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106 Part III: Epochal Hematology Chapter 7: Hematology of the Fetus and Newborn 107

myeloperoxidase (bacterial killing) and defensins (antimicrobial pro- normally is performed, and for a minimal incision to avoid scarring of
teins), are not diminished. the skin. Bleeding times were measured using an automatic device to
Monocytes from newborn infants have normal nitroblue tetrazo- minimize trauma in normal neonates, with venous occlusion of 20 torr
lium (NBT) reduction, normal antibody-dependent cellular cytotoxic- for infants who weigh less than 1000 g, 25 torr for those who weigh
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ity, and normal in vitro killing of S. aureus and E. coli. However, they 1000 to 2000 g, and 30 torr for those who weigh more than 2000 g.
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are slower than monocytes from adults in phagocytosis of polystyrene In 82 observations, 97 percent of the measurements were below 3.5
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spheres, and they have reduced ATP production. Furthermore, che- minutes, which was suggested as the upper limit for normal in these
motaxis to serum-derived factors is decreased, as is monocyte appear- infants. A similar upper limit (200 seconds) for the bleeding time of
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ance in skin windows. These functional aspects may contribute to the normal infants has been obtained using an automated device and verti-
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observed susceptibility of newborns to a variety of infectious agents. cal incisions. Generally, newborn infants have shorter bleeding times
Cytokine Effects on Neonatal Phagocytic Function There is a than do children and adults, which may reflect their higher hematocrit,
complex interaction between cytokines produced by lymphocytes and increased concentration of von Willebrand factor, and higher propor-
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macrophages, and the activation status of neutrophils during infec- tion of high-molecular-weight multimers of von Willebrand factor.
tion. There is decreased production of interferon-γ by neonatal leuko- Children have longer bleeding times than either adults or newborns,
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cytes. 199,200 Interferon-γ causes the upregulation of the C3bi receptor and the upper limit measured with an automated pediatric device may
and induces the surface expression of the high-affinity immunoglobulin be as high as 13 minutes before age 10 years, compared to an upper limit
receptor FcRI (CD64) on neutrophils. C3bi is required for adherence of 7 minutes in adults measured with the same device. 217
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and efficient chemotaxis by neutrophils. Low levels of this receptor also The bleeding times in newborns may be prolonged for a variety of
impair complement-mediated phagocytosis and oxidative metabolism. reasons, including neonatal infection and respiratory distress syndrome,
FcRI also mediates oxidative responses, and appears on neutrophils which do not necessarily result in thrombocytopenia. Platelets from
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of adults during infection. The diminished production of G-CSF healthy newborns are relatively deficient in phospholipid metabolism,
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and GM-CSF by neonatal mononuclear cells 137–139 may not only limit granule secretion, and aggregation, but there is heightened platelet
progenitor colony growth, but may also impair neonatal neutrophil adhesion because of increased large von Willebrand multimers. The
functions, including chemotaxis, superoxide production, and C3bi result of these differences is shortened bleeding and closure times in
expression, which are enhanced by these factors. 202,203 Tumor necrosis normal neonates (see below).
factor (TNF)-α and IL-4, cytokines that modulate neutrophil functions, The use of indomethacin for treatment of patent ductus arterio-
also may be produced at lower levels in neonates. 204 sus in preterm infants has been questioned because this agent interferes
with prostaglandin metabolism and the production of thromboxane A ,
2
an important initiator of platelet aggregation. Although bleeding times
THROMBOPOIESIS AND PLATELETS are prolonged from a normal 3.5 minutes to approximately 9 minutes
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The platelet counts in term and preterm infants are between 150 and in indomethacin-treated patients, indomethacin did not result in an
400 × 10 /L (150,000 to 400,000/μL), comparable to adult values. 205,206 increase in periventricular or intraventricular hemorrhage in preterm
9
Thrombocytopenia of fewer than 100 × 10 /L (100,000/μL) may infants treated for patent ductus arteriosus.
9
occur in high-risk infants with respiratory distress or sepsis, small- The closure time to assess platelet function may replace the bleed-
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for-date infants, and newborns with trisomy syndromes. Even nor- ing time, particularly for neonates and young children in whom bleed-
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mal newborns are unable to regulate thrombopoiesis and myelopoiesis ing times are difficult to perform and interpret. Newborn infants have
in a wholly effective manner. Although committed megakaryocyte closure times that are shorter than those of adults, likely related to their
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progenitors (colony-forming unit–megakaryocyte [CFU-Meg]) are higher hematocrits, increased von Willebrand multimers and hence ris-
increased in the marrow and cord blood of newborns, they are less tocetin cofactor, and higher leukocyte counts. 221–223 The normal adult
able to produce adequate numbers of platelets when severely stressed. value for collagen-epinephrine closure time is less than 164 seconds,
Reduced levels of G-CSF, GM-CSF, and IL-3 may play a role in the and for collagen-ADP closure time is less than 116 seconds. However,
impaired response. Thrombopoietin (TPO) is a major regulator of each laboratory must determine its own normal range for these tests.
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platelet production in adults. TPO transcripts have been detected as Platelet Aggregation and Metabolism A variety of differences
early as 6 weeks postconception and the primary source of TPO in the have been described in the platelet function of neonates. These include
fetus and neonate is thought to be the liver. Serum TPO levels are decreases in ADP release, in platelet factor 3 activity, in platelet adhe-
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higher in preterm and term neonates compared to adults. However, siveness, and in platelet aggregation in response to ADP, epinephrine,
thrombocytopenic newborns do not increase serum TPO levels as collagen, or thrombin. 224,225 These defects result from intrinsic differ-
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robustly as thrombocytopenic adults, which may contribute to the high ences in neonatal compared to adult platelets. Paradoxically, these
incidence of thrombocytopenia seen in sick infants. 212 insufficiencies have little effect on the bleeding time of neonates. The in
vitro findings do not appear related to a significant defect in prostaglan-
Platelet Functions din synthesis or to storage pool deficiency of adenine nucleotides.
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Bleeding Time and Closure Time The expected inverse relationship Furthermore, electron micrographs of neonatal platelets do not differ
between the platelet count and bleeding time has been described in from those of platelets from normal adults. This leaves unexplained
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term and preterm newborns. However, the bleeding time often is lon- the in vitro observations in neonatal platelets, which may be related
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ger than would be predicted by the platelet count because of sepsis or to platelet membrane immaturity. These in vitro abnormalities may
respiratory distress resulting in impaired platelet function, aggravating aggravate the impairment in platelet function and the predisposition
the effects of thrombocytopenia. to bleeding that result from neonatal diseases, particularly respiratory
The bleeding time reflects platelet function and capillary integrity, distress syndrome and sepsis.
as well as the platelet count, and traditionally has been used to assess Maternal aspirin ingestion also results in abnormalities in plate-
these parameters. However, there are technical difficulties in applying a let aggregation in the newborn in response to collagen. 228,229 However,
technique for measuring bleeding time to neonates or preterm infants aspirin has been studied extensively in patients with preeclampsia, and
because of the need for venous occlusion of the forearm, where the test there is no significant bleeding in the fetus or newborn. 230,231

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