<br>先天性纤维蛋白原疾病：前瞻性罕见出血性疾病数据库的回顾性临床和遗传学分析,Blood Advances

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先天性纤维蛋白原疾病：前瞻性罕见出血性疾病数据库的回顾性临床和遗传学分析
Blood Advances ( IF 7.4 ) Pub Date : 2024-01-30 , DOI: 10.1182/bloodadvances.2023012186
Samin Mohsenian ₁ , Roberta Palla ₁ , Marzia Menegatti ₂ , Andrea Cairo ₂ , Anna Lecchi ₂ , Alessandro Casini ₃ , Marguerite Neerman-Arbez ₄ , Rosanna Asselta _{5,

6} , Sara Scardo ₂ , Simona Maria Siboni ₂ , Jan Blatny ₇ , Ondrej Zapletal ₇ , Jean-Francois Schved ₈ , Muriel Giansily-Blaizot ₈ , Susan Halimeh ₉ , Mohamad Ayman Daoud ₉ , Helen Platokouki ₁₀ , Helen Pergantou ₁₀ , Roger E G Schutgens ₁₁ , Monique Van Haaften-Spoor ₁₁ , Paul Brons ₁₂ , Britta Laros-van Gorkom ₁₃ , Elise Van Pinxten ₁₃ , Munira Borhany ₁₄ , Naveena Fatima ₁₄ , Danijela Mikovic ₁₅ , Marko Saracevic ₁₅ , Gül Nihal Özdemir ₁₆ , Yılmaz Ay ₁₇ , Michael Makris ₁₈ , Caryl Lockley ₁₈ , Andrew Mumford ₁₉ , Andrew Harvey ₁₉ , Steve Austin ₂₀ , Amy Shapiro ₂₁ , Adrianna Williamson ₂₁ , Catherine McGuinn ₂₁ , Ilene Goldberg ₂₂ , Philippe De Moerloose ₃ , Flora Peyvandi _{1,

2}

Affiliation

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy.
Division of Angiology and Hemostasis, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Department of Biomedical Sciences, Humanitas University, Milan, Italy.
IRCCS Humanitas Research Hospital, Milan, Italy.
Department of Paediatrics Haematology and Biochemistry, University Hospital Brno and Masaryk University, Brno, Czech Republic.
Department of Biological Hematology, CHU Montpellier, Université de Montpellier, Montpellier, France.
Coagulation Centre Rhein-Ruhr, Duisburg, Germany.
Haemophilia-Centre-Haemostasis Unit, Aghia Sophia Children's Hospital, Athens, Greece.
Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Department of Pediatric Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
Clinical Hematology, National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan.
Hemostasis Department, Blood Transfusion Institute of Serbia, Belgrade, Serbia.
Pediatric Hematology Department, Istinye University, Istanbul, Turkey.
University of Health Sciences Kartal Health Application and Research Center, Pediatric Hematology and Oncology Clinic, Istanbul, Turkey.
Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, United Kingdom.
School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
Department of Haematology, Guys and St Thomas' NHS Foundation Trust, London, United Kingdom.
Indiana Hemophilia and Thrombosis Center, Indianapolis, IN.
Division of Pediatric Hematology Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY.

先天性纤维蛋白原缺乏症（CFD）是一种罕见的出血性疾病，由、和突变引起。我们试图使用 PRO-RBDD （前瞻性罕见出血性疾病数据库）全面表征 CFD 患者。使用来自 PRO-RBDD 的回顾性数据调查临床表型、实验室和遗传特征。根据出血严重程度将患者从无症状分类为 3 级。此外，对、和进行了测序以查找致病变异。共纳入来自 16 个国家的 166 例 CFD 病例，其中 123 例（30 例纤维蛋白原血症、33 例低纤维蛋白原血症、55 例非纤维蛋白原血症和 5 例低纤维蛋白原血症）特征良好。考虑到先前建立的因子活性和抗原水平阈值，在 58% 的病例中正确识别了出血严重程度。纤维蛋白生成不良患者和低纤维纤维蛋白生成患者的血栓形成事件发生率相对相似（分别为 11% 和 10%），并且出人意料地高于纤维纤维蛋白生成异常病例。68 例妊娠的自然流产率为 31%，其中 86% 为纤维蛋白生成不良妇女，14% 为低纤维蛋白原血症。86 名患者接受了治疗（69 名按需和/或 17 名预防性治疗），纤维蛋白原浓缩物是最常用的产品。对 91 例病例进行了基因分析，并确定了 41 个不同的变异。热点变体（p.Arg301Cys/His 和 p.Arg35Cys/His）存在于 51% 的纤维蛋白原血症中。产科并发症常见于纤维蛋白原异常血症。这项大型多中心研究提供了对 CFD 患者的临床、实验室和遗传史的全面见解。我们得出结论，在近一半的定量缺陷病例中，出血严重程度等级与既定的因子活性阈值一致。

"点击查看英文标题和摘要"

Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database

Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in , , and . We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, , , and were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (, p.Arg301Cys/His and , p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.

更新日期：2024-01-30

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