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In healthy term human newborns a unique hemostatic balance exists with reduced plasma concentrations of several coagulant and anticoagulant proteins, including antithrombin III (AT III). In preterm newborns even lower AT III concentrations are observed, with an associated thromboembolic risk. As part of our study program on the gene regulation of AT III, we investigated whether the increase in plasma AT III activity during fetal and neonatal development is particularly controlled at the transcriptional level. Plasma AT III activity and liver AT III mRNA content between the 8th wk of gestation and the 4th wk after birth were determined in sheep. AT III activity gradually increased from 34% of the mean adult level at 8-10 wk of gestation to 86% (2.5-fold) at term (21 wk), and remained in the adult range after birth. The mean body weight, and thus plasma volume, increased 57-fold. Therefore, the total plasma AT III activity increased 140-fold. The total liver AT III mRNA content increased only 14-fold between these fetal stages, mainly due to increased liver weight. Therefore, the total plasma AT III activity increased 10-fold more than the liver AT III mRNA content. In the neonatal period between d 1-3 and 28, the total plasma AT III activity increased only 2-fold more than the liver AT III mRNA content. We conclude that the increase in plasma AT III activity during the fetal period, and similarly the neonatal period, is not regulated at the transcriptional level. Furthermore, a unique fetal isoform of AT III was detected in sheep. This isoform had a 2500-D higher molecular mass compared with the other fetal, neonatal, and adult AT III isoform, and disappeared from the circulation between d 2 and 7 after birth. These AT III isoforms differ in their carbohydrate moiety.

Fetal and Neonatal Development of Antithrombin III Plasma Activity and Liver Messenger RNA Levels in Sheep