Maturation of the hemostatic system during childhood

Abstract

The hemostatic system is assumed to be similar in children and adults and reference ranges established for adults are commonly used to evaluate children suspected of having congenital or acquired hemostatic problems. However, we know that the hemostatic system is not fully mature by 6 months of age and comprehensive studies of healthy older children have not been published. Therefore, we conducted a prospective cohort study of the hemostatic system in healthy children having minor, elective day surgery. After obtaining informed consent, a 3-mL blood sample was obtained at the time routine preoperative blood work was drawn. The plasma was fractioned and stored at -70 degrees C for batch assaying. We measured the concentration of 33 components of the hemostatic system (functional and immunologic assays) and the bleeding time (automated pediatric device) in 246 children aged 1 to 16 inclusive (a minimum of four subjects at each age). Eleven components of hemostasis (fibrinogen, prekallikrein, high-molecular weight kininogen, factors VIII and XIII, antithrombin III [ATIII], heparin cofactor II [HCII], alpha 1-antitrypsin [alpha 1AT], protein S, plasminogen, alpha 2-antiplasmin [alpha 2AP]) had mean values and ranges of normal that were similar to adults. Mean values of seven coagulants (II, V, VII, IX, X, XI, XII) were significantly lower than adult values and varied with age. Values for three inhibitors, alpha 2- macroglobulin (alpha 2M), protein C, and protein C1-inhibitor (C1-Inh) also differed from adults. Alpha 2M and C1-Inh inhibitor levels were elevated throughout childhood, whereas protein C levels were low, with a lower limit of normal of 0.40 U/mL until the age of 11. Finally, the upper limit of normal for the bleeding time was longer in children during the first 10 years of life, but decreased to adult values in the teenage years. In summary, there are important physiologic differences in the hemostatic system in children compared with adults. The decreased levels of several critical coagulants and increased levels of alpha 2M may contribute in part to the lower risk of thrombotic events in childhood. Age-matched controls should be used for evaluation of the hemostatic system in children with suspected congenital or acquired defects.

Pharmacokinetics, efficacy, and safety of LMWHs in venous thrombosis and stroke in neonates, infants and children

“…After 2-4 h treatment, target anti-Xa ranges reported for children were 0.5-1.0 U ml À1 for dalteparin, nadroparin and tinzaparin (Nohe et al, 1999;Hofmann et al, 2001;Kuhle et al, 2005), and 0.4-1.0 U ml À1 for enoxaparin and reviparin-sodium (Massicotte et al, 1996(Massicotte et al, , 2003b; target ranges administered for prophylaxis in children following the initial treatment phase were 0.1-0.3 U ml À1 for enoxaparin, dalteparin and reviparin-sodium, and 0.2-0.4 U ml À1 for nadroparin, respectively (Massicotte et al, 1996(Massicotte et al, , 2003aHofmann et al, 2001). The LMWHs enoxaparin, dalteparin, nadroparin, reviparin and tinzaparin have all been used off-label in children (Andrew et al, 1992;Streif et al, 2003;Massicotte et al, 1996;Nohe et al, 1999;Dix et al, 2000;Punzalan et al, 2000;DeVeber et al, 2001;Hofmann et al, 2001;Nowak-Göttl et al, 2001a, b;Shama et al, 2002;Ho et al, 2004;Kosch et al, 2004;Michaels et al, 2004;Revel-Vilk et al, 2004;Kreuz et al, 2006;Merkel et al, 2006;Schobess et al, 2006). The aforementioned LMWHs have been used effectively for the treatment of venous thrombosis, including pulmonary embolism, thrombosis of the upper and lower venous system, catheter-induced thromboses, renal vein thrombosis, and cerebral venous thrombosis.…”

Thrombosis in infants in the neonatal intensive care unit: Analysis of a large national database

“…Adopting therapies and treatment guidelines developed for adult populations for use in infants is problematic 3 . Nearly every component of the hemostatic system undergoes qualitative and quantitative changes from neonatal life to adulthood 7‐12 . Recent studies have shown that even the structure of fibrin clots differs substantially between infants and adults, and both differ in structure from clots produced from infant blood mixed with adult blood 13 .…”

Reconstituted fresh whole blood improves clinical outcomes compared with stored component blood therapy for neonates undergoing cardiopulmonary bypass for cardiac surgery: A randomized controlled trial

“…These include factors such as hemostatic system immaturity, hemodilution, systemic inflammation, prolonged bypass times, and the use of deep hypothermic circulatory arrest (DHCA). [4][5][6][7] Increased bleeding and allogeneic blood transfusion requirements have been shown to vary inversely with the age and size of infants requiring cardiac surgery. 8 Transfusion of allogeneic blood products is associated with a number of adverse effects such as infectious agent transmission, the development of postoperative infections, and other transfusion reactions.…”