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中华临床实验室管理电子杂志

中华临床实验室管理电子杂志 ›› 2017, Vol. 05 ›› Issue (04) : 226 -231. doi: 10.3877/cma.j.issn,2095-5820.2017.04.007

所属专题： 文献；

实验研究

抗磷脂综合征病态妊娠患者中抗磷脂抗体谱的临床意义
张蜀澜1, 吴子燕1, 张文1, 赵久良1, 曾小峰1, 张奉春1, 李永哲1,†()   
  1. 1. 100730　中国医学科学院北京协和医学院北京协和医院风湿免疫科　风湿免疫病学教育部重点实验室
  • 收稿日期:2017-09-12 出版日期:2017-11-28
  • 通信作者: 李永哲
  • 基金资助:
    国家自然科学基金资助项目(81771661)

Clinical significance of antiphospholipid antibodies in pregnant women with antiphospholipid syndrome

Shulan Zhang1, Ziyan Wu1, Wen Zhang1, Jiuliang Zhao1, Xiaofeng Zeng1, Fengchun Zhang1, Yongzhe Li1,†()   

  1. 1. Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100730, China
  • Received:2017-09-12 Published:2017-11-28
  • Corresponding author: Yongzhe Li
  • About author:
    Corresponding author: Li Yongzhe, Email:
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引用本文：

张蜀澜, 吴子燕, 张文, 赵久良, 曾小峰, 张奉春, 李永哲. 抗磷脂综合征病态妊娠患者中抗磷脂抗体谱的临床意义[J]. 中华临床实验室管理电子杂志, 2017, 05(04): 226-231.

Shulan Zhang, Ziyan Wu, Wen Zhang, Jiuliang Zhao, Xiaofeng Zeng, Fengchun Zhang, Yongzhe Li. Clinical significance of antiphospholipid antibodies in pregnant women with antiphospholipid syndrome[J]. Chinese Journal of Clinical Laboratory Management(Electronic Edition), 2017, 05(04): 226-231.

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，aAXN5)、抗凝血酶原抗体(anti-prothrombin antibodies，aPT)、抗磷脂酰丝氨酸抗体(anti-phosphatidylserine antibodies，aPS)、抗磷脂酰乙醇胺抗体(anti-phosphatidylethanolamine antibodies，aPE)、抗磷脂酰肌醇抗体(anti-phosphatidylinositol antibodies，aPI)、抗磷脂酰胆碱抗体(anti-phosphatidylcholine antibodies，aPC)、抗鞘磷脂抗体(anti-sphingomyelin antibodies，aSPH)和抗凝血酶原/丝氨酸复合物抗体(anti-phosphatidylserine-prothrombin complex antibodies，aPT/PS)水平，并用改良的稀释蝰蛇毒时间法(Dilute Russell′s viper venom time，dRVVT)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aCL-IgM、aβ2GP1-IgG、aβ2GP1-IgA、aPT/PS-IgG、aPT/PS-IgM、aPS-IgG、aPI-IgG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IgG aPT/PS(57.1%)和IgM aCL(50%)。除aPT/PS-IgM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aCL-IgM为[中位数(四分位距)19.3(43.2)MPL/ml比8.3(17.7)MPL/ml]、aPT/PS-IgG[71.4(78.2)U/ml比16.7(31.5) U/ml]、aPT/PS-IgM[95.0(127.7)U/ml比15.3(15.1)U/ml]、aPT-IgG[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、aCL-IgM和aPI-IgG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。

关键词: 抗磷脂综合征, 病态妊娠, 抗磷脂抗体
Objective

To evaluate the clinical significance of 24 antiphospholipid antibodies in pregnant women with antiphospholipid syndrome(APS).

Methods

Case-control study was carried out: 28 APS pregnant women, 34 non-APS pregnant women and 39 health controls were enrolled. Anti-cardiolipin (aCL), anti-β2-glycoprotein 1(aβ2GP1), anti-annexin-A5 anti-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 vs 8.3(17.7) MPL/ml], aPT/PS-IgG [71.4(78.2) U/ml vs 16.7(31.5) U/ml], aPT/PS-IgM [95.0(127.7) U/ml vs 15.3(15.1) U/ml], aPT-IgG [9.1(18.1) U/ml vs 5.0(4.1) U/ml] and LA [1.70(0.29) vs 1.21(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.

Key words: Antiphospho1ipid syndrome, Pregnancy complications, Antiphospholipid antibodies
表1 各组间aPLs阳性率比较[例(%)]
抗磷脂抗体 APS病态妊娠组(1)(n=28) 非APS病态妊娠组(2)(n=34) 健康对照组(3)(n=39) (1)比(2) (1)比(3)
χ2值 P值 χ2值 P值
aCL IgG 4(14.3) 1(2.9) 0(0.0) 2.665 0.166 5.925 0.027
? IgM 14(50.0) 0(0.0) 0(0.0) 21.958 <0.0001 24.651 <0.0001
? IgA 4(14.3) 1(2.9) 0(0.0) 2.665 0.166 5.925 0.027
aβ2GP1 IgG 5(17.9) 0(0.0) 1(2.6) 6.604 0.015 4.675 0.075
? IgM 4(14.3) 1(2.9) 1(2.6) 2.665 0.166 3.243 0.152
? IgA 4(14.3) 0(0.0) 0(0.0) 5.192 0.037 5.925 0.027
aPT/PS IgG 16(57.1) 0(0.0) 0(0.0) 26.186 <0.0001 29.227 <0.0001
? IgM 12(42.9) 6(17.6) 0(0.0) 4.736 0.030 20.361 <0.0001
aAXN5 IgG 3(10.7) 0(0.0) 0(0.0) 3.828 0.087 4.374 0.068
? IgM 3(10.7) 1(2.9) 0(0.0) 1.537 0.32 4.374 0.068
aPT IgG 5(17.9) 1(2.9) 1(2.6) 3.908 0.082 5.925 0.027
? IgM 0(0.0) 0(0.0) 1(2.6) N.A. N.A. 0.729 1.000
? IgA 0(0.0) 0(0.0) 1(2.6) N.A. N.A. 0.729 1.000
aPE IgG 2(7.1) 0(0.0) 0(0.0) 2.510 0.200 2.871 0.171
? IgM 1(3.6) 0(0.0) 0(0.0) 1.235 0.452 1.414 0.418
aPS IgG 7(25.0) 1(2.9) 0(0.0) 6.880 0.018 10.887 0.001
? IgM 3(10.7) 0(0.0) 0(0.0) 3.828 0.087 4.374 0.068
aSPH IgG 2(7.1) 0(0.0) 0(0.0) 2.510 0.200 2.871 0.171
? IgM 2(7.1) 0(0.0) 1(2.6) 2.510 0.200 0.799 0.567
aPI IgG 13(46.4) 1(2.9) 0(0.0) 16.611 <0.0001 22.466 <0.0001
? IgM 2(7.1) 0(0.0) 0(0.0) 2.510 0.200 2.871 0.171
aPC IgG 2(7.1) 0(0.0) 0(0.0) 2.510 0.200 2.871 0.171
? IgM 3(10.7) 0(0.0) 0(0.0) 3.828 0.087 4.374 0.068
LA ? 21(75.0) 1(2.9) 0(0.0) 34.827 <0.0001 42.603 <0.0001
表2 APS病态妊娠伴血栓组和APS病态妊娠不伴血栓组的抗磷脂抗体谱的阳性率比较[例(%)]
抗磷脂抗体 APS病态妊娠伴血栓组(n=15) APS病态妊娠不伴血栓组(n=13) χ2值 P值
aCL IgG 3(20.0) 1(7.7) 0.862 0.600
? IgM 10(66.7) 5(38.5) 1.688 0.194
? IgA 2(13.3) 2(15.4) 0.024 1.000
aβ2GP1 IgG 2(13.3) 3(23.1) 0.451 0.639
? IgM 3(20.0) 1(7.7) 0.862 0.600
? IgA 3(20.0) 1(7.7) 0.862 0.600
aPT/PS IgG 11(73.3) 7(53.8) 1.152 0.433
? IgM 9(60.0) 3(23.1) 3.877 0.067
aAXN5 IgG 2(13.3) 1(7.7) 0.232 1.000
? IgM 3(20.0) 0(0.0) 2.912 0.226
aPT IgG 4(26.7) 1(7.7) 1.709 0.333
? IgM 0(0.0) 0(0.0) N.A. N.A.
? IgA 0(0.0) 0(0.0) N.A. N.A.
aPE IgG 1(6.7) 1(7.7) 0.011 1.000
? IgM 1(6.7) 0(0.0) 0.899 1.000
aPS IgG 5(33.3) 2(15.4) 1.197 0.396
? IgM 3(20.0) 0(0.0) 2.912 0.226
aSPH IgG 1(6.7) 1(7.7) 0.011 1.000
? IgM 1(6.7) 1(7.7) 0.011 1.000
aPI IgG 8(53.3) 7(53.8) 0.001 0.978
? IgM 2(13.3) 0(0.0) 1.867 0.484
aPC IgG 1(6.7) 1(7.7) 0.011 1.000
? IgM 3(20.0) 0(0.0) 2.912 0.226
LA ? 14(93.3) 9(69.2) 2.758 0.153
表3 APS病态妊娠伴血栓组和APS病态妊娠不伴血栓组的抗磷脂抗体浓度比较[中位数(四分位距)]
抗磷脂抗体 APS病态妊娠伴血栓组(n=15) APS病态妊娠不伴血栓组(n=13) P值
aCL IgG(GPL/ml) 1.5(2.6) 1.1(5.0) 0.928
? IgM(MPL/ml) 19.3(43.2) 8.3(17.7) 0.006
? IgA(U/ml) 3.3(9.7) 1.5(4.0) 0.387
aβ2GP1 IgG(U/ml) 8.0(5.3) 4.3(11.4) 0.130
? IgM(U/ml) 7.0(8.6) 8.2(4.1) 0.683
? IgA(U/ml) 1.5(10.2) 0.1(3.3) 0.142
aPT/PS IgG(U/ml) 71.4(78.2) 16.7(31.5) 0.041
? IgM(U/ml) 95.0(127.7) 15.3(15.1) 0.019
aAXN5 IgG(U/ml) 6.8(12.3) 2.7(5.5) 0.052
? IgM(U/ml) 2.3(2.0) 1.7(2.9) 0.786
aPT IgG(U/ml) 9.1(18.1) 5.0(4.1) 0.041
? IgM(U/ml) 2.4(3.4) 3.2(3.5) 0.555
? IgA(U/ml) 6.0(5.8) 3.7(5.2) 0.339
aPE IgG(U/ml) 2.7(1.3) 1.7(2.3) 0.650
? IgM(U/ml) 2.2(3.0) 1.5(1.3) 0.683
aPS IgG(U/ml) 8.3(15.2) 2.7(8.3) 0.080
? IgM(U/ml) 2.6(3.7) 2.8(2.4) 0.928
aSPH IgG(U/ml) 5.1(3.3) 3.4(3.5) 0.200
? IgM(U/ml) 3.7(5.7) 3.6(3.3) 0.200
aPI IgG(U/ml) 19.6(39.6) 11.1(18.6) 0.108
? IgM(U/ml) 1.7(2.4) 1.5(2.0) 0.650
aPC IgG(U/ml) 3.2(3.2) 0.8(4.8) 0.118
? IgM(U/ml) 2.3(3.0) 2.3(2.2) 0.751
LA (比值) 1.70(0.29) 1.21(0.41) 0.006
图1 APS病态妊娠伴血栓组和APS病态妊娠不伴血栓组检测抗磷脂抗体阳性率种类比较
表4 抗磷脂抗体谱鉴别诊断APS病态妊娠与非APS病态妊娠的诊断效能
抗磷脂抗体 敏感度(%) 特异度(%) PPV(%) NPV(%) ＋LR -LR AC(%)
aCL IgG 14.3 97.1 80.0 57.9 4.86 0.88 59.7
? IgM 50.0 100.0 100.0 70.8 N.A. 0.50 77.4
? IgA 14.3 97.1 80.0 57.9 4.86 0.88 59.7
aβ2GP1 IgG 17.9 100.0 100.0 59.6 N.A. 0.82 62.9
? IgM 14.3 97.1 80.0 57.9 4.86 0.88 59.7
? IgA 14.3 100.0 100.0 58.6 N.A. 0.86 61.3
aPT/PS IgG 57.1 100.0 100.0 73.9 N.A. 0.43 80.6
? IgM 42.9 82.4 66.7 63.6 2.43 0.69 64.5
aAXN5 IgG 10.7 100.0 100.0 57.6 N.A. 0.89 59.7
? IgM 10.7 97.1 75.0 56.9 3.64 0.92 58.1
aPT IgG 17.9 97.1 83.3 58.9 6.07 0.85 61.3
? IgM 0.0 100.0 N.A. 54.8 N.A. 1.00 54.8
? IgA 0.0 100.0 N.A. 54.8 N.A. 1.00 54.8
aPE IgG 7.1 100.0 100.0 56.7 N.A. 0.93 58.1
? IgM 3.6 100.0 100.0 55.7 N.A. 0.96 56.5
aPS IgG 25.0 97.1 87.5 61.1 8.50 0.77 64.5
? IgM 10.7 100.0 100.0 57.6 N.A. 0.89 59.7
aSPH IgG 7.1 100.0 100.0 56.7 N.A. 0.93 58.1
? IgM 7.1 100.0 100.0 56.7 N.A. 0.93 58.1
aPI IgG 46.4 97.1 92.9 68.8 15.79 0.55 74.2
? IgM 7.1 100.0 100.0 56.7 N.A. 0.93 58.1
aPC IgG 7.1 100.0 100.0 56.7 N.A. 0.93 58.1
? IgM 10.7 100.0 100.0 57.6 N.A. 0.89 59.7
LA ? 75.0 97.1 95.5 82.5 25.50 0.26 87.1
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