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Pharmacokinetics of Protein C and Antithrombin in the Fetal Lamb: A Model to Predict Human Neonatal Replacement DosingManco-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 Corresponding Author
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 firstname.lastname@example.org
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.
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