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遗传性凝血因子ⅩⅢ缺乏症（congenital factor ⅩⅢ deficiency，FⅩⅢCD）是一种极罕见的凝血障碍性疾病，其发病机制主要与凝血因子ⅩⅢ（factor ⅩⅢ，FⅩⅢ） 的A亚基基因（F13A1）和B亚基基因（F13B）突变有关，为常染色体隐性遗传性疾病[1-2]。该疾病占罕见遗传性出血性疾病的 4.7%，患病率约 1/200 万，男女均可罹患，近亲家庭出生的患儿更易发生[3]。 FⅩⅢCD 常见临床表型为脐部出血、软组织血肿、伤口愈合时间延长、终身出血倾向及颅内出血等[2]。本研究围绕南京医科大学附属儿童医院血液肿瘤科诊治的2例由F13A1基因突变导致的FⅩⅢCD患儿的临床资料展开，旨在通过全外显子测序明确遗传基因，深入分析其临床表型及基因突变特征。鉴于该疾病的罕见性，临床上极易漏诊或误诊。本文通过综合回顾相关文献，讨论了疾病的早期诊断、治疗及长期预防策略，旨在为临床医生早期识别这一罕见凝血因子异常疾病提供参考。
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1 临床资料
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病例1，男，9岁8个月，因“左膝关节疼痛1周” 于 2023 年 1 月就诊于南京医科大学附属儿童医院血液肿瘤科。患儿自出生起，先后因“突发脐部残端出血、头颅血肿、外伤后右下腹血肿、外伤后下肢软组织血肿”至南京医科大学附属儿童医院就诊，期间多次予白眉蛇毒血凝酶、人凝血酶原复合物、悬浮少白红细胞及新鲜冰冻血浆（flash frozen plasma， FFP）等输注治疗，肿胀、疼痛等症状可缓解。患儿多年来病情反复，多次常规凝血检验结果均显示基本正常，病因一直未明确，否认家族史。2022年12月患儿出现左侧髋关节疼痛，左股骨及双侧髋关节核磁共振检查示左侧大腿根外侧肌群及内侧腹股沟区、腹盆腔左侧大片状异常信号（图1）。在患儿父母知情同意下，对患儿及其父亲完善全外显子组测序，结果显示患儿 F13A1 基因存在复合杂合变异，为 4 号外显子c.468_c.469insG（p.K157fs*34）移码变异（父亲为野生型）和c.799⁃12（IVS6）G>A错义变异 （来源于父亲）（图2A，图3），与FⅩⅢ缺乏相关。2023年 1月患儿出现左膝关节疼痛，完善凝血因子八项活性测定，凝血因子Ⅱ、Ⅴ、Ⅶ、Ⅷ、Ⅸ、Ⅹ、Ⅺ、Ⅻ活性均正常。对FⅩⅢ抗原及活性进行2次测定，抗原含量分别为13.3%和4.4%，较正常值明显低下，活性定性检验结果均正常，诊断为FⅩⅢ缺乏。诊疗及随访：患儿于 2023 年 3 月因“左膝关节血肿”至南京医科大学附属儿童医院就诊，输注FFP后症状缓解，治疗中未见不良反应。
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病例2，男，1岁，因“外伤后腕关节肿胀1 d”于 2023年6月至南京医科大学附属儿童医院血液肿瘤科就诊。患儿有血液系统疾病家族史，2022年7月家长要求完善凝血异常相关基因检测，结果显示患儿F13A1基因存在复合杂合变异，分别是11号外显子 c.1352_c.1353del（p.His451fs）移码变异（来源于父亲）和14号外显子c.2015G>A（p.Gly672Glu）错义变异（来源于母亲）（图2B，图4）。2023年5月患儿至南京医科大学附属儿童医院血液肿瘤科进一步诊断，完善凝血常规检验、凝血因子八项活性检测、 FⅩⅢ活性定性检验及抗原含量测定。其中，凝血常规检验结果及凝血因子Ⅱ、Ⅴ、Ⅶ、Ⅷ、Ⅸ、Ⅹ、Ⅺ、Ⅻ活性均基本正常。FⅩⅢ活性定性检验结果为阳性，抗原含量为0.1%，表明FⅩⅢ活性及抗原水平均降低。患儿诊断为FⅩⅢ缺乏，输注FFP后症状缓解。家族史：患儿同胞哥哥曾因“脐部残端出血、头部血肿”行手术治疗，期间完善凝血障碍性疾病相关基因检测，结果示F13A1基因有2个杂合突变，与FⅩⅢ缺乏相关，后因“暴发性心肌炎”去世。诊疗及随访：患儿于 2023年8月、9月分别因“右面颊肿胀”“右下肢软组织血肿”至南京医科大学附属儿童医院血液肿瘤科就诊，予FFP或冷沉淀输注后症状缓解，治疗中均未见不良反应。
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图1 病例1入院后左股骨及双侧髋关节MRI平扫T2压脂序列
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Figure1 T2 lipid ⁃ pressure sequence of left femur and bilateral hip joint by MRI plain scan of case 1
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图2 FⅩⅢCD患儿F13A1基因致病突变位点示意图
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Figure2 Schematic diagram of pathogenic mutation site of F13A1 gene in children with FⅩⅢCD
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2 讨论
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FⅩⅢ是一种谷氨酰胺转氨酶[4]，是由A亚基二聚体和B亚基二聚体紧密结合形成的四聚体[5]，在凝血、抗纤溶、伤口愈合、骨代谢及心肌保护等方面起重要作用[6]。F13A1和F13B突变与FⅩⅢ缺乏所致凝血障碍性疾病密切相关，其中F13A1突变约占95%，是FⅩⅢCD的主要原因[7]。
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与血友病不同，FⅩⅢCD常见临床表现为脐部出血、软组织血肿、伤口愈合时间延长、终身出血倾向和颅内出血等，通常不引起关节出血。颅内出血是 FⅩⅢCD最严重的临床表型，也是导致患者死亡的主要原因[8]，该疾病引起的颅内出血约占所有遗传性出血性疾病的30%[9]。FⅩⅢ在正常情况下能够抑制血管通透性[10]，缺乏时易导致软组织血肿。本报道中 2 例患儿均为复合杂合变异，其中 c.1352_c.1353del 已在 1 例颅内出血患儿体内被发现[11]，其余3个变异位点暂未有文献报道。国外研究表明杂合型患者通常不表现出自发性出血倾向，常在外伤、术后等有较高止血需求时会出现明显的凝血障碍[12-14]，本文中 2 例患儿常见症状为反复外伤后软组织血肿，与该研究结论相符。
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FⅩⅢCD的诊断具有挑战性，临床表现和常规凝血试验缺乏特异性。诊断方法主要包括：凝血溶解度试验、FⅩⅢ活性定量分析、FⅩⅢ抗原含量检测和全外显子组测序等。凝血溶解度试验是发展中国家诊断FⅩⅢCD的一线筛查试验，但其仅在FⅩⅢ严重缺乏时表现为阳性[12]，对于杂合型患者灵敏度更低[15]，不能作为主要诊断手段[16]。FⅩⅢ活性定量分析具有较高的灵敏度，是FⅩⅢCD 的重要诊断方式，但准确性受限于实验室条件。当FⅩⅢ活性极低时，该测试准确性受限，因此FⅩⅢ活性定量分析尚不能独立用于诊断 FⅩⅢCD。有研究表明，FⅩⅢ活性与抗原含量之间存在正相关[17]。抗原测定和分子检测有助于精确诊断，此外，全外显子组测序可明确基因位点及突变类型。
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图3 病例1及其父亲基因测序
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Figure3 Genetic sequencing of case 1 and his father
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图4 病例2患儿及其父母亲基因测序
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Figure4 Genetic sequencing of case 2 and his parents
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FⅩⅢCD的治疗主要依赖替代疗法，补充缺失的 FⅩⅢ。传统替代治疗包括 FFP 和冷沉淀，但引起过敏反应和血源性病原体感染的风险更高[18]，新型治疗产品如血浆衍生FⅩⅢ浓缩物、重组凝血因子ⅩⅢ （recombinant factor ⅩⅢ，rFⅩⅢ）已在国际上获得批准[16]。rFⅩⅢ因具有良好的耐受性[19]，已成为国际首选治疗产品，但国内尚未引入。有研究表明，FⅩⅢCD 患者采用rFⅩⅢ进行预防治疗后，仅个别18岁以下患者产生抗体[20]，但该抗体无抑制活性，患者并未出现抗体相关不良反应如出血表现[21]。因此，rFⅩⅢ预防治疗被认为是最佳治疗选择，可显著减少患者年出血次数，从而改善生活质量[22]。意大利开展的一项多中心临床试验已证实rFⅩⅢ在FⅩⅢCD患者中应用的疗效和安全性，并强调治疗中需重视个体差异[23]。FⅩⅢCD出血严重程度与FⅩⅢ活性水平有强相关性[24]，FⅩⅢ活性低于15 U/dL时，自发性出血的概率会显著增加。因此，有研究建议将FⅩⅢ活性低于15 U/dL作为采取预防性治疗以减少大出血的标准[25]，可每4~6周输注 25~35 U/kg FⅩⅢ[26]。但若要发挥抗纤溶功能，使凝块稳定时间延长，FⅩⅢ应补充至正常循环水平的50%[2]。
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本报道中病例1存在病情反复、病程长的特点，诊断较困难。现结合该患者临床表现、FⅩⅢ活性及抗原含量测定、全外显子组测序等检验结果，疾病虽已确诊，但既往原因不明的反复出血已对患儿日常生活产生负面影响。病例2因有明确的家族史，给诊断提供了重要线索，虽因年龄小常发生意外磕碰出血，但均通过替代治疗及早缓解症状。一项关于 FⅩⅢCD 预防治疗的研究表明，每毫升冷沉淀中FⅩⅢ浓度比FFP多2~3倍，但输注FFP相较冷沉淀可减少受体的血浆暴露[27]。我国目前尚未引进新型治疗产物，建议患者每 4~6 周输注 10 mL/kg FFP进行预防治疗[28]。
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FⅩⅢCD因其低发病率和非特异性的临床表现，容易漏诊或误诊。对于重型患者，延迟诊断将对生命产生极大威胁，因此当患者存在频繁出血且凝血常规检验结果基本正常时，可尽早进行FⅩⅢ活性、抗原水平测定以及基因测序等协助诊断。
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参考文献
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[2] ALSHEHRI F S M,WHYTE C S,MUTCH N J.FactorⅩⅢ⁃ A:an indispensable“factor”in haemostasis and wound healing[J].Int J Mol Sci,2021,22(6):3055
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[3] BOUTTEFROY S,MEUNIER S,MILIEN V,et al.Congenital factor ⅩⅢ deficiency:comprehensive overview of the FranceCoag cohort[J].Br J Haematol,2020,188(2):317-320
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[4] CAI R M,LI Y,WANG W Y,et al.A novel Cys328⁃terminator mutant implicated in severe coagulation factor ⅩⅢ deficiency:a case report[J].BMC Med Genet,2020,21(1):175
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[5] BYRNES J R,LEE T,SHARABY S,et al.Reciprocal stabilization of coagulation factor ⅩⅢ⁃A and⁃B subunits is a determinant of plasma F ⅩⅢ concentration[J].Blood,2024,143(5):444-455
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[6] DORGALALEH A,RASHIDPANAH J.Blood coagulation factor ⅩⅢ and factor ⅩⅢ deficiency[J].Blood Rev,2016,30(6):461-475
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[7] KARIMI M,PEYVANDI F,NADERI M,et al.Factor ⅩⅢ deficiency diagnosis:challenges and tools[J].Int J Lab Hematol,2018,40(1):3-11
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[8] BISWAS A,IVASKEVICIUS V,SEITZ R,et al.An update of the mutation profile of factor 13 A and B genes[J].Blood Rev,2011,25(5):193-204
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[10] HIRAHARA K,SHINBO K,TAKAHASHI M,et al.Suppressive effect of human blood coagulation factor ⅩⅢ on the vascular permeability induced by anti-guinea pig endothelial cell antiserum in guinea pigs[J].Thromb Res,1993,71(2):139-148
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[11] BRIGGS B,JAMES K N,CHOWDHURY S,et al.Novel Factor ⅩⅢ variant identified through whole-genome sequencing in a child with intracranial hemorrhage[J].Cold Spring Harb Mol Case Stud,2018,4(6):a003525
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[12] BISWAS A,IVASKEVICIUS V,THOMAS A,et al.Coagulation factor ⅩⅢ deficiency.Diagnosis,prevalence and management of inherited and acquired forms[J].Hamosta⁃seologie,2014,34(2):160-166
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[13] MINNO G D,NAVARRO D,PERNO C F,et al.Pathogen reduction/inactivation of products for the treatment of bleeding disorders:what are the processes and what should we say to patients?[J].Ann Hematol,2017,96(8):1253-1270
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[18] INBAL A,OLDENBURG J,CARCAO M,et al.Recombinant factor ⅩⅢ:a safe and novel treatment for congenital factor ⅩⅢ deficiency[J].Blood,2012,119(22):5111-5117
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[19] POULSEN L H,KERLIN B A,CASTAMAN G,et al.Safety and effectiveness of recombinant factor ⅩⅢ⁃A2 in congenital factor ⅩⅢ deficiency:real-world evidence[J].Res Pract Thromb Haemost,2022,6(2):e12628
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[21] CARCAO M,ALTISENT C,CASTAMAN G,et al.Recombinant FⅩⅢ(rFⅩⅢ⁃A2)prophylaxis prevents bleeding and allows for surgery in patients with congenital F ⅩⅢ A-subunit deficiency[J].Thromb Haemost,2018,118(3):451-460
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[22] LI B J,BORHANY M,ABID M,et al.Identification of a novel nonsense mutation leading to congenital factor ⅩⅢ deficiency[J].Thromb Res,2018,165:83-85
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[23] ZANON E,PASCA S,SOTTILOTTA G,et al.A multicenter,real ⁃world experience with recombinant FⅩⅢ for the treatment of patients with FⅩⅢ deficiency:from pharmacokinetics to clinical practice.The Italian FⅩⅢ Study[J].Trasfu⁃sione Del Sangue,2023,21(4):350-355
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[27] CAUDILL J S,NICHOLS W L,PLUMHOFF E A,et al.Comparison of coagulation factor ⅩⅢ content and concentration in cryoprecipitate and fresh-frozen plasma[J].Transfusion,2009,49(4):765-770
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[28] JAVED H,SINGH S,RAMARAJE URS S U,et al.Genetic landscape in coagulation factor ⅩⅢ associated defects⁃advances in coagulation and beyond[J].Blood Rev,2023,59:101032
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基本信息
中图分类号: R554
文献标识码: A
DOI: 10.7655/NYDXBNSN240161
文章编号: 1007-4368(2024)09-1318-05
基金信息
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引用信息
稿件历史
收稿日期: 2024-02-20
参考文献
-
[1] 李可成,张华玲,唐宁.凝血因子(ⅩⅢ)缺乏症与纤溶亢进的临床分析[J].临床内科杂志,2021,38(2):130-131
-
[2] ALSHEHRI F S M,WHYTE C S,MUTCH N J.FactorⅩⅢ⁃ A:an indispensable“factor”in haemostasis and wound healing[J].Int J Mol Sci,2021,22(6):3055
-
[3] BOUTTEFROY S,MEUNIER S,MILIEN V,et al.Congenital factor ⅩⅢ deficiency:comprehensive overview of the FranceCoag cohort[J].Br J Haematol,2020,188(2):317-320
-
[4] CAI R M,LI Y,WANG W Y,et al.A novel Cys328⁃terminator mutant implicated in severe coagulation factor ⅩⅢ deficiency:a case report[J].BMC Med Genet,2020,21(1):175
-
[5] BYRNES J R,LEE T,SHARABY S,et al.Reciprocal stabilization of coagulation factor ⅩⅢ⁃A and⁃B subunits is a determinant of plasma F ⅩⅢ concentration[J].Blood,2024,143(5):444-455
-
[6] DORGALALEH A,RASHIDPANAH J.Blood coagulation factor ⅩⅢ and factor ⅩⅢ deficiency[J].Blood Rev,2016,30(6):461-475
-
[7] KARIMI M,PEYVANDI F,NADERI M,et al.Factor ⅩⅢ deficiency diagnosis:challenges and tools[J].Int J Lab Hematol,2018,40(1):3-11
-
[8] BISWAS A,IVASKEVICIUS V,SEITZ R,et al.An update of the mutation profile of factor 13 A and B genes[J].Blood Rev,2011,25(5):193-204
-
[9] ALAVI S E R,JALALVAND M,ASSADOLLAHI V,et al.Intracranial hemorrhage:a devastating outcome of congenital bleeding disorders⁃prevalence,diagnosis,and management,with a special focus on congenital factor ⅩⅢ deficiency[J].Semin Thromb Hemost,2018,44(3):267-275
-
[10] HIRAHARA K,SHINBO K,TAKAHASHI M,et al.Suppressive effect of human blood coagulation factor ⅩⅢ on the vascular permeability induced by anti-guinea pig endothelial cell antiserum in guinea pigs[J].Thromb Res,1993,71(2):139-148
-
[11] BRIGGS B,JAMES K N,CHOWDHURY S,et al.Novel Factor ⅩⅢ variant identified through whole-genome sequencing in a child with intracranial hemorrhage[J].Cold Spring Harb Mol Case Stud,2018,4(6):a003525
-
[12] BISWAS A,IVASKEVICIUS V,THOMAS A,et al.Coagulation factor ⅩⅢ deficiency.Diagnosis,prevalence and management of inherited and acquired forms[J].Hamosta⁃seologie,2014,34(2):160-166
-
[13] MINNO G D,NAVARRO D,PERNO C F,et al.Pathogen reduction/inactivation of products for the treatment of bleeding disorders:what are the processes and what should we say to patients?[J].Ann Hematol,2017,96(8):1253-1270
-
[14] DORGALALEH A.Novel insights into heterozygous factor ⅩⅢ deficiency[J].Semin Thromb Hemost,2024,50(2):200-212
-
[15] LAWRIE A S,GREEN L,MACKIE I J,et al.Factor ⅩⅢ⁃ an under diagnosed deficiency-are we using the right assays?[J].J Thromb Haemost,2010,8(11):2478-2482
-
[16] DORGALALEH A.The history of factor ⅩⅢ deficiency[J].Semin Thromb Hemost,2024,50(1):34-42
-
[17] LEITNER M,BÜCHOLD C,PASTERNACK R,et al.Clinical validation of an automated fluorogenic factor ⅩⅢ activity assay based on isopeptidase activity[J].Int J Mol Sci,2021,22(3):1002
-
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