Fibrinogen Has a Rapid Turnover in the Healthy Newborn Lamb

Andrew, Maureen; Mitchell, Lisa M.; Berry, Leslie R.; Schmidt, Barbara; Hatton, M. W. C.

doi:10.1203/00006450-198803000-00002

Cited by 26 publications

(10 citation statements)

References 13 publications

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“…These data are similar to plasma t ½ studies of ovine fibrinogen conducted in neonatal lambs in comparison to adult sheep [36] . Our data support both increased dose and dose frequency for replacement of AT or PC newborn infants relative to dosing in adults.…”

Section: Discussionsupporting

confidence: 76%

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

Manco‐Johnson¹,

Hacker²,

Jacobson³

et al. 2008

Neonatology

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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 (V_d), clearance (Cl) and half-life (t_½), in the fetal lamb relative to the ewe. Results: AT studies showed statistically significant differences between ewes and fetuses in recovery (p < 0.0001), V_d (p = 0.0002) and Cl (p < 0.0001). The AT t_½ 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), V_d (p < 0.0001) and Cl (p = 0.004) differed significantly between ewes and singleton fetuses as did the t_½: 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 t_½ 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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Section: Discussionsupporting

confidence: 76%

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

Manco‐Johnson¹,

Hacker²,

Jacobson³

et al. 2008

Neonatology

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“…Animal experiments have indicated increased clearance of fibrinogen but not of prothrombin in newborns, and observations in humans have shown increased clearance of recombinant factor VIIa and factor VIII but not of factor IX and activated protein C in children. [13][14][15][16][17] Collectively, these observations are not fully consistent with a role of clearance the altered coagulation profile of children. Moreover, because coagulation factors are mainly cleared by the liver, the regulation of clearance rate should determined by the results presented in this report be present outside of the liver.…”

mentioning

confidence: 47%

The hemostatic status of pediatric recipients of adult liver grafts suggests that plasma levels of hemostatic proteins are not regulated by the liver

Lisman

Platto

Meijers

et al. 2011

Blood

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Plasma levels of coagulation factors differ profoundly between adults and children, but are remarkably stable throughout adulthood. It is unknown which factors determine plasma levels of coagulation factors in a given individual. We hypothesized that the liver, which synthesizes coagulation factors, also controls plasma levels. We measured a panel of coagulation factors in samples taken from either adults or young children who underwent a liver transplantation with adult donor livers. Samples were taken 1-3 months after transplantation, when the patients were clinically stable with adequate graft function. After liver transplantation, the hemostatic profile of the pediatric group was remarkably different from that of the adult group, and resembled the hemostatic profile of normal children. Thus, children transplanted with an adult liver graft maintain a pediatric hemostatic profile after transplantation despite receiving an adult liver graft. These findings suggest that plasma levels of hemostatic proteins are not controlled by the liver. IntroductionThe liver plays a central role in hemostasis because it synthesizes many of the plasma proteins involved in coagulation and fibrinolysis. 1 Although plasma levels of the various proteins vary between individuals, levels of these proteins within an individual are remarkably stable throughout adulthood, 2 although subtle elevations in coagulation factors are observed with increasing age. 3 In young children, the hemostatic system is still in development, and plasma levels of various hemostatic proteins in young children are profoundly different from that of adults. [4][5][6][7][8] Although levels of many coagulation factors increase toward values found in adults in the first year of life, striking differences between infants and adults are still present in children at 6 months of age. 6 More subtle differences between children and adults are still observed between the ages of 1 and 16 years. 4 It is not known which factors control the levels of coagulation factors in a given individual, but it appears plausible that the liver may be involved.Children with end-stage liver disease may undergo liver transplantation. These children will frequently obtain a split-liver graft from an adult donor. In these children undergoing transplantation, a unique situation occurs in which liver mass is not significantly different from children who do not, but liver tissue is of adult origin. Here we investigated whether transplantation of an adult (split) liver graft into very young children would convert the pediatric hemostatic status to a hemostatic profile similar to that of adults. Methods PatientsEleven children who underwent a primary (n ϭ 10) or second (n ϭ 1) liver transplantation for biliary atresia (n ϭ 10) or metabolic disease (n ϭ 1) with a mean of age 8.5 months (range, 4.2-11.7 months) and 9 adults with a mean age of 56 years (range, 46-65 years) who underwent transplantation for cirrhosis of various etiology (primary sclerosing cholangitis, 2 [one of which was a retrans...

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“…The age-dependent, physiological differences of the fibrinolytic system in the young (reduced plasminogen, a fetal plasminogen, reduced PAI-1, increased tPA and a fetal fibrinogen) suggest that the regulation of plasmin generation by fibrin and/or an endothelial surfaces will differ from adults [22, 23, 31]. However, whether age-related variation in fibrinolysis is due to increased plasmin generation or overcoming plasmin inhibition (to verify the mechanism) has not previously been studied.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Age on in vitro Plasmin Generation in the Presence of Fibrin Monomer

Parmar¹,

Mitchell²,

Berry³

et al. 2006

Acta Haematol

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Background and Objectives: The components of the fibrinolytic system interact to generate plasmin from its zymogen form, plasminogen. At birth, all the components of the fibrinolytic system are present but with differing plasma concentrations. The present study was undertaken to explore the effect of physiological, age-dependent factors of the fibrinolytic system during childhood on the capacity to generate plasmin. Design and Methods: Total plasmin generation was measured in venous plasma from umbilical cords and adults, on plastic and cell surfaces, in the presence of fibrin monomer, Desafib. Plasminogen, its inhibitors α₂-antiplasmin and plasminogen activator inhibitor type 1, and plasmin-α₂-antiplasmin complex in the time samples were assayed by enzyme-linked immunosorbent assay. The effect of addition of plasminogen on the plasmin generation in cord plasma and the effect of lipoprotein on adult and cord plasmin generation were measured. Results: On the surface of human umbilical vein endothelial cells, onset of plasmin generation was earlier (40 min) compared to plastic (60 min) but total plasmin generation was similar on both surfaces. The addition of plasminogen to cord plasma increased plasmin generation. Supplementation of lipoprotein in adult plasma had an inhibitory effect, but there was no significant effect in cord plasma. Interpretations and Conclusions: Plasmin generation is reduced in newborn compared to adult plasma. Decreased plasmin generation in cord plasma is likely due to decreased plasminogen concentration. The antifibrinolytic effect of lipoprotein is more pronounced in adults as compared to newborns due to the presence of higher plasminogen concentration.

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Fibrinogen Has a Rapid Turnover in the Healthy Newborn Lamb

Cited by 26 publications

References 13 publications

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

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

The hemostatic status of pediatric recipients of adult liver grafts suggests that plasma levels of hemostatic proteins are not regulated by the liver

The Influence of Age on in vitro Plasmin Generation in the Presence of Fibrin Monomer

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