Modulation of Trophoblast Angiogenic Factor Secretion by Antiphospholipid Antibodies is Not Reversed by Heparin

Abstract

PROBLEM Women with antiphospholipid antibodies (aPL) are at risk of miscarriage and pre-eclampsia, obstetrical disorders associated with reduced trophoblast invasion and spiral artery transformation. aPL target the placenta by binding beta(2) -glycoprotein I (β(2) GPI) on the trophoblast. In this study, we determined whether aPL alter the trophoblast secretion of angiogenic factors and evaluated the effect of low molecular weight heparin (LMWH) on this response. METHOD OF STUDY First-trimester trophoblast was treated with anti-β(2) GPI antibodies with or without LMWH. Angiogenic factor secretion was measured by enzyme-linked immunosorbent assay. RESULTS Trophoblast cells produced more vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), and soluble endoglin following exposure to anti-β(2) GPI Abs, and this occurred in both a MyD88-dependent and MyD88-independent manner. LMWH was unable to reverse the effects of the anti-β(2) GPI Abs on trophoblast VEGF secretion, but enhanced PlGF. Strikingly, LMWH upregulated soluble fms-like tyrosine kinase receptor-1 (sFlt-1) secretion independently of aPL. CONCLUSION This study demonstrates that aPL perturb the secretion of trophoblast angiogenic factors. LMWH does not reverse this effect but exacerbates sFlt-1 secretion, a potent anti-angiogenic factor. These findings may help to explain why women with antiphospholipid syndrome, who are treated with heparin to prevent early pregnancy loss, remain at increased risk of developing late obstetrical complications, such as pre-eclampsia.

Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study

“…The results of studies in mouse models suggest that obstetrical APS may be a nonthrombogenic syndrome, [34][35][36][37] but mechanisms of pregnancy loss involving thrombosis have been described recently [36][37][38] and this agrees with our observational results, at least in a subset of patients. LDA-mediated primary prophylaxis was well tolerated in our purely obstetric APS patients, which might have limited the numbers of subsequent thrombotic events.…”

Is heparin a placental anticoagulant in high-risk pregnancies?

“…71 sFlt1 is locally retained on the surface of placental villi, where it can be released via the heparanase action of LMWH. 70,72 Interestingly, LMWH induces transcription and translation of sFlt1 in floating first-trimester villous explants, further contributing to the LMWH-induced secretion in a manner that antagonizes VEGF receptor phosphorylation. 73 This disparity in clinical and in vitro observations suggests more complex interactions between the placenta and LMWH to mediate a preventive role of heparin in women at high risk of severe PE.…”

“…We demonstrated that both unfractionated heparin (UFH) and LMWH, in comparable doses used clinically in pregnancy, are capable of reversing the natural antiangiogenic tendency of first-trimester placental villi. 97 These heparins exert this proangiogenic effect despite increasing secretion of sFLT1 70,72 that at least in vitro impairs VEGF receptor signaling. 75 This paradox between in vitro and in vivo data in the context of sFLT1 may be because of the restoration additional functions of the outer syncytiotrophoblast that override the endothelial-specific effects of excess sFLT1.…”

Heparin Elevates Circulating Soluble fms-Like Tyrosine Kinase-1 Immunoreactivity in Pregnant Women Receiving Anticoagulation Therapy

“…Our in vitro data confirmed the in vivo findings and are consistent with recently published observations. 33 In search for a mechanistic explanation, we explored whether heparin alters placental transcription of sFlt-1. We demonstrated that, in vitro, neither UFH nor LMWH increased expression of sFlt-1 mRNA.…”