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

Abstract

OBJECTIVE 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. METHODS The human first-trimester trophoblast cell line (HTR-8) was treated with or without antiphospholipid antibody in the presence of: 1) no medication, 2) low-dose LMW heparin, 3) low-dose ASA, or 4) combination therapy. Interleukin (IL)-6, IL-8, IL-1β, growth-regulated oncogene-alpha, vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble FMS-like tyrosine kinase-1 (sFlt-1) and soluble endoglin were measured in the supernatant. Cell migration was performed using a two-chamber assay. RESULTS LMW heparin improved basal trophoblast migration, and induced potent increases in growth-regulated oncogene-alpha and sFlt-1. ASA did not affect basal function. Combined therapy promoted migration, but did not reverse the LMW heparin-induced sFlt-1 effect. Antiphospholipid antibody increased IL-8, IL-1β, growth-regulated oncogene-alpha, VEGF, PlGF, and soluble endoglin secretion, while decreasing cell migration and IL-6 and sFlt-1 secretion. The antiphospholipid antibody-induced cytokine changes were best reversed with LMW heparin, with partial reversal of IL-8 and IL-1β up-regulation. The antiphospholipid antibody-induced angiogenic changes were worsened by LMW heparin, with increased sFlt-1 secretion. The therapies did not reverse antiphospholipid antibody-induced decrease in migration. CONCLUSION 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.

Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1

“…We also saw an effect of aspirin on sFlt1 in HTR-8/SV Neo, a transformed extravillous trophoblast cell line. Others, however, have reported that, in HTR-8/SV Neo cells, aspirin at 10 µg/ml had no effect on sFlt1 secretion by ELISA although no RNA or immunoblotting studies were done (41). In vivo a single oral immediate release or single IV dose of 50 mg of aspirin produced a maximum plasma concentration of 1.3 µg/ml and 6 µg/ml of aspirin respectively in normal human volunteers (42).…”

Emerging Treatment Models in Rheumatology: Antiphospholipid Syndrome and Pregnancy: Pathogenesis to Translation

“…Although aspirin does not alter the effects of aPL on trophoblast function in vitro , there may be some clinical benefits. 63,65 Stable analogs of aspirin-triggered lipoxins (ATL) that resolve inflammation may have potential clinical use. The ATL, 15-epi-lipoxin A4, in vitro reversed inhibitory effects of aPL and sera from APS patients on trophoblast migration and trophoblast-endothelial cell interactions.…”

Anticoagulation in Management of Antiphospholipid Antibody Syndrome in Pregnancy

“…22 APL may also interfere with trophoblast development, maturation, and invasion. 28 Under normal circumstances β 2 GP-I is thought to be a molecule that protects endothelial integrity. 29 …”