凝血因子Ⅺ缺乏症是一种罕见的常染色体遗传性出血性疾病，又称为血友病C，与血友病A和B不同，其在两性中都存在，该病主要表现为高纤溶区出血，如口腔和泌尿生殖系统等，多见于创伤或术后。凝血因子Ⅺ缺乏症出血倾向较轻，难以预测，国内鲜有报道。随着产前检查的不断规范以及基因检测技术的提高，可能有助于发现更多患有凝血因子Ⅺ缺乏症的孕妇。本文报告汕头大学医学院第二附属医院（我院）收治的2例凝血因子Ⅺ缺乏症病例，旨在为该病妇女的妊娠和分娩管理提供参考。
1 病例报告
1.1 病例1
患者 30岁，孕3产2，因停经40+6周，发现活化部分凝血活酶时间（activated partial thromboplastin time，APTT）异常7个月，下腹痛3+ h，于2024年6月17日收入院。患者既往自然分娩2次，无产后出血等不良孕产史。患者孕早期于外院查凝血功能示：APTT 72.7 s（升高，↑；参考范围：25.1~36.5 s），活化部分凝血活酶时间比值（activated partial thromboplastin time ratio，APTT-R）2.17↑（参考范围：0.83~1.20），D-二聚体（D-dimer）0.14 mg/L（参考范围：0~0.5 mg/L）。2023年11月30日于我院门诊血液科复查凝血功能示：APTT 67.1 s↑，凝血因子Ⅷ活性148.80%（参考范围：70%~150%），凝血因子Ⅷ活性抑制物为0（参考范围：0~0.6）。进一步完善凝血因子缺陷基因检查，提示F11基因存在致病性遗传突变（4号染色体F11基因杂合突变基因突变位点1：NM_000128:exon8:c.841 C>T:p.Gln281Ter；杂合突变基因突变位点2：NM_000128:exon10:c.1107 C>A:p.Tyr369Ter），凝血因子Ⅺ缺乏。狼疮抗凝物蝰蛇毒稀释试验（diluted russell viper venom time，DRVVT）筛查试验阴性。全套凝血因子活性测定：Ⅷ 152.2%↑（70%~150%）；Ⅸ 94.7%（70%~120%）；Ⅺ 1.1%（下降，↓；70%~120%）；Ⅻ 108.9%（70%~150%）；Ⅱ 126.5%↑（70%~120%）；Ⅴ 98.0%（70%~120%）；Ⅶ 141.7%↑（70%~120%）；Ⅹ 117.4%（70%~120%）。孕妇孕期无自发出血倾向，无产科并发症，根据辅助检查提示APTT延长，凝血因子Ⅺ活动度降低，结合凝血因子缺陷基因检查结果，诊断为遗传性凝血因子Ⅺ缺乏症。考虑孕妇发生出血和栓塞的风险较低，可动态监测出血、栓塞、凝血因子Ⅺ活动度等情况，临产时可使用新鲜冷冻血浆或抗纤溶药物预防产后出血。2024年5月24日—6月17日动态复查APTT波动于64.6~70.0 s，D-二聚体波动于0.14~1.10 mg/L。
2024年6月17日入院后查凝血功能示：APTT 67.30 s↑，APTT-R 2.18↑；其他检验结果未见明显异常。妇产科彩色超声提示孕晚期，头位。胎心监测示无应激试验（non-stress test，NST）反应型评分10分。考虑孕妇为遗传性凝血因子Ⅺ缺乏症，入院后请血液科、麻醉科、重症监护病房（intensive care unit，ICU）、新生儿科进行多学科会诊，血液科建议临产时加用抗纤溶药物预防产后出血，同时予新鲜冰冻血浆备用，注意预防产后静脉血栓形成。麻醉科评估出血风险后不建议行椎管内麻醉术，新生儿科建议新生儿出生后进一步评估是否需转科治疗。
患者为第三胎经产妇，入院后第2天自然临产，予静脉滴注氨甲环酸1 g抗纤溶处理，产程进展迅速（总产程2 h 10 min），自然分娩一活男婴，胎盘、胎膜自然娩出完整，宫缩好，予肌内注射卡前列素氨丁三醇250 μg及宫颈注射缩宫素20 U加强宫缩预防产后出血，分娩过程顺利，阴道总出血量约200 mL。产妇产后静脉血栓形成评估较高风险，予双下肢气压治疗及机械性预防血栓形成。经住院观察4 d后于2024年6月21日出院，2024年7月30日经电话随访，母儿情况好，无并发症发生。
1.2 病例2
患者 女，32岁，孕1产0，因停经40+2周，发现凝血因子Ⅺ减少6+个月，下腹痛3+ h，于2024年9月6日收入院。患者既往无分娩史，无手术史，月经史正常。患者孕早期凝血功能示：APTT 74.1 s↑，APTT-R 2.41↑。2024年2月26日我院血液内科完善血栓弹力图试验（thromboelastograms，TEG）：凝血因子活性反应时间（response time，R）16.30 min↑（参考范围：5~10 min），纤维蛋白原功能动力学时间（kinetic time，K）4.40 min↑（参考范围：1~3 min），血小板聚集功能最大振幅（maximum amplitude，MA）70.00 mm（参考范围：50~70 mm），纤维蛋白原功能α角（alpha angle）45.10°↓（参考范围：53°~72°），纤维蛋白溶解功能30 min纤溶率（Lysis at 30 min，LY30）0.50%（参考范围：0%~7.5%），综合凝血指数（clottometry index，CI）-8.10↓（参考范围：-3~3）。血浆凝血因子Ⅶ活性测定：186.60%↑（参考范围：50%~150%）。自身免疫抗体检查示：抗核抗体阳性（+），抗核抗体滴度1（1∶320阳性），双链DNA抗体阴性（-），单链DNA抗体（-），抗心磷脂抗体组（-），抗可提取核抗原（extractable nuclear antigen，ENA）抗体组均（-）。外送狼疮抗凝物初筛试验1（LA1）：40.1 s（参考范围：31~44 s）；狼疮抗凝物确定试验1（LA2）：34.1 s（参考范围：30~38 s）；LA1/LA2比值1.18（参考范围：0.8~1.2）。凝血因子Ⅷ活性：106.3%（70%~150%）；凝血因子Ⅸ活性：100.4%（70%~120%）；凝血因子Ⅺ活性：<0.8%↓（70%~120%）；凝血因子Ⅻ活性：68.3%↓（70%~150%）；血管性血友病因子（von Willebrand factor，vWF）活性：186.9%（49.5%~187%）。结合上述辅助检查，综合考虑诊断为凝血因子Ⅺ缺乏症。孕妇孕期无自发出血及血栓形成倾向，嘱定期复查凝血功能：APTT波动于64.6~70.0 s，APTT-R波动于0.86~2.02。
2024年9月6日入院后查TEG：R 18.30 min↑，K 3.80 min↑，MA 63.20 mm，α角46.80°↓，LY30为 0.90%，CI 为-9.80↓，D-二聚体0.61 μg/mL↑。凝血功能示：APTT 69.20 s↑，余未见明显异常。妇产科彩色超声及双下肢动静脉彩色超声未见明显异常。请血液科医师会诊后建议备新鲜冰冻血浆预防产后出血，必要时予以输注氨甲环酸抗纤溶处理。
孕妇入院后第2天自然临产，予静脉滴注氨甲环酸注射液1 g抗纤溶处理，产程进展顺利，产时胎心监护Ⅰ类图形。临产4 h后宫口开全，自然分娩一活女婴，胎盘、胎膜自然娩出完整，宫缩好，予肌内注射卡前列素氨丁三醇1 mL加强宫缩及静脉滴注氨甲环酸1 g预防产后出血，会阴Ⅰ度裂伤予常规缝合，检查软产道无血肿，产后2 h阴道总出血200 mL。产妇产后静脉血栓形成评估较高风险，予双下肢气压治疗及穿戴弹力袜机械性预防血栓形成。经住院观察4 d后于2024年9月10日出院，2024年11月12日于我院产后复诊，查凝血功能示：APTT 79.60 s↑，APTT-R 2.58↑，余未见异常。母儿情况好，无并发症发生。
2 讨论
2.1 凝血因子Ⅺ缺乏症的临床特征
凝血因子Ⅺ是一种丝氨酸蛋白酶[1]，其是一种在人血浆中循环的独特的双亚基结构组成的同型二聚体[2]。凝血因子Ⅺ是APTT测定中凝块形成的驱动因素，几乎所有严重凝血因子Ⅺ缺乏症患者的APTT显著延长[3]。凝血因子Ⅺ缺乏症是一种罕见的常染色体遗传性出血性疾病，编码凝血因子Ⅺ的F11基因位于4号染色体（4q35）的长臂上[4]。该病于1953年首次报道[5]，也被称为血友病C。目前根据凝血因子活性分为轻度（20%<凝血因子Ⅺ活性<70%）和重度（凝血因子Ⅺ活性<20 %）[6]。F11基因变异的全球流行病学研究表明，p.Q281*和p.L442Cfs*8是东亚人特有的变异[7]。Zhang等[4]对中国东南地区凝血因子Ⅺ缺乏谱进行了分析，发现p.Gln281*（谷氨酰胺密码子无义突变）是中国东南部最常见的变异，表明可能存在奠基者效应，其发病率可能被严重低估。
本研究病例1孕妇即属于复合杂合子携带者（F11:p.Gln281Ter和F11:p.Tyr369Ter），该患者两种变异均为无义突变，均属于较为常见的变异类型，碱基替换导致编码第369位酪氨酸密码子与第281位谷氨酰胺密码子转变为终止密码子，该患者外周血凝血因子Ⅺ活性为1.1%，属于重度缺乏症。病例2孕妇外周血凝血因子Ⅺ活性<0.8%，属于重度缺乏症。2例既往均无凝血功能异常相关临床表现，均在产检时首次被发现。因此，加强围产期管理，可避免产后出血等不良妊娠结局的发生。
2.2 妊娠合并凝血因子Ⅺ缺乏症患者妊娠早中期管理
2.3 凝血因子Ⅺ缺乏症患者的出血风险评估
凝血因子Ⅺ缺乏不会引起自发性出血，出血通常与外伤或手术有关，特别是在局部纤维蛋白溶解活性高的部位，如泌尿生殖道、鼻腔和口腔等。最强预测因子是阳性出血史[10]。有报道指出存在以下6项中任意2项及以上可认为有阳性出血史：①重度月经出血，持续时间超过1周，每2 h或更短时间需要更换卫生巾，导致贫血；②需要止血治疗的牙科手术；③不明原因的易瘀伤；④需要止血治疗的鼻出血、血尿、血便等；⑤产科出血；⑥需要止血治疗的术后出血[6]。本文病例1孕妇既往无手术史，经阴道分娩2次，无产后出血表现，月经规律，经期5 d，经量正常。病例2孕妇既往无手术史，月经规律，经期7 d，经量正常。2例患者出血史均可被视为阴性。
对于出血史阴性的患者，临床可以通过相关的实验室检查评估孕妇潜在的出血风险。TEG是一种黏弹性测试[11]，可显示相关指标的动态变化趋势，临床医生能够获得凝血状态的变化。TEG除了评估患者出血风险外，亦可用于指导孕妇围产期预防性促凝药物的使用，以便于评估用药后的总体疗效。总之，TEG比传统的检测方法有特殊优势，但其诊断特异度不高。TEG的判读往往对特定因子的缺乏不敏感，特别是根据某一种指标进行治疗时会使得相关参数发生变化，掩盖其他凝血因子或凝血状态的异常[12]。本文病例2入院时（未使用任何促凝药物）查TEG示：CI为-9.80↓（表示机体处于低凝状态），R 18.30 min↑（凝血因子性低凝），K 3.80 min↑（纤维蛋白原功能性低凝），α角46.80°↓（纤维蛋白原功能性低凝），MA 63.20 mm，LY30为0.90%。根据其低凝状态特点，在临产时静脉滴注氨甲环酸1 g纠正纤维蛋白原功能性低凝，预备新鲜冰冻血浆防止凝血因子性低凝。因此，临床上需要对孕妇的所有检验指标进行综合评估。
2.4 妊娠合并凝血因子Ⅺ缺乏产妇的围产期管理
2.4.1 预防性治疗
Wiewel-Verschueren等[13]对患有凝血因子Ⅺ缺乏症孕妇的产后出血情况的系统综述发现，在372例妇女的498次妊娠中，18%（90/498）发生了产后出血，接受预防性治疗者产后出血风险较未接受预防者低[9%（6/66） vs. 19%（84/432）]。预防性治疗选择包括氨甲环酸、凝血因子Ⅺ浓缩物和新鲜冰冻血浆。对于这3种制剂，英国血液学标准委员会对凝血因子Ⅺ缺乏症的管理有以下指导：①对于妊娠晚期凝血因子Ⅺ活性<15%的妇女，在分娩或剖宫产前考虑使用凝血因子Ⅺ浓缩物10~15 IU/kg或新鲜冰冻血浆15~25 mL/kg和氨甲环酸15~20 mg/kg；②对于妊娠晚期凝血因子Ⅺ活性为15%~70%且有阳性出血史的产妇，可考虑使用15~20 mg/kg或1 g的氨甲环酸，每天4次，持续使用至少3 d；③对于妊娠晚期凝血因子Ⅺ活性为15%~70%且无阳性出血史的孕妇，如果出现异常出血，仅考虑使用凝血因子Ⅺ浓缩物10~15 IU/kg或氨甲环酸15~20 mg/kg[14]。以上这3种制剂的使用各有利弊，对于轻度凝血因子Ⅺ缺乏症患者，氨甲环酸足以预防分娩时出血[1]。有严重凝血因子Ⅺ缺乏症或阳性出血史的患者需要凝血因子Ⅺ浓缩物或新鲜冰冻血浆进行预防治疗。凝血因子Ⅺ浓缩物可能导致血栓形成，这种不良反应在妊娠期的高凝状态下进一步增强。有文献报道，自2002年以来，继发于凝血因子Ⅺ浓缩物的血栓栓塞事件共有12例，均产生了严重的不良后果[15]。因此，对于凝血因子Ⅺ严重缺乏且有阳性出血史的患者，首选新鲜冰冻血浆，但需要注意的是使用同种异体血浆存在发生不良事件的风险，如急性肺损伤和输血引起循环系统超负荷而导致的心衰等。对于轻度凝血因子Ⅺ缺乏、无阳性出血史且有阴道分娩条件的患者，有学者认为阴道分娩后产后出血的发生率较低，在轻度凝血因子Ⅺ缺乏的情况下，使用药物预防产后出血可能是非必要的[16]。
本研究2例孕妇均无手术指征，考虑经阴道分娩产后出血的发生率较低，同时为避免过度治疗引起不良并发症，临产后给予静脉滴注氨甲环酸预防产后出血，同时联系血库准备同种异体新鲜冰冻血浆400 mL备用，胎盘娩出后积极使用强效宫缩剂卡前列素氨丁三醇注射液1 mL加强子宫收缩，产后严密监测生命体征及阴道出血情况。对于此类必须手术终止妊娠的患者，术前输注新鲜冰冻血浆是非常有必要的。
2.4.2 分娩方式及麻醉方式的选择
对于患有凝血因子Ⅺ缺乏症的孕妇来说，分娩方式的选择尤为重要，充分评估孕妇的阴道分娩条件，积极鼓励阴道试产，避免不必要的剖宫产是减少此类患者产后出血发生率的重要措施。Stoeckle等[16]报道了40例轻度凝血因子Ⅺ缺乏妇女的71次分娩，其中45次经阴道分娩，26次经剖宫产分娩，其中45次经阴道分娩无任何产后出血发生，但经剖宫产分娩者，产后出血发生率高达38.4%（10/26），可见此类患者经剖宫产伴有产后出血的风险明显高于经阴道分娩。椎管内麻醉是分娩镇痛和剖宫产的主要麻醉方式，一般来说，任何类型的凝血功能障碍都是椎管内麻醉手术的禁忌证。对于合并凝血因子Ⅺ缺乏的孕妇，我国缺乏相关报道及指南，麻醉师对待此类患者更应谨慎，但是经过麻醉科、血液科及产科医生的多学科讨论，对孕妇进行个体化分析，在严密监护下可进行椎管内麻醉，以改善孕妇分娩体验感及避免由全身麻醉而引起的不良母儿结局。
本文2例均属于重度凝血因子Ⅺ缺乏症，理论上均不建议行椎管内麻醉。病例1为第三胎经产妇，无阴道分娩禁忌证，麻醉科会诊后为避免形成硬膜外血肿及脊髓血肿，不建议行椎管内麻醉。但考虑到病例1孕妇既往经阴道分娩2次，分娩后阴道出血量较正常孕妇无明显差别。因此，既往无产后出血史的经产妇，可酌情考虑行椎管内麻醉术。病例2为第一胎初产妇，无阴道分娩禁忌证，对于这类孕妇，考虑经剖宫产分娩产后出血风险明显大于经阴道分娩，为避免因孕妇不能耐受疼痛而要求剖宫产，可在输注新鲜冰冻血浆或凝血因子Ⅺ浓缩物后进行复测凝血因子Ⅺ活性及APTT，若凝血因子Ⅺ活性及APTT有所纠正，且孕妇分娩过程中强烈要求行分娩镇痛术，可经麻醉医师充分评估后，在严密监护下行椎管内麻醉，可在保证良好母儿妊娠结局的前提下提高患者的分娩体验。
综上，随着产前检查的不断规范以及基因检测技术的提高，未来可能发现更多患有凝血因子Ⅺ缺乏症的孕妇，临床医生需要进一步深化对于该疾病的理解以及规范诊治原则，加强围产期管理，尽可能改善不良妊娠结局，但目前具体的管理和诊疗方案尚无明确指南，仍需进一步探索。
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