Effect of Low Molecular Weight Heparins (LMWHs) on antiphospholipid Antibodies (aPL) – Mediated Inhibition of Endometrial Angiogenesis

D’Ippolito, Silvia; Marana, Riccardo; Nicuolo, Fiorella Di; Castellani, Roberta; Veglia, Manuela; Stinson, J.; Scambia, Giovanni; Simone, Nicoletta Di

doi:10.1371/journal.pone.0029660

Cited by 41 publications

(38 citation statements)

References 43 publications

(71 reference statements)

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“…Furthermore, in vitro coexposure of serum of high-risk women with LMWH restored endothelial tube formation, consistent with previous reports from our group and others. 20,21 These results illustrate a potential mechanism whereby LMWH could exert a beneficial effect on maternal endothelial function, as previously demonstrated in patients with coronary artery disease. 13,14 These observations are consistent with a previous trial demonstrating that LMWH therapy throughout pregnancy prevented the rise of systolic and diastolic blood pressure and resistance of uterine arteries in pregnant women at high risk of preeclampsia, in addition to reducing the recurrence of preeclampsia.…”

Section: Discussionsupporting

confidence: 74%

Low Molecular Weight Heparin Improves Endothelial Function in Pregnant Women at High Risk of Preeclampsia

et al. 2017

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Preeclampsia is a hypertensive disorder of pregnancy characterized by new-onset hypertension with evidence of organ injury, affecting 2% to 8% of all pregnancies worldwide. 1 The majority of women with preeclampsia present clinically near term with favorable maternal and infant outcomes; however, a subset of women develop severe disease characterized by the need for preterm delivery typically before 34 weeks of gestation because of end-organ injury, severe hypertension, or intrauterine growth restriction.2 Women with severe preeclampsia demonstrate significant cardiovascular impairment during pregnancy and the immediate postpartum period and a higher risk of cardiovascular disease later in life.3-7 Given the significant shortand long-term maternal cardiovascular effects of preeclampsia, elucidating its pathogenesis has been of much interest in recent years. However, as yet, there is no agreement concerning the most effective pharmacological therapy for the prevention of preeclampsia in screen-positive women beyond aspirin, with clinical symptoms typically only resolving on delivery. Low molecular weight heparin (LMWH) has been evaluated for the prevention of various placenta-mediated pregnancy complications, including severe preeclampsia and recurrent miscarriage. Multiple trials and systematic reviews have concluded that LMWH reduces the incidence of recurrent severe preeclampsia in high-risk women, as well as perinatal mortality, preterm birth, and infant birth weight <10th percentile for gestational age, whereas other studies have found no treatment effect.9,10 Because the majority of previous trials have consisted of clinical end points, the mechanism of action of LMWH for the possible prevention of severe preeclampsia is currently unknown. Evidence suggests that observed beneficial effects do not result from heparin's anticoagulant actions within the placenta.11,12 An alternative hypothesis is that LMWH exerts vascular actions in the maternal compartment that reverse the systemic vascular dysfunction characteristic of preeclampsia. Previous trials in patients with coronary artery disease have determined that LMWH demonstrates beneficial endothelial effects, possibly through increased bioavailability of NO. 13,14The objective of the current study was to investigate the endothelial effects of LMWH in pregnant women at high risk of preeclampsia. We first compared baseline cardiovascular Abstract-Low molecular weight heparin (LMWH) has been investigated for the prevention of severe preeclampsia, although the mechanisms of action are unknown. The objective of this study was to investigate the cardiovascular effects of LMWH in pregnant women at high risk of preeclampsia. Pregnant women at high risk of preeclampsia (n=25) and low-risk pregnant controls (n=20) at 22 to 26 weeks' gestation underwent baseline cardiovascular assessments. Highrisk women were then randomized to LMWH or saline placebo (30 mg IV bolus and 1 mg/kg subcutaneous dose). Cardiovascular function was assessed 1 and 3 hours post randomization. T...

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Section: Discussionsupporting

confidence: 74%

Low Molecular Weight Heparin Improves Endothelial Function in Pregnant Women at High Risk of Preeclampsia

et al. 2017

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“…In a mouse-in-vitro-system, HB-EGF has been demonstrated to promote [26]. It also increases the production of both prolactin and IGF-1, inhibits the production of IGFBP-1 that play a role in endometrial receptivity [22] [27].…”

Section: Khalife G Ghazeeri Open Journal Of Obstetrics and Gynecmentioning

confidence: 99%

Recurrent Implantation Failure and Low Molecular Weight Heparin

Khalife¹,

Ghazeeri²

2018

OJOG

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Implantation of the embryo into the endometrium is the first step in the establishment of pregnancy. This process is complex, and depends on many factors. Recurrent implantation failure is a source of distress to patients and specialists. It is defined as failure to achieve a viable pregnancy, following ">3 embryo transfers with high quality embryos or the transfer of ≥ 10 embryos in multiple transfers". Thrombophilic conditions that contribute to recurrent implantation failure are the main concern in this review. The mechanism of implantation failure is believed to be due to decreased blood flow to the endometrium and placenta which can hinder normal endometrial receptivity leading to miscarriage. Defects in early placentation resulting in pregnancy failure, have focused attention on the therapeutic potential of low molecular weight heparin in the implantation process. Heparin has a role at all stages of implantation to improve pregnancy outcomes. There are controversies in literature regarding the association between thrombophilia and recurrent implantation failure and available literature regarding this issue is very heterogeneous. Various investigators, have shown that women with RIF are more likely to have a thrombophilia disorder, yet a clear cause cannot be acknowledged from these studies. Heparin treatment has been evaluated in several studies, showing conflicting evidence. However, several studies have pointed out that it may play a role in a subset of patients who presents a thrombophilia mutation, thus the group of patients that might benefit is needed to be identified. This review is dedicated to evaluate the published literature about the role of low molecular weight heparin in case of recurrent implantation failure with or without the presence of thrombophilia.

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“…Laboratory findings on endometrial cells were different from those found on other cell types. Anti β 2GP1 antibodies purified from APS patients were found to inhibit angiogenesis, VEGF secretion, and NF κ B activation in a dose-dependent way in endometrial cells [13, 14]. This implicates that pathological mechanisms of aPL can differ between various cell types which could explain variations in treatment efficiency.…”

Section: Pathogenesis Of Apl During Pregnancymentioning

confidence: 99%

“…(2) Mechanisms on endometrial cells [13, 14]Angiogenesis inhibitionDecrease in VEGF secretionNF κ B activation inhibition. …”

Section: Pathogenesis Of Apl During Pregnancymentioning

confidence: 99%

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Obstetrical Antiphospholipid Syndrome: From the Pathogenesis to the Clinical and Therapeutic Implications

Marchetti

Cohen

Moerloose

2013

Clinical and Developmental Immunology

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Antiphospholipid syndrome (APS) is an acquired thrombophilia with clinical manifestations associated with the presence of antiphospholipid antibodies (aPL) in patient plasma. Obstetrical APS is a complex entity that may affect both mother and fetus throughout the entire pregnancy with high morbidity. Clinical complications are as various as recurrent fetal losses, stillbirth, intrauterine growth restriction (IUGR), and preeclampsia. Pathogenesis of aPL targets trophoblastic cells directly, mainly via proapoptotic, proinflammatory mechanisms, and uncontrolled immunomodulatory responses. Actual first-line treatment is limited to low-dose aspirin (LDA) and low-molecular weight heparin (LMWH) and still failed in 30% of the cases. APS pregnancies should be a major field in obstetrical research, and new therapeutics are still in progress.

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Effect of Low Molecular Weight Heparins (LMWHs) on antiphospholipid Antibodies (aPL) – Mediated Inhibition of Endometrial Angiogenesis

Cited by 41 publications

References 43 publications

Low Molecular Weight Heparin Improves Endothelial Function in Pregnant Women at High Risk of Preeclampsia

Low Molecular Weight Heparin Improves Endothelial Function in Pregnant Women at High Risk of Preeclampsia

Recurrent Implantation Failure and Low Molecular Weight Heparin

Obstetrical Antiphospholipid Syndrome: From the Pathogenesis to the Clinical and Therapeutic Implications

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