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C H A P T E R 150

DISORDERS OF COAGULATION IN THE NEONATE

Mihir D. Bhatt, Karin Ho, and Anthony K.C. Chan

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The neonatal stage is a period of rapid physiologic changes, some of from adults. The activated partial thromboplastin time (aPTT) is
which affect the hemostatic system. The hemostatic system is a prolonged in newborns, which is attributed to relative deficiencies
dynamic system that evolves gradually from birth into the mature in the contact factors. Other tests, such as the thrombin time and
adult form. Evaluation of disorders of coagulation in the neonate thromboelastography, are less sensitive to age-related changes. The
requires an understanding of the evolution of physiologic normal thrombin time in neonates is similar to that in adults when measured
values for age, the congenital disorders that present in early life, and in the presence of calcium, which compensates for the unique fetal
the clinical settings common in neonatology that affect hemostasis form of fibrinogen that has increased sialic acid content. Thrombo-
and thrombosis risks. The rapid evolution of the blood coagulation elastography values vary very little with age. The template bleeding
system after birth leads to a dynamic group of age-dependent refer- time is reported to be normal in neonates, but this is an unreliable test
ence ranges for the levels of the various components that should be in neonates and is not recommended for evaluation of bleeding dis-
considered physiologically normal. Developmental hemostasis is the orders. Investigations into neonatal hemostatic pathology are limited
term applied to the evolution of the hemostatic and fibrinolytic by the lack of normal reference values for the neonatal population
systems through infancy and childhood into adult age. and the difficulties associated with obtaining clean blood samples for
testing.
DEVELOPMENTAL HEMOSTASIS
Blood Coagulation Proteins
The coagulation system in children provides innate protection from
thrombosis without an increased risk for bleeding. The hemostatic The synthesis of fetal and neonatal coagulation proteins begins at
system evolves throughout childhood and most rapidly during the approximately 10 weeks of gestation, and plasma concentrations of
neonatal period. Changes in the plasma concentrations of proteins these proteins increase with gestational age. Maternal coagulation
involved in blood coagulation lead to a dynamic group of reference proteins cannot cross the placenta. However, maternal drug intake
ranges for preterm and term infants. Although different from adult can affect the synthesis of fetal vitamin K–dependent coagulation
values, these reference ranges are neither abnormal nor pathologic. proteins, with warfarin, phenytoin, barbiturates, and antibiotics
The relative rarity of hemorrhagic or thrombotic complications in serving as examples.
this population suggests that the neonatal coagulation system is In the healthy newborn, plasma levels of procoagulant factors such
physiologically replete. as thrombin, factor (F)VII, FIX, FX, and prothrombin (the vitamin
K–dependent coagulation factors), as well as FXI, FXII, prekallikrein,
and high-molecular-weight kininogen (the contact factors), are about
Laboratory Evaluation 50% lower than adult values (Table 150.1). The levels rise as the
1,2
infant ages, and they reach about 80% of normal adult values by 6
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The pioneering work of the late Dr. Maureen Andrew paved the way months of age but remain decreased throughout childhood. The
for research into developmental hemostasis. The concept of develop- levels of fibrinogen, FV, FVIII, and FXIII in neonates are similar to
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mental hemostasis is now widely accepted, and her seminal papers those in adults and remain so throughout childhood. The level of
describing the reference ranges for healthy premature and full-term von Willebrand factor (vWF) in newborns is about twofold higher
1,2
neonates are still widely quoted. Laboratory evaluation of throm- than adult values and gradually decrease over the first 6 months
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bosis or bleeding in neonates must take into account the age-related of life, whereas the levels of antithrombin (AT) are lower than
reference ranges for healthy newborns, which differ significantly from adult levels in the first 3 months of life and are comparable to
adult levels. In addition, because coagulation assay results vary the levels seen in patients with heterozygous AT deficiency. The
depending on the type of analyzer and reagents used, caution should physiologic ranges for coagulation factors in healthy newborns who
be taken when prior publications of defined reference ranges for have received intramuscular vitamin K after delivery are shown in
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neonates are used. Each laboratory that performs coagulation tests Table 150.2.
on neonatal samples must therefore develop their own age-related
reference ranges specific to their analyzer and reagent combination in
order to effectively diagnose and manage neonates with suspected Regulation of Thrombin
hemostatic abnormalities. Neonatal samples should be drawn by
experienced staff. Samples are processed in 1-mL tubes containing Despite decreased and delayed thrombin generation, neonates have
0.1 mL of 3.2% buffered sodium citrate, aiming for a final ratio of excellent hemostasis. Thrombin regulation in neonatal plasma is
one part citrate to nine parts blood. similar to that in plasma from adults who are receiving therapeutic
Although recently researchers have started to look into age- doses of anticoagulants. The concentration of thrombin generated in
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specific differences in the quantitative levels of hemostatic proteins, neonatal plasma is proportional to the available prothrombin con-
functional assays that are reagent and analyzer specific are still centration, whereas the rate of thrombin generation depends on the
predominantly used in pediatric studies for hemostatic diagnosis. level of other procoagulant proteins. Clots formed from neonatal
Changes in functional protein levels correspond to changes in plasma bind less thrombin than clots formed from adult plasma, in
global tests of coagulation. The prothrombin time (PT), expressed part because of reduced thrombin generation. The reduced capacity
in seconds, in full-term and premature neonates is similar to that to generate thrombin and the reduction in fibrin-bound thrombin
in adults, despite the fact that neonates have relative deficiencies may protect neonates from thrombosis.
of the vitamin K–dependent coagulation factors. However, samples Thrombin is inhibited by AT, α 2-macroglobulin, and heparin
from cord blood exhibit a prolonged PT compared with samples cofactor II. In neonates, the α 2-macroglobulin concentration is

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