Heparin prevents programmed cell death in human trophoblast

Hills, Frank; Abrahams, Vikki M.; González-Timón, Belen; Francis, Julia M.; Cloke, Brianna; Hinkson, Larry; Rai, Raj; Mor, Gil; Regan, Lesley; Sullivan, Mark; Lam, Eric W.‐F.; Brosens, Jan J.

doi:10.1093/molehr/gal026

Cited by 112 publications

(72 citation statements)

References 51 publications

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“…94 Heparin also induces cytotrophoblast proliferation in trophoblastderived cell lines. 94,95 These observations are consistent with previous data, suggesting that heparin reverses the proapoptotic effects in villous explant syncytiotrophoblast induced by serum from antiphospholipid antibody syndrome, 96 presumably by promoting mitosis in the trophoblast progenitors within the explants that express FGFR2. We recently demonstrated a more direct and beneficial effect of heparin on placental villi in the context of preventing severe PE.…”

Section: Heparin For Prevention Of Obstetric Complications 4783 Bloodsupporting

confidence: 91%

Is heparin a placental anticoagulant in high-risk pregnancies?

Kingdom

Drewlo

2011

Blood

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Randomized control trials show beneficial effects of heparin in high-risk pregnancies to prevent preeclampsia and intrauterine growth restriction. However, the lack of placental pathology data in these trials challenges the assumption that heparin is a placental anticoagulant. Recent data show that placental infarction is probably associated with abnormalities in development of the placenta, characterized by poor maternal perfusion and an abnormal villous trophoblast compartment in contact with maternal blood, than with maternal thrombophilia. At-risk pregnancies may therefore be predicted by noninvasive prenatal testing of placental function in mid-pregnancy. Heparin has diverse cellular functions that include direct actions on the trophoblast. Dissecting the non-anticoagulant actions of heparin may indicate novel and safer therapeutic targets to prevent the major placental complications of pregnancy. IntroductionA small subset of reproductive-aged women require anticoagulation in the context of a mechanical heart valve 1 or to prevent recurrent venous thromboembolism as in women with antiphospholipid syndrome. 2 When planning pregnancy, they mostly convert from an oral anticoagulant such as Coumadin to subcutaneous injections of heparin to avoid the potential embryopathy induced by transplacental passage of Coumadin. 3 By doing so, they expose themselves to relatively minor side effects such as skin bruising and, because heparin promotes bone loss, to the rare possibility of vertebral bone compression fractures and neurologic complications. 4 In this context heparin is a success story for women whose predecessors were counseled to avoid attempts at motherhood. More than 35 years ago the concept of placental anticoagulation was proposed for women in subsequent pregnancies after recurrent placental infarction. 5 Since then we have witnessed an exponential increase in the prescription of heparin to pregnant women for a wide variety of indications, based on a common theme that superior placental function can be attained via its anticoagulant properties. The fashion has spread widely according to claims that heparin promotes successful implantation after in vitro fertilization, 6,7 prevents recurrent miscarriages, 8 promotes better outcomes in the perinatal period, 9 and, finally, may be used vaginally to induce labor in full-term pregnancies. 10 A common aspect of these studies is the use of safer low molecular weight heparins (LMWHs) in prophylactic regimes that have a low risk of serious side effects when used over a relatively short duration of time in pregnancy. However, the current cost per pregnancy to prescribe prophylactic LMWH is ϳ $3000, a significant burden to uninsured women in countries, such as Canada, with variable employer-based drug plans. Ongoing use of such drugs for these indications in pregnancy therefore deserves more rigorous evidence. Recent impressive but negative trials are making progress by limiting the scope of use in women with recurrent miscarriage. Heparins are complex macromol...

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Section: Heparin For Prevention Of Obstetric Complications 4783 Bloodsupporting

confidence: 91%

Is heparin a placental anticoagulant in high-risk pregnancies?

Kingdom

Drewlo

2011

Blood

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“…This direct effect acts as survival factor for trophoblast. It induces phosphorylation of EGF receptor exerting an anti-apoptotic signal transduction pathway in human trophoblast, promoting the early stages of embryo development [28].…”

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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“…Clinically, heparin and aspirin are used throughout pregnancy for the prevention of miscarriage (Derksen & de Groot, 2008). Heparin inhibits the TLR4-mediated aPLinduced pro-inflammatory responses in trophoblasts by activating the epidermal growth factor receptor survival pathway, and protects against apoptosis in response to a variety of noxious stimuli, including aPL (Bose et al, 2005;Hills et al, 2006).…”

Section: Trophoblastsmentioning

confidence: 99%

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

et al. 2013

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SummaryThe antiphospholipid syndrome (APS) is an autoimmune disease characterized by the clinical features of recurrent thrombosis in the venous or arterial circulation and fetal losses. Antiphospholipid antibodies (aPL), particularly against the phospholipid binding protein beta-2 glycoprotein I (b2GPI), play an important role in APS pathological mechanisms. aPL can activate intracellular signal transduction in a b2GPI-dependent manner to induce inflammatory responses, and promote hypercoagulable state and recurrent spontaneous abortion when b2GPI is associated with the cell surface receptor. In vivo and in vitro studies show that Annexin A2 (ANXA2) is the high affinity receptor that connects b2GPI to the target cells. However, ANXA2 is not a transmembrane protein and lacks an intracellular signal transduction pathway. Growing evidences suggest that the transmembrane protein toll-like receptor 4 (TLR4) might act as an 'adaptor' for intracellular signal transduction. This review focuses on the role of TLR4 and its signalling pathway in APS pathological mechanisms which will help us better understand the pathological processes of this syndrome.

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Heparin prevents programmed cell death in human trophoblast

Cited by 112 publications

References 51 publications

Is heparin a placental anticoagulant in high-risk pregnancies?

Is heparin a placental anticoagulant in high-risk pregnancies?

Recurrent Implantation Failure and Low Molecular Weight Heparin

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

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