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Are heparins effective in some patients with recurrent pregnancy loss because they inhibit complement activation?

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  2. Are heparins effective in some patients with recurrent pregnancy loss because they inhibit complement activation?
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Although heparin is administered to prevent pregnancy loss in patients with recurrent miscarriage, its efficacy is uncertain, the association of thrombophilia with recurrent pregnancy loss is controversial and the pathogenesis of the disease is unclear. Indeed, the effectiveness of heparin in pregnant patients with thrombophilias, other than the antiphospholipid syndrome (APS), is debatable. Brenner et al. [1] recently compared the efficacy of two doses of low-molecular-weight heparin (LMWH) with the presumption that antithrombotic therapy is beneficial. The Commentaries by Lindqvist and by Gris underscore the strengths and weaknesses of that study, particularly from the epidemiologic standpoint [2,3]. Nevertheless, even if heparin protects some pregnancies, the basis for its effectiveness is unknown.

We have challenged the concept that prevention of thrombosis is the relevant activity of heparin in preventing pregnancy loss. Mediators of recurrent pregnancy loss are unknown even in patients with thrombophilias, and anticoagulation, in and of itself, may not be sufficient prophylaxis. For example, heparins enhance trophoblast invasiveness and differentiation and may thereby facilitate implantation and reduce fetal loss [4,5]. Alternatively, heparins may be acting as anti-inflammatory agents. When heparin is used to treat and prevent thrombotic disorders, the dose is adjusted to induce anticoagulation as determined by laboratory parameters. Yet, heparin administered in sub-anticoagulant doses improves pregnancy outcomes in some trials of thrombophilic patients (discussed in Refs [6,7]). Low doses of heparins, as well as chemically modified heparinoids lacking anticoagulant effects, inhibit inflammatory responses at the level of leukocyte adhesion and influx, and limit tissue injury [8,9]. Brenner et al. found no difference in pregnancy outcome in patients treated with 40 and 80 mg day−1 LMWH (the lower dose generally considered ‘prophylactic’ and sub-anticoagulant, the higher anticoagulant) emphasizing that LMWH may have critical activities beyond preventing thrombosis.

As early as 1929, heparin was shown to have ‘anti-complementary effects’ [10]. Several mechanisms by which heparin can inhibit complement activation at various points in the classical, alternative and terminal pathways have been identified [11–13]. That complement activation and deposition at the fetomaternal interface has emerged as a common pathway in the pathogenesis of recurrent miscarriage in experimental models [14] suggests that heparin may be efficacious in some patients with recurrent pregnancy loss due to its capacity to inhibit complement. In the APS, a prototypic hypercoagulable state defined by thrombosis and recurrent pregnancy loss in the presence of antiphospholipid (aPL) antibodies, heparin therapy at sub-anticoagulant doses has been shown to improve pregnancy outcomes [15,16].

Using a mouse model of APS induced by passive transfer of human aPL antibodies, we have shown that excessive complement activation at the maternal–fetal interface plays an essential and causative role in pregnancy loss. Inhibition of complement activation protects pregnancies from growth restriction or fetal death [17,18]. The mechanism of injury involves activation of both classical and alternative complement pathways, and mice deficient in complement components factor B, C4, C3 and C5, or treated with inhibitors of C3 convertase or C5a–C5a receptor interactions are resistant to fetal injury induced by aPL antibodies. This work, along with studies in mouse models of spontaneous, antibody-independent miscarriage, established the importance of complement in reproductive biology and showed that therapeutic modulation of the complement cascade alters pregnancy outcome in mice [14].

Given the importance of complement split products as mediators of aPL antibody-induced fetal injury, we tested the hypotheses that heparin treatment protects mice from fetal loss caused by aPL antibodies by preventing complement activation on trophoblasts and that anticoagulation, in and of itself, is not sufficient to prevent pregnancy complications in APS. Treatment with heparin (unfractionated or low molecular weight at sub-anticoagulant doses) prevented complement activation in vivo and in vitro and protected mice from pregnancy complications induced by aPL antibodies [19]. Neither fondaparinux nor hirudin inhibited the generation of complement split products or prevented pregnancy loss, despite inhibiting of factor Xa activity and increasing partial thromboplastin times, respectively, demonstrating that anticoagulation is insufficient therapy for APS-associated miscarriage. Our data indicate that heparins prevent obstetrical complications in women with APS because they block activation of complement induced by aPL antibodies, rather than by their anticoagulant effects. That Brenner et al. found no difference in pregnancy outcomes in patients with thrombophilias treated with anticoagulant and sub-anticoagulant doses of LMWH supports our findings.

The results of our studies suggest that the mechanisms by which heparin exerts its beneficial effects are more complicated than simply inhibition of thrombin generation, and underscore the importance of defining mediators of fetal and placental damage in order identify appropriate targets for treatment. Both Commentaries to the Letter by Brenner et al. make the point that patients with different thrombophilic disorders may have different risks for pregnancy loss and different responses to therapy. Understanding such heterogeneity may allow us to elucidate distinct pathogenic mechanisms and devise more focused and effective therapies.

References

  1. Top of page
  2. Are heparins effective in some patients with recurrent pregnancy loss because they inhibit complement activation?
  3. References