Skip to main content

Advertisement

SpringerLink
Log in

The Complement Alternative Pathway and Preeclampsia

  • Preeclampsia (VD Garovic, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Significant and intricate immune adaptations are essential for the establishment and maintenance of normal pregnancy. Preeclampsia is a morbid, potentially life-threatening disease for both mother and neonate that occurs uniquely in pregnancy, at least in part, due to maternal immune maladaptation. We aim to review the literature that focuses on case reports, diagnostic approaches, and treatment strategies for disorders of the complement alternative pathway (CAP) as related to preeclampsia.

Recent Findings

There is evidence of complement dysregulation in preeclampsia and HELLP syndrome, similar to that observed in a few rare types of thrombotic microangiopathies. Complement dysregulation may be identified with functional laboratory testing as well as genetic testing.

Summary

Increased utilization of a standardized diagnostic approach to establish whether persistent and/or severe cases of preeclampsia and HELLP syndrome are complement-mediated may lead to development of future treatment strategies, such as complement-targeted therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance ••Of major importance

  1. •• American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Obstet Gynecol. 2013;122:1122–31. https://doi.org/10.1097/01.AOG.0000437382.03963.88. There are the guidelines for definitions and management of all forms of preeclampsia.

    Article  Google Scholar 

  2. Saito S, Shiozaki A, Nakashima A, et al. The role of the immune system in preeclampsia. Mol Asp Med. 2007;28:192–209. https://doi.org/10.1016/j.mam.2007.02.006.

    Article  CAS  Google Scholar 

  3. Marzi M, Vigano A, Trabattoni D, et al. Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy. Clin Exp Immunol. 1996;106:127–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Mellor AL, Sivakumar J, Chandler P, Smith K, Molina H, Mao D, et al. Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat Immunol. 2001;2:64–8. https://doi.org/10.1038/83183.

    Article  PubMed  CAS  Google Scholar 

  5. Ban Y, Zhao Y, Liu F, Dong B, Kong B, Qu X. Effect of indoleamine 2,3-dioxygenase expressed in HTR-8/SVneo cells on decidual NK cell cytotoxicity. Am J Reprod Immunol. 2016;75:519–28. https://doi.org/10.1111/aji.12481.

    Article  PubMed  CAS  Google Scholar 

  6. Richani K, Soto E, Romero R, Espinoza J, Chaiworapongsa T, Nien JK, et al. Normal pregnancy is characterized by systemic activation of the complement system. J Matern Fetal Neonatal Med. 2005;17:239–45. https://doi.org/10.1080/14767050500072722.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785–97. https://doi.org/10.1038/ni.1923.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Frazer-Abel A, Sepiashvili L, Mbughuni MM, Willrich MAV (2016) Overview of laboratory testing and clinical presentations of complement deficiencies and dysregulation. pp 1–75.

  9. Botto M, Kirschfink M, Macor P, Pickering MC, Würzner R, Tedesco F. Complement in human diseases: lessons from complement deficiencies. Mol Immunol. 2009;46:2774–83. https://doi.org/10.1016/j.molimm.2009.04.029.

    Article  PubMed  CAS  Google Scholar 

  10. •• Hoffman MC, Rumer KK, Kramer A, Lynch AM, Winn VD. Maternal and fetal alternative complement pathway activation in early severe preeclampsia. Am J Reprod Immunol. 2014;71:55–60. https://doi.org/10.1111/aji.12162. Cross-section study in preeclampsia with severe features versus normal controls. Complement factor B activation fragment Bb (specific for complement alternative pathway) in bmaternal and umbilical venous blood appears to be increased in preeclamptics when compared to controls.

    Article  PubMed  CAS  Google Scholar 

  11. •• Sones JL, Merriam AA, Seffens A, et al (2017) Angiogenic factor imbalance precedes complement deposition in placentae of the BPH/5 model of preeclampsia. FASEB J fj.201701008R. doi: https://doi.org/10.1096/fj.201701008R. An animal study on gravid mice revealed complement gene up-regulation in high blood pressure mice compared to controls. Altered expression of VEGF pathway genes in high blood pressure mice implantation sites preceded complement dysregulation.

  12. Einarsson JI, Sangi-Haghpeykar H, Gardner MO. Sperm exposure and development of preeclampsia. Am J Obstet Gynecol. 2003;188:1241–3.

    Article  PubMed  Google Scholar 

  13. Robillard PY, Hulsey TC, Périanin J, et al. Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception. Lancet (London, England). 1994;344:973–5.

    Article  CAS  Google Scholar 

  14. Koelman CA, Coumans AB, Nijman HW, et al. Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid? J Reprod Immunol. 2000;46:155–66.

    Article  PubMed  CAS  Google Scholar 

  15. • Tsai H-M, Kuo E. From gestational hypertension and preeclampsia to atypical hemolytic uremic syndrome. Obstet Gynecol. 2016;127:907–10. https://doi.org/10.1097/AOG.0000000000001340. A case report in which a patient was misdiagnosed with preeclampsia and HELLP syndrome one pregnancy, TTP in another pregnancy, and was finally given the correct diagnosis for atypical HUS in her third pregnancy, demostrating the great imitators.

    Article  PubMed  Google Scholar 

  16. Abraham KA, Kennelly M, Dorman AM, Walshe JJ. Pathogenesis of acute renal failure associated with the HELLP syndrome: a case report and review of the literature. Eur J Obstet Gynecol Reprod Biol. 2003;108:99–102.

    Article  PubMed  Google Scholar 

  17. Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16:1035–50. https://doi.org/10.1681/ASN.2004100861.

    Article  PubMed  CAS  Google Scholar 

  18. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87. https://doi.org/10.1056/NEJMra0902814.

    Article  PubMed  CAS  Google Scholar 

  19. Sibai BM. Imitators of severe preeclampsia. Obstet Gynecol. 2007;109:956–66. https://doi.org/10.1097/01.AOG.0000258281.22296.de.

    Article  PubMed  Google Scholar 

  20. Fakhouri F. Pregnancy-related thrombotic microangiopathies: clues from complement biology. Transfus Apher Sci. 2016;54:199–202. https://doi.org/10.1016/j.transci.2016.04.009.

    Article  PubMed  Google Scholar 

  21. •• Sabau L, Terriou L, Provot F, Fourrier F, Roumier C, Caron C, et al. Are there any additional mechanisms for haemolysis in HELLP syndrome? Thromb Res. 2016;142:40–3. https://doi.org/10.1016/j.thomres.2016.03.014. Prospective observational study of 16 HELLP patients demonstrated that complement dysregulation is a prominent mechanism in hemolysis in these patients.

    Article  PubMed  CAS  Google Scholar 

  22. • Burwick RM, Fichorova RN, Dawood HY, Yamamoto HS, Feinberg BB. Urinary excretion of C5b-9 in severe preeclampsia: tipping the balance of complement activation in pregnancy. Hypertension. 2013;62:1040–5. https://doi.org/10.1161/HYPERTENSIONAHA.113.01420. Case–control study in which those with preeclampsia had marked elevations in urinary C5b-9. Although complement elevations of complement components were noted, they did not differ preeclampsia from chronic hypertension, supporting the hypothesis that complement markers in urine, rather than plasma, better reflect complement dysregulation.

    Article  PubMed  CAS  Google Scholar 

  23. Lynch AM, Gibbs RS, Murphy JR, Giclas PC, Salmon JE, Holers VM. Early elevations of the complement activation fragment C3a and adverse pregnancy outcomes. Obstet Gynecol. 2011;117:75–83. https://doi.org/10.1097/AOG.0b013e3181fc3afa.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lynch AM, Murphy JR, Byers T, Gibbs RS, Neville MC, Giclas PC, et al. Alternative complement pathway activation fragment Bb in early pregnancy as a predictor of preeclampsia. Am J Obstet Gynecol. 2008;198:385.e1–9. https://doi.org/10.1016/j.ajog.2007.10.793.

    Article  CAS  Google Scholar 

  25. • Ma Y, Kong L-R, Ge Q, et al. Complement 5a-mediated trophoblasts dysfunction is involved in the development of pre-eclampsia. J Cell Mol Med. 2017; https://doi.org/10.1111/jcmm.13466. This study demonstrates that complement 5a (C5a) plays a pivotal role in aberrant placentation by detecting elevated C5a deposition in macrophages and C5a receptor expression in trophoblasts of preeclamptic placentas.

  26. •• Frazer-Abel A, Sepiashvili L, Mbughuni MM, Willrich MAV. Overview of laboratory testing and clinical presentations of complement deficiencies and dysregulation. Adv Clin Chem. 2016;77:1–75. https://doi.org/10.1016/bs.acc.2016.06.001. The basis of complement testing in common diseases affected by complement dysregulation is described in depth in this article.

    Article  PubMed  CAS  Google Scholar 

  27. • Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2016;31:15–39. https://doi.org/10.1007/s00467-015-3076-8. An international consensus to approaching the diagnosis and management of atypical HUS in children. Here, HELLP syndrome is classified as as TMA.

    Article  PubMed  Google Scholar 

  28. • Go RS, Winters JL, Leung N, Murray DL, Willrich MA, Abraham RS, et al. Thrombotic microangiopathy care pathway: a consensus statement for the Mayo Clinic complement alternative pathway-thrombotic microangiopathy (CAP-TMA) disease-oriented group. Mayo Clin Proc. 2016;91:1189–211. https://doi.org/10.1016/j.mayocp.2016.05.015. The Mayo Clinic approach to diagnosis of complement alternative pathway thrombotic microangiopathy disorders is described here, which includes atypical HUS.

    Article  PubMed  Google Scholar 

  29. • Fakhouri F, Jablonski M, Lepercq J, Blouin J, Benachi A, Hourmant M, et al. Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome. Blood. 2008;112:4542–5. https://doi.org/10.1182/blood-2008-03-144691. An early report of genetic variants in complement alternative pathway regulatory proteins in 11 patients with HELLP syndrome.

    Article  PubMed  CAS  Google Scholar 

  30. Crovetto F, Borsa N, Acaia B, Nishimura C, Frees K, Smith RJH, et al. The genetics of the alternative pathway of complement in the pathogenesis of HELLP syndrome. J Matern Fetal Neonatal Med. 2012;25:2322–5. https://doi.org/10.3109/14767058.2012.694923.

    Article  PubMed  CAS  Google Scholar 

  31. Józsi M, Licht C, Strobel S, et al. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood. 2008;111:1512–4. https://doi.org/10.1182/blood-2007-09-109876.

    Article  PubMed  CAS  Google Scholar 

  32. Dragon-Durey M-A, Sethi SK, Bagga A, Blanc C, Blouin J, Ranchin B, et al. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol. 2010;21:2180–7. https://doi.org/10.1681/ASN.2010030315.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sellier-Leclerc A-L, Fremeaux-Bacchi V, Dragon-Durey M-A, Macher MA, Niaudet P, Guest G, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18:2392–400. https://doi.org/10.1681/ASN.2006080811.

    Article  PubMed  CAS  Google Scholar 

  34. •• Vaught AJ, Gavriilaki E, Hueppchen N, Blakemore K, Yuan X, Seifert SM, et al. Direct evidence of complement activation in HELLP syndrome: a link to atypical hemolytic uremic syndrome. Exp Hematol. 2016;44:390–8. https://doi.org/10.1016/j.exphem.2016.01.005. A comprehensive study demonstrating alternative complement pathway activation in preeclamptics and those with HELLP syndrome, in addition to demonstrating a significant decrease in cell killing after mizing HELLP serum with eculizumab-containing serum.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Ardissino G, Wally Ossola M, Baffero GM, et al. Eculizumab for atypical hemolytic uremic syndrome in pregnancy. Obstet Gynecol. 2013;122:487–9. https://doi.org/10.1097/AOG.0b013e31828e2612.

    Article  PubMed  Google Scholar 

  36. Kelly RJ, Höchsmann B, Szer J, Kulasekararaj A, de Guibert S, Röth A, et al. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2015;373:1032–9. https://doi.org/10.1056/NEJMoa1502950.

    Article  PubMed  CAS  Google Scholar 

  37. Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J, et al. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol. 2010;149:446–50. https://doi.org/10.1111/j.1365-2141.2010.08099.x.

    Article  PubMed  CAS  Google Scholar 

  38. Hallstensen RF, Bergseth G, Foss S, Jæger S, Gedde-Dahl T, Holt J, et al. Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn. Immunobiology. 2015;220:452–9. https://doi.org/10.1016/j.imbio.2014.11.003.

    Article  PubMed  CAS  Google Scholar 

  39. •• Burwick RM, Feinberg BB. Eculizumab for the treatment of preeclampsia/HELLP syndrome. Placenta. 2013;34:201–3. https://doi.org/10.1016/j.placenta.2012.11.014. A report of one case of HELLP syndrome at 26 weeks in which the patient was started on eculizumab and the pregnancy was safely prolonged by approximately 3 weeks.

    Article  PubMed  CAS  Google Scholar 

  40. • McNamara LA, Topaz N, Wang X, et al. High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine. MMWR Morb Mortal Wkly Rep. 2017;66:734–7. https://doi.org/10.15585/mmwr.mm6627e1. A report by the Center for Disease Control and Prevention demonstrating 16 cases of meningococcal disease in those receiving eculizumab between 2008–2016, despite receipt of the vaccine.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sinha A, Gulati A, Saini S, Blanc C, Gupta A, Gurjar BS, et al. Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney Int. 2014;85:1151–60. https://doi.org/10.1038/ki.2013.373.

    Article  PubMed  CAS  Google Scholar 

  42. Heggermont WA, Verhelst C, De Wilde K, et al. A case of HELLP syndrome: an immuno-“logical” approach. Acta Clin Belg. 67:375–7. https://doi.org/10.2143/ACB.67.5.2062695.

  43. Chou M-M, Chen Y-F, Kung H-F, Liu CK, Sun L, Chen WC, et al. Extensive hepatic infarction in severe preeclampsia as part of the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): evolution of CT findings and successful treatment with plasma exchange therapy. Taiwan J Obstet Gynecol. 2012;51:418–20. https://doi.org/10.1016/j.tjog.2012.07.018.

    Article  PubMed  Google Scholar 

  44. Vafaeimanesh J, Nazari A, Hosseinzadeh F. Plasmapheresis: lifesaving treatment in severe cases of HELLP syndrome. Casp J Intern Med. 2014;5:243–7.

    Google Scholar 

  45. Diamante Chiodini B, Davin J-C, Corazza F, Khaldi K, Dahan K, Ismaili K, et al. Eculizumab in anti-factor H antibodies associated with atypical hemolytic uremic syndrome. Pediatrics. 2014;133:e1764–8. https://doi.org/10.1542/peds.2013-1594.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Wendy White, associate professor of Obstetrics and Gynecology at the division of Maternal Fetal Medicine at Mayo Clinic, Rochester, MN, for her comments and critical review of the manuscript.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA

    Layan Alrahmani

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Maria Alice V. Willrich

Authors
  1. Layan Alrahmani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Alice V. Willrich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Alice V. Willrich.

Ethics declarations

Conflict of Interest

The authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Preeclampsia

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alrahmani, L., Willrich, M.A.V. The Complement Alternative Pathway and Preeclampsia. Curr Hypertens Rep 20, 40 (2018). https://doi.org/10.1007/s11906-018-0836-4

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-018-0836-4

Keywords

Search

Navigation