Is heparin a placental anticoagulant in high-risk pregnancies?

Abstract

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...

Risk factors for pregnancy-associated venous thromboembolism: a review

“…Two clinical phases have been described: a "placental" phase and a "maternal" phase. During the placental phase, which begins in early pregnancy at the feto-maternal interface, extravillous cytotrophoblast invasion is attenuated, and maternal spiral arteries are abnormally narrowed [33]. Consequently, uteroplacental insufficiency occurs, which results in foetal growth restriction [33].…”

“…During the placental phase, which begins in early pregnancy at the feto-maternal interface, extravillous cytotrophoblast invasion is attenuated, and maternal spiral arteries are abnormally narrowed [33]. Consequently, uteroplacental insufficiency occurs, which results in foetal growth restriction [33]. The maternal phase of preeclampsia occurs later and is characterised by maternal systemic inflammation and a procoagulant state due to excessive generation of activated coagulation proteases and platelet activation [41] and the secretion into maternal blood of procoagulant, TF-expressing syncytiotrophoblast microvesicles [21].…”

Heparin rescues factor V Leiden–associated placental failure independent of anticoagulation in a murine high-risk pregnancy model

“…Other candidate mechanisms include inhibition of p-selectin-mediated platelet tethering to trophoblast cells or to immune cells 38,39 and possible direct actions of LMWH on trophoblast cells. 17,40,41 The failure to suppress placental pathology with lepirudin, fondaparinux, or C921-78, despite demonstrated efficacy of anticoagulation, was puzzling. Because Par4 can also be activated by agonists other than thrombin, 29,30 we asked whether the genetic absence of Par3, a second thrombin receptor on mouse platelets, ameliorates fetal loss.…”

“…15,16 In the last few years, new nonanticoagulant roles of LMWH have emerged, some of which are directly related to trophoblast function. 17 Thus, any beneficial effects of LMWH treatment may not necessarily reflect a causal thrombotic link between thrombophilia mutations and pregnancy loss.…”

Heparin – not only thinning the blood

“…5,6 We were also able to present first measurements of in vivo-generated free AP-FXIII circulating in plasma of patients with an acute thrombotic event. 7 The characterization of the processes on the molecular level has implications for the better understanding of these processes and also for development of new therapeutic strategies. In addition to that, there may be further implications.…”