From the Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut; Warwick Medical School, Clinical Sciences Research Institute, Coventry, United Kingdom; and the Department of Obstetrics and Gynecology, University of Auckland, Auckland, New Zealand.
Obstet Gynecol. 2011 Nov;118(5):1021-1028. doi: 10.1097/AOG.0b013e31823234ad.
Low molecular weight (LMW) heparin, with or without aspirin (acetylsalicylic acid [ASA]), is used to prevent complications in antiphospholipid syndrome in pregnancy. Our objective was to elucidate the actions of low-dose LMW heparin and ASA on basal and antiphospholipid antibody-induced modulation of trophoblast function.
The human first-trimester trophoblast cell line (HTR-8) was treated with or without antiphospholipid antibody in the presence of no medication, low-dose LMW heparin, low-dose ASA, or combination therapy. Interleukin (IL)-6, IL-8, IL-1β, growth-regulated oncogene-α, vascular endothelial growth factor (VEGF), placental growth factor, soluble FMS-like tyrosine kinase-1, and soluble endoglin were measured in the supernatant. Cell migration was performed using a two-chamber assay.
Low molecular weight heparin improved basal trophoblast migration and induced potent increases in growth-regulated oncogene-α and soluble FMS-like tyrosine kinase-1. Aspirin did not affect basal function. Combined therapy promoted migration but did not reverse the LMW heparin-induced soluble FMS-like tyrosine kinase-1 effect. Antiphospholipid antibody increased IL-8, IL-1β, growth-regulated oncogene-alpha, VEGF, placental growth factor, and soluble endoglin secretion, while decreasing cell migration and IL-6 and soluble FMS-like tyrosine kinase-1 secretion. The antiphospholipid antibody-induced cytokine changes were best reversed with LMW heparin, with partial reversal of IL-8 and IL-1β upregulation. The antiphospholipid antibody-induced angiogenic changes were worsened by LMW heparin, with increased soluble FMS-like tyrosine kinase-1 secretion. The therapies did not reverse antiphospholipid antibody-induced decrease in migration.
In the absence of antiphospholipid antibodies, LMW heparin induces potentially detrimental proinflammatory and antiangiogenic profile in the trophoblast. In the presence of antiphospholipid antibodies, single-agent LMW heparin may be the optimal therapy to counter trophoblast inflammation, but also induces an antiangiogenic response. These findings may explain the inability of current therapies to consistently prevent adverse outcomes.
低分子量肝素（LMWH）联合或不联合阿司匹林（乙酰水杨酸[ASA]）用于预防妊娠期间抗磷脂综合征的并发症。我们的目的是阐明小剂量 LMWH 和 ASA 对基础和抗磷脂抗体诱导的滋养层功能调节的作用。
人早孕滋养层细胞系（HTR-8）在无药物、低剂量 LMWH、低剂量 ASA 或联合治疗的情况下，用或不用抗磷脂抗体处理。在培养上清液中测定白细胞介素（IL）-6、IL-8、IL-1β、生长调节致癌基因-α（GRO-α）、血管内皮生长因子（VEGF）、胎盘生长因子（PLGF）、可溶性 FMS 样酪氨酸激酶-1（sFlt-1）和可溶性内皮糖蛋白。采用双室法进行细胞迁移实验。
低分子量肝素改善了基础滋养层的迁移，并诱导了 GRO-α和 sFlt-1的强烈增加。阿司匹林不影响基础功能。联合治疗促进迁移，但不能逆转 LMWH 诱导的 sFlt-1效应。抗磷脂抗体增加了 IL-8、IL-1β、GRO-α、VEGF、PLGF 和可溶性内皮糖蛋白的分泌，同时降低了细胞迁移和 IL-6 和 sFlt-1的分泌。LMWH 可逆转抗磷脂抗体诱导的细胞因子变化，部分逆转 IL-8 和 IL-1β的上调。LMWH 加重了抗磷脂抗体诱导的血管生成变化，增加了 sFlt-1的分泌。这些治疗方法不能逆转抗磷脂抗体诱导的迁移减少。
在没有抗磷脂抗体的情况下，LMWH 在滋养层中诱导潜在的促炎和抗血管生成的特征。在存在抗磷脂抗体的情况下，单一 LMWH 治疗可能是对抗滋养层炎症的最佳治疗方法，但也会引起抗血管生成反应。这些发现可能解释了为什么目前的治疗方法不能始终预防不良结局。
