Thromb Haemost 2005; 93(01): 118-123
DOI: 10.1160/TH04-02-0093
Platelets and Blood Cells
Schattauer GmbH

Changes in thrombopoiesis and platelet reactivity in extremely low birth weight infants undergoing erythropoietin therapy for treatment of anaemia of prematurity

Nadja Haiden
1   Department of Pediatrics, Division of Neonatology and Intensive Care, University of Vienna, Austria
,
Francesco Cardona
2   Department of Clinical Pharmacology, University of Vienna, Austria
,
Jens Schwindt
1   Department of Pediatrics, Division of Neonatology and Intensive Care, University of Vienna, Austria
,
Angelika Berger
1   Department of Pediatrics, Division of Neonatology and Intensive Care, University of Vienna, Austria
,
Stefan Kuhle
3   Department of Neonatology, University Children's Hospital, Tübingen, Germany
,
Monika Homoncik
2   Department of Clinical Pharmacology, University of Vienna, Austria
,
Petra Jilma-Stohlawetz
4   Department of Blood Group Serology and Transfusion Medicine, University of Vienna, Austria
,
Arnold Pollak
1   Department of Pediatrics, Division of Neonatology and Intensive Care, University of Vienna, Austria
,
Bernd Jilma
2   Department of Clinical Pharmacology, University of Vienna, Austria
› Author Affiliations
Further Information

Correspondence to:

Nadja Haiden, MD
Department of Pediatrics
Division of Neonatology and Intensive Care
University of Vienna
Währinger Gürtel 18–20
1090 Vienna, Austria
Phone: +43 1 40400–3232   
Fax: +43 1 40400–3296   

Publication History

Received 14 February 2004

Accepted after revision 19 October 2004

Publication Date:
14 December 2017 (online)

 

Summary

Erythropoietin (Epo) is frequently administered to premature infants to stimulate erythropoiesis. There is evidence from studies in animals and healthy adults that Epo also interacts with thrombopoiesis and platelet function.This study investigates the effect of Epo therapy on platelet reactivity, peripheral platelet counts and thiazole orange-positive (TO+) platelets in extremely low birth weight (ELBW) infants. In a randomised-controlled trial, ELBW infants with a birth weight ≤ 800g and a gestational age ≤ 32 weeks were either randomised to a group receiving Epo during the first weeks of life or to a control group. Our results show that thrombin receptor-activating peptide (TRAP-6) -induced expression of P-selectin increased significantly during the first two weeks of Epo treatment.With the exception of week five, the number of TO+ platelets was significantly higher during the first eight weeks in Epo-treated infants compared to controls. The increase of TO+ platelets was not paralleled by an increase in total platelet count.We can conclude that Epo therapy has a short-lasting effect on platelet reactivity toTRAP-6 in ELBW infants during the first two weeks of life.Furthermore, Epo therapy is associated with an increase in the number of TO+ platelets compared to controls.


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  • References

  • 1 Brown MS, Garcia JF, Phibbs RH. et al Decreased response of plasma immunoreactive erythropoietin to „available oxygen" in anemia of prematurity. J Pediatr 1984; 105: 793-8.
  • 2 Shannon KM, Keith JF 3rd, Mentzer WC. et al Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics 1995; 95: 1-8.
  • 3 Strauss RG. Red blood cell transfusion practices in the neonate. Clin Perinatol 1995; 22: 641-55.
  • 4 Sullivan JL. Iron, plasma antioxidants, and the 'oxygen radical disease of prematurity. Am J Dis Child 1988; 142: 1341-4.
  • 5 Strauss RG. Transfusion therapy in neonates. Am J Dis Child 1991; 145: 904-11.
  • 6 Strauss RG, Burmeister LF, Johnson K. et al AS-1 red cells for neonatal transfusions: a randomized trial assessing donor exposure and safety. Transfusion 1996; 36: 873-8.
  • 7 Ohls RK. Human recombinant erythropoietin in the prevention and treatment of anemia of prematurity. Paediatr Drugs 2002; 4: 111-21.
  • 8 Maier RF, Obladen M, Scigalla P. et al The effect of epoetin beta (recombinant human erythropoietin) on the need for transfusion in very-low-birth-weight infants. European Multicentre Erythropoietin Study Group. N Engl J Med 1994; 330: 1173-8.
  • 9 Maier RF, Obladen M, Kattner E. et al High-versus low-dose erythropoietin in extremely low birth weight infants. The European Multicenter rhEPO Study Group. J Pediatr 1998; 132: 866-70.
  • 10 Meyer MP, Meyer JH, Commerford A. et al Recombinant human erythropoietin in the treatment of the anemia of prematurity: results of a double-blind, placebo- controlled study. Pediatrics 1994; 93: 918-23.
  • 11 Donato H, Vain N, Rendo P. et al Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: results of a randomized, placebo-controlled, multicenter trial. Pediatrics 2000; 105: 1066-72.
  • 12 Pollak A, Hayde M, Hayn M. et al Effect of intravenous iron supplementation on erythropoiesis in erythropoietin- treated premature infants. Pediatrics 2001; 107: 78-85.
  • 13 Al-Kharfy T, Smyth JA, Wadsworth L. et al Erythropoietin therapy in neonates at risk of having bronchopulmonary dysplasia and requiring multiple transfusions. J Pediatr 1996; 129: 89-96.
  • 14 Strauss RG. Recombinant erythropoietin for the anemia of prematurity: still a promise, not a panacea. J Pediatr 1997; 131: 653-5.
  • 15 Ohls RK, Ehrenkranz RA, Wright LL. 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: 934-42.
  • 16 Ohls RK, Harcum J, Schibler KR. et al The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double-blind, placebo-controlled study. J Pediatr 1997; 131: 661-5.
  • 17 Soubasi V, Kremenopoulos G, Diamanti E. et al Follow-up of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity. J Pediatr 1995; 127: 291-7.
  • 18 Bader D, Blondheim O, Jonas R. et al Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity. Acta Paediatr 1996; 85: 496-501.
  • 19 Wolf RF, Peng J, Friese P. et al Erythropoietin administration increases production and reactivity of platelets in dogs. Thromb Haemost 1997; 78: 1505-9.
  • 20 Jilma-Stohlawetz P, Dzirlo L, Hergovich N. et al Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 2000; 95: 2983-9.
  • 21 Rajasekhar D, Kestin AS, Bednarek FJ. et al Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood. Thromb Haemost 1994; 72: 957-63.
  • 22 Rajasekhar D, Barnard MR, Bednarek FJ. et al Platelet hyporeactivity in very low birth weight neonates. Thromb Haemost 1997; 77: 1002-7.
  • 23 Israels SJ, Cheang T, Roberston C. et al Impaired signal transduction in neonatal platelets. Pediatr Res 1999; 45: 687-91.
  • 24 Pietrucha T, Wojciechowski T, Greger J. et al Differentiated reactivity of whole blood neonatal platelets to various agonists. Platelets 2001; 12: 99-107.
  • 25 Worthington-White DA, Behnke M , Gross S. Premature infants require additional folate and vitamin B-12 to reduce the severity of the anemia of prematurity. Am J Clin Nutr 1994; 60: 930-5.
  • 26 Stohlawetz P, Folman CC, von dem Borne AE. et al Effects of endotoxemia on thrombopoiesis in men. Thromb Haemost 1999; 81: 613-7.
  • 27 Jilma-Stohlawetz P, Homoncik M, Jilma B. et al High levels of reticulated platelets and thrombopoietin characterize fetal thrombopoiesis. Br J Haematol 2001; 112: 466-8.
  • 28 Cox D. Methods for monitoring platelet function. Am Heart J 1998; 135: S160-9.
  • 29 Gatti L, Guarneri D, Caccamo ML. et al Platelet activation in newborns detected by flow-cytometry. Biol Neonate 1996; 70: 322-7.
  • 30 Grosshaupt B, Muntean W , Sedlmayr P. Hyporeactivity of neonatal platelets is not caused by preactivation during birth. Eur J Pediatr 1997; 156: 944-8.
  • 31 Simak J, Holada K, Janota J. et al Surface expression of major membrane glycoproteins on resting and TRAP-activated neonatal platelets. Pediatr Res 1999; 46: 445-9.
  • 32 Homoncik M, Jilma B, Donham DC. et al Activation of calcium-dependent calmodulin by calcium( II)3(3,5-diisopropylsalicylate)6(H2O)6 decreases thrombin receptor activating peptide-induced P-selectin expression. Blood Coagul Fibrinolysis 2003; 14: 131-8.
  • 33 Hezard N, Potron G, Schlegel N. et al Unexpected persistence of platelet hyporeactivity beyond the neonatal period: a flow cytometric study in neonates, infants and older children. Thromb Haemost 2003; 90: 116-23.
  • 34 Robinson M, Machin S, Mackie I. et al In vivo biotinylation studies: specificity of labelling of reticulated platelets by thiazole orange and mepacrine. Br J Haematol 2000; 108: 859-64.
  • 35 Joseph MA, Adams D, Maragos J. et al Flow cytometry of neonatal platelet RNA. J Pediatr Hematol Oncol 1996; 18: 277-81.
  • 36 Peterec SM, Brennan SA, Rinder HM. et al Reticulated platelet values in normal and thrombocytopenic neonates. J Pediatr 1996; 129: 269-74.

Correspondence to:

Nadja Haiden, MD
Department of Pediatrics
Division of Neonatology and Intensive Care
University of Vienna
Währinger Gürtel 18–20
1090 Vienna, Austria
Phone: +43 1 40400–3232   
Fax: +43 1 40400–3296   

  • References

  • 1 Brown MS, Garcia JF, Phibbs RH. et al Decreased response of plasma immunoreactive erythropoietin to „available oxygen" in anemia of prematurity. J Pediatr 1984; 105: 793-8.
  • 2 Shannon KM, Keith JF 3rd, Mentzer WC. et al Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics 1995; 95: 1-8.
  • 3 Strauss RG. Red blood cell transfusion practices in the neonate. Clin Perinatol 1995; 22: 641-55.
  • 4 Sullivan JL. Iron, plasma antioxidants, and the 'oxygen radical disease of prematurity. Am J Dis Child 1988; 142: 1341-4.
  • 5 Strauss RG. Transfusion therapy in neonates. Am J Dis Child 1991; 145: 904-11.
  • 6 Strauss RG, Burmeister LF, Johnson K. et al AS-1 red cells for neonatal transfusions: a randomized trial assessing donor exposure and safety. Transfusion 1996; 36: 873-8.
  • 7 Ohls RK. Human recombinant erythropoietin in the prevention and treatment of anemia of prematurity. Paediatr Drugs 2002; 4: 111-21.
  • 8 Maier RF, Obladen M, Scigalla P. et al The effect of epoetin beta (recombinant human erythropoietin) on the need for transfusion in very-low-birth-weight infants. European Multicentre Erythropoietin Study Group. N Engl J Med 1994; 330: 1173-8.
  • 9 Maier RF, Obladen M, Kattner E. et al High-versus low-dose erythropoietin in extremely low birth weight infants. The European Multicenter rhEPO Study Group. J Pediatr 1998; 132: 866-70.
  • 10 Meyer MP, Meyer JH, Commerford A. et al Recombinant human erythropoietin in the treatment of the anemia of prematurity: results of a double-blind, placebo- controlled study. Pediatrics 1994; 93: 918-23.
  • 11 Donato H, Vain N, Rendo P. et al Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: results of a randomized, placebo-controlled, multicenter trial. Pediatrics 2000; 105: 1066-72.
  • 12 Pollak A, Hayde M, Hayn M. et al Effect of intravenous iron supplementation on erythropoiesis in erythropoietin- treated premature infants. Pediatrics 2001; 107: 78-85.
  • 13 Al-Kharfy T, Smyth JA, Wadsworth L. et al Erythropoietin therapy in neonates at risk of having bronchopulmonary dysplasia and requiring multiple transfusions. J Pediatr 1996; 129: 89-96.
  • 14 Strauss RG. Recombinant erythropoietin for the anemia of prematurity: still a promise, not a panacea. J Pediatr 1997; 131: 653-5.
  • 15 Ohls RK, Ehrenkranz RA, Wright LL. 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: 934-42.
  • 16 Ohls RK, Harcum J, Schibler KR. et al The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double-blind, placebo-controlled study. J Pediatr 1997; 131: 661-5.
  • 17 Soubasi V, Kremenopoulos G, Diamanti E. et al Follow-up of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity. J Pediatr 1995; 127: 291-7.
  • 18 Bader D, Blondheim O, Jonas R. et al Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity. Acta Paediatr 1996; 85: 496-501.
  • 19 Wolf RF, Peng J, Friese P. et al Erythropoietin administration increases production and reactivity of platelets in dogs. Thromb Haemost 1997; 78: 1505-9.
  • 20 Jilma-Stohlawetz P, Dzirlo L, Hergovich N. et al Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 2000; 95: 2983-9.
  • 21 Rajasekhar D, Kestin AS, Bednarek FJ. et al Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood. Thromb Haemost 1994; 72: 957-63.
  • 22 Rajasekhar D, Barnard MR, Bednarek FJ. et al Platelet hyporeactivity in very low birth weight neonates. Thromb Haemost 1997; 77: 1002-7.
  • 23 Israels SJ, Cheang T, Roberston C. et al Impaired signal transduction in neonatal platelets. Pediatr Res 1999; 45: 687-91.
  • 24 Pietrucha T, Wojciechowski T, Greger J. et al Differentiated reactivity of whole blood neonatal platelets to various agonists. Platelets 2001; 12: 99-107.
  • 25 Worthington-White DA, Behnke M , Gross S. Premature infants require additional folate and vitamin B-12 to reduce the severity of the anemia of prematurity. Am J Clin Nutr 1994; 60: 930-5.
  • 26 Stohlawetz P, Folman CC, von dem Borne AE. et al Effects of endotoxemia on thrombopoiesis in men. Thromb Haemost 1999; 81: 613-7.
  • 27 Jilma-Stohlawetz P, Homoncik M, Jilma B. et al High levels of reticulated platelets and thrombopoietin characterize fetal thrombopoiesis. Br J Haematol 2001; 112: 466-8.
  • 28 Cox D. Methods for monitoring platelet function. Am Heart J 1998; 135: S160-9.
  • 29 Gatti L, Guarneri D, Caccamo ML. et al Platelet activation in newborns detected by flow-cytometry. Biol Neonate 1996; 70: 322-7.
  • 30 Grosshaupt B, Muntean W , Sedlmayr P. Hyporeactivity of neonatal platelets is not caused by preactivation during birth. Eur J Pediatr 1997; 156: 944-8.
  • 31 Simak J, Holada K, Janota J. et al Surface expression of major membrane glycoproteins on resting and TRAP-activated neonatal platelets. Pediatr Res 1999; 46: 445-9.
  • 32 Homoncik M, Jilma B, Donham DC. et al Activation of calcium-dependent calmodulin by calcium( II)3(3,5-diisopropylsalicylate)6(H2O)6 decreases thrombin receptor activating peptide-induced P-selectin expression. Blood Coagul Fibrinolysis 2003; 14: 131-8.
  • 33 Hezard N, Potron G, Schlegel N. et al Unexpected persistence of platelet hyporeactivity beyond the neonatal period: a flow cytometric study in neonates, infants and older children. Thromb Haemost 2003; 90: 116-23.
  • 34 Robinson M, Machin S, Mackie I. et al In vivo biotinylation studies: specificity of labelling of reticulated platelets by thiazole orange and mepacrine. Br J Haematol 2000; 108: 859-64.
  • 35 Joseph MA, Adams D, Maragos J. et al Flow cytometry of neonatal platelet RNA. J Pediatr Hematol Oncol 1996; 18: 277-81.
  • 36 Peterec SM, Brennan SA, Rinder HM. et al Reticulated platelet values in normal and thrombocytopenic neonates. J Pediatr 1996; 129: 269-74.