The Developing Balance of Thrombosis and Hemorrhage in Pediatric Surgery: Clinical Implications of Age-Related Changes in Hemostasis

Abstract

Bleeding and thrombosis in critically ill infants and children is a vexing clinical problem. Despite the relatively low incidence of bleeding and thrombosis in the overall pediatric population relative to adults, these critically ill children face unique challenges to hemostasis due to extreme physiologic derangements, exposure of blood to foreign surfaces and membranes, and major vascular endothelial injury or disruption. Caring for pediatric patients on extracorporeal support, recovering from solid organ transplant or invasive surgery, and after major trauma is often complicated by major bleeding or clotting events. As our ability to care for the youngest and sickest of these children increases, the gaps in our understanding of the clinical implications of developmental hemostasis have become increasingly important. We review the current understanding of the development and function of the hemostatic system, including the complex and overlapping interactions of coagulation proteins, platelets, fibrinolysis, and immune mediators from the neonatal period through early childhood and to young adulthood. We then examine scenarios in which our ability to effectively measure and treat coagulation derangements in pediatric patients is limited. In these clinical situations, adult therapies are often extrapolated for use in children without taking age-related differences in pediatric hemostasis into account, leaving clinicians confused and impacting patient outcomes. We discuss the limitations of current coagulation testing in pediatric patients before turning to emerging ideas in the measurement and management of pediatric bleeding and thrombosis. Finally, we highlight opportunities for future research which take into account this developing balance of bleeding and thrombosis in our youngest patients.

Prophylactic antithrombotic management in adult and pediatric kidney transplantation: A systematic review and meta‐analysis

“…The RGT incidence as well as the more frequent occurrence of RGT in children in the included study populations were comparable to previously published data. Several modifiable and non‐modifiable factors such as surgical challenges due to small donor and recipients may play a pivotal role 44‐46 . This consideration might support the observation that the suggested benefit of aP in KTx recipients could not be demonstrated anymore when children were excluded.…”

Hemostatic Challenges in Neonates

“…In 2006, Monagle et al published comprehensive reference ranges for coagulation tests measured in healthy term neonates on days of life 1 and 3 and in children ranging from 1 month to 16 years, using more modern coagulation testing systems ( 44 ), and confirmed the concept of developmental hemostasis initially described by Andrew et al The physiologic changes in the coagulation system over the course of development and their implications for clinical practice have been described in detail in recent reviews ( 39 , 46 ). However, it is important to keep in mind that the actual values of the various tests vary depending on the reagents and analyzer system utilized, in addition to the patient's age ( 44 ).…”

“…The levels of most coagulation factors increase during gestation and post-natally, and therefore are lower in pre-term compared to term neonates, and in term neonates compared to older children and adults. In full term infants, levels of most coagulation factors (particularly the vitamin K-dependent ones) are ~50% of the adult levels, and increase to near-adult values by 6 months of age ( 38 , 39 ). The activity of vitamin K-dependent factors is further reduced in pre-term infants, to ~30% in 24–29 weeks' gestation infants.…”

“…Indeed, just like most coagulation factors are decreased in neonates, most natural anticoagulants are also reduced at birth ( 30 , 31 , 41 ), which results in a balanced neonatal hemostatic system. Specifically, antithrombin (AT), heparin cofactor II and proteins C and S levels are significantly reduced in neonates (both term and pre-term), ~50% of adult levels at birth ( 39 ). Levels of these anti-coagulants increase slowly after birth, and AT and heparin cofactor II reach adult levels by 3 months of age ( 41 ).…”

Neonatal coagulopathies: A review of established and emerging treatments

“…During the first weeks of life, the newborn exhibits lower levels of the anticoagulants Protein C, Protein S, and antithrombin; however, it counteracts this in part with higher levels of the thrombin inhibitor a 2 -macroglobulin. 15 Neonatal hemostasis is balanced by having concurrent lower levels of the vitamin K-dependent pro-coagulant factors, II, VII, IX, and X (Figure 1). This is partially counterbalanced by higher levels of von Willebrand factor and ultra-large von Willebrand factor multimers.…”