Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Thrombosis and Haemostasis Center, Department of Internal Medicine, Clinical Center, University of Debrecen, Debrecen, Hungary.
J Thromb Haemost. 2016 Apr;14(4):704-15. doi: 10.1111/jth.13252. Epub 2016 Feb 16.
Antithrombin (AT) is a key regulator of the coagulation. In type II deficiency, the heparin-binding-site defect (type II HBS) is considered to be relatively low thrombosis risk.
Our aims were to search for SERPINC1 mutation(s) and to describe the clinical and laboratory phenotype of a large number of AT Budapest3 (ATBp3, p.Leu131Phe) carriers and confirm the presence of a founder effect.
PATIENTS/METHODS: AT-deficient patients were recruited and carriers of ATBp3, n = 102 (63 families) were selected. To investigate the founder effect, eight intragenic single nucleotide polymorphisms, a 5'-length dimorphism, and five microsatellite markers were detected. Clinical and laboratory data of the patients were collected and analyzed.
In AT deficiency, 16 different causative mutations were found, and the great majority of patients were of type II HBS subtype. Most of them (n = 102/118, 86.5%) carried the ATBp3 mutation. The ATBp3 mutant allele was associated with one single haplotype, while different haplotypes were detected in the case of normal allele. The anti-factor Xa-based AT activity assay that we used could detect all ATBp3 patients with high sensitivity in our cohort. ATBp3 homozygosity (n = 26) was associated with thrombosis at a young age and conferred a high thrombotic risk. Half of the heterozygotes (n = 41/76, 53.9%) also had venous and/or arterial thrombosis, and pregnancy complications were also recorded.
In Hungary, the founder mutation, ATBp3, is the most common AT deficiency. Our study is the first in which the clinical characterization of ATBp3 mutation was executed in a large population.
抗凝血酶（AT）是凝血的关键调节剂。在 II 型缺陷中，肝素结合位点缺陷（II 型 HBS）被认为是相对较低的血栓形成风险。
我们的目的是寻找 SERPINC1 突变，并描述大量 AT 布达佩斯 3（ATBp3，p.Leu131Phe）携带者的临床和实验室表型，并确认存在创始突变。
患者/方法：招募了 AT 缺乏的患者，并选择了 102 名（63 个家庭）ATBp3 携带者。为了研究创始突变，检测了 8 个内含子单核苷酸多态性、5'长度二态性和 5 个微卫星标记。收集并分析了患者的临床和实验室数据。
在 AT 缺乏中，发现了 16 种不同的致病突变，大多数患者为 II 型 HBS 亚型。他们中的大多数（n = 102/118，86.5%）携带 ATBp3 突变。ATBp3 突变等位基因与单一单倍型相关，而在正常等位基因中检测到不同的单倍型。我们使用的基于抗因子 Xa 的 AT 活性测定法在我们的队列中能够高灵敏度地检测所有 ATBp3 患者。ATBp3 纯合子（n = 26）与年轻时血栓形成相关，并具有较高的血栓形成风险。杂合子的一半（n = 41/76，53.9%）也有静脉和/或动脉血栓形成，并且也记录了妊娠并发症。
在匈牙利，创始突变 ATBp3 是最常见的 AT 缺乏症。我们的研究是首次在大量人群中对 ATBp3 突变进行临床特征描述。
