Vol. 95, No. 4, 2009
Issue release date: June 2009
Free Access
Neonatology 2009;95:279–285
Original Paper
Add to my selection

Pharmacokinetics of Protein C and Antithrombin in the Fetal Lamb: A Model to Predict Human Neonatal Replacement Dosing

Manco-Johnson M.J.a, b · Hacker M.R.a, d · Jacobson L.J.a, b · Hay, Jr. W.W.b, c
aMountain States Regional Hemophilia and Thrombosis Center, bDepartment of Pediatrics, and cPerinatal Research Center, University of Colorado Denver, Aurora, Colo., and dDepartment of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass., USA
email Corresponding Author

 goto top of outline Key Words

  • Protein C
  • Antithrombin
  • Pharmacokinetics
  • Lamb
  • Replacement protein

 goto top of outline Abstract

Background: The preterm infant is at risk for consumptive coagulopathy and thrombosis due to late maturation of coagulation regulatory proteins. Replacement proteins are available, but neonatal pharmacokinetic data are lacking. Objective: The objective was to determine the pharmacokinetic properties of antithrombin (AT) and protein C (PC) in order to provide data for estimating doses in human infants. Methods: A catheterized ovine model was used to determine pharmacokinetic properties of AT and PC, including plasma recovery, volume of distribution (Vd), clearance (Cl) and half-life (t½), in the fetal lamb relative to the ewe. Results: AT studies showed statistically significant differences between ewes and fetuses in recovery (p < 0.0001), Vd (p = 0.0002) and Cl (p < 0.0001). The AT t½ was significantly shortened among fetuses (5.55 h, 95% CI: 4.01–7.08) compared to ewes (18.7 h, 95% CI: 11.6–25.8). PC recovery (p < 0.0001), Vd (p < 0.0001) and Cl (p = 0.004) differed significantly between ewes and singleton fetuses as did the t½: 3.86 h (95% CI: 3.35–4.36) and 11.9 h (95% CI: 10.9–12.9) in the singletons and ewes, respectively. All PC parameters were significantly different for twins compared to ewes. Conclusions: AT and PC show decreased recovery and t½ in the fetal lamb. These data can be used to estimate dosing for human neonates in comparison with human adult dosing recommendations.

Copyright © 2008 S. Karger AG, Basel

 goto top of outline References
  1. Journeycake JM, Manco-Johnson MJ: Thrombosis during infancy and childhood: what we know and what we do not know. Hematol Oncol Clin North Am 2004;18:1315–1319.
  2. Manco-Johnson MJ: Pathophysiology of neonatal disseminated intravascular coagulation and thrombosis; in Polin RA, Fox WW (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 2002.
  3. Andrew M, Paes B, Johnston M: Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990;12:95–104.
  4. Manco-Johnson MJ: Development of hemostasis in the fetus. Thromb Res 2005;115 (suppl 1):55–63.

    External Resources

  5. Manco-Johnson MJ, Marlar RA, Jacobson LJ, Hays T, Warady BA: Severe protein C deficiency in newborn infants. J Pediatr 1988;113:359–363.
  6. Manco-Johnson MJ, Abshire TC, Jacobson LJ, Marlar RA: Severe neonatal protein C deficiency: prevalence and thrombotic risk. J Pediatr 1991;119:793–798.
  7. McDonald MM, Jacobson LJ, Hay WW Jr, Hathaway WE: Heparin clearance in the newborn. Pediatr Res 1981;15:1015–1018.
  8. McDonald MM, Hathaway WE: Anticoagulant therapy by continuous heparinization in newborn and older infants. J Pediatr 1982;101:451–457.
  9. Roman K, Rosenthal E, Razavi R: Pulmonary arterial thrombosis in a neonate with homozygous deficiency of antithrombin III: successful outcome following pulmonary thrombectomy and infusions of antithrombin III concentrate. Cardiol Young 2000;10:275–278.
  10. Sanchez J, Velasco F, Alvarez R, Roman J, Torres A: Aortic thrombosis in a neonate with hereditary antithrombin III deficiency: successful outcome with thrombolytic and replacement treatment. Acta Paediatr 1996;85:245–247.
  11. Seguin J, Weatherstone K, Nankervis C: Inherited antithrombin III deficiency in the neonate. Arch Pediatr Adolesc Med 1994;148:389–393.
  12. Petaja J, Peltola K, Rautiainen P: Disappearance of symptomatic venous thrombosis after neonatal cardiac operations during antithrombin III substitution. J Thorac Cardiovasc Surg 1999;118:955–956.
  13. Shapiro A: Antithrombin deficiency in special clinical syndromes. I. Neonatal and pediatric/physiologic deficiency: extracorporeal membrane oxygenation. Semin Hematol 1995;32:33–36.
  14. Ishiguro K, Kojima T, Kadomatsu K, Nakayama Y, Takagi A, Suzuki M, Takeda N, Ito M, Yamamoto K, Matsushita T, Kusugami K, Muramatsu T, Saito H: Complete antithrombin deficiency in mice results in embryonic lethality. J Clin Invest 2000;106:873–878.
  15. Menache D, O’Malley JP, Schorr JB, Wagner B, Williams C; and the Cooperative Study Group: Alving BM, Ballard JO, Goodnight SH, Hathaway WE, Hultin MB, Kitchens CS, Lessner HE, Maltary AZ, Manco-Johnson M, McGehee WG, Penner JA, Sanders JE: Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Blood 1990;75:33–39.
  16. Inomoto T, Takamoto M, Tamura R, Maegawa M, Kamada M, Takayanagi M: Effective prophylaxis of thrombosis by antithrombin III concentrate in a pregnant woman with congenital antithrombin III deficiency: relations between plasma antithrombin III activity and the plasma levels of hemostatic molecular markers. Haemostasis 1991;21:147–154.
  17. Shiozaki A, Arai T, Izumi R, Niiya K, Sakuragawa N: Congenital antithrombin III deficient neonate treated with antithrombin III concentrates. Thromb Res 1993;70:211–216.
  18. Coccheri S, Palareti G: Antithrombin III replacement in orthotopic liver transplantation. Semin Thromb Hemost 1993;19:268–272.
  19. Mitchell L, Andrew M, Hanna K, Abshire T, Halton J, Wu J, Anderson R, Cherrick I, Desai S, Mahoney D, McCusker P, Chait P, Abdolell M, de VG, Mikulis D: Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving L-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost 2003;90:235–244.
  20. Munteanu C, Bloodworth LL, Korn TH: Antithrombin concentrate with plasma exchange in purpura fulminans. Pediatr Crit Care Med 2000;1:84–87.
  21. Nowak-Gottl U, Groll A, Kreuz WD, Brand M, Breddin HK, von Lowevenich V, Kornhuber B: Treatment of disseminated intravascular coagulation with antithrombin III concentrate in children with verified infection (in German). Klin Pädiatr 1992;204:134–140.
  22. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L: Maturation of the hemostatic system during childhood. Blood 1992;80:1998–2005.
  23. McDonald MM, Johnson ML, Rumack CM, Koops BL, Guggenheim MA, Babb C, Hathaway WE: Role of coagulopathy in newborn intracranial hemorrhage. Pediatrics 1984;74:26–31.
  24. Branson HE, Katz J, Marble R, Griffin JH: Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 1983;ii:1165–1168.

    External Resources

  25. Hartman KR, Manco-Johnson M, Rawlings JS, Bower DJ, Marlar RA: Homozygous protein C deficiency: early treatment with warfarin. Am J Pediatr Hematol Oncol 1989;11:395–401.
  26. Marlar RA, Montgomery RR, Broekmans AW: Diagnosis and treatment of homozygous protein C deficiency. Report of the Working Party on Homozygous Protein C Deficiency of the Subcommittee on Protein C and Protein S, International Committee on Thrombosis and Haemostasis. J Pediatr 1989;114:528–534.
  27. Manco-Johnson M, Nuss R: Protein C concentrate prevents peripartum thrombosis. Am J Hematol 1992;40:69–70.
  28. Zimbelman J, Lefkowitz J, Schaeffer C, Hays T, Manco-Johnson M, Manhalter C, Nuss R: Unusual complications of warfarin therapy: skin necrosis and priapism. J Pediatr 2000;137:266–268.
  29. Dreyfus M, Magny JF, Bridey F, Schwarz HP, Planche C, Dehan M, Tchernia G: Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med 1991;325:1565–1568.
  30. Nardi M, Karpatkin M: Prothrombin and protein C in early childhood: normal adult levels are not achieved until the fourth year of life. J Pediatr 1986;109:843–845.
  31. Manco-Johnson MJ, Carver T, Jacobson LJ, Townsend SF, Hay WW Jr: Hyperglycemia-induced hyperinsulinemia decreases maternal and fetal plasma protein C concentration during ovine gestation. Pediatr Res 1994;36:293–299.
  32. Manco-Johnson MJ, Spedale S, Peters M, Townsend SF, Jacobson LJ, Christian J, Krugman SD, Hay WW Jr, Sparks JW: Identification of a unique form of protein C in the ovine fetus: developmentally linked transition to the adult form. Pediatr Res 1995;37:365–372.
  33. Manco-Johnson MJ, Jacobson LJ, Hacker MR, Townsend SF, Murphy J, Hay W Jr: Development of coagulation regulatory proteins in the fetal and neonatal lamb. Pediatr Res 2002;52:580–588.
  34. Creasy RK, Drost M, Green MV, Morris JA: Determination of fetal, placental and neonatal blood volumes in the sheep. Circ Res 1970;27:487–494.
  35. Loughnan PM, Sitar DS, Ogilvie RI, Neims AH: The two-compartment open-system kinetic model: a review of its clinical implications and applications. J Pediatr 1976;88:869–873.
  36. Andrew M, Mitchell L, Berry LR, Schmidt B, Hatton MW: Fibrinogen has a rapid turnover in the healthy newborn lamb. Pediatr Res 1988;23:249–252.
  37. Dreyfus M, Masterson M, David M, Rivard GE, Muller FM, Kreuz W, Beeg T, Minford A, Allgrove J, Cohen JD: Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency. Semin Thromb Hemost 1995;21:371–381.
  38. Baliga V, Thwaites R, Tillyer ML, Minford A, Parapia L, Allgrove J: Homozygous protein C deficiency – management with protein C concentrate. Eur J Pediatr 1995;154:534–538.
  39. Guilcher GM, Scully MF, Harvey M, Hand JP: Treatment of intracranial and extracranial haemorrhages in a neonate with severe haemophilia B with recombinant factor IX infusion. Haemophilia 2005;11:411–414.
  40. Douvas MG, Monahan PE: Life-threatening thrombosis complicating the management of hepatic hemorrhage: anticoagulant treatment in a newborn with hemophilia B. J Pediatr Hematol Oncol 2004;26:258–263.
  41. Bidlingmaier C, Bergmann F, Kurnik K: Haemophilia A in two premature infants. Eur J Pediatr 2005;164:70–72.

 goto top of outline Author Contacts

Marilyn J. Manco-Johnson
Mountain States Regional Hemophilia and Thrombosis Center
PO Box 6507, MS F416
Aurora, CO 80045-0507 (USA)
Tel. +1 303 724 0365, Fax +1 303 724 0947, E-Mail marilyn.manco-johnson@uchsc.edu

 goto top of outline Article Information

Received: November 29, 2007
Accepted after revision: May 19, 2008
Published online: November 27, 2008
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 1, Number of References : 41

 goto top of outline Publication Details

Neonatology (Fetal and Neonatal Research)

Vol. 95, No. 4, Year 2009 (Cover Date: June 2009)

Journal Editor: Halliday H.L. (Belfast), Speer C.P. (Würzburg)
ISSN: 1661–7800 (Print), eISSN: 1661–7819 (Online)

For additional information: http://www.karger.com/NEO

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.