Aspirin and Heparin Effect on Basal and Antiphospholipid Antibody Modulation of Trophoblast Function

Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.
Obstetrics and Gynecology (Impact Factor: 5.18). 11/2011; 118(5):1021-8. DOI: 10.1097/AOG.0b013e31823234ad
Source: PubMed


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.

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    • "In the mouse model of aPL-induced pregnancy failure, pravastatin was administered prior to aPL exposure, whereas in our in vitro model, trophoblast cells were treated simultaneously with aPL and pravastatin. Furthermore, the mouse model explains the pathogenesis of APS-associated pregnancy failure, and the success of pravastatin in preventing this is based on its ability to prevent aPL-induced neutrophil tissue factor and proteinase-activated receptor-2 expression (Redecha et al., 2008; Girardi, 2009), rather than the direct effects of aPL on the trophoblast, as in our model (Mulla et al., 2009Mulla et al., , 2010 Carroll et al., 2011; Han et al., 2011 ). Thus, we can conclude that in our study, pravastatin fails to prevent the direct effects of aPL on the placenta. "
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