Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Heparin prevents antiphospholipid antibody–induced fetal loss by inhibiting complement activation

Nature Medicine volume 10, pages 1222–1226 (2004)Cite this article

Abstract

The antiphospholipid syndrome (APS) is defined by thrombosis and recurrent pregnancy loss in the presence of antiphospholipid (aPL) antibodies and is generally treated with anticoagulation therapy. Because complement activation is essential and causative in aPL antibody–induced fetal injury, we hypothesized that heparin protects pregnant APS patients from complications through inhibition of complement. Treatment with heparin (unfractionated or low molecular weight) prevented complement activation in vivo and in vitro and protected mice from pregnancy complications induced by aPL antibodies. Neither fondaparinux nor hirudin, other anticoagulants, inhibited the generation of complement split products or prevented pregnancy loss, demonstrating that anticoagulation therapy is insufficient protection against 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 targeted to decidual tissues, rather than by their anticoagulant effects.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Heparins protect mice from aPL-IgG induced pregnancy loss.
Figure 2: UFH and LMWH prevent complement deposition in deciduas of mice treated with aPL antibodies.
Figure 3: Heparin does not inhibit aPL-antibody binding to deciduas.

Similar content being viewed by others

References

  1. Wilson, W.A. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 42, 1309–1311 (1999).

    Article  CAS  Google Scholar 

  2. Lockshin, M.D., Sammaritano, L.R. & Schwartzman, S. Validation of the Sapporo criteria for antiphospholipid syndrome. Arthritis Rheum. 43, 440–443 (2000).

    Article  CAS  Google Scholar 

  3. Levine, J.S., Branch, D.W. & Rauch, J. The antiphospholipid syndrome. N. Engl. J. Med. 346, 752–763 (2002).

    Article  CAS  Google Scholar 

  4. Branch, D.W. et al. Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss. Am. J. Obstet. Gynecol. 163, 210–216 (1990).

    Article  CAS  Google Scholar 

  5. Blank, M., Cohen, J., Toder, V. & Shoenfeld, Y. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc. Natl. Acad. Sci. USA 88, 3069–3073 (1991).

    Article  CAS  Google Scholar 

  6. Simantov, R. et al. Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J. Clin. Invest. 96, 2211–2219 (1995).

    Article  CAS  Google Scholar 

  7. Piona, A. et al. Placental thrombosis and fetal loss after passive transfer of mouse lupus monoclonal or human polyclonal anti-cardiolipin antibodies in pregnant naive BALB/c mice. Scand. J. Immunol. 41, 427–432 (1995).

    Article  CAS  Google Scholar 

  8. Pierangeli, S.S. et al. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation 99, 1997–2002 (1999).

    Article  CAS  Google Scholar 

  9. Holers, V.M. et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J. Exp. Med. 195, 211–220 (2002).

    Article  CAS  Google Scholar 

  10. Girardi, G. et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J. Clin. Invest. 112, 1644–1654 (2003).

    Article  CAS  Google Scholar 

  11. Derksen, R.H., Khamashta, M.A. & Branch, D.W. Management of the obstetric antiphospholipid syndrome. Arthritis Rheum. 50, 1028–1039 (2004).

    Article  CAS  Google Scholar 

  12. Out, H.J., Kooijman, C.D., Bruinse, H.W. & Derksen, R.H. Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies. Eur. J. Obstet. Gynecol. Reprod. Biol. 41, 179–186 (1991).

    Article  CAS  Google Scholar 

  13. Magid, M.S. et al. Placental pathology in systemic lupus erythematosus: a prospective study. Am. J. Obstet. Gynecol. 179, 226–234 (1998).

    Article  CAS  Google Scholar 

  14. Ecker, E. & Gross, P. Anticomplementary power of heparin. J. Infect. Dis. 44, 250 (1929).

    Article  CAS  Google Scholar 

  15. Ecker, E. & Pillemer, L. Anti-coagulants and complementary activity: an experimental study. J. Immunol. 40, 73 (1941).

    CAS  Google Scholar 

  16. Baker, P.J., Lint, T.F., McLeod, B.C., Behrends, C.L. & Gewurz, H. Studies on the inhibition of C56-induced lysis (reactive lysis). VI. Modulation of C56-induced lysis polyanions and polycations. J. Immunol. 114, 554–558 (1975).

    CAS  Google Scholar 

  17. Loos, M., Volanakis, J.E. & Stroud, R.M. Mode of interaction of different polyanions with the first (C1, C1), the second (C2) and the fourth (C4) component of complement—III. Inhibition of C4 and C2 binding site(s) on C1s by polyanions. Immunochemistry 13, 789–791 (1976).

    Article  CAS  Google Scholar 

  18. Rent, R., Myhrman, R., Fiedel, B.A. & Gewurz, H. Potentiation of C1-esterase inhibitor activity by heparin. Clin. Exp. Immunol. 23, 264–271 (1976).

    CAS  Google Scholar 

  19. Weiler, J.M., Yurt, R.W., Fearon, D.T. & Austen, K.F. Modulation of the formation of the amplification convertase of complement, C3b, Bb, by native and commercial heparin. J. Exp. Med. 147, 409–421 (1978).

    Article  CAS  Google Scholar 

  20. Kazatchkine, M.D., Fearon, D.T., Metcalfe, D.D., Rosenberg, R.D. & Austen, K.F. Structural determinants of the capacity of heparin to inhibit the formation of the human amplification C3 convertase. J. Clin. Invest. 67, 223–228 (1981).

    Article  CAS  Google Scholar 

  21. Edens, R.E., Linhardt, R.J., Bell, C.S. & Weiler, J.M. Heparin and derivatized heparin inhibit zymosan and cobra venom factor activation of complement in serum. Immunopharmacology 27, 145–153 (1994).

    Article  CAS  Google Scholar 

  22. Ninomiya, H., Kawashima, Y. & Nagasawa, T. Inhibition of complement-mediated haemolysis in paroxysmal nocturnal haemoglobinuria by heparin or low-molecular weight heparin. Br. J. Haematol. 109, 875–881 (2000).

    Article  CAS  Google Scholar 

  23. Mollnes, T.E. et al. Essential role of the C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation. Blood 100, 1869–1877 (2002).

    CAS  Google Scholar 

  24. Wetsel, R.A., Kildsgaard, J. & Haviland, D.L. Complement anaphylatoxins (C3a, C4a, C5a) and their receptors (C3aR, C5aR/CD88) as therapeutic targets in inflammation. in Therapeutic Interventions in the Complement System, Vol. 9 (eds. Lambris, J.D. & Holers, V.M.) 113–153 (Humana Press, Totowa, NJ, 2000).

    Chapter  Google Scholar 

  25. Di Simone, N. et al. Heparin and low-dose aspirin restore placental human chorionic gonadotrophin secretion abolished by antiphospholipid antibody-containing sera. Hum. Reprod. 12, 2061–2065 (1997).

    Article  CAS  Google Scholar 

  26. Franklin, R.D. & Kutteh, W.H. Effects of unfractionated and low molecular weight heparin on antiphospholipid antibody binding in vitro. Obstet. Gynecol. 101, 455–462 (2003).

    CAS  Google Scholar 

  27. Wagenknecht, D.R. & McIntyre, J.A. Interaction of heparin with beta 2-glycoprotein I and antiphospholipid antibodies in vitro. Thromb. Res. 68, 495–500 (1992).

    Article  CAS  Google Scholar 

  28. Di Simone, N. et al. Low-molecular weight heparin restores in-vitro trophoblast invasiveness and differentiation in presence of immunoglobulin G fractions obtained from patients with antiphospholipid syndrome. Hum. Reprod. 14, 489–495 (1999).

    Article  CAS  Google Scholar 

  29. Friedrichs, G.S., Kilgore, K.S., Manley, P.J., Gralinski, M.R. & Lucchesi, B.R. Effects of heparin and N-acetyl heparin on ischemia/reperfusion-induced alterations in myocardial function in the rabbit isolated heart. Circ. Res. 75, 701–710 (1994).

    Article  CAS  Google Scholar 

  30. Koenig, A., Norgard-Sumnicht, K., Linhardt, R. & Varki, A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. J. Clin. Invest. 101, 877–889 (1998).

    Article  CAS  Google Scholar 

  31. Wang, L., Brown, J.R., Varki, A. & Esko, J.D. Heparin's anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins. J. Clin. Invest. 110, 127–136 (2002).

    Article  CAS  Google Scholar 

  32. Rops, A.L. et al. Heparan sulfate proteoglycans in glomerular inflammation. Kidney Int. 65, 768–785 (2004).

    Article  CAS  Google Scholar 

  33. Hirsh, J. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 119, 64S–94S (2001).

    Article  CAS  Google Scholar 

  34. Menon, V., Berkowitz, S.D., Antman, E.M., Fuchs, R.M. & Hochman, J.S. New heparin dosing recommendations for patients with acute coronary syndromes. Am. J. Med. 110, 641–650 (2001).

    Article  CAS  Google Scholar 

  35. Ikematsu, W. et al. Human anticardiolipin monoclonal autoantibodies cause placental necrosis and fetal loss in BALB/c mice. Arthritis Rheum. 41, 1026–1039 (1998).

    Article  CAS  Google Scholar 

  36. Salmon, J.E., Millard, S.S., Brogle, N.L. & Kimberly, R.P. Fc gamma receptor IIIb enhances Fc gamma receptor IIa function in an oxidant-dependent and allele-sensitive manner. J. Clin. Invest. 95, 2877–2885 (1995).

    Article  CAS  Google Scholar 

  37. Gu, J.M. et al. Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J. Biol. Chem. 277, 43335–43343 (2002).

    Article  CAS  Google Scholar 

  38. Gutierrez, G. et al. Regulation of interleukin-6 fetoplacental levels could be involved in the protective effect of low-molecular weight heparin treatment on murine spontaneous abortion. Am. J. Reprod. Immunol. 51, 160–165 (2004).

    Article  CAS  Google Scholar 

  39. Rote, N.S., Vogt, E., DeVere, G., Obringer, A.R. & Ng, A.K. The role of placental trophoblast in the pathophysiology of the antiphospholipid antibody syndrome. Am. J. Reprod. Immunol. 39, 125–136 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Holers, R. Silverstein and M. Lockshin for discussions, P. Casali for providing human monoclonal antibodies and M. Guerra for help in preparing the manuscript. This research was supported in part by the Alliance for Lupus Research (J.E.S.), the Mary Kirkland Center for Lupus Research at Hospital for Special Surgery (G.G. and J.E.S.), and the S.L.E. Foundation, Inc. (G.G.).

Author information

Authors and Affiliations

  1. Department of Medicine, Hospital for Special Surgery and Weill Medical College, Cornell University, 535 East 70th Street, New York, 10021, New York, USA

    Guillermina Girardi, Patricia Redecha & Jane E Salmon

Authors
  1. Guillermina Girardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patricia Redecha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jane E Salmon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jane E Salmon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Girardi, G., Redecha, P. & Salmon, J. Heparin prevents antiphospholipid antibody–induced fetal loss by inhibiting complement activation. Nat Med 10, 1222–1226 (2004). https://doi.org/10.1038/nm1121

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1121

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing