α_1-抗胰蛋白酶基因突变致家族性出血倾向

Alpha_1-Antitrypsin Gene Mutation and Protein C Deficiency in A Family with Bleeding Tendency

目的探讨一出血倾向家系的临床和实验室特点与α1-抗胰蛋白酶(α1-antitrypsin,α1-AT)基因Pitts-burgh突变(α1-AT-P)以及抗凝蛋白C(PC)缺乏的关系。方法采用凝固法或发色法进行凝血项目的检测;比浊法测定血小板聚集功能(PAgT);血清蛋白电泳采用毛细管电泳法;PCR扩增产物DNA片段直接测序检测α1-AT-P突变。结果家系中女性先证者和其父亲均有阳性的出血史,且有相似的凝血检查结果 :aPTT、PT、TT明显延长,不为1:1正常混和血浆所纠正;凝血因子Ⅹ、Ⅺ、Ⅻ水平降低;PC活性水平0;PAgT:ADP诱导正常,对终浓度为1u/ml凝血酶无反应,但升至4u/ml时,PAgT恢复正常;DNA测序结果显示两患者系α1-AT-P的杂合子;其余7位家系成员凝血相正常,基因测序未发现有α1-AT-P突变,证实患者的出血倾向系α1-AT-P突变所致。结论α1-AT-P突变是罕见的出血原因。本文系世界首个α1-AT-P家系和女性α1-AT-P患者报道,证实该病系按常染色体显性的方式进行遗传;继发性蛋白C缺乏在体内起到平衡止血的作用。

Objective To explore the clinical characteristics,laboratory findings and pathogenesis of a familial bleeding tendency.Methods Clotting and chromogenic substrate methods were used for coagulation screening tests,factors and anticoagulant assays.Platelet aggregation was evaluated by aggregometry.α 1-AT Pittsburgh mutation was detected by direct DNA sequencing.Results Both the proband and her father had a dramatic prolongation of all standard clotting assays,undetectable levels of plasma protein C activity,and low or borderline levels of factors Ⅹ,Ⅺ and Ⅻ.Platelet aggregation by thrombin （final concentration 1 u/ml） was absent in both patients,and this inhibition can be overcome by increasing the concentration of thrombin （4 u/ml）.Both patients are heterozygous for Alpha-1-antitrypsin Met 358 to Arg （α 1-antitrypsin Pittsburgh）.7 other members of this pedigree had normal coagulation tests and do not carry the same genetic mutation.Conclusion This unique family with α 1-antitrypsin Pittsburgh may shed some light on the study of this mutation and its inheritance,and protein C deficiency plays an important role in vivo hemostasis banlance.