Prothrombin Expression in the Adult and Fetal Rabbit Liver

Karpatkin, Margaret; Blei, Francine; Hurlet, A.; Greco, Alba; Tang, Zhichun

doi:10.1203/00006450-199109000-00014

“…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: 82%

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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“…In animal models, prothrombin mRNA expression by fetal liver nuclei is normal 71 and levels of prothrombin mRNA in fetal liver cells has been shown to be as high or higher than an adult liver. 72 Plasma clearance of coagulation factors has not been studied in the human fetus. However, in newborn infants, clearance of fibrinogen 73 and AT III 74 are increased.…”

Section: Fetal Physiologic Changesmentioning

confidence: 99%

Thrombin Regulation in Mother and Fetus During Pregnancy

Delorme

¹

,

Burrows²,

Ofosu³

et al. 1992

Semin Thromb Hemost

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Pregnancy is characterized by an increase in plasma concentration of several coagulants and with little or no change in plasma concentrations of inhibitors of thrombin or thrombin generation with the exception of a decrease in protein S. The net effect of these physiologic differences from nonpregnant adults is that, in vitro, thrombin generation is slightly increased in pregnancy plasma. Thrombin inhibition may be altered by the presence of circulating dermatan sulfate proteoglycan. Based on information on placental structure and function and ex vivo markers of thrombin generation, it is clear that there must be local generation of thrombin with fibrin deposition in the placenta. The roles of the alterations in the hemostatic system in regulating this increased thrombin activity remain to be elucidated. In addition, regulation of thrombin at the vessel wall of the placenta needs to be further explored, since it is likely important in preventing locally increased thrombin generation from producing systemic effects, that is, thrombosis. The fetal coagulation system is an immature, developing system, as is evident from low and gradually increasing plasma concentrations of both coagulants and inhibitors. Some of these low levels result from decreased gene expression in the immature liver. However, others (Factors II, VII and VIII) are related to other processes that remain to be determined. There is a progressive increase in the levels of these factors with increasing gestational age but most remain below adult values at term. As a result, thrombin generation and inhibition in vitro are decreased. Since bleeding and thrombotic complications are not a feature of normal fetal life, it is likely that the hemostatic system is balanced. In vivo data on thrombin generation and inhibition are lacking and the interaction of the physiologically different plasma of the fetus with the vessel wall is only now being explored.

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Prothrombin Expression in the Adult and Fetal Rabbit Liver

Cited by 14 publications

References 24 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

Thrombin Regulation in Mother and Fetus During Pregnancy

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