凝血因子XI基因变异致下消化道出血病因分析

目的：对1 例遗传性凝血因子Ⅺ（FⅪ）缺陷症患者行内镜下直肠息肉摘除术后出现下消化道异常出血进行病因分析，探讨FⅪ基因变异与治疗后下消化道出血的关系。方法：家系调查（共3 代5 人）。检测患者及其家系成员相关凝血指标。提取外周血基因组DNA进行PCR扩增，采用DNA直接测序法分析患者FⅪ基因的全部外显子、侧翼序列、5’和3’端非翻译区序列，及家系成员相应的变异位点区域。用PyMol软件构建基因变异前后蛋白模型。结果：患者因“直肠息肉摘除术后3 d，血便2 d”入院。凝血指标检查显示患者的活化部分凝血活酶时间（APTT）、FⅪ活性（FⅪ:C）和FⅪ抗原（FⅪ:Ag）分别为50.9 s、53%和47.2%；其父亲上述3 项指标分别为45.4 s、44%和43.1%。DNA测序发现患者及其父亲的FⅪ基因第8号外显子均存在c.841C＞T杂合无义变异（p.Gln281*）。蛋白模型分析显示p.Gln281*变异会产生截短蛋白。结论：该家系FⅪ基因第8号外显子c.841C＞T（NM_000128）杂合无义变异与其FⅪ水平减低有关，可能也是该患者行内镜下直肠息肉摘除术后出现下消化道异常出血的主要原因。

Analysis of lower gastrointestinal bleeding caused by FXI gene mutation

Objective: To analyze the pathogenesis of abnormal lower gastrointestinal bleeding after endoscopic rectal polypectomy in a patient with hereditary coagulation factor XI (FXI) deficiency, and to explore the relationship between the FXI mutation and lower gastrointestinal bleeding after treatment. Methods: Pedigree investigation (5 people of 3 generations in total) was made and relevant coagulation factor indexes of the patient and her family members were detected. Genomic DNA of peripheral blood was extracted for PCR amplification.All the exons, flanking sequences, 5’ and 3’ untranslated regions of FXI gene of the patient were analyzed by direct sequencing. And the corresponding mutation site was subjected to sequencing in other family members.The PyMol software was used to construct protein model before and after gene mutation. Results: The patient was admitted to hospital for abnormal lower gastrointestinal bleeding after endoscopic rectal polypectomy. The activated partial thromb oplastin time (APTT), FXI activity (FXI:C) and FXI antigen (FXI:Ag) of the patient was 50.9 s, 53% and 47.2%, respectively; The above three indicators for her father were 45.4 s, 44% and 43.1%,respectively. Gene sequencing revealed that the patient and her father had a heterozygous nonsense mutation c.841C>T (p.Gln281*) in exon 8 of the FXI gene. Protein model analysis demonstrated that the p.Gln281*mutation producing truncated protein. Conclusion: A heterozygous nonsense mutation c.841C>T (NM_000128) in exon 8 of the FXI gene is responsible for the low FXI level in this pedigree, which might be the main reason for abnormal lower gastrointestinal bleeding after endoscopic rectal polypectomy in this patient.