomatic patients with clotting inhibitors defects. We first assessed the presence of previous VTE, and then followed prospectively subjects without prior VTE. VTE episodes had occurred in 26 individuals: 18 in 139 carriers of clotting inhibitors defects alone (annual incidence, 0.55%), four in 33 carriers of clotting inhibitors defects combined with HR2 (0.52%) and four in 151 non-carriers (0.1%), resulting in a relative risk (RR) for VTE of 4.9 (95% CI: 1.7-14.4) and 4.62 (95% CI: 1.2-18.4), respectively. After an overall follow-up of 2557 patient-years, VTE episodes developed in 12 subjects: nine in 121 carriers of clotting inhibitors defects alone (annual incidence, 0.92%), three in 29 carriers of clotting inhibitors defects combined with HR2 (1.0%) and none in 147 non-carriers. In family members of patients with AT, PC or PS defects the coinheritance of HR2 haplotype does not seem to increase the thromboembolic risk.

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Section: Discussionsupporting

confidence: 91%

The incidence of venous thromboembolism in carriers of antithrombin, protein C or protein S deficiency associated with the HR2 haplotype of factor V: a family cohort study

Tormene

Fortuna

Tognin

et al. 2005

Journal of Thrombosis and Haemostasis

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“…We have found in this individual that the factor V molecule that is characterized by the mutations included in the R2 haplotype is resistant to APC inactivation because of impaired cleavage by APC at both Arg506 and Arg306. 148 These findings suggest the possibility that one or more of the amino acid substitutions, which are predicted by the R2 haplotype, impair factor Va cleavage by APC at Arg506/Arg306. The patient studied was also a carrier of the Asp2194Gly substitution that is tightly associated with the R2 haplotype and is the most likely candidate for the observed APC resistance of factor Va. Studies by Kim et al 73 using alanine-scanning mutagenesis suggested that several amino acid residues within the COOHterminal portion of the C2 domain of factor V are crucial for the interaction of the cofactor with phosphatidyl serine.…”

Section: Defects In the Inactivation Of Factor V/va Associated With Tmentioning

confidence: 91%

“…147 One of these individuals was found to be doubly heterozygous for the factor V HR2 haplotype and for the Tyr1702Cys mutation. The latter mutation was shown to be at the origin of factor V deficiency, resulting in the absence of circulating normal factor V. 147,148 Thus, because the factor V allele predicting the Tyr1702Cys substitution and encoding for a non-R2 haplotype factor V is not expressed at the protein level, the plasma of this patient contains only molecules encoded by the R2 haplotype. 148 This individual had also mild APC resistance and was classified as a pseudohomozygous R2 haplotype.…”

Section: Defects In the Inactivation Of Factor V/va Associated With Tmentioning

confidence: 99%

“…The latter mutation was shown to be at the origin of factor V deficiency, resulting in the absence of circulating normal factor V. 147,148 Thus, because the factor V allele predicting the Tyr1702Cys substitution and encoding for a non-R2 haplotype factor V is not expressed at the protein level, the plasma of this patient contains only molecules encoded by the R2 haplotype. 148 This individual had also mild APC resistance and was classified as a pseudohomozygous R2 haplotype. We have found in this individual that the factor V molecule that is characterized by the mutations included in the R2 haplotype is resistant to APC inactivation because of impaired cleavage by APC at both Arg506 and Arg306.…”

Section: Defects In the Inactivation Of Factor V/va Associated With Tmentioning

confidence: 99%

“…The R2 haplotype demonstrates resistance to APC because of impaired cleavage at both Arg506 and/or Arg306. 148 Thus, it is possible that the factor Va mutations surrounding Asp2194 impair its inactivation by APC.…”

Section: Defects In the Inactivation Of Factor V/va Associated With Tmentioning

confidence: 99%

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Factor V: a combination of Dr Jekyll and Mr Hyde

Mann

Kalafatis

2003

Blood

Self Cite

225

246

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Characterization of an immunologic polymorphism (D79H) in the heavy chain of factor V

Kolfschoten

Dirven

Poort

et al. 2004

Journal of Thrombosis and Haemostasis

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Summary. Background: During the study of a family with hereditary factor (F)V deficiency (FV Amersfoort, 1102 A > T in exon 7) we identified an individual with 5% FV heavy chain antigen (FV HC ) and 50% FV light chain antigen (FV LC ). Further testing revealed that apart from the FV Amersfoort allele a second variant FV allele was segregating in this family, which encodes for a FV molecule with a reduced affinity for mAb V-23 used in the FV heavy chain ELISA (ELISA HC ). Objective: Identification and characterization of the molecular basis responsible for the reduced affinity of the variant FV for mAb V-23. Methods: Family members of the proband were screened for mutations in the exons coding for the heavy chain of FV, after which the recombinant variant FV could be generated and characterized. Next, the cases and controls of the Leiden Thrombophilia Study (LETS) were genotyped for carriership of the variant FV. Results: In the variant FV allele a polymorphism in exon 3 (409G > C) was identified, which predicts the replacement of aspartic acid 79 by histidin (D79H). Introduction of this mutation in recombinant FV confirmed that it reduces the affinity for binding to mAb V-23. The substitution has no effect on FV(a) stability and Xa-cofactor activity. In Caucasians the frequency of the FV-79H allele is 5%. Analysis of the LETS revealed that the FV-79H allele is not associated with FV levels (FV LC ), activated protein C sensitivity (using an activated partial thromboplastin time-based test) or risk of venous thrombosis (OR 1.07, CI 95: 0.7-1.7). Conclusion: The D79H substitution in FV should be considered as a neutral polymorphism. The monoclonal antibody V-23, which has a strongly reduced affinity for FV-79H, is not suitable for application in diagnostic tests.

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Phenotype and genotype expression in pseudohomozygous R2 factor V

Cited by 6 publications

References 8 publications

The incidence of venous thromboembolism in carriers of antithrombin, protein C or protein S deficiency associated with the HR2 haplotype of factor V: a family cohort study

The incidence of venous thromboembolism in carriers of antithrombin, protein C or protein S deficiency associated with the HR2 haplotype of factor V: a family cohort study

Factor V: a combination of Dr Jekyll and Mr Hyde

Characterization of an immunologic polymorphism (D79H) in the heavy chain of factor V

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