Prothrombin Synthesis in the Adult and Fetal Liver

Cohen, Leon; McKinnell, James; Puglisi, Vincent J.; Greco, Alba; Nardi, Michael A.; Lee, Margaret; Karpatkin, Margaret

doi:10.1055/s-0038-1665435

“…Regulation of vitamin K-dependent proteins may be unique. Karpatkin et al (40,41) documented expression of fetal hepatic mRNA for rabbit prothrombin equal to or greater than expression in adult liver while plasma concentrations of prothrombin remained low, similar to our findings for PS and our perinatal results for PC as well as the FX results of Hassan et al (39). The discordance between relative abundance of mRNA for vitamin K-dependent proteins and plasma concentrations supports that regulation is not at the level of gene transcription.…”

Section: Discussionsupporting

confidence: 90%

Development of Coagulation Regulatory Proteins in the Fetal and Neonatal Lamb

Manco‐Johnson

¹

,

Jacobson

²

,

Hacker

³

et al. 2002

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To investigate the development of coagulation regulatory proteins-protein C (PC), protein S (PS), and antithrombin (AT)-in relationship to the procoagulant protein factor X (FX), a chronically catheterized fetal ovine model was used. Infusion and sampling catheters were placed into pregnant ewes and their fetuses and maintained from mid-gestation. From a total of 110 fetuses, 17 lambs, and 63 ewes that were studied on one to 15 occasions, 212 fetal, 88 neonatal, and 157 maternal samples were obtained. Liver tissue was obtained from 31 fetuses and 15 ewes. Plasma levels of all proteins studied were higher in the ewe than in the fetus (p < 0.0001). Plasma levels of FX, PC, and PS achieved neonatal levels by mid-gestation with mild but significant decreases during mid- and late gestation. Fetal and early neonatal plasma concentrations of these vitamin K-dependent proteins fit a model with both quadratic (p < 0.01) and linear (p < 0.01) components. The discrepant levels in mRNA relative to plasma concentration were consistent with regulatory control beyond the level of transcription. In contrast, a simple linear increase in plasma protein levels was determined for the vitamin K-independent coagulation regulatory protein, AT (p for quadratic component > 0.05). This study suggests that fetal regulation of coagulation proteins follows characteristic patterns relative to the vitamin K dependence of the protein rather than its role as a procoagulant versus regulatory protein.

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“…Karpatkin et al (40,41) documented expression of fetal hepatic mRNA for rabbit prothrombin equal to or greater than expression in adult liver while plasma concentrations of prothrombin remained low, similar to our findings for PS and our perinatal results for PC as well as the FX results of Hassan et al (39). The discordance between relative abundance of mRNA for vitamin K-dependent proteins and plasma concentrations supports that regulation is not at the level of gene transcription.…”

Section: Coagulation Proteins In the Lambsupporting

confidence: 91%

Development of Coagulation Regulatory Proteins in the Fetal and Neonatal Lamb

Manco‐Johnson

¹

2002

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To investigate the development of coagulation regulatory proteins-protein C (PC), protein S (PS), and antithrombin (AT)-in relationship to the procoagulant protein factor X (FX), a chronically catheterized fetal ovine model was used. Infusion and sampling catheters were placed into pregnant ewes and their fetuses and maintained from mid-gestation. From a total of 110 fetuses, 17 lambs, and 63 ewes that were studied on one to 15 occasions, 212 fetal, 88 neonatal, and 157 maternal samples were obtained. Liver tissue was obtained from 31 fetuses and 15 ewes. Plasma levels of all proteins studied were higher in the ewe than in the fetus (p Ͻ 0.0001). Plasma levels of FX, PC, and PS achieved neonatal levels by mid-gestation with mild but significant decreases during mid-and late gestation. Fetal and early neonatal plasma concentrations of these vitamin K-dependent proteins fit a model with both quadratic (p Ͻ 0.01) and linear (p Ͻ 0.01) components. The discrepant levels in mRNA relative to plasma concentration were consistent with regulatory control beyond the level of transcription. In contrast, a simple linear increase in plasma protein levels was determined for the vitamin K-independent coagulation regulatory protein, AT (p for quadratic component Ͼ 0.05). This study suggests that fetal regulation of coagulation proteins follows characteristic patterns relative to the vitamin K dependence of the protein rather than its role as a procoagulant versus regulatory protein. The hemostatic systems of the fetus and neonate differ from that of the adult. Plasma concentrations of coagulation proteins mature at different rates during in utero and postnatal development (1-3). In particular, vitamin K-dependent factors, prothrombin, PC, PS, and factors VII, IX, and X, as well as contact factors XI, XII, prekallikrein, and high-molecular-weight kininogen, are present in very low concentrations in the fetus and do not achieve normal adult levels until later infancy to adolescence (2-7). Clinically, the well neonate has a functionally intact hemostatic system. However, the stressed infant demonstrates an increased predisposition to thrombosis, both induced and spontaneous (8). The increased rate of thrombosis in neonates is generally attributed to physiologically low levels of coagulation regulatory proteins, particularly PC, PS, and AT.PC is a vitamin K-dependent serine protease that serves a critical role in the regulation of coagulation. Activated PC, with its cofactor PS, inactivates activated procoagulant factors V and VIII (9). Infants with severe genetic deficiencies of either PC or PS manifest spontaneous thrombosis in utero or within hours of birth (10, 11). Our previous work showed that the mean concentration of PC in the extremely preterm infant is 0.20 U/mL, as compared with 1.00 U/mL in healthy adults (6, 7). An increased risk of catheter-related and spontaneous thrombosis was demonstrated in preterm infants with plasma concentrations of PC Ͻ0.10 U/mL (7).AT is an essential regulatory protein that functions through i...

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“…[23][24][25] Essentially, the levels of coagulation protease zymogens strongly correlate with gestational age and in premature infants may be as low as 10% of adults, [26][27][28] though they are synthesized equally efficiently both in the fetuses and in adults. 23,29 According to this biological observation, the term developmental hemostasis was expressly coined by Andrew et al in the late 1980s (See Monagle et al 21 for an overview). Basically, Andrew and colleagues observed that the concentrations of most coagulation proteins vary significantly with age.…”

Section: Hemostatic Abnormalities In the Newbornmentioning

confidence: 99%

Coagulation Testing in Pediatric Patients: The Young Are Not Just Miniature Adults

Lippi

¹

,

Franchini

²

,

Montagnana

³

et al. 2007

Semin Thromb Hemost

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During the past few decades, great progress has been made toward a better understanding of the development of the hemostatic system. It is now clear that the physiology of hemostasis in pediatric patients differs widely from that in adults, supporting the hypothesis that children might have natural protective mechanisms that justify such variations. However, the correct interpretation of hemostasis test results in young patients, along with a deep understanding of the normal postnatal development in the human coagulation system, are essential prerequisites to the proper investigation of thrombotic and hemorrhagic problems in pediatric patients. Because the hemostatic system is not fully mature by 3 to 6 months of age, it is important to recognize that interpretation of laboratory data in pediatric patients must be accompanied by appropriate age-dependent reference ranges, which should also be specific for the testing system used, to prevent misclassification of children as having defects of factors and inhibitors of the coagulation system.

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Prothrombin Synthesis in the Adult and Fetal Liver

Cited by 7 publications

References 18 publications

Development of Coagulation Regulatory Proteins in the Fetal and Neonatal Lamb

Development of Coagulation Regulatory Proteins in the Fetal and Neonatal Lamb

Development of Coagulation Regulatory Proteins in the Fetal and Neonatal Lamb

Coagulation Testing in Pediatric Patients: The Young Are Not Just Miniature Adults

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