抗磷脂综合征病态妊娠患者中抗磷脂抗体谱的临床意义

Clinical significance of antiphospholipid antibodies in pregnant women with antiphospholipid syndrome

目的探讨检测24种抗磷脂抗体的抗体谱对诊断和鉴别诊断抗磷脂综合征(antiphospholipid syndrome,APS)病态妊娠的临床意义。方法采用病例对照研究。收集2013年1月至2015年9月北京协和医院风湿免疫科确诊为APS并有不良孕史的28例患者,和2014年1月至2015年2月同院确诊的除外APS的有不良孕史的患者34例和同期健康体检者39名。用酶联免疫吸附试验(enzyme-linked immununosorbent assay,ELISA)检测待检者抗心磷脂抗体(anticardiolipin,CL)、抗β2糖蛋白1抗体(anti-β2-glycoprotein 1,aβ2GP1)、抗膜联蛋白A5抗体(anti-annexin-A5 antibodies,a AXN5)、抗凝血酶原抗体(anti-prothrombin antibodies,a PT)、抗磷脂酰丝氨酸抗体(anti-phosphatidylserine antibodies,a PS)、抗磷脂酰乙醇胺抗体(anti-phosphatidylethanolamine antibodies,a PE)、抗磷脂酰肌醇抗体(anti-phosphatidylinositol antibodies,a PI)、抗磷脂酰胆碱抗体(anti-phosphatidylcholine antibodies,a PC)、抗鞘磷脂抗体(anti-sphingomyelin antibodies,a SPH)和抗凝血酶原/丝氨酸复合物抗体(anti-phosphatidylserine-prothrombin complex antibodies,a PT/PS)水平,并用改良的稀释蝰蛇毒时间法(Dilute Russell′s viper venom time,d RVVT)检测狼疮抗凝物(lupus anticoagulant,LA)水平。然后,用卡方检验(理论频数T<5时,采用Fisher精确检验)比较APS病态妊娠组、非APS病态妊娠组及健康对照组中24种抗磷脂抗体的阳性率;同时进行不同组间抗体浓度比较分析,并以APS临床诊断为金标准,用四格表统计抗磷脂抗体诊断APS的效能。结果 APS病态妊娠组的a CL-Ig M、aβ2GP1-Ig G、aβ2GP1-Ig A、a PT/PS-Ig G、a PT/PS-Ig M、a PS-Ig G、a PI-Ig G及LA的阳性率显著高于非APS病态妊娠组(P值分别为<0.0001、0.015、0.037、<0.0001、0.030、0.018、<0.0001和<0.0001)。LA对鉴别诊断APS病态妊娠与非APS病态妊娠的敏感度最高(75%),其次为Ig G a PT/PS(57.1%)和Ig M a CL(50%)。除a PT/PS-Ig M鉴别诊断APS病态妊娠与非APS病态妊娠的特异度较低(82.4%)外,其他抗磷脂抗体的特异度均高于97.1%。虽然所有检测的抗磷脂抗体阳性率在APS病态妊娠伴血栓组与APS病态妊娠不伴血栓组的差异均无统计学意义(P均>0.05),但a CL-Ig M为[中位数(四分位距)19.3(43.2)MPL/ml比8.3(17.7)MPL/ml]、a PT/PS-Ig G[71.4(78.2)U/ml比16.7(31.5)U/ml]、a PT/PS-Ig M[95.0(127.7)U/ml比15.3(15.1)U/ml]、a PT-Ig G[9.1(18.1)U/ml比5.0(4.1)U/ml]和LA[1.70(0.29)比1.21(0.41)]的水平在APS病态妊娠伴血栓组均显著高于APS病态妊娠不伴血栓组(P值分别为0.006、0.041、0.019、0.041和0.006)。且APS病态妊娠伴血栓组的抗磷脂抗体阳性的种类多于APS病态妊娠不伴血栓组,两组中抗磷脂抗体阳性种类超过3种的阳性率分别为86.67%比38.46%,3种以下抗磷脂抗体的阳性率分别为13.33%比61.54%,且差异有统计学意义差异(P=0.016)。结论 LA、a CL-Ig M和a PI-Ig G指标对诊断APS病态妊娠具有重要价值,APS病态妊娠伴血栓患者与APS病态妊娠不伴血栓患者中的抗磷脂抗体谱的临床分布具有不同特征,前者比后者的抗磷脂抗体阳性种类更多,且浓度水平更高。

Objective To evaluate the clinical significance of24antiphospholipid antibodies in pregnant women with antiphospholipid syndrome(APS).Methods Case-control study was carried out:28APS pregnant women,34non-APS pregnant women and39health controls were enrolled.Anti-cardiolipin(aCL),anti-β2-glycoprotein1(aβ2GP1),anti-annexin-A5anti-prothrombin antibodies(aPT),anti-phosphatidylserine antibodies aPS,anti-phosphatidyl ethanolamine antibodies(aPE),anti-phosphatidyl inositol antibodies(aPI),anti-phosphatidyl choline antibodies(aPC),anti-sphingomyelin antibodies(aSPH),antibodies(aAXN5),and anti-phosphatidylserine-prothrombin complex antibodies(aPT/PS)were detected by enzyme-linked immununosorbent assay(ELISA).Lupus anticoagulant(LA)was tested by Dilute Russell′s viper venom time(dRVVT).The prevalence of antiphospholipid antibodies in the three groups were compared(Chi-Square test or Fisher′s exact test).The antibody levels in different groups were compared using nonparametric Mann-Whitney U tests.The diagnostic efficacy of antiphospholipid antibodies was analyzed by cross table using clinical diagnosis of APS as gold standard.Results The prevalence of aCL-IgM,aβ2GP1-IgG,aβ2GP1-IgA,aPT/PS-IgG,aPT/PS-IgM,aPS-IgG,aPI-IgG,and LA were higher in APS pregnant women than those in non-APS pregnant women(P<0.0001,P<0.015,P<0.037,P<0.0001,P<0.030,P<0.018,P<0.0001,and P<0.001,respectively).For differentiating APS pregnant woman from non-APS pregnant woman,LA displayed the highest sensitivity(75%),followed by IgG aPT/PS(57.1%)and IgM aCL(50%).All the aPLs,except aPT/PS-IgM demonstrated a high specificity(>97.1%)in differentiating APS pregnant women from non-APS in pregnant women.Although there was no significantly differenct prevalence of aPLs between patients with thrombosis and without thrombosis,the median levels of aCL-IgM[19.3(43.2)MPL/ml vs8.3(17.7)MPL/ml],aPT/PS-IgG[71.4(78.2)U/ml vs16.7(31.5)U/ml],aPT/PS-IgM[95.0(127.7)U/ml vs15.3(15.1)U/ml],aPT-IgG[9.1(18.1)U/ml vs5.0(4.1)U/ml]and LA[1.70(0.29)vs1.21(0.41)]were significantly higher in patients with thrombosis(P=0.006,P=0.041,P=0.019,P=0.041,and P=0.006,respectively).Furthermore,the prevalence of multiple aPLs was significantly higher in APS pregnant women with thrombosis than those without thrombosis(86.67%vs.38.46%,P=0.016).Conclusions LA,aCL-IgM and aPI-IgG play important roles in diagnosising APS in pregnant women.More antiphospholipid antibodies could be found in patients with thrombosis than those without thrombosis,and the levels of these antibodies are higher in the patients with thrombosis than in the without thrombosis.