Evolution of blood coagulation activators and inhibitors in the healthy human fetus

Abstract

Blood coagulation proteins were determined in 285 healthy fetuses from 19 to 38 weeks' gestation and compared with those of 60 normal full- term newborns and 40 adult controls. Prolongation of the coagulation screening tests, prothrombin time, activated partial prothrombin time, and thrombin clotting time, in fetuses throughout intrauterine life was explained by low levels of vitamin K-dependent factors (II, VII, IX, and X), contact factors (XI, XII, prekallikrein, and high-molecular- weight kininogen), factor V, factor VIII, and fibrinogen. Low levels of antithrombin III, heparin cofactor II, protein C and protein S, and tissue factor pathway inhibitor were also found, and these probably contributed to a satisfactory hemostatic balance. Some of these parameters were evaluated by both immunologic and functional assays to detect possible “fetal” proteins. An increase in factor levels was observed after the thirty-fourth week of intrauterine life for most of the coagulation activators and inhibitors, but only factors V and VIII reached adult values at birth. This study therefore showed that fetal hemostasis is a dynamic system that evolves gradually toward the neonatal state and then toward the adult state.

TEG® and ROTEM® Traces: Clinical Applications of Viscoelastic Coagulation Monitoring in Neonatal Intensive Care Unit

“…Healthy neonates are born with an apparent combined deficiency in plasma coagulation factors, natural inhibitors of hemostasis, and components of the fibrinolytic system directly dependent on gestational age, birth weight, and maturation of hepatic function. Neonatal plasma concentrations of vitamin K-dependent coagulation factors (II, VII, IX, X) and contact factors (XII, XI, high-molecular-weight kininogen and prekallikrein) are about 50% of adult values and reach adult plasma levels between a few months of age and 16 years old [24,25,37]. Nevertheless, the hemostatic system is functionally balanced with no tendency toward coagulopathy or prothrombosis [26,[38][39][40][41][46][47][48][49][50][51].…”

“…Maternal coagulation factors are unable to cross the placental barrier because of their size [30][31][32]; fetal synthesis of coagulation proteins begins at 11 weeks of gestation. Physiological concentrations of coagulation proteins gradually increase with time; levels are lower in premature infants compared to full-term babies and healthy children [25][26][27][33][34][35][36][37].…”

“…Adult plasma levels of most coagulation proteins are reached between a few months of age and 16 years old. Neonatal plasma concentrations of vitamin K-dependent coagulation factors (II, VII, IX, X) and contact factors (XII, XI, high-molecular-weight kininogen and prekallikrein) are about 50% of adult values [24,25,37]. However, in contrast, the major inhibitors of the coagulation system antithrombin (AT), protein C (PC), and protein S (PS) show low levels at birth.…”

“…Overall, a shorter primary hemostasis bleeding time, reflecting an interaction between platelets and damaged endothelial cells to form a platelet plug, was found in healthy neonates compared with adults, which was normalized before the first month of life [46][47][48][49]. Reasons reported are an increased concentration and activity of von Willebrand factor (vWf; i.e., a high-molecular-weight adhesive glycoprotein that plays an essential role in primary hemostasis) potentiating vWF-mediated platelet adhesion and high hematocrit with the presence of large nucleated red cells [24,37,50,51].…”

“…Neonatal data are very limited because of the scarcity of viscoelastic reference values, the extreme variability of the NICU patients, and the differences in coagulation status, which is influenced by gestational age, weight, and maturation of hepatic functions [24][25][26][27][28][33][34][35][36][37]. TEG ® and ROTEM ® clinical applications in children have been almost entirely anesthesiology-driven, especially in newborn candidates for surgery, including cardiac procedures and ExtraCorporeal Membrane Oxygenation (ECMO) [79,80].…”