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Successful anticoagulant therapy for two pregnant PNH patients, and prospects for the eculizumab era

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Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder characterized by intravascular hemolysis and thrombosis. The most serious complication is thrombosis, the risk of which is augmented by the hyper-coagulable state that occurs during pregnancy; despite this risk, however, young female PNH patients often desire to have a baby. We recently experienced two successful deliveries in PNH patients, who were treated with anticoagulant therapy during their pregnancies. Meanwhile, given the potential benefit of eculizumab (Soliris), a humanized monoclonal antibody against C5, in reducing thrombosis and hemolysis, it represents a promising therapeutic option for the treatment of pregnant PNH patients in combination with, or in replacement of, anticoagulant therapy.

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References

  1. Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005;106:3699–709.

    Article  PubMed  CAS  Google Scholar 

  2. Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993;73:703–11.

    Article  PubMed  CAS  Google Scholar 

  3. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal hemoglobinuria. N Engl J Med. 1995;333:1253–8.

    Article  PubMed  CAS  Google Scholar 

  4. Shichishima T, Saitoh Y, Noji H, Terasawa T, Maruyama Y. In vivo effects of various therapies on complement-sensitive erythrocytes in paroxysmal nocturnal hemoglobinuria. Int J Hematol. 1996;6:291–302.

    Article  Google Scholar 

  5. Issaragrisil S, Piankijagum A, Tang-naitrisorana Y. Corticosteroids therapy in paroxysmal nocturnal hemoglobinuria. Am J Hematol. 1987;25:77–83.

    Article  PubMed  CAS  Google Scholar 

  6. Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004;350:552–9.

    Article  PubMed  CAS  Google Scholar 

  7. Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355:1233–43.

    Article  PubMed  CAS  Google Scholar 

  8. Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111:1840–7.

    Article  PubMed  CAS  Google Scholar 

  9. Kanakura Y, Ohyashiki K, Schishima T, Okamoto S, Ando K, Ninomiya H, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS clinical trial. Int J Hematol. 2011;93:36–46.

    Article  PubMed  CAS  Google Scholar 

  10. Socie G, Mary JY, de Gramont A, Rio B, Leporrier M, Rose C, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. Lancet. 1996;31:573–7.

    Article  Google Scholar 

  11. Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007;110:4123–8.

    Article  PubMed  CAS  Google Scholar 

  12. Nishimura J, Kanakura Y, Ware RE, Shichishima T, Nakakuma H, Ninomiya H, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine. 2004;83:193–207.

    Article  PubMed  Google Scholar 

  13. Bais J, Pel M, von dem Borne A, van der Lelie H. Pregnancy and paroxysmal nocturnal hemoglobinuria. Eur J Obstet Gynecol Reprod Biol. 1994;53:211–4.

    Article  PubMed  CAS  Google Scholar 

  14. Tichelli A, Socie G, Marsh J, Barge R, Frickhofen N, McCann S, et al. Outcome of pregnancy and disease course among women with aplastic anemia treated with immunosuppression. Ann Intern Med. 2002;136:164–72.

    Google Scholar 

  15. James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol. 2005;193:216–9.

    Article  PubMed  Google Scholar 

  16. Ray JG, Burows RF, Ginsberg JS, Burrows EA. Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient. Haemostasis. 2000;30:103–17.

    PubMed  CAS  Google Scholar 

  17. Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2003;102:3587–91.

    Article  PubMed  CAS  Google Scholar 

  18. Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv. 1999;54:265–71.

    Article  PubMed  CAS  Google Scholar 

  19. Moyo VM, Mukhina GL, Garrett ES, Brodsky RA. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. Br J Haematol. 2004;126:133–8.

    Article  PubMed  CAS  Google Scholar 

  20. Danilov AV, Brodsky RA, Craigo S, Smith H, Miller KB. Managing a pregnant patient with paroxysmal nocturnal hemoglobinuria in the era of eculizumab. Leuk Res. 2010;34:566–71.

    Article  PubMed  CAS  Google Scholar 

  21. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood. 2005;106:401–7.

    Article  PubMed  CAS  Google Scholar 

  22. Meyers G, Parker CJ. Management issues in paroxysmal nocturnal hemoglobinuria. Int J Hematol. 2003;77:125–32.

    Article  PubMed  Google Scholar 

  23. Bjørge L, Ernst P, Haram KO. Paroxysmal nocturnal hemoglobinuria in pregnancy. Acta Obstet Gynecol Scand. 2003;82:1067–71.

    Article  PubMed  Google Scholar 

  24. Allen TK, George RB, Olufolabi AJ, James AH, Muir HA, Habib AS. The management of Cesarean delivery in a parturient with paroxysmal nocturnal hemoglobinuria complicated by severe preeclampsia. Can J Anaesth. 2007;54:646–51.

    Article  PubMed  Google Scholar 

  25. Solal-Céligny P, Tertian G, Fernandez H, Pons JC, Lambert T, Najean Y, et al. Pregnancy and paroxysmal nocturnal hemoglobinuria. Arch Intern Med. 1988;148:593–5.

    Article  PubMed  Google Scholar 

  26. de Guibert S, Peffault de Latour R, Varoqueaux N, Labussière H, Rio B, Jaulmes D, et al. Paroxysmal nocturnal hemoglobinuria and pregnancy before the eculizumab era: the French experience. Haematologica. 2011;96:1276–83.

    Google Scholar 

  27. Melo A, Gorgal-Carvalho R, Amaral J, Marques MC, Andrade J, Guimarães JT, et al. Clinical management of paroxysmal nocturnal haemoglobinuria in pregnancy: three case reports. Blood Transfus. 2011;9:99–103.

    PubMed  Google Scholar 

  28. Greene MF, Frigoletto FD Jr, Claster S, Rosenthal D. Pregnancy and paroxysmal nocturnal hemoglobinuria: report of a case and review of the literature. Obstet Gynecol Surv. 1983;38:591–6.

    Article  PubMed  CAS  Google Scholar 

  29. Shibasaki T, Matsuda H, Furuya K. Haptoglobin therapy during pregnancy for paroxysmal nocturnal hemoglobinuria with renal failure. Int J Gynaecol Obstet. 2007;98:267–8.

    Article  PubMed  CAS  Google Scholar 

  30. Chen ML, Yu CH, Chang FM, Kuo PL. Paroxysmal nocturnal hemoglobinuria superimposed with preeclampsia. Taiwan J Obstet Gynecol. 2006;45:276–8.

    Article  PubMed  Google Scholar 

  31. Fieni S, Bonfanti L, Gramellini D, Benassi L, Delsignore R. Clinical management of paroxysmal nocturnal hemoglobinuria in pregnancy: a case report and updated review. Obstet Gynecol Surv. 2006;61:593–601.

    Article  PubMed  Google Scholar 

  32. Paech MJ, Pavy TJ. Management of a parturient with paroxysmal nocturnal haemoglobinuria. Int J Obstet Anesth. 2004;13:188–91.

    Article  PubMed  CAS  Google Scholar 

  33. Kjaer K, Comerford M, Gadalla F. General anesthesia for cesarean delivery in a patient with paroxysmal nocturnal hemoglobinuria and thrombocytopenia. Anesth Analg. 2004;98:1471–2.

    Article  PubMed  Google Scholar 

  34. Higgins SP, McMahon LP, Brennecke SP. Paroxysmal nocturnal haemoglobinuria in pregnancy—not to be confused with pre-eclampsia or HELLP syndrome. Case report and literature review. J Obstet Gynaecol. 2004;24:83–5.

    Article  PubMed  CAS  Google Scholar 

  35. Stocche RM, Garcia LV, Klamt JG. Labor analgesia in a patient with paroxysmal nocturnal hemoglobinuria with thrombocytopenia. Reg Anesth Pain Med. 2001;26:79–82.

    PubMed  CAS  Google Scholar 

  36. Svigos JM, Norman J. Paroxysmal nocturnal haemoglobinuria and pregnancy. Aust N Z J Obstet Gynaecol. 1994;34:104–6.

    Article  PubMed  CAS  Google Scholar 

  37. Imai A, Takagi H, Kawabata I, Sumi H, Shiraki S, Tamaya T. Successful pregnancy in a patient with paroxysmal nocturnal hemoglobinuria: case report. Arch Gynecol Obstet. 1989;246:121–4.

    Article  PubMed  CAS  Google Scholar 

  38. Mori H, Okada S, Takizawa Y, Hagiwara S, Niikura H, Terada H. Pregnancy in paroxysmal nocturnal hemoglobinuria–report of two cases. Rinsho Ketsueki. 1987;28:1645–50.

    PubMed  CAS  Google Scholar 

  39. Beresford CH, Gudex DJ, Symmans WA. Paroxysmal nocturnal haemoglobinuria and pregnancy. Lancet. 1986;2:1396–7.

    Article  PubMed  CAS  Google Scholar 

  40. Jacobs P, Wood L. Paroxysmal nocturnal haemoglobinuria and pregnancy. Lancet. 1986;2:1099.

    Article  PubMed  CAS  Google Scholar 

  41. Tomaru T, Nakai K, Takeda S, Kagawa T, Ozawa K. Anesthetic management of caesarean section in a patient with paroxysmal nocturnal hemoglobinuria. Masui. 1986;35:807–11.

    PubMed  CAS  Google Scholar 

  42. Colvin BT. Thrombocytopenia. Clin Haematol. 1985;14:661–81.

    PubMed  CAS  Google Scholar 

  43. Hurd WW, Miodovnik M, Stys SJ. Pregnancy associated with paroxysmal nocturnal hemoglobinuria. Obstet Gynecol. 1982;60:742–6.

    PubMed  CAS  Google Scholar 

  44. Wozniak AJ, Kitchens CS. Prospective hemostatic studies in a patient having paroxysmal nocturnal hemoglobinuria, pregnancy, and cerebral venous thrombosis. Am J Obstet Gynecol. 1982;142:591–3.

    PubMed  CAS  Google Scholar 

  45. Kawamura S, Shiosaka T, Saito S, Ikeda K, Matsumoto I, Fujita S, et al. A case of paroxysmal nocturnal hemoglobinuria; successful gestation and labor. Rinsho Ketsueki. 1980;21:1226–31.

    PubMed  CAS  Google Scholar 

  46. Spencer JA. Paroxysmal nocturnal haemoglobinuria in pregnancy: case report. Br J Obstet Gynaecol. 1980;87:246–8.

    Article  PubMed  CAS  Google Scholar 

  47. Frakes JT, Burmeister RE, Giliberti JJ. Pregnancy in a patient with paroxysmal nocturnal hemoglobinuria. Obstet Gynecol. 1976;47:22S–4S.

    PubMed  CAS  Google Scholar 

  48. Payne PR. Paroxysmal nocturnal haemoglobinuria in pregnancy. Proc R Soc Med. 1968;61:679.

    PubMed  CAS  Google Scholar 

  49. Röth A, Hock C, Konik A, Christoph S, Dührsen U. Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena. Int J Hematol. 2011;93:704–14.

    Article  PubMed  Google Scholar 

  50. Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, et al. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol. 2010;149:446–50.

    Article  PubMed  CAS  Google Scholar 

  51. Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin Microbiol Rev. 1991;4:359–95.

    PubMed  CAS  Google Scholar 

  52. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol. 2007;25:1256–64.

    Article  PubMed  CAS  Google Scholar 

  53. van Bijnen ST, van Rijn RS, Koljenovic S, Te Boekhorst P, de Witte T, Muus P. Possible high risk of thrombotic events in patients with paroxysmal nocturnal haemoglobinuria after discontinuation of eculizumab. Br J Haematol. 2012;157:762–3.

    Article  PubMed  Google Scholar 

  54. Marasca R, Coluccio V, Santachiara R, Leonardi G, Torelli G, Notaro R, et al. Pregnancy in PNH: another eculizumab baby. Br J Haematol. 2010;150:707–8.

    Article  PubMed  Google Scholar 

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Acknowledgments

We would like to thank all members of the Working Group on Pregnancy of the Japan PNH Study Group.

Conflict of interest

Drs. Morita Y, Nishimura J, Kanakura Y, and Matsumura I received a Grant for research from Alexion Pharmaceuticals. All other authors declare no conflicts of interest.

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Authors and Affiliations

  1. Division of Hematology and Rheumatology, Department of Internal Medicine, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, 589-8511, Japan

    Yasuyoshi Morita, Takahiro Shimada, Hirokazu Tanaka, Kentaro Serizawa, Yasuhiro Taniguchi & Itaru Matsumura

  2. Department of Hematology and Oncology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan

    Jun-ichi Nishimura & Yuzuru Kanakura

  3. Department of Obstetrics and Gynecology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan

    Mitsuhiro Tsuritani

Authors
  1. Yasuyoshi Morita
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  2. Jun-ichi Nishimura
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  3. Takahiro Shimada
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  4. Hirokazu Tanaka
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  5. Kentaro Serizawa
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  7. Mitsuhiro Tsuritani
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  8. Yuzuru Kanakura
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  9. Itaru Matsumura
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Correspondence to Yasuyoshi Morita.

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Morita, Y., Nishimura, Ji., Shimada, T. et al. Successful anticoagulant therapy for two pregnant PNH patients, and prospects for the eculizumab era. Int J Hematol 97, 491–497 (2013). https://doi.org/10.1007/s12185-013-1302-3

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  • DOI: https://doi.org/10.1007/s12185-013-1302-3

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