Current advances in diagnosis and treatment of antiphospholipid syndrome
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摘要: 抗磷脂综合征(APS)是一种以血清中持续存在高滴度的抗磷脂抗体(aPL)伴反复动/静脉血栓或微血管血栓形成、病理妊娠等临床表现为特征的自身免疫性、炎症性疾病。目前研究认为，APS的发病是由aPL(抗体途径)与天然免疫成分(非抗体途径)共同参与并相互作用所致，多种免疫细胞、凝血系统、补体系统和细胞因子等均参与其中。除了特征性的血栓形成和病理妊娠，APS患者还常伴有未被以往诊断标准纳入的所谓“标准外”临床表现如血小板减少、心脏瓣膜病变、认知功能障碍、网状青斑或其他自身免疫或炎症并发症。随着对APS发病机制和临床特征的深入认识和越来越多的临床实践，旧的分类诊断标准已经不能满足当前的临床和研究需要，因此美国风湿病学会/欧洲抗风湿联盟于2023年共同发布了最新版本的APS分类标准。根据现有的指南及诊疗规范，抗凝和抗血小板治疗是该病治疗的基石，但临床上常面临许多未被满足的治疗需求，近年来APS发病机制的研究进展揭示出了许多新的治疗靶点，为部分难治性患者提供了更多的治疗选择。本文综述了APS的诊疗研究现状，以提高临床医生及相关领域研究者对本病的认识水平，帮助临床医生更好地管理APS患者。Abstract: Antiphospholipid syndrome (APS) is an autoimmune and inflammatory disease that is characterized by the persistent presence of high titers of antiphospholipid antibodies (aPL) in serum, recurrent arteriovenous or microvascular thrombosis, and pregnancy morbidity. It is currently believed that the aetiology of APS is based on the interaction between aPL (antibody-driven) and the innate immune system (non-antibody-driven). A variety of immune cells, the coagulation system, the complement system and cytokines are all involved in the pathogenetic process of APS. In addition to the characteristic manifestations of thrombosis and pregnancy morbidity, patients with APS frequently present with so-called "extra-criteria" clinical manifestations that have not been included in previous classification criteria. These may include thrombocytopenia, cardiac valve involvement, cognitive dysfunction, livedo reticularis, or other autoimmune/inflammatory complications. As our understanding of the pathogenesis and clinical characteristics of APS has deepened, and as our clinical practice has broadened, it has become increasingly clear that the previous classification criteria are unable to meet the current clinical and research needs. Accordingly, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have jointly published the latest iteration of the APS classification criteria, dated 20 August 2023. In accordance with the prevailing management recommendations, anticoagulation and antiplatelet therapy represent the fundamental cornerstones of APS treatment. However, there invariably remain numerous unmet clinical needs. The research progress in the pathogenesis of APS has revealed numerous new potential therapeutic targets in recent years, which may provide more treatment options for some refractory patients. The objective of this article is to provide a comprehensive review of the current status of research into the diagnosis and treatment of APS. The objective is to enhance the understanding of this disease among clinicians and researchers in related fields, thereby facilitating more effective management of APS patients by clinicians.
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Key words:
- Antiphospholipid syndrome /
- Antiphospholipid antibody /
- Diagnosis /
- Treatment
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表 1 2023 ACR/EULAR APS分类诊断标准[7]
Table 1. 2023 ACR/EULAR APS classification criteria
入选标准： 至少满足一项临床标准和一项实验室标准(aPL阳性与临床表现之间相差不超过3年) 
如果不符合，不要试图分类诊断为APS；如果符合，则查看附加条件 
附加条件： 如果某项临床标准可被APS以外的疾病所解释，则该项不计算权重； 每个诊断领域中仅将所符合的最高权重的标准纳入总分计算。 临床领域及标准(D1-D6) 权重 临床领域及标准(D1-D6) 权重 D1. 大血管[静脉血栓栓塞(VTE)] D2. 大血管[动脉血栓形成(AT)] VTE伴高危VTE特征 1 AT伴高危CVD特征 2 VTE不伴高危VTE特征 3 AT不伴高危CVD特征 4 D3. 微血管 D4.病理性妊娠 怀疑(≥以下1项) 2 ≥3次胚胎前(孕10周以内)和/或早期胎儿死亡(孕10周0天至15周6天) 1 葡萄状青斑(查体) 无重度先兆子痫或重度胎盘功能不全的胎儿死亡(孕16周0天至33周6天) 1 青斑样血管病变(查体) 有/无胎儿死亡的重度先兆子痫或重度胎盘功能不全(孕34周0天以前) 3 急性或慢性aPL肾病(查体或实验室检查) 有/无胎儿死亡的重度先兆子痫和重度胎盘功能不全(孕34周0天以前) 4 肺出血(症状和影像学检查) 确定(≥以下1项) 5 青斑样血管病变(病理) 急性或慢性aPL肾病(病理) 肺出血(支气管肺泡灌洗或病理) 心肌病变(影像学或病理) 肾上腺出血(影像学或病理) D5. 瓣膜病变 D6. 血液系统 增厚 2 血小板减少(20~130×109/L) 2 赘生物 4 实验室领域(D7-D8) 权重 实验室领域(D7-D8) 权重 D7.基于凝血功能测定的aPL(狼疮抗凝物LAC) D8. aPL固相检测[ELISA测定aCL ELISA和/或aβ2GPⅠ (持续阳性a)] LAC单次检测阳性 1 IgM型aCL和/或aβ2GPⅠ中高度阳性 1 LAC持续性阳性* 5 IgG型aCL和/或aβ2GPⅠ中度阳性 4 IgG型aCL或aβ2GPⅠ高度阳性 5 IgG型aCL和aβ2GPⅠ高度阳性 7 
诊断标准 如果临床领域积分≥3分且实验室领域积分≥3分，则可归类于用于研究目的的APS。 注：APS分类诊断流程，必须满足入选标准方能根据各诊断领域的表现计算权重，有关高危VTE特征、高危CVD特征及各临床标准及实验室标准的详细定义见参考文献[7]。aPL检测方法需参照国际血栓与止血学会科学与标准化委员会的指南[24]。在血栓发生后不久或合并感染等急性炎症反应时期、妊娠期间、应用抗凝药物治疗期间检测LAC容易出现假阳性或假阴性，此类结果应谨慎解读，必要时调整检测策略[25-27]。a持续阳性是指检测间隔12周以上，至少连续2次阳性。 
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