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2190 Part XII Hemostasis and Thrombosis

TABLE Neonatal Versus Adult Hemostasis its increased sialic acid and mannose content. Although healthy
150.1 neonates have lower plasmin-generating potential than adults, base-
line levels of t-PA can increase up to eightfold with illness. Neonates
Component Neonatal Versus Adult Level with severe plasminogen deficiency have only a minimally increased
Primary hemostasis ↔ Platelet count risk for thrombosis, and most of their clinical findings are the result
↑ vWF of impaired extravascular fibrinolysis. The major plasmin inhibitors
Coagulation factors ↓ FII, FVII, FIX, FX circulate at near-adult levels in the neonate.
The contribution of differences in the neonatal and adult fibrino-
↓ FXI, FXII lytic systems to the protection from thromboembolic complications
↓ to ↔ FV, FXIII in childhood remains to be elucidated. Imbalance in the fibrinolytic
↔ Fibrinogen system, whether hereditary or acquired, can lead to thrombotic or
↔ FVIII
bleeding complications. Hereditary disorders, although rare, include
Anticoagulant factors ↓ TFPI, AT, PC, PS plasminogen deficiency, PAI-1 deficiency, and α 2AP deficiency. The
↑ α 2 M efficacy and safety of fibrinolytic therapy may be influenced by age-
Fibrinolysis ↓ Plasminogen dependent differences in the fibrinolytic system. Data are lacking on
↔ to ↑ PAI the optimal doses of fibrinolytic agents for the pediatric population,
especially for neonates. t-PA is the agent of choice, with the most
α 2M, α 2-Macroglobulin; AT, antithrombin; F, factor; PAI, plasminogen activator
inhibitor; PC, protein C; PS, protein S; TFPI, tissue factor pathway inhibitor; common dose and duration of treatment being 0.5 mg/kg per hour
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vWF, von Willebrand factor. infused over 6 hours.
Modified from Guzzetta NA, Miller BE: Principles of hemostasis in children:
Models and maturation. Paediatr Anaesth 21:3, 2011.
Platelets
Platelet production starts around the end of the first trimester of
twofold higher than that in adults. The overall capacity of newborn gestation and reaches adult values in the middle of the third trimester.
plasma to inhibit thrombin is similar to that of adult plasma, owing Therefore platelet counts in term and premature newborns are not
in part to the increased binding of thrombin by α 2 -macroglobulin. different from those in adults. Similarly, mean platelet volume and
Thrombin inhibition by heparin cofactor II is catalyzed by a dermatan platelet ultrastructure in neonates closely resemble those in adults.
sulfate–like proteoglycan, which is produced by the placenta and is Yet, all the main platelet functions are deficient at birth. Neonatal
found in both maternal and fetal plasma. platelets exhibit reduced phospholipid metabolism, calcium mobili-
Regulation of thrombin generation is accomplished by upstream zation, granule secretion, and aggregation in response to agonists
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inhibition of the clotting proteins in the prothrombinase and tenase compared with adult platelets. Although thrombocytopenia is
complexes (see Chapter 126). Plasma concentrations of protein C are common in neonates, thrombocytosis is rare and is associated with
low at birth and gradually increase to adult levels by 6 months of age. prematurity.
Although the total concentration of protein S is low at birth, the There are two proposed theories behind the reduced platelet
functional activity of protein S is comparable to that in adults because function at birth. One hypothesis suggests that platelet activation and
low levels of C4b-binding protein result in more free protein S. The degranulation at the time of labor and delivery lead to exhausted
interaction of protein S with activated protein C in neonatal plasma circulating platelets; the other suggests that intrinsic platelet pecu-
may be limited by the elevated levels of α 2 -macroglobulin. Free tissue liarities account for neonatal platelet deficiency. Indeed, differences
factor pathway inhibitor levels are lower than in adults, although total in intrinsic signal transduction in the neonatal platelets alter platelet
levels of tissue factor pathway inhibitor in neonatal plasma are similar aggregation and activation responses. Platelet aggregation studies
to those in adult plasma. showed that aggregation of neonatal platelets was reduced in response
to a number of agonists, including ADP, epinephrine, collagen, and
thrombin and thromboxane analogues. This is especially true in
The Fibrinolytic System preterm infants. Flow cytometric studies using monoclonal antibod-
ies directed against platelet activation markers also indicate that
Although the levels of some of the components of the fibrinolytic platelets from cord blood or from neonates on the first postnatal day
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system in neonates are different from those in adults, the clinical are hyporeactive compared with adult platelets. This hyporespon-
relevance of this finding is probably minimal. The fibrinolytic system siveness is transient, and the platelets regain normal reactivity 10 to
regulates fibrin deposition by generating plasmin, which solubilizes 14 days after delivery. However, the exact duration of hyporeactivity
fibrin. At birth, the fibrinolytic system has all the key components, remains to be elucidated because some studies suggest that functional
but there are important age-related differences in the quantity and defects persist beyond the neonatal period. 9
quality of the fibrinolytic proteins and enzymes. Plasma concentra- Despite the reduced platelet reactivity at birth, platelet adhesion
tions of plasminogen, tissue plasminogen activator (t-PA), and α 2 - may be enhanced because of the presence of higher concentration of
antiplasmin (α 2 AP) are decreased, whereas plasma concentrations of functionally more potent high-molecular-weight vWF multimers in
plasminogen activator inhibitor 1 (PAI-1) are increased. As well, the plasma. Consistent with this concept, the bleeding time and the
6
plasmin generation and overall fibrinolytic activity are decreased. platelet function analyzer (PFA-100) closure time are shorter in
8
The capacity to generate plasmin in newborn plasma is generally neonates than in adults. In healthy neonates, enhanced platelet
reduced compared with adult plasma, which likely reflects the adhesion immediately after delivery may compensate for the reduced
decreased plasminogen concentration. Despite lower levels of platelet activation in response to agonists. Nonetheless, sick neonates
fibrinolytic components, the newborn fibrinolytic system is still may be at increased risk for bleeding. 8
effective. If available, the PFA-100 closure time is preferred over the bleed-
The whole-blood clotting time and euglobulin clot lysis time are ing time as a means of assessing platelet-related hemostasis. Bleeding
global assays of fibrinolytic activity but reflect only part of the physi- time is an in vivo screening test that reflects the interaction between
ologic fibrinolytic potential. Maneuvers that induce the release of platelets and the blood vessel wall, but it is as variable in neonates as
endogenous fibrinolytic components, such as venous occlusion, it is in adults. Also, the devices used for measuring bleeding time are
desmopressin infusion, or exercise, provide more sensitive measures not suitable for use in small infants. Consequently, the bleeding time
of in vivo fibrinolytic activity. 6 is rarely determined. Although the PFA-100 will not detect mild
Plasminogen levels are lower in neonates than in adults, and fetal defects in platelet function, such defects rarely cause serious bleeding
plasminogen binds to cellular receptors with lower affinity because of in neonates.