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.

  • State of the Art
  • Published:

State-of-the-Art

Increasing platelets without transfusion: is it time to introduce novel thrombopoietic agents in neonatal care?

Journal of Perinatology volume 30, pages 765–769 (2010)Cite this article

Subjects

Abstract

The Food and Drug Administration recently approved two novel thrombopoiesis-stimulating agents, Romiplostim (AMG-531, Nplate) and Eltrombopag (Promacta), for the treatment of adults with immune thrombocytopenic purpura. For physicians taking care of critically ill neonates, this offers the opportunity of decreasing platelet transfusions and potentially improving the outcomes of neonates with severe and prolonged thrombocytopenia. However, several developmental factors need to be taken into consideration. First, the population of thrombocytopenic neonates likely to benefit from these agents needs to be carefully selected. Second, the mechanisms underlying neonatal and adult thrombocytopenia differ from each other and are incompletely understood, and pre-clinical evidence suggests that the response of neonates to thrombopoietic factors might be different from that of adults. Finally, the potential non-hematopoietic effects of thrombopoietin have not been well established. Here, we will discuss these issues in detail, and will highlight the critical developmental differences between neonates and adults that need to be considered as we think about introducing these agents into neonatal care.

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

References

  1. Bishara N, Ohls RK . Current controversies in the management of the anemia of prematurity. Semin Perinatol 2009; 33: 29–34.

    Article  Google Scholar 

  2. Roberts I, Stanworth S, Murray NA . Thrombocytopenia in the neonate. Blood Rev 2008; 22: 173–186.

    Article  Google Scholar 

  3. Christensen RD, Calhoun DA . Congenital neutropenia. Clin Perinatol 2004; 31: 29–38.

    Article  Google Scholar 

  4. Ohls RK, Ehrenkranz RA, Wright LL, Lemons JA, Korones SB, Stoll BJ et al. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics 2001; 108: 934–942.

    Article  CAS  Google Scholar 

  5. Bernstein HM, Calhoun DA, Christensen RD . Use of myeloid colony-stimulating factors in neonates with septicemia. Curr Opin Pediatr 2002; 14: 91–94.

    Article  Google Scholar 

  6. Basser RL, O'Flaherty E, Green M, Edmonds M, Nichol J, Menchaca DM et al. Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. Blood 2002; 99: 2599–2602.

    Article  CAS  Google Scholar 

  7. Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 2001; 98: 3241–3248.

    Article  CAS  Google Scholar 

  8. Nurden AT, Viallard JF, Nurden P . New-generation drugs that stimulate platelet production in chronic immune thrombocytopenic purpura. Lancet 2009; 373: 1562–1569.

    Article  CAS  Google Scholar 

  9. George JN, Terrell DR . Novel thrombopoietic agents: a new era for management of patients with thrombocytopenia. Haematologica 2008; 93: 1445–1449.

    Article  CAS  Google Scholar 

  10. Bussel JB, Kuter DJ, George JN, McMillan R, Aledort LM, Conklin GT et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 2006; 355: 1672–1681.

    Article  CAS  Google Scholar 

  11. Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007; 357: 2237–2247.

    Article  CAS  Google Scholar 

  12. Christensen RD, Henry E, Wiedmeier SE, Stoddard RA, Sola-Visner MC, Lambert DK et al. Thrombocytopenia among extremely low birth weight neonates: data from a multihospital healthcare system. J Perinatol 2006; 26: 348–353.

    Article  CAS  Google Scholar 

  13. Josephson CD, Su LL, Christensen RD, Hillyer CD, Castillejo MI, Emory MR et al. Platelet transfusion practices among neonatologists in the United States and Canada: results of a survey. Pediatrics 2009; 123: 278–285.

    Article  Google Scholar 

  14. Del Vecchio A, Sola MC, Theriaque DW, Hutson AD, Kao KJ, Wright D et al. Platelet transfusions in the neonatal intensive care unit: factors predicting which patients will require multiple transfusions. Transfusion 2001; 41: 803–808.

    Article  CAS  Google Scholar 

  15. Baer VL, Lambert DK, Henry E, Snow GL, Sola-Visner MC, Christensen RD . Do platelet transfusions in the NICU adversely affect survival? Analysis of 1600 thrombocytopenic neonates in a multihospital healthcare system. J Perinatol 2007; 27: 790–796.

    Article  CAS  Google Scholar 

  16. Kaushansky K . The molecular mechanisms that control thrombopoiesis. J Clin Invest 2005; 115: 3339–3347.

    Article  CAS  Google Scholar 

  17. Levine RF, Olson TA, Shoff PK, Miller MK, Weisman LE . Mature micromegakaryocytes: an unusual developmental pattern in term infants. Br J Haematol 1996; 94: 391–399.

    Article  CAS  Google Scholar 

  18. Olson TA, Levine RF, Mazur EM, Wright DG, Salvado AJ . Megakaryocytes and megakaryocyte progenitors in human cord blood. Am J Pediatr Hematol Oncol 1992; 14: 241–247.

    Article  CAS  Google Scholar 

  19. Mattia G, Vulcano F, Milazzo L, Barca A, Macioce G, Giampaolo A et al. Different ploidy levels of megakaryocytes generated from peripheral or cord blood CD34+ cells are correlated with different levels of platelet release. Blood 2002; 99: 888–897.

    Article  CAS  Google Scholar 

  20. Murray NA, Watts TL, Roberts IA . Endogenous thrombopoietin levels and effect of recombinant human thrombopoietin on megakaryocyte precursors in term and preterm babies. Pediatr Res 1998; 43: 148–151.

    Article  CAS  Google Scholar 

  21. Nishihira H, Toyoda Y, Miyazaki H, Kigasawa H, Ohsaki E . Growth of macroscopic human megakaryocyte colonies from cord blood in culture with recombinant human thrombopoietin (c-mpl ligand) and the effects of gestational age on frequency of colonies. Br J Haematol 1996; 92: 23–28.

    Article  CAS  Google Scholar 

  22. Harker LA . Kinetics of thrombopoiesis. J Clin Invest 1968; 47: 458–465.

    Article  CAS  Google Scholar 

  23. Harker LA . Thrombokinetics in idiopathic thrombocytopenic purpura. Br J Haematol 1970; 19: 95–104.

    Article  CAS  Google Scholar 

  24. Sola-Visner MC, Christensen RD, Hutson AD, Rimsza LM . Megakaryocyte size and concentration in the bone marrow of thrombocytopenic and nonthrombocytopenic neonates. Pediatr Res 2007; 61: 479–484.

    Article  Google Scholar 

  25. Hu Z, Slayton WB, Rimsza LM, Bailey M, Sallmon H, Sola-Visner MC . Differences between newborn and adult mice in their response to immune thrombocytopenia. Neonatology 2010; 98: 100–108.

    Article  Google Scholar 

  26. Sola MC, Calhoun DA, Hutson AD, Christensen RD . Plasma thrombopoietin concentrations in thrombocytopenic and non-thrombocytopenic patients in a neonatal intensive care unit. Br J Haematol 1999; 104: 90–92.

    Article  CAS  Google Scholar 

  27. Sola MC, Dame C, Christensen RD . Toward a rational use of recombinant thrombopoietin in the neonatal intensive care unit. J Pediatr Hematol Oncol 2001; 23: 179–184.

    Article  CAS  Google Scholar 

  28. Murray NA, Howarth LJ, McCloy MP, Letsky EA, Roberts IA . Platelet transfusion in the management of severe thrombocytopenia in neonatal intensive care unit patients. Transfus Med 2002; 12: 35–41.

    Article  CAS  Google Scholar 

  29. Dame C . Developmental biology of thrombopoietin in the human fetus and neonate. Acta Paediatr Suppl 2002; 91: 54–65.

    Article  CAS  Google Scholar 

  30. Garcia MG, Duenas E, Sola MC, Hutson AD, Theriaque D, Christensen RD . Epidemiologic and outcome studies of patients who received platelet transfusions in the neonatal intensive care unit. J Perinatol 2001; 21: 415–420.

    Article  CAS  Google Scholar 

  31. Dohner ML, Wiedmeier SE, Stoddard RA, Null Jr D, Lambert DK, Burnett J et al. Very high users of platelet transfusions in the neonatal intensive care unit. Transfusion 2009; 49: 869–872.

    Article  Google Scholar 

  32. Brown RE, Rimsza LM, Pastos K, Young L, Saxonhouse MA, Bailey M et al. Effects of sepsis on neonatal thrombopoiesis. Pediatr Res 2008; 64: 399–404.

    Article  Google Scholar 

  33. Fleming GM, Gurney JG, Donohue JE, Remenapp RT, Annich GM . Mechanical component failures in 28,171 neonatal and pediatric extracorporeal membrane oxygenation courses from 1987 to 2006. Pediatr Crit Care Med 2009; 10: 439–444.

    Article  Google Scholar 

  34. Cremer M, Paetzold J, Schmalisch G, Hammer H, Loui A, Dame C et al. Immature platelet fraction as novel laboratory parameter predicting the course of neonatal thrombocytopenia. Br J Haematol 2009; 144: 619–621.

    Article  Google Scholar 

  35. Erhardt JA, Erickson-Miller CL, Aivado M, Abboud M, Pillarisetti K, Toomey JR . Comparative analyses of the small molecule thrombopoietin receptor agonist eltrombopag and thrombopoietin on in vitro platelet function. Exp Hematol 2009; 37: 1030–1037.

    Article  CAS  Google Scholar 

  36. Geddis AE . Congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii. Hematol Oncol Clin North Am 2009; 23: 321–331.

    Article  Google Scholar 

  37. Sola MC, Du Y, Hutson AD, Christensen RD . Dose-response relationship of megakaryocyte progenitors from the bone marrow of thrombocytopenic and non-thrombocytopenic neonates to recombinant thrombopoietin. Br J Haematol 2000; 110: 449–453.

    Article  CAS  Google Scholar 

  38. Sola MC, Christensen RD, Hutson AD, Tarantal AF . Pharmacokinetics, pharmacodynamics, and safety of administering pegylated recombinant megakaryocyte growth and development factor to newborn rhesus monkeys. Pediatr Res 2000; 47: 208–214.

    Article  CAS  Google Scholar 

  39. Pastos KM, Slayton WB, Rimsza LM, Young L, Sola-Visner MC . Differential effects of recombinant thrombopoietin and bone marrow stromal-conditioned media on neonatal versus adult megakaryocytes. Blood 2006; 108: 3360–3362.

    Article  CAS  Google Scholar 

  40. Jelkmann W . Erythropoietin after a century of research: younger than ever. Eur J Haematol 2007; 78: 183–205.

    Article  CAS  Google Scholar 

  41. Ohlsson A, Aher SM . Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006; 3: CD004863.

    Google Scholar 

  42. Dame C, Wolber EM, Freitag P, Hofmann D, Bartmann P, Fandrey J . Thrombopoietin gene expression in the developing human central nervous system. Brain Res Dev Brain Res 2003; 143: 217–223.

    Article  CAS  Google Scholar 

  43. Ehrenreich H, Hasselblatt M, Knerlich F, von Ahsen N, Jacob S, Sperling S et al. A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain. Proc Natl Acad Sci USA 2005; 102: 862–867.

    Article  CAS  Google Scholar 

  44. Samoylenko A, Byts N, Rajalingam K, von Ahsen N, Rapp UR, Ehrenreich H et al. Thrombopoietin inhibits nerve growth factor-induced neuronal differentiation and ERK signalling. Cell Signal 2008; 20: 154–162.

    Article  CAS  Google Scholar 

  45. Widness JA, Veng-Pedersen P, Modi NB, Schmidt RL, Chestnut DH . Developmental differences in erythropoietin pharmacokinetics: increased clearance and distribution in fetal and neonatal sheep. J Pharmacol Exp Ther 1992; 261: 977–984.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Supported by a German Academic Exchange Service (DAAD) Fellowship (HS).

Author information

Authors and Affiliations

  1. Division of Newborn Medicine, Children's Hospital Boston and Harvard Medical School, Boston, MA, USA

    H Sallmon, R K Gutti, F Ferrer-Marin, Z-J Liu & M C Sola-Visner

  2. Department of Neonatology, Charité—Universitätsmedizin Berlin, Berlin, Germany

    H Sallmon

  3. Department of Haematology and Medical Oncology, Centro Regional de Hemodonación, University of Murcia, Murcia, Spain

    F Ferrer-Marin

Authors
  1. H Sallmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R K Gutti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Ferrer-Marin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Z-J Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M C Sola-Visner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M C Sola-Visner.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sallmon, H., Gutti, R., Ferrer-Marin, F. et al. Increasing platelets without transfusion: is it time to introduce novel thrombopoietic agents in neonatal care?. J Perinatol 30, 765–769 (2010). https://doi.org/10.1038/jp.2010.50

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2010.50

Keywords

This article is cited by

Search

Advanced search

Quick links