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.
© 2008 S. Karger AG, Basel
- Protein C
- Replacement protein
- 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.
- Manco-Johnson MJ: Pathophysiology of neonatal disseminated intravascular coagulation and thrombosis; in Polin RA, Fox WW (eds): Fetal and Neonatal Physiology. Philadelphia, Saunders, 2002.
- 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.
- Manco-Johnson MJ: Development of hemostasis in the fetus. Thromb Res 2005;115 (suppl 1):55–63.
- Manco-Johnson MJ, Marlar RA, Jacobson LJ, Hays T, Warady BA: Severe protein C deficiency in newborn infants. J Pediatr 1988;113:359–363.
- Manco-Johnson MJ, Abshire TC, Jacobson LJ, Marlar RA: Severe neonatal protein C deficiency: prevalence and thrombotic risk. J Pediatr 1991;119:793–798.
- McDonald MM, Jacobson LJ, Hay WW Jr, Hathaway WE: Heparin clearance in the newborn. Pediatr Res 1981;15:1015–1018.
- McDonald MM, Hathaway WE: Anticoagulant therapy by continuous heparinization in newborn and older infants. J Pediatr 1982;101:451–457.
- 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.
- 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.
- Seguin J, Weatherstone K, Nankervis C: Inherited antithrombin III deficiency in the neonate. Arch Pediatr Adolesc Med 1994;148:389–393.
- 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.
- Shapiro A: Antithrombin deficiency in special clinical syndromes. I. Neonatal and pediatric/physiologic deficiency: extracorporeal membrane oxygenation. Semin Hematol 1995;32:33–36.
- 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.
- 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.
- 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.
- 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.
- Coccheri S, Palareti G: Antithrombin III replacement in orthotopic liver transplantation. Semin Thromb Hemost 1993;19:268–272.
- 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.
- Munteanu C, Bloodworth LL, Korn TH: Antithrombin concentrate with plasma exchange in purpura fulminans. Pediatr Crit Care Med 2000;1:84–87.
- 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.
- Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L: Maturation of the hemostatic system during childhood. Blood 1992;80:1998–2005.
- 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.
- 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.
- 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.
- 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.
- Manco-Johnson M, Nuss R: Protein C concentrate prevents peripartum thrombosis. Am J Hematol 1992;40:69–70.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Bidlingmaier C, Bergmann F, Kurnik K: Haemophilia A in two premature infants. Eur J Pediatr 2005;164:70–72.
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 email@example.com
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
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)
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