因 Leu1821Ser 和 Gly2192Cys 的新型复合杂合突变而导致凝血因子 V 型止血障碍,影响凝血酶活化、膜结合和循环抗原水平。

IF 3 2区 医学 Q2 HEMATOLOGY
Haemophilia Pub Date : 2024-08-08 DOI:10.1111/hae.15087
Kimberley Talbot, Jina Song, John R. Perrier, Shannon Jackson, Ross T. A. MacGillivray, Edward L. G. Pryzdial
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引用次数: 0

摘要

导言:先天性第五因子(FV)缺乏症是一种罕见的凝血功能障碍,发病率为1/100,000,000,出血严重程度差异很大,其原因尚不清楚。目的:为了帮助理解FV缺乏症患者所观察到的表型的分子基础,我们对导致患者FV缺乏症的遗传学和生物化学进行了评估:一位 71 岁的女性患者,因长期严重出血而导致子宫切除术,她的血浆 FV 抗原只有正常值的 3%,且电泳迁移率正常。血小板 FV 含量同样很低,但其条带形态不如正常人那么破碎。血浆凝血活性为结论:这些发现与观察到的表型一致,强调了了解 FV 生化功能的重要性,以便在循环抗原水平不一致时合理判断临床出血严重程度。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Factor V haemostatic diathesis impairing thrombin activation, membrane binding and circulating antigen level due to a novel compound heterozygous mutation, Leu1821Ser and Gly2192Cys

Factor V haemostatic diathesis impairing thrombin activation, membrane binding and circulating antigen level due to a novel compound heterozygous mutation, Leu1821Ser and Gly2192Cys

Introduction

Congenital factor V (FV) deficiency is a rare clotting disorder affecting ∼1 in 1,000,000, with bleeding severity that ranges broadly for poorly understood reasons.

Aim

To help understand the molecular basis of the observed phenotype in FV deficient patients, the genetics and biochemistry causing a patient's FV deficiency were evaluated.

Methods and Results

A 71-year-old female, who had serious life-long bleeding upon provocation and profound menorrhagia that lead to hysterectomy, was found to have 3% of normal plasma FV antigen with normal electrophoretic mobility. Platelet FV was similarly low, although the banding pattern was less fragmented than normal. Plasma clotting activity was <1% of normal. Familial inheritance and DNA sequence analysis from peripheral blood leukocytes were consistent with novel compound heterozygosity with missense mutations in exon XVII, Leu1821 to Ser (L1821S) and exon XXV, Gly2192 to Cys (G2192C). The respective single-mutation variants were expressed and purified. Explaining why the antigen level and activity were inequivalent, thrombin activation of recombinant (r) FV/L1821S was impaired, and rFV/G2192C was unable to bind to a procoagulant phospholipid membrane.

Conclusion

These findings are consistent with the observed phenotype, highlighting the importance of understanding FV biochemical function to rationalize clinical bleeding severity when the circulating antigen level is discordant.

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来源期刊
Haemophilia
Haemophilia 医学-血液学
CiteScore
6.50
自引率
28.20%
发文量
226
审稿时长
3-6 weeks
期刊介绍: Haemophilia is an international journal dedicated to the exchange of information regarding the comprehensive care of haemophilia. The Journal contains review articles, original scientific papers and case reports related to haemophilia care, with frequent supplements. Subjects covered include: clotting factor deficiencies, both inherited and acquired: haemophilia A, B, von Willebrand''s disease, deficiencies of factor V, VII, X and XI replacement therapy for clotting factor deficiencies component therapy in the developing world transfusion transmitted disease haemophilia care and paediatrics, orthopaedics, gynaecology and obstetrics nursing laboratory diagnosis carrier detection psycho-social concerns economic issues audit inherited platelet disorders.
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