Key points

Introduction

Hemostasis refers to the process by which ruptures in the wall of blood vessels are occluded by a fibrin clot and involves the interaction of the blood vessel wall, platelets, and coagulation proteins. In addition to preventing excessive bleeding, the fibrin clot provides the structure for wound repair. Developmental hemostasis describes the evolution of the coagulation system from fetal life to adolescence. The coagulation system, which includes both procoagulant and anticoagulant proteins, forms early in utero, although the levels of many of these proteins are different than those seen in normal adults. Many of these proteins exhibit levels that are far less than those seen in adults, although a few are, in fact, more than adult levels. Although much of the evolution to normal adult levels takes place within the first 6 months, some proteins do not reach normal adult levels until adolescence. The evolving changes in the functional level of the coagulation proteins lead to several challenges for the clinician. First, the changes make it more difficult to correctly diagnose a child with a disorder of coagulation. Second, the particularly rapid changes that occur during the neonatal period can affect the choice and monitoring of anticoagulant agents. Third, the changes create significant challenges for the clinical coagulation laboratory as it relates to establishing normal ranges for various laboratory assays. This article reviews the current data on the development of the coagulation system as it matures from early fetal life into the teenage years and explains how these changes impact the diagnosis and treatment of pediatric coagulation disorders.

Hemostasis physiology

A basic overview of the coagulation cascade is crucial to understanding developmental hemostasis. Damaged endothelium exposes tissue factor (TF) present in the subendothelium, which then activates the coagulation cascade, consisting of multiple procoagulant proteins that interact together to lead to the formation of a fibrin clot. The procoagulant proteins, mostly known as factors, include fibrinogen and factors (F) II, V, VII, VIII, IX, X, XI, and XIII. Of note, there are several factors (FXIII, prekallikrein, and high-molecular-weight kininogen) in the so-called contact activation system that are not currently considered to be involved in hemostasis, although abnormal levels will result in an abnormal activated partial thromboplastin time (aPTT). In order to prevent excessive clotting, there exist several natural inhibitors to the procoagulant factors (also known as natural anticoagulants ), including antithrombin (AT), α ₂ -macroglobulin (α ₂ -M), heparin cofactor II (HCII), protein C, protein S, and TF pathway inhibitor (TFPI).

The activation of the coagulation cascade results in the formation of large quantities of thrombin (FIIa) at the site of bleeding. Thrombin plays a pivotal role in the formation of the fibrin clot. It activates FV and FVIII, which are the main catalysts of the coagulation cascade resulting in the generation of even more thrombin. This large amount of thrombin leads to the conversion of the soluble protein fibrinogen into its insoluble form, fibrin, which forms the structure of the clot ( Fig. 1 ). Thrombin also activates 2 proteins, FXIII and thrombin-activatable fibrinolysis inhibitor, both of which are critical to the formation of a stable clot that is resistant to fibrinolysis. Lastly, thrombin also activates platelets at the site of bleeding.

Overview of the coagulation cascade showing procoagulant interactions. TF from the subendothelium activates the coagulation cascade, which causes interaction of multiple coagulation factors (II, V, VII, VIII, IX, X, XI and XIII) to form a fibrin clot. a, activated form of the factor; TAFI, thrombin activatable fibrinolysis inhibitor.

Thrombin plays the key role in its own downregulation by forming a complex with thrombomodulin that serves to activate protein C, which, along with its cofactor, protein S, inactivates the catalysts FV and FVIII. The prohemostatic effect of thrombin remains local to the site of endothelial damage because any thrombin that remains in the circulation is quenched by AT.

Introduction

Hemostasis refers to the process by which ruptures in the wall of blood vessels are occluded by a fibrin clot and involves the interaction of the blood vessel wall, platelets, and coagulation proteins. In addition to preventing excessive bleeding, the fibrin clot provides the structure for wound repair. Developmental hemostasis describes the evolution of the coagulation system from fetal life to adolescence. The coagulation system, which includes both procoagulant and anticoagulant proteins, forms early in utero, although the levels of many of these proteins are different than those seen in normal adults. Many of these proteins exhibit levels that are far less than those seen in adults, although a few are, in fact, more than adult levels. Although much of the evolution to normal adult levels takes place within the first 6 months, some proteins do not reach normal adult levels until adolescence. The evolving changes in the functional level of the coagulation proteins lead to several challenges for the clinician. First, the changes make it more difficult to correctly diagnose a child with a disorder of coagulation. Second, the particularly rapid changes that occur during the neonatal period can affect the choice and monitoring of anticoagulant agents. Third, the changes create significant challenges for the clinical coagulation laboratory as it relates to establishing normal ranges for various laboratory assays. This article reviews the current data on the development of the coagulation system as it matures from early fetal life into the teenage years and explains how these changes impact the diagnosis and treatment of pediatric coagulation disorders.

Hemostasis physiology

A basic overview of the coagulation cascade is crucial to understanding developmental hemostasis. Damaged endothelium exposes tissue factor (TF) present in the subendothelium, which then activates the coagulation cascade, consisting of multiple procoagulant proteins that interact together to lead to the formation of a fibrin clot. The procoagulant proteins, mostly known as factors, include fibrinogen and factors (F) II, V, VII, VIII, IX, X, XI, and XIII. Of note, there are several factors (FXIII, prekallikrein, and high-molecular-weight kininogen) in the so-called contact activation system that are not currently considered to be involved in hemostasis, although abnormal levels will result in an abnormal activated partial thromboplastin time (aPTT). In order to prevent excessive clotting, there exist several natural inhibitors to the procoagulant factors (also known as natural anticoagulants ), including antithrombin (AT), α ₂ -macroglobulin (α ₂ -M), heparin cofactor II (HCII), protein C, protein S, and TF pathway inhibitor (TFPI).

The activation of the coagulation cascade results in the formation of large quantities of thrombin (FIIa) at the site of bleeding. Thrombin plays a pivotal role in the formation of the fibrin clot. It activates FV and FVIII, which are the main catalysts of the coagulation cascade resulting in the generation of even more thrombin. This large amount of thrombin leads to the conversion of the soluble protein fibrinogen into its insoluble form, fibrin, which forms the structure of the clot ( Fig. 1 ). Thrombin also activates 2 proteins, FXIII and thrombin-activatable fibrinolysis inhibitor, both of which are critical to the formation of a stable clot that is resistant to fibrinolysis. Lastly, thrombin also activates platelets at the site of bleeding.

Overview of the coagulation cascade showing procoagulant interactions. TF from the subendothelium activates the coagulation cascade, which causes interaction of multiple coagulation factors (II, V, VII, VIII, IX, X, XI and XIII) to form a fibrin clot. a, activated form of the factor; TAFI, thrombin activatable fibrinolysis inhibitor.

Thrombin plays the key role in its own downregulation by forming a complex with thrombomodulin that serves to activate protein C, which, along with its cofactor, protein S, inactivates the catalysts FV and FVIII. The prohemostatic effect of thrombin remains local to the site of endothelial damage because any thrombin that remains in the circulation is quenched by AT.

Hemostasis in the infant and child

At birth, an infant’s coagulation system differs significantly from that of an adult. The levels of many of their procoagulant and natural anticoagulants are low; as a result, the screening coagulation tests, the aPTT and the prothrombin time (PT), are prolonged compared with adults. Some of the components of the hemostatic system even have fetal forms whose actions vary from the adult forms, such as protein C and fibrinogen. These fetal forms have been shown to generate and regulate thrombin differently or to be synthesized at a different rate.

All coagulation factors are present at birth; but most coagulation factors do not reach typical adult levels until 6 months of age and some not until adolescence. Fig. 2 shows the evolution of the components of the coagulation system throughout fetal life. Because coagulation factors cannot cross the placenta, the fetus starts to produce its own procoagulants and anticoagulants in the liver at about 5 weeks’ gestation. At 20 weeks’ gestation, the coagulation factors can be measured in plasma, yet they are still at very low levels. As a result of this process, premature infants have even lower levels of procoagulant and anticoagulant factors than term infants; but their levels quickly mature toward adulthood, with most components reaching near adult levels by 6 months of age.

Development of the coagulation system in the human fetus.

( Data from Reverdiau-Moalic P, Delahousse B, Body G, et al. Evolution of blood coagulation activators and inhibitors in the healthy human fetus. Blood 1996;88:900–6; and Hassan HJ, Leonardi A, Chelucci C, et al. Blood coagulation factors in human embryonic-fetal development: preferential expression of the FVII/tissue factor pathway. Blood 1990;76:1158–64.)

At birth, the only procoagulant factors that are within the adult range are fibrinogen, FV, and FVIII. The vitamin K-dependent coagulant factors (II, VII, IX and X) and contact factors (XI, XII, prekallikrein), high-molecular-weight kininogen are approximately 50% of the adult values at birth. These factors rapidly increase in the first few weeks of life and overlap substantially with the adult range by 6 months of age, although the average values of most remain 20% lower until the teenage years. Prothrombin, which is the precursor to thrombin, is decreased by 20% throughout childhood. FVIII levels are normal to high at birth, and von Willebrand factor levels are elevated until about 3 months of age. Andrew and colleagues created an extensive database of normal reference ranges for the human coagulation system in healthy term and preterm infants as well as children and adolescents. It should be noted that the levels in the Andrew publications are specific to the methodology for the assays performed in her laboratory; thus, specific values cannot be extrapolated to results from other laboratories. Table 1 summarizes, in a qualitative fashion, the main differences of the coagulation system found between the developing child and adult.

Studies from ultrasound-guided umbilical sampling have shown that between 19 and 30 weeks’ gestation, the PT, aPTT, and thrombin clotting time (TCT) are all prolonged secondary to low levels of vitamin K–dependent factors, contact factors, FV, FVIII, and fibrinogen. These factors began to increase after the 34th week of gestation, but only FV and FVIII reached adults levels at birth.

The anticoagulants, AT and HCII, are 50% of adult values at birth and increase to adult levels by 3 months of age. Protein C and S are even lower at birth; protein C, which starts out in a fetal form, remains markedly low until 6 months of age. Theoretically, to compensate for the low level of AT, another anticoagulant, α ₂ -M, is produced at levels that are increased over adult values at birth, are twice adult values at 6 months of age, and continue to be increased until the third decade of life.

Andrew and colleagues also compared components of the fibrinolytic system, which is involved in fibrin clot degradation, of children with adults. The levels of plasminogen, which is a pro-fibrinolytic, and α2-antiplasmin, which is an anti-fibrinolytic, were similar to adults throughout childhood (after 1 year of age). Although, the pro-fibrinolytic, tissues plasminogen activator (TPA), was found to be lower in children and the anti-fibrinolytic, plasminogen activator inhibitor, had increased levels in children.

Of note, the differences in the hemostatic system between children and adults may be important not only in hemostasis. Some of these coagulant proteins, such as TF and thrombomodulin, are also involved in angiogenesis, inflammation, and wound repair, which may be the driving force behind the coagulation system changes.