Aspirin and heparin effect on basal and antiphospholipid antibody modulation of trophoblast function.
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 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.


RESULTS
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.


CONCLUSIONS
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.
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.
Christina S
CS
Han
Melissa J
MJ
Mulla
Jan J
JJ
Brosens
Larry W
LW
Chamley
Michael J
MJ
Paidas
Charles J
CJ
Lockwood
Vikki M
VM
Abrahams
D042501:Angiogenic Proteins / Q000378:metabolism; D017152:Antibodies, Antiphospholipid / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000188:drug therapy* / Q000276:immunology; D001241:Aspirin / Q000009:adverse effects*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D006495:Heparin, Low-Molecular-Weight / Q000009:adverse effects*; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy* / Q000276:immunology; D011261:Pregnancy Trimester, First / Q000187:drug effects; D014327:Trophoblasts / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D042501:Angiogenic Proteins; D017152:Antibodies, Antiphospholipid; D016207:Cytokines; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D001241:Aspirin