张洋:抗磷脂综合征与心血管疾病

2020-11-30 《门诊》杂志 门诊新视野

临床中,许多自身免疫疾病均有心脏等器官受累,心血管疾病是最常见的临床表现,对于心血管患者原发病的诊断和排除十分重要。

一位年轻女性,3年前发生深静脉血栓,近期又因急性心肌梗死入院,是什么原因导致如此年轻的女性反复发作动静脉血栓?一位年轻女性,反复动静脉栓塞,本次诊断为心脏瓣膜病,预行外科换瓣手术。术前,经“纠正试验”后患者活化部分凝血活酶时间(APTT)仍显着延长,是凝血因子缺陷还是什么其他原因?

临床中,许多自身免疫疾病均有心脏等器官受累,血管疾病是最常见的临床表现,对于心血管患者原发病的诊断和排除十分重要;面对复杂多样的疾病表现,只有拥有系统的专业知识、缜密的思维逻辑,才可站立于“谜团”中仍能把握正确的决策方向。在近日举行的第十一届海峡心血管病高峰研讨会(CSCSF 2020)“检验论坛”上,中国医学科学院阜外医院张洋教授结合大量循证医学证据和多个病例,生动系统地阐述了抗磷脂综合征(APS)与心血管疾病的关系及针对不同情况的临床思考角度。

抗磷脂综合征的定义与诊断

抗磷脂综合征(APS)是指由抗磷脂抗体(aPL)引起的一种自身免疫性疾病,以反复发作的动静脉血栓形成、自发性流产、血小板减少以及血清aPL阳性为主要临床特征。aPL是一组能与磷脂结合的自身蛋白表位反应的异质性抗体家族,可通过干扰依赖磷脂的各种凝血与抗凝血因子的功能而导致血栓形成,主要包括抗心磷脂抗体(aCL)、狼疮抗凝物(LA)、抗β2糖蛋白I。APS不仅能引起动静脉血栓和病态妊娠,还可导致严重的心血管病变。

按照2006年札幌标准悉尼修订版,诊断APS需满足“至少1项临床症状+1项实验室指标”。(1)临床症状:1. 血栓形成:任何器官或组织发生一次以上动、静或小血管血栓;2. 妊娠丢失:至少一次10周以上的不明原因、形态正常的胎儿死亡;或三次以上不明原因的早期自发性流产(<10周);或≤34周,子痫、先兆子痫或胎盘功能不全致胎儿早产一次。(2)实验室指标:间隔≥12周,且≥2次检出。1. 血浆LA阳性;2. 中→高滴度IgG/M类ACL(≥40单位);3. IgG/M类抗β2-GP1(≥40单位)。

抗磷脂综合征与心血管疾病

APS分为原发性和继发性两类,前者无任何诱因,后者继发于多种疾病,以结缔组织病为主,如系统性红斑狼疮(SLE)、类风湿性关节炎以及各种感染、肿瘤、应用某些药物等。近年来,APS患者伴发的心血管疾病备受关注,主要包括心脏瓣膜病变、冠状动脉病变、肺动脉高压等,临床上常因其症状复杂、认识不足而导致误诊或漏诊。对于临床医师,应充分认识APS心血管系统表现、了解相应的治疗策略。

APS与瓣膜病

心脏瓣膜病是APS患者最常见的心脏表现,包括疣状赘生物、瓣膜增厚、纤维钙化等,并可伴发心肌病、二尖瓣或主动脉瓣反流,可能与血栓沉积继发炎症反应有关。研究显示,15-30%APS患者罹患瓣膜性心脏病,即Libman-Sacks心内膜炎或非细菌性血栓性心内膜炎。临床中,对于反复动静脉血栓的瓣膜病年轻患者,临床医师需谨慎对待;如果患者APTT显着延长,经纠正试验后并未恢复正常,此时应积极进行抗磷脂综合征抗体谱检测,明确病因,从而调整术前、术中、术后的治疗管理方案。需注意,对于有心脏瓣膜病的APS患者,外科换瓣手术时血栓及出血风险均显着增高。

同样,感染性心内膜炎(IE)作为循环系统常见的感染性疾病,其与aPL同样存在一定关系。2018年发表于HEART杂志的一项旨在探索aPL与IE患者血栓事件关系的研究显示,aCL-lgM阳性组脑栓塞发生率显着高于aCL-lgM阴性组。β2GP1-lgM阳性组脑栓塞发生率显着高于β2GP1-lgM阴性组;回归分析结果显示,β2GP1-lgM、aCL-lgM是IE患者脑栓塞的两个独立危险因素。

APS与肺动脉栓塞、肺动脉高压

APS静脉血栓形成比动脉血栓形成多见,静脉血栓又以下肢深静脉血栓(DVT)最常见。国外研究显示,APS可使患者肺动脉栓塞(PE)复发风险增加2.3-8.5倍。2019年发表于Tuber Respir Dis杂志的一项旨在比较APS阳性、APS阴性的PE患者临床特征间差异的研究显示,APS阳性的PE患者年龄较小、病态妊娠及动脉栓塞病史比例较高。临床中,对于具有无诱因咯血的PE,如果年龄<40岁、肺动脉栓塞严重程度指数(PESI)低风险(风险I或II级)和/或APTT延长(参考区间的75百分位以上),可怀疑存在APS,应积极进行aPL实验室检测、寻找病因,特别对于年轻的PE患者。

反复的肺动脉栓塞是引起APS患者慢性血栓栓塞性肺动脉高压(CTEPH)的首要原因。一项发表于Thromb Haemost杂志的研究显示,总体CTEPH患者中,7.7%为APS(23/297);APS-CTEPH患者中,74%(17/23)抗体三重阳性;APS-CTEPH患者,43%%(10/23)罹患其他自身免疫病,绝大多数为系统性红斑狼疮(8/10);相较于非APS-CTEPH患者,APS-CTEPH患者更年轻,与三重抗磷脂抗体阳性和反复血栓史有关。APS是CTEPH的重要亚群,具有独特的临床症状和血流动力学特征。对于PE患者,应早期检测aPL,积极进行病因学诊断,酌情采取相应的抗凝治疗,限制PE进一步进展为CTEPH。

APS与心肌梗死

临床中,APS以急性心肌梗死(AMI)为首发表现的较为少见。多数学者认为APS发生AMI常因冠状动脉内血栓形成,对于年轻APS患者中更是如此。2017年一项共纳入27项研究的荟萃分析显示,40例合并AMI的APS患者中,33例为原发性APS、4例为继发性APS;平均年龄41.10±13.61岁,无显着性别优势。既往阜外医院的一项旨在分析aCL阳性的AMI患者临床特征的研究显示,相较于aCL阴性组,aCL阳性组年龄较低;既往心肌梗死、VTE、动静脉血栓等比例较高;冠心病传统风险因素,如高血压、高脂血症等比例较低。同时,针对年龄<55岁人群的亚组分析显示,低年龄AMI患者抗磷脂抗体阳性组既往发生动静脉血栓的风险增高。临床中,AMI可出现于正常的APS患者,尤其是未绝经的妇女或无传统动脉粥样硬化危险因素的患者。当无冠心病危险因素的年轻患者存在血栓形成或血栓栓塞性冠状动脉闭塞,而血管造影并无动脉粥样硬化证据时需考虑APS。

高滴度的aCL、aPL除可增加正常冠状动脉发生心脏事件的风险,还可增加冠状动脉旁路移植术(CABG)患者移植血管闭塞的风险以及经皮冠状动脉介入治疗(PCI)后再狭窄风险。2000年发表于CIRCULATION杂志的一项旨在探索抗磷脂抗体与心血管事件复发风险的前瞻性研究显示,高Acl-lgG、低lgM抗体的患者风险最高。1998年一项发表于Autoimmunity杂志的研究显示,PCI术后,aPL阴性组再狭窄率为3/45(15%)、aPL阳性组再狭窄率为6/15(40%),差异具有统计学意义;aPL阳性患者术后再狭窄时间为2.2个月、而aPL阴性患者术后再狭窄时间为3.5个月。2012年发表于Cardiology杂志的一项旨在探索PCI术后APS患者长期预后的研究显示,与经PCI治疗的ST段抬高型AMI患者相比,同期接受PCI治疗APS患者6个月、1年、2年、3年主要不良心血管事件(MACE)均显着增高。

研究显示,抗磷脂综合征导致心血管疾病可能的机制主要涉及:

aPL介导内皮一氧化氮抑制、NO产生和释放受损以及内皮功能障碍——“第一次打击”;

炎症损伤后内皮细胞上b2-Gp1受体上调——“第二次打击”;

aPL介导的内皮细胞增殖、内膜增生和非动脉粥样硬化性血管狭窄;

APS相关的动脉粥样硬化加速;

aPL介导的血小板细胞激活、聚集和血栓形成;

补体系统激活和血栓形成。

APS与心腔内血栓

心腔内血栓形成在APS患者很少见,往往是个案报道。但是,其却非常重要并有潜在致命风险。心腔内血栓形成引起的多系统表现包括深静脉血栓形成、肺栓塞、脑卒中、充血性心力衰竭、周围动脉缺血、多动脉或静脉栓塞,有些患者也可无任何临床症状。临床中,对于出现心腔内血栓而没有心脏基础疾病的年轻患者,应积极筛查aPL。

总 结

心脏是APS的重要靶器官之一,临床上约40%APS患者具有心血管系统表现,了解相关情况可提高对此类疾病的诊治水平。鉴于APS和心血管疾病的密切关系,临床医师有必要对一些不明原因导致的心血管疾病筛查抗磷脂综合征相关抗体,以明确病因,为临床诊治提供依据。

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GetPortalCommentsPageByObjectIdResponse(id=903923, encodeId=dcf99039233c, content=感染性心内膜炎(IE)作为循环系统常见的感染性疾病,其与aPL同样存在一定关系。。, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201128/928bf083b196415cbaa5a8292d70e333/cdfe5f3f34794434be595ee70b8766e8.jpg, createdBy=69a95401355, createdName=ms9000001235733856, createdTime=Tue Dec 01 17:08:08 CST 2020, time=2020-12-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=903884, encodeId=bbae903884d1, content=心脏受累, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201211/3bb57304272c4b2b86735fa78a30e9bf/99e093a7c19f492aa0811287a9a91807.jpg, createdBy=a0701982805, createdName=无知, createdTime=Tue Dec 01 15:28:55 CST 2020, time=2020-12-01, status=1, ipAttribution=)]
    2020-12-19 412048642

    感觉可以研究一下APS与眼底血管改变了

    0

  3. 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    2020-12-06 gqylhd

    心腔血栓需要高度警惕APS

    0

  4. 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    2020-12-05 gqylhd

    学习了

    0

  5. 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    2020-12-05 145df198m92暂无昵称

    学习,对于不明原因心脏疾病多了思路

    0

  6. 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  7. 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  8. 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01 15:28:55 CST 2020, time=2020-12-01, status=1, ipAttribution=)]
    2020-12-01 Lizhihua6

    抗磷脂综合征与心血管疾病

    0

  9. 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href='/topic/show?id=bb6f89e145a' target=_blank style='color:#2F92EE;'>#血管疾病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=89714, encryptionId=bb6f89e145a, topicName=血管疾病)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ccb99370406, createdName=andy2090, createdTime=Wed Dec 02 14:59:39 CST 2020, time=2020-12-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=903969, encodeId=f29e90396919, content=抗磷脂综合征与心血管疾病, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201120/58e01f5adcbf4aae90dfc25bd03c739f/1aca8d53476d43fca347e4819bda61f4.jpg, createdBy=b2d85436799, createdName=Lizhihua6, createdTime=Tue Dec 01 18:40:55 CST 2020, time=2020-12-01, status=1, ipAttribution=), 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    2020-12-01 ms9000001235733856

    感染性心内膜炎(IE)作为循环系统常见的感染性疾病,其与aPL同样存在一定关系。。

    0

  10. [GetPortalCommentsPageByObjectIdResponse(id=950287, encodeId=f3be95028eb6, content=赞, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=66942067627, createdName=1881ef655dm, createdTime=Tue Mar 23 10:18:22 CST 2021, time=2021-03-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=909346, encodeId=0978909346b6, content=感觉可以研究一下APS与眼底血管改变了, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201202/97a0a559a44c405796432b627680bd86/d3c0d31b810b4791bccace3222c1683c.jpg, createdBy=f4c03009353, createdName=412048642, createdTime=Sat Dec 19 11:28:22 CST 2020, time=2020-12-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=905312, encodeId=086390531207, content=心腔血栓需要高度警惕APS, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3c31528806, createdName=gqylhd, createdTime=Sun Dec 06 07:59:35 CST 2020, time=2020-12-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=905282, encodeId=380a90528274, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=84, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3c31528806, createdName=gqylhd, createdTime=Sat Dec 05 23:36:58 CST 2020, time=2020-12-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=905117, encodeId=33b690511e1a, content=学习,对于不明原因心脏疾病多了思路, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=5fa45094814, createdName=145df198m92暂无昵称, createdTime=Sat Dec 05 09:55:40 CST 2020, time=2020-12-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1431976, encodeId=f6c114319e6fb, content=<a href='/topic/show?id=f9b9e9124a8' target=_blank style='color:#2F92EE;'>#综合征#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=79124, encryptionId=f9b9e9124a8, topicName=综合征)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Wed Dec 02 14:59:39 CST 2020, time=2020-12-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1498797, encodeId=5fb11498e972d, content=<a href='/topic/show?id=bb6f89e145a' target=_blank style='color:#2F92EE;'>#血管疾病#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=89714, encryptionId=bb6f89e145a, topicName=血管疾病)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ccb99370406, createdName=andy2090, createdTime=Wed Dec 02 14:59:39 CST 2020, time=2020-12-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=903969, encodeId=f29e90396919, content=抗磷脂综合征与心血管疾病, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201120/58e01f5adcbf4aae90dfc25bd03c739f/1aca8d53476d43fca347e4819bda61f4.jpg, createdBy=b2d85436799, createdName=Lizhihua6, createdTime=Tue Dec 01 18:40:55 CST 2020, time=2020-12-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=903923, encodeId=dcf99039233c, content=感染性心内膜炎(IE)作为循环系统常见的感染性疾病,其与aPL同样存在一定关系。。, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201128/928bf083b196415cbaa5a8292d70e333/cdfe5f3f34794434be595ee70b8766e8.jpg, createdBy=69a95401355, createdName=ms9000001235733856, createdTime=Tue Dec 01 17:08:08 CST 2020, time=2020-12-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=903884, encodeId=bbae903884d1, content=心脏受累, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20201211/3bb57304272c4b2b86735fa78a30e9bf/99e093a7c19f492aa0811287a9a91807.jpg, createdBy=a0701982805, createdName=无知, createdTime=Tue Dec 01 15:28:55 CST 2020, time=2020-12-01, status=1, ipAttribution=)]
    2020-12-01 无知

    心脏受累

    0

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