REVIEW
published: 02 March 2021
doi: 10.3389/fped.2021.627715
Frontiers in Pediatrics | www.frontiersin.org 1 March 2021 | Volume 9 | Article 627715
Edited by:
Oliver Karam,
Children’s Hospital of Richmond at
VCU, United States
Reviewed by:
Paul Monagle,
The University of Melbourne, Australia
Anna Curley,
National Maternity Hospital, Ireland
*Correspondence:
Martha Sola-Visner
martha.sola-visner@
childrens.harvard.edu
Specialty section:
This article was submitted to
Pediatric Critical Care,
a section of the journal
Frontiers in Pediatrics
Received: 10 November 2020
Accepted: 18 January 2021
Published: 02 March 2021
Citation:
Davenport P and Sola-Visner M
(2021) Hemostatic Challenges in
Neonates. Front. Pediatr. 9:627715.
doi: 10.3389/fped.2021.627715
Hemostatic Challenges in Neonates
Patricia Davenport and Martha Sola-Visner
*
Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA, United States
The neonatal hemostatic system is strikingly different from that of adults. Among
other differences, neonates exhibit hyporeactive platelets and decreased levels of
coagulation factors, the latter translating into prolonged clotting times (PT and PTT).
Since pre-term neonates have a high incidence of bleeding, particularly intraventricular
hemorrhages, neonatologists frequently administer blood products (i.e., platelets and
FFP) to non-bleeding neonates with low platelet counts or prolonged clotting times
in an attempt to overcome these “deficiencies” and reduce bleeding risk. However,
it has become increasingly clear that both the platelet hyporeactivity as well as the
decreased coagulation factor levels are effectively counteracted by other factors in
neonatal blood that promote hemostasis (i.e., high levels of vWF, high hematocrit and
MCV, reduced levels of natural anticoagulants), resulting in a well-balanced neonatal
hemostatic system, perhaps slightly tilted toward a prothrombotic phenotype. While
life-saving in the presence of active major bleeding, the administration of platelets and/or
FFP to non-bleeding neonates based on laboratory tests has not only failed to decrease
bleeding, but has been associated with increased neonatal morbidity and mort alit y in the
case of platelets. In this review, we will present a clinical overview of bleeding in neonates
(incidence, sites, risk factors), followed by a description of the key developmental
differences between neonates and adults in primary and secondary hemostasis. Next,
we will review the clinical tests available for the e va luation of bleeding neonates and their
limitations in the context of the deve lopmentally unique neonatal hemostatic system, and
will discuss current and emerging approaches to more accurately predict, evaluate and
treat bleeding in neonates.
Keywords: neonate, bleeding, platelet function, hemostasis, platelet transfusion, FFP transfusion
CLINICAL OVERVIEW OF BLEEDING IN THE NEONATE
Neonates, especially those born pre-term, are at high risk of bleeding, making this a commonly
encountered problem in the Neonatal Intensive Care Unit (NICU). A recent study utilizing a
standardized and validated neonatal bleeding assessment tool (NeoBAT) found that 25% of all
neonates admitted to eight different NICUs experienced an episode of bleeding during their
hospitalization, with 11% of episodes categorized as major/severe bleeds, 1% as moderate, and 13%
as minor bleeds (
1). In the same study, pre-term neonates <28 weeks’ gestational age were found to
have a higher incidence of bleeding compared to infants born at >28 weeks’ gestation, highlighting
the increased bleeding risk associated with a lower gestational age at birth.
This high incidence of bleeding, particularly among pre-term neonates, is at least partially
related to factors specific to the neonatal population. These unique risk factors include the
trans-placental passage of some hemostatically active vitamins (i.e., vitamin K) or maternal
Davenport and Sola-Visner Hemostatic Challenges in Neonates
anti-platelet antibodies, and the developmental stage of
blood vessels, the gastrointestinal tract, and the hemostatic
system at varying gestational ages. In addition to these
developmental stage-specific risk factors for bleeding, neonates
are also at risk for more universal causes of bleeding due to
their high incidence of sepsis, DIC, and frequent need for
mechanical ventilation and critical care after birth. As such,
the differential diagnosis for neonatal bleeding is broad and a
thorough understanding of developmental stage, risk factors
and underlying pathophysiology is critical to appropriately
treat and try to prevent major bleeding in this vulnerable
patient population. The goals of this review are to describe
common clinical presentations of bleeding i n neonates admitted
to the Neonatal Intensive Care Unit (NICU), discuss the
main developmental differences bet ween neonatal and adult
platelet function and hemostasis, review the tests available to
evaluate and predict bleeding in neonates and their limitations,
and evaluate current approaches to the management and
prevention of clinically significant bleeding in infants. Of
note, this review will not cover the hemostatic challenges of
neonates on ECMO or neonates requiring cardiac surgery with
cardiopulmonary bypass.
Intraventricular Hemorrhage (IVH)
Intraventricular hemorrhage (IVH) is one of the most serious
complications of prematurity owing to the critical window for
brain development that occurs during fetal and neonata l life.
IVH puts infants at risk for long term neurodevelopmental
morbidity and mortality and, despite improvements in IVH
rates over recent dec ades, its incidence remains hig h , affecting
15–25% of very- and extremely- premature infants (<32 and
<28 weeks’ gestational age, respectively) in the first week
of life (
2). Intraventricular h emorrhages often originate in
a highly vascularized collection of neuronal-glial precursor
cells ca lled the germinal matrix (3). This region is selectively
vulnerable to hemorrhage in premature infants due to its
developmental paucity of pericytes, immature basa l lamina, and
deficiency of glial fibrillary acidic protein, all of which result in
vascular fragility (3). When this fragile vasculature encounters
disturbances in cerebral blood flow due to the impaired cerebral
autoregulation of premature infants, hemorrhage can result.
If the hemorrhage in the germinal matrix is substantial, the
immature ependyma breaks and the cerebral ventricles fill
with blood, becoming visible on head ultrasound evaluation
(
3). A number of antenatal, perinatal, and post-natal factors
have been found to be associated with disturbances in cerebral
blood flow and possibly IVH (most importantly gestational
age), but most times the specific clinical circumstance or factor
leading to hemorrhage remains unidentified. Currently, the
only proven intervention to decrease the rate of IVH is the
administration of antenatal steroids to the mother. A recent study
demonstrated that administration of antenatal steroids decreased
the rate of IVH by 16% in 24-25+6/7-week gestation infants, by
12.9% in the 26-27+6/7-week gestation infants, and by 19.4%
across the entire cohort (
4). Research is ongoing to find better
strategies to prevent and manage this significant complication
of prematurity.
Pulmonary Hemorrhage
Pulmonary hemorrhage (PH) occurs in 3–5% of mechanically
ventilated pre-term infants and in up to 8.6% of those born
extremely premature (23–24 weeks’ gestation) (
5, 6). Additional
risk factors include small for gestational age status, low Apgar
scores, sepsis, presence of a patent ductus arteriosus (PDA),
and severe respiratory distress syndrome (7). It most commonly
occurs in the first 2 days of life and is associated with
an increase in mortality overall and at 7 days of life (5).
It has been hypot hesized that PH occurs due to the rapid
lowering of intrapulmonary pressure after administration of
exogenous surfactant, which allows for an increase in pulmonary
blood flow as blood shunts from the systemic to pulmonary
circulation across the PDA (
6). Currently, PH is managed with
ventilator titration (increased positive end-expiratory pressure),
administration of epinephrine via the endotracheal tube, and
(after the acute phase) additional doses of surfactant. Platelet
and/or FFP transfusions are frequently given to neonates with
active PH, sometimes empiric a lly in the setting of active
bleeding and sometimes in response to decreased platelet
counts or prolonged PT/PTT. However, the contribution of
thrombocytopenia and/or coagulopathy to these hemorrhages
remains uncertain.
Lower Gastrointestinal (GI) Hemorrhage
Bloody stools can be seen in well-appearing newborns due
to common causes such as swallowed maternal blood during
delivery, the presence of an anal fissure, or allergic colitis.
These cases are not associated with disorders of hemostasis,
and typically resolve with close monitoring and the removal
of cow’s milk protein from the diet (in the case of allergic
colitis). In contrast, in critically ill premature infants, frank
rectal bleeding is most frequently seen in the setting of
necrotizing enterocolitis (NEC). Necrotizing enterocolitis is one
of the most common and devastating diseases in pre-term
neonates with an estimated incidence of 7% among infants
with a birth weight between 500 and 1,500 g (
8) and a n
estimated incidence of death of 20–30%, with the highest
mortality seen in those infants who require surgery (9). The
typical presentation of NEC is feeding intolerance, abdominal
distension, and bloody stools in a pre-term infant after 8–
10 days of life, associated with bowel wall is chemia and
bacterial overgrowth. These s ymptoms progress rapidly over
hours often leading to systemic hypotension and respiratory
failure, and can culminate with bowel perforation requiring
surgery. Infants with severe disease also frequently develop severe
thrombocytopenia ± coagulopathy associated with disseminated
intravascular coagulation, further predisposing them to bleeding
in the GI tract and other sites. Recent work in an animal model
of NEC identified thrombin generation as an early event in the
pathogenesis of NEC (
10), which might trigger platelet activation
as well as intravascular thrombosis. In this mouse model,
thrombin inhibition as well as platelet depletion attenuated the
severity of the intestinal injury and reduced mortality, pointing
to a contribution of this pathway to the pathophysiology of the
disease and highligh ting potential mechanisms through which
platelets could worsen the disease process.
Frontiers in Pediatrics | www.frontiersin.org 2 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
Minor Bleeding Events
In addition to the serious etiologies of neonatal bleeding
mentioned above, neonates frequently experience minor bleeding
events throughout their hospitalization. The presentations are
numerous but include cephalohematoma sustained at birth,
blood tinged endotracheal tube secretions in mechanically
ventilated infants, and oozing from the umbilical stump or from
sites of blood draws. It is unclear whether minor bleeding events
are harbingers of more serious bleeding, but t hey often resolve
with only close monitoring.
DEVELOPMENTAL DIFFERENCES IN
HEMOSTASIS
Platelet Counts and Platelet Function in
Neonates
The largest study on neonat al platelet counts conducted to date,
which included ∼47,000 infants delivered between 22 and 42
weeks’ gestation (
11), showed that platelet counts incre ased
during gestation by ∼2 × 10
9
/L per week. Importantly, the mean
platelet count was ≥200 x 10
9
/L (well within the normal adult
range) even in the most pre-term infants, but the 5th percentile
was 104 × 10
9
/L for those ≤ 32 weeks gestation and 123 ×
10
9
/L for late-pre-term and term neonates (11). This suggested
that platelet counts between 100 and 150 × 10
9
/L might be more
frequent among extremely pre-term infants than among full term
neonates or older children/adults, and that perhaps different
definitions of thrombocytopenia should be applied to neonates
at different gestational ages. Nevertheless, even in the most pre-
term neonates –just like in adults- platelet counts <100 x 10
9
/L
are considered abnormal.
While platelet counts are similar in neonates and adults,
there are substantial developmental differences in regard to
platelet function. In in vitro platelet function assays, platelets
from neonatal (full term) cord blood activate and aggregate less
than adult platelets in response to traditional platelet agonists
such as adenosine diphosphate (ADP), epinephrine, collagen,
thrombin, and thromboxane analogs (
12, 13). More recently,
neonatal platelets were also found to exhibit a pronounced
hyporesponsiveness to collagen-related peptide (CRP) and to
the snake venom toxin rhodocytin, which activate the collagen
receptor GPVI and the C-type lectin-like receptor 2 (CLEC-
2), respectively (
14). The few studies that have investigated
platelet activation in pre-term neonates suggest that the platelet
hyporeactivity might be more pronounced in premature infants
compared to those born at term (13–15).
Different mechanisms contribute to the reduced responses of
neonatal platelets to various agonists: 1. the hyporesponsiveness
to epinephrine is due to a marked reduction in the number of
α2-adrenergic receptors, the binding sites for epinephrine, on the
surface of neonatal platelets; 2. the decreased responsiveness to
thrombin is related to reduced expression of the thrombin
receptors PAR-1 and PAR-4 in neonatal platelets (16);
3. the decreased response to thromboxane results from
reduced signaling downstream from the receptor (
17); 4. the
reduced responses to collagen and rhodocytin result from
mildly reduced expression of GPVI and CLEC-2, respectively,
coupled with an intracellular signaling defect evidenced by
reduced Syk and PLCγ2 phosphorylation following stimulation
(
14). Recently, developmental differences have also been
described in regard to platelet inhibitory pathways, specifically
a hypersensitivity of neonatal platelets to the inhibitory effects
of prostaglandin E1 (PGE
1
) during ADP- and collagen-induced
platelet aggregation, associated with a functional increase in the
PGE
1
-cAMP-PKA axis (
18).
Upon activation, in addition to experiencing a conformational
change in the surface receptor GPIIb/IIIa that increases its affinity
to fibrinogen, platelets secrete the content of their dense and
alpha granules. In comparison with adult platelets, agonist-
induced secretion of platelet granule content is reduced in
both term and pre-term human neonates. In the case of dense
granules, this might be related to the presence of fewer dense
granules in neonat al compared to adult platelets (19). However,
the 10-fold more abundant α-granules are present in similar
numbers in neonatal and adult platelets (19–24). Recently,
Caparros et al. demonstrated that the reduced exocytosis of alpha
granules in neonatal platelets was associated with significantly
reduced levels of syntaxin-11 and its regulator, Munc18b,
which are SNARE proteins that mediate the fusion between
vesicles and plasma membranes required for exocytosis (23).
This provided a potential additional mechanism to explain
the reduced degranulation of neonatal platelets in response
to agonists.
Surprisingly, while the hypofunctional in vitro platelet
phenotype would predict impaired primary hemostasis and a
bleeding tendency, bleeding times (BTs) in healthy term neonates
(using a de vi ce and technique modified to make a smaller
skin incision) were found to be paradoxically shorter than BTs
in adults (
25). Similarly, studies using the Platelet Function
Analyzer (PFA-100
R
, an in vitro test of primary hemostasis that
measures the time it takes to occlude a small aperture, or Closure
Time) found that cord blood samples from term neonates
exhibited shorter closure times (CTs) than blood samples from
older children or adults (
26–29). These paradoxical findings,
in the setting of platelet hyporeactivity, are explained by the
presence of multiple factors in the blood of healthy neonates
that enhance platelet/vessel wall interactions, including high er
concentrations of circulating vWF with enhanced adhesive
activity due to a predominance of ultralong polymers (30–
33), higher hematocrits, and a higher MCV (34). These factors
effectively counteract the platelet hyporeactivity, with the net
effect of shorter bleeding times in neonates compared to adults
(Figure 1). In support of the import a nce of the hematocrit on
neonatal primary hemostasis, hematocrits below 28% in pre-
term neonates were associated with longer bleeding times, which
improved following red cell transfusion (35).
These compensatory mechanisms might be less well-
developed in pre-term infants, whose platelets are also more
hyporeactive than those of full-term infa nts, potentially leading
to a more vulnerable primary hemostatic system. In fact,
BTs performed on t he first d a y of life were longer in pre-
term compared with term infants, with neonates <33 weeks
gestation exhibiting the longest BTs (
36). PFA-100 CTs from
Frontiers in Pediatrics | www.frontiersin.org 3 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
FIGURE 1 | Neonatal Hemostasis. The hemostatic system of neonates is
characterized by decreased platelet reactivity and decreased levels of multiple
coagulation factors, which would predict a bleeding phenotype. However,
these findings are exquisitely equilibrated by other factors in neonatal blood
that promote clotting, such as the increased hematocrit, MCV, VWF levels and
the low levels of natural anticoagulants. The overall hemostatic balance in
healthy term neonates is different from that of adults but well-balanced, and
perhaps slightly tilted toward thrombosis, with shorter bleeding times and
faster initiation of coagulation compared to healthy adults.
non-thrombocytopenic neonates were also inversely correlated
to gestational age in both cord blood and neonatal peripheral
blood samples obtained on the first day of life (37). H owever,
CTs in pre-term neonates were still near or within the normal
range for adults, suggesting that healthy pre-term neonates also
have adequate primary hemostasis.
Neonatal platelet function, measured as platelet activation by
flow cytometry, improves signific antly post-natally and ne a rly
normalizes by 10–14 days, in term as well as pre-term infants
(
13, 15). Consistently, Del Vecchio et al. found that all infants
had shorter BTs by day of life 10 than at birth, and that
early gest a tional age-related differences disappeared by then.
Moreover, little or no further shortening occurred between days
10 and 30 (36). PFA-100 CTs are also significantly longer in the
blood of neonates as early as on day of life 1–2 compared to cord
blood, but remain similar to or shorter than those of adults (
37).
Taken together, while the decreased platelet function of
neonates has been invoked as a potential contributor to
the high incidence of bleeding among neonates, particularly
those born pre-term, the evidence suggests that–under normal
circumstances- this platelet hyporeactivity is not a developmental
defect, but rather an integral part of a developmentally distinct,
but well-b alanced neonatal primary hemostatic system. Key
points related to neonatal primary hemostasis are summarized
in Table 1.
Ontogenetically, these differences in platelet reactivity
might be an important mechanism to prevent unwanted
platelet activation and thrombosis during birth, a process
frequently associated with tissue injury and epinephrine surges.
However, how disease processes perturb this delicate system,
and whether these disturbances contribute to bleeding, are
unanswered questions.
The Neonatal Hemostatic System
There are also substantial differences between the fetal/neonatal
and the adult coagulation system. In the classical coagulation
cascade model, clotting factors interact and undergo a series
of enzymatic reactions via the contact activation (intrinsic)
and tissue factor (extrinsic) pathways, which converge on a
final common pathway that culminates in thrombin formation.
Coagulation factors do not cross the placenta because of their
size, and are produced in the fetus st arting at 11 weeks
gestation. 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. In contrast to vit amin K-dependent
factors, neonates have normal levels of factor VIII, factor XIII and
fibrinogen, and elevated levels of vWF, as described above (40).
Keeping in mind these developmental differences in the activity
levels of the different coagulation factors is essential to adequately
interpret laboratory results in neonates.
The PT and PTT, the two most commonly used tests
to evaluate coagulation status, are measures of the intrinsic
and the extrinsic clotting pathways, respectively. Both tests
were developed specifically to investigate coagulation factor
deficiencies, and thus are longer in healthy pre-term and term
neonates compared to adults, reflecting the lower activity levels
of most coagulation factors in these populations. Andrew et
al. published the first PT, PTT and fibrinogen reference ranges
for healthy near-term and term infants in 1987 (
30), followed
by a study in pre-term neonates 30–36 weeks in 1988 (31).
These studies included reference ranges for infants on days
of life 1, 5, 30, 90, and 180, which showed rapid changes
in the first few days after birth and through infancy. In a
subsequent study, the same group measured the concentration
of 33 components of the hemostatic system in children ages 1
to 16 and showed import ant physiologic differences between the
hemostatic system of children and that of adults (
41). Taken
together, these observations led to the concept of “developmental
hemostasis” to describe a series of age-related physiological
changes of the coagulation system from feta l to neonatal to
pediatric and ultimately to adult life.
Focusing on more pre-term infants, Christensen et al.
published reference ranges for infants <34 weeks’ gestation,
using cord blood samples (
42), and Neary et al. reported PT, PTT
and fibrinogen reference ranges obtained on day of life 1 in a
cohort of 183 infants born at <27 weeks’ gestation, the group
at highest risk of clinically significant bleeding. In this high-
risk cohort, the median (range) PT was 20.2 (1 4.4–3 6.7) s, PTT
was 67.4 (34.9–191.6) s and fibrinogen 1.4 (0.5–4.8) g/L (43).
These values were higher than those reported by Christensen
et al., which could have been related to the source of the blood
(cord blood vs. neonatal blood) and/or to the use of different
reagents and testing systems (
44). Taken together, these studies
indicated that the upper limits for both PT and PTT values are
Frontiers in Pediatrics | www.frontiersin.org 4 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
TABLE 1 | Key points regarding neonatal primary hemostasis and platelet transfusions.
Platelet count and function • Mean platelet counts are within the normal adult range even in the most pre-term neonates
• Neonatal platelets are hyporeactive in response to most agonists in vitro (pre-term > term)
• Platelet reactivity improves to near-adult levels by day of life 10–14
Compensatory factors This platelet hyporeactivity is balanced by factors in neonatal blood that enhance platelet/vascular wall interaction:
• Increased hematocrit
• Increased MCV
• Increased vWF and predominance of ultralong multimers
Tests of primary hemostasis • Bleeding times are shorter in healthy neonates than in adults
• PFA-100 closure times are shorter in term cord blood samples than in adult blood samples.
• These suggest enhanced primary hemostasis in neonates, despite their platelet hyporeactivity.
Effects of platelet transfusions • Platelet transfusions should be administered to thrombocytopenic neonates with active bleeding
• Non-bleeding pre-term neonates who received prophylactic platelet transfusions for PC <50 × 10
9
/L had
significantly higher bleeding and mortality compared to neonates transfused only for PC <25 × 10
9
/L.
• High risk, critically ill neonates benefit from the lower transfusion threshold as much as low risk stable neonates.
TABLE 2 | Neonatal reference ranges for common coagulation tests measured on
day of life 1, by gestational age.
PT (s) PTT (s) Fibrinogen (mg/dL)
<27 weeks* 14.4–36.7 40.5–158.5 70–480
28–34 weeks** 13.9–20.6 30–57 87–470
30–36 weeks* 10.6–16.2 27.5–79.4 150–373
Full Term*** 10.1–15.9 31.3–54.5 167–399
*Reference ranges reflect 2.5th−97.5th percentiles (31, 43).
**Reference ranges reflect 5th−95th percentiles (
42).
***Reference ranges calculated from mean ±SD (2SD below and above the mean) (
30).
higher among healthy extremely pre-term neonates than among
moderately pre-term or term infants (Table 2), consistent with
the development al differences in clotting factor levels. However,
both PT and PTT decrease rapidly in the first few days after birth,
with significantly lower levels noted on day of life 3 compared to
day of life 1 in extremely pre-term neonates (
45).
In 2006, Monagle et al. published comprehensive reference
ranges for coagulation tests measured in healthy term neonates
on days of life 1 and 3 a nd 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). Thus, individual coagulation laboratories need
to develop age-related reference ranges using their own testing
systems, in order to interpret the results adequately.
The “ prolongation” of the PT and PTT in neonates and
particularly in extremely pre-term neonates, who have the highest
incidence of major bleeding, has been frequently interpreted as a
hemostatic defect and has led to the practice in many Neonatal
Intensive Care Units (NICUs) of routinely checking coagulation
tests and administering FFP to non-bleeding pre-term neonates
with “abnormal” values to try to prevent bleeding, particularly
IVH (
43, 47). Paradoxic ally , however, studies by Cvirn et al.
using assays with physiologic amounts of tissue factor found
adequate and faster thrombin generation (the final product of
the coagulation cascade) in neonates compared to adults (
48).
More recently, Neary et al. found that thrombin generation was
similar in very pre-term compared to term cord blood samples,
despite differences in PT and PTT levels. Interestingly, lag time
and time to peak thrombin generation were shorter in pre-term
compared to term cord blood samples, indicating faster thrombin
generation in the pre-term infants (45).
While the reasons for the dis crepancy between prolonged
coagulation times and adequate/faster thrombin generation in
pre-term compared to term infants (and in neonates compared
to adults) are not fully understood, they likely involve the co-
existent developmental differences in anticoagulant pathways
in neonates, which are not well-reflected in the PT and PTT
assays. Indeed, just like most coagulation factors are de creased in
neonates, most natural anticoagulants are also reduced at birth
(
30, 31, 41), which results in a ba lanced 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). Perhaps to compensate for t h ese low levels, another
anticoagulant, α2-macroglobulin, is present at higher levels in
neonates than in adults, and further increases over the first 6
months of age (
30, 41). Taken together, the evidence suggests that
the prolonged PT and PTT found in otherwise healthy pre-term
and term neonates should not be interpreted as a developmental
deficiency or a bleeding tendency, but rather as a limitation
of these tests to reflect the complexities of a developmentally
unique but well-balanced neonatal hemostatic system (Figure 1
and Table 3).
EVALUATION OF BLEEDING AND
PREDICTION OF BLEEDING RISK IN
NEONATES
Platelet Counts
Platelets are essential for primary hemostasis. For that reason,
a platelet count is always part of the initial evaluation of a
neonate who presents with abnormal bleeding. In that setting,
Frontiers in Pediatrics | www.frontiersin.org 5 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
TABLE 3 | Key points regarding neonatal secondary hemostasis and FFP transfusions.
Coagulation factor levels • Neonates have reduced levels of most coagulation factors, particularly vitamin K-dependent factors
• FVIII, FXIII, and fibrinogen levels are normal
• vWF levels are elevated
• Coagulation factor levels change in neonatal life, infancy and childhood following specific patterns
(developmental hemostasis).
Natural anticoagulant levels • Neonates have low levels of AT, HCII, protein C and protein S
• α2-macroglobulin is present at higher levels in neonates than in adults
Laboratory evaluation of hemostasis • PT and PTT are longer in healthy neonates than in healthy adults (pre-term > term) and decrease in the first few
days after birth
• Actual values for tests of coagulation vary depending on the source of the sample (cord blood vs. neonatal blood),
reagents and testing systems used.
• However, thrombin generation is faster in neonates than in adults (pre-term > term)
• Tests of whole blood hemostasis (TEG, ROTEM) show faster initiation and propagation of coagulation in
neonates compared to adults
FFP transfusions • FFP should be administered to neonates who present with bleeding associated with coagulation factor(s)
deficiency, if the specific factor is not known or available.
• Prophylactic FFP transfusions given empirically to pre-term neonates or in response to “pro longed” PT or PTT
do not decrease the incidence or severity of IVH.
vWF, von Willebrand Factor; AT, antithrombin; HCII, Heparin cofactor II; IVH, Intraventricular hemorrhage.
the finding of thrombocytopenia (either isolated or as part of
a coagulopathy) is an important diagnostic clue. Severe isolated
thrombocytopenia in an otherwise healthy neonate should raise
suspicion for Fetal/Neonatal Alloimmune Thrombocytopenia
(caused by the transplacental passage of maternal alloantibodies
directed against antigens in the fetal platelets) which is associated
with a n incidence of bleeding of 10–20% (
49, 50). Isolated
thrombocytopenia can also be found in neonates with a history
of intrauterine growt h restriction or with viral, bacterial or fungal
infections. I n critically ill neonates with bleeding in the setting of
sepsis, NEC, or severe perinatal asphyxia, thrombocytopenia is
frequently present, either in isolation or as part of a picture of
disseminated intravascular coagulation (DIC).
The utility of the platelet count as a predictor of bleeding
risk in neonates without abnormal bleeding is much
more controversial, although in neonatal clinical practice
thrombocytopenia has been widely considered a risk factor
for bleeding, particularly among pre-term infants. In support
of an association between thrombocytopenia and bleeding,
a recent study of 972 very-low-birth-weight infants ( VLBW,
<1,500 g at birt h) found that having a platelet count <150
× 10
9
/L in the first week of life was associated with a higher
incidence of IVH (hazard ratio 2.17; 95% CI, 1.53–3.08; p <
0.001). However, association does not imply causa lity, and
the same study found no correlation between the severity
of t h rombocytopenia and the risk for IVH (
51). The latter
finding, consistent with several other studies (52–56), raised
serious questions regarding the value of the platelet count
as a marker of bleeding risk in pre-term neonates, and the
effectiveness of platelet transfusions at preventing hemorrhage in
non-bleeding neonates with mild to moderate thrombocytopenia
(see Platelet Transfusions below). Interestingly, the same lack
of correlation between severity of thrombocytopenia and
significant bleeding has been reported in pediatric patients
with chemotherapy-induced thrombocytopenia (
57), suggesting
that factors other than t he platelet count might be the main
determinants of bleeding risk in thrombocytopenic children as
well as neonates.
Recently, other approaches have been suggested to assess
bleeding risk in thrombocytopenic pre-term neonates. In a study
evaluating platelet function in pre-term and term neonates by
flow cytometry, fibrinogen binding a nd degranulation responses
to ADP were significantly reduced in septic compared to
healthy neonates, raising the possibility that tests of platelet
function might eventually contribute to identify neonates at
high risk of bleeding (
58). However, whether these platelet
functional differences are associated with a higher incidence
or severity of bleeding remains to be determined. Given the
unique features and dynamic nature of the neonatal primary
hemostatic system, we hypothesized that a whole blood test of
primary hemostasis, such as the closure time in response to
collagen and ADP (CT-ADP) measured in the Platelet Function
Analyzer-100 (PFA-100), would be a better marker of bleeding
risk in pre-term neonates than the plat elet count or the platelet
function alone, since it would measure the combined effects of
platelet count, platelet function, hematocrit, and vWF levels on
a baby’s primary hemostatic ability. Indeed, in a cohort of 54
infants with gestational age <27 weeks, we found a significant
correlation between median CT-ADP (but not platelet count) and
bleeding severity, quantified using a validated neonatal Bleeding
Assessment Tool (
55). Furthermore, changes in the CT-ADP
were strongly correlated with changes in the bleeding score, while
changes in platelet counts were not (59). This study suggested
that tests of whole blood primary hemostasis might be more
useful markers of bleeding risk among thrombocytopenic pre-
term neonates than platelet counts, although the relatively high
volume of blood required for the CT-ADP (800 µL) precludes
its current widespread use in this population. Finally, Fustolo-
Gunnink and collaborators developed a dynamic model to
predict major bleeding in pre-term neonates at any time-point
during the first week after the onset of severe thrombocytopenia,
which incorporated the variables gestational age, post-natal age,
Frontiers in Pediatrics | www.frontiersin.org 6 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
intrauterine growth retardation, NEC, sepsis, platelet count
and mechanical ventilation (60). While not yet prospectively
validated, this is a promising approach to making individualized
treatment decisions in this population and has the unique
advantage of incorporating in vivo risk factors that cannot be
captured by any laboratory test.
PT/PTT
As previously described, the PT and PTT can be prolonged in
neonates at baseline, especially in those born premature, likely
reflecting an aspect of the developmentally unique neonatal
hemostatic system. Thus, it is difficult to decide how to interpret
and respond to these values in a non-bleeding neonate, and
studies have shown no association between results of these tests
and IVH rates in pre-term neonates (
42, 45). However, when
faced with neonatal bleeding of unclear etiology, the PT and
PTT can be very useful to evaluate for specific coagulation
factor deficiencies, which can present with clinical bleeding and a
prolongation of either the PT or PTT beyond that seen in healthy
neonates (Table 4).
Vitamin K Deficiency of the Newborn (Previously
Hemorrhagic Disease of the Newborn)
Clinically, infants suffering from Vit K deficiency present with
visible frank bleeding from the nose, umbilicus, skin, urinary
tract, GI tract, and from sites of needle pricks. Less visible,
but more devastating, they also can suffer from intracranial,
pulmonary, and massive GI bleeding (
61). Vit K deficiency
leads to a reduction in the activity of the Vit K-dependent
coagulation factors II, VII, IX, X, and of the anticoagulant protein
C and protein S. It should be suspected in a neonate who
presents with abnormal bleeding and a marked prolongation
of the PT, which measures the activity of three of the four
Vit K-dependent factors (II, VII, and X) (61). Vit K deficiency
has been classified into early, classical, and late disease, each
with unique etiologies and present ations (Table 5). Early Vit K
deficiency is rare and presents in the first 24 h of life in an infant
whose mother took medications during pregnancy that interfere
with Vit K metabolism (such as warfarin, phenytoin, rifampin,
and isoniazid). Classical Vit K deficiency presents between 2
and 7 days of birth and is likely due to inadequate oral feeding,
given how critical the successful establishment of breast feeding
TABLE 4 | Typical test result patterns in bleeding disorders that can present in the
neonatal period.
Disease PT PTT Platelets
Hemophilia A Normal ↑ ↑ ↑ Normal
Hemophilia B Normal ↑ ↑ ↑ Normal
Factor XIII Deficiency Normal Normal Normal
Vitamin K Deficiency of
the Newborn
↑ ↑ Normal Normal
vWD type 3 Normal ↑ ↑ ↑ Normal
DIC ↑ ↑ ↑ ↑ ↓ ↓ ↓
vWD, Von Willebrand Disease; DIC, Disseminated Intravascular Coagulation.
is to Vi t K status (
62). Late Vit K deficiency presents between
8 days and 6 months of life. This form nearly always occurs
in exclusively breast-fed infants and has a higher incidence of
intracranial hemorrhage, which is often the presenting sign (63).
Many of the affected infants have hepatobiliary dysfunction,
resulting in cholestasis and impaired secretion of bile salts that
lead to malabsorption of Vit K (
64). With the nearly universal
administration of intramuscular Vit K after birth, the incidence
of Vit K deficiency (in particular the classical form) markedly
decreased. However, the increasingly frequent refusal to Vit K
administration among parents in westernized countries has led to
a trend of increasing cases. Some healthcare systems or families
opt for a multi-dose oral regimen of Vitamin K after birth,
but this is not recommended due to concerns for poor enteral
absorption and compliance. Neonates who present with acute
bleeding due to Vit K deficiency should be tre at ed upon suspicion
with intravenous Vit K, which will reverse the coagulopathy (
62).
However, due to the time required for Vit K to take effect, FFP
should also be administered immediately to prevent devastating
intracranial hemorrhage.
TABLE 5 | Classification of vitamin K deficiency of the newborn.
Risk factors Clinical
presentation
Early (24 h of life) Maternal medications:
• Vitamin K
antagonists
• Anticonvulsants
• Tuberculosis drugs
• Umbilical stump
bleeding
• Cephalohematoma
• ICH
Classical (1–7 days of
life)
Inadequate Vitamin K
due to:
• Lack of prophylaxis
• Poor breastfeeding
• GI bleeding
• Mucocutaneous
bleeding
• Oozing at umbilicus
or circumcision site
• ICH
Late (8 days to 6
months of life)
• Exclusive
breastfeeding
• Poor feeding
• GI disorders
• Liver disease
• Pancreatic disease
• GI bleeding
• Mucocutaneus
bleeding
• Very high risk for ICH
• Death
ICH, Intracranial hemorrhage; GI, Gastrointestinal.
TABLE 6 | Reasons for diagnostic testing in newborns with hemophilia*.
Number of infants ages 0–2 years 864
Number diagnosed within 1 month of birth 633 (73%)
Reason for diagnosis
Carrier mother 299 (47.2%)
Other family history 147 (23.2%)
Bleeding event 182 (28.8%)
Unknown 5 (0.8%)
*Data from the Universal Data Collection (UDC) 2010 update (65).
Frontiers in Pediatrics | www.frontiersin.org 7 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
Hemophilia A and B
Hemophilia A and B, caused by deficiencies of Factor VII I and
Factor IX, respectively, are the most common inherited bleeding
disorders that present in neonatal life. They are classically
inherited in a X-linked recessive pattern, but ∼1/3 of cases are
due to spontaneous genetic mutations with no f amily history.
The diagnosis of hemophilia is occurring at earlier ages, with
over half of cases now being diagnosed in the neonatal period
(
65). Reasons prompting testing and leading to the diagnosis
in newborn infants are listed in Table 6. Unlike older children
with hemophilia, who present with hemarthroses, neonates
typically present with iatrogenic bleeding (oozing or excessive
hematoma formation after venipuncture or intramuscular Vit
K administration), excessive bleeding after circumcision, or
intracranial/extracranial bleeding (
66–68). In a survey of 102
neonates with cranial bleeds and hemophilia, the mean age
at diagnosis was 4.5 days, and intracranial hemorrhages (most
frequently subdural) were more common than extracranial
bleeds (such as cephalohematomas and subgaleal h emorrhages)
(69). A clinical suspicion of hemophilia is supported by an
isolated prolongation of the PTT, but definitive diagnosis requires
measurement of Factor VIII or IX. Since factor VIII levels
are within t h e normal adult range in both pre-term and term
neonates, it is possible to diagnose hemophilia A of any severity
in the neonatal period. Howe ver, this is not true for Factor
IX, which shows reduced levels at birth and an even further
reduction in infants born pre-term. Thus, severe hemophilia
B can be diagnosed at birth, but confirmation of mild cases
requires repeat testing at 6 months of age or genetic analysis (if a
familial genetic defect is known). The delivery room management
of an infant with known or suspected hemophilia has been
the subject of multiple retrospective studies (
69–72). Current
recommendations state that there is no contraindication to a
vaginal delivery, but an instrumented delivery (i.e., forceps,
vacuum extraction, and the use of scalp electrodes) should be
avoided and early transition to c esarean delivery is recommended
if th ere is a failure of labor (
73, 74).
Isolated Coagulation Factor Deficiencies
Outside of hemophilia A and B, neonates can inherit deficiencies
of other isolated coagulation factors (
75). Von Willebrand disease
(VWD) is the most frequent inherited bleeding disorder, affecting
∼1% of the population. It is classified into three categories based
on the quantitative level or function of von Willebrand Factor
(vWF). Type I is due to a quantitative deficiency of vWF and
typically has a mild presentation with mucosal bleeding. Type
II is due to a qualitative defect in vWF and is divided into
four subtypes, which are associated with more severe bleeding
phenotypes than Type I. Due to the increased levels of vWF
and the presence of high molecular weight vWF multimers in
neonates, these types do not typically present in neonatal life.
However, type III VWD is the most severe form, due to a
complete or almost complete deficiency of vWF, and this form
can present in neonates with a phenotype similar to severe
hemophilia A (
76).
Other factor deficiencies can present in the neonatal period
but are rare and diagnosis requires an astute clinician with
a h igh index of suspicion and often assistance by a pediatric
hematologist. Deficiency of Factor XIII, which is responsible for
cross linking fibrin and stabilizing clots, classically presents with
delayed umbilical cord hemorrhage but a normal PT and PTT.
Thus, the diagnosis requires a high index of suspicion prompting
the measurement of Factor XIII levels. Alpha2-antiplasmin and
plasminogen activator inhibitor-1 both act to reduce plasmin
activity and deficiency of either is extremely rare, but should also
be considered when the PT and PTT are normal in a neonate
with abnormal bleeding (
76). In afibrinogenemia and in Factor II,
V, and X deficiency the PT and PTT are both prolonged (76–78).
Finally, Factor VII deficiency is a rare, heritable bleeding disorder
with variable presentation and over 250 causal mutations (79).
Neonates often present with multifocal spontaneous bleeding
in the first few days of life that can range from epistaxis, gum
bleeding and hematomas to hemarthrosis and life-threatening
cerebral and gastrointestinal hemorrhages (
80). Coagulation
studies reveal a prolonged PT, a nd the diagnosis is confirmed by
low Factor VII levels (75).
Tests of Global Hemostasis: TEG and
ROTEM
Thromboelastography (TEG) and Rotating Thromboelastometry
(ROTEM) are both viscoelastic point-of-care tests that offer rapid
global assessments of whole blood hemostasis in small volumes
of whole blood, making them ideal tests for neonata l patients
with small blood volumes. Both assays provide information on
platelet function, clot formation, tensile strength of the clot, and
subsequent clot lysis. While similar, the values obtained from
TEG and ROTEM assays are not interchangeable, but bot h can
help guide the selection of blood products for transfusion in a
bleeding patient. Given the developmental differences in neonatal
hemostasis suggested by standard coagulation tests (PT/PTT),
investigators have been interested in comparing measures of
global hemostasis between neonates and adults using these
assays. Multiple studies have found contrasting results, likely
due to differences in sample collection (umbilical cord blood vs.
peripheral venous or arterial blood) and in anticoagulant used.
Initial small studies using the TEG assay in neonates did not
demonstrate differences in fibrin clot formation, clot strength, or
rate of fibrinolysis (
81, 82), but more recent studies found that
neonates have faster initiation and propagation of coagulation
(83–86), consistent with the faster thrombin generation described
above. This relative pro-coagulant state seen on TEG, despite
prolongation of conventional coagulation tests, reinforces the
theory that neonatal hemostasis is not defective, but rather
carefully balanced in a developmental stage-specific manner. A
study comparing ROTEM values in pre-term vs. full-term infants
found that maximal clot firmness (MCF) was significantly lower
in pre-term compared to full-term neonates (87). However, this
and a subsequent study (84) found no association between any
TEG parameter and the occurrence of post-natal complications
in pre-term infants, including intraventricular hemorrhage
(IVH). Conversely, a recent study comparing values of healthy
neonates to those of bleeding neonates at different gestational
ages found st at istically significant differences in assay values
Frontiers in Pediatrics | www.frontiersin.org 8 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
that were associated with clinical bleeding (86). This study
also described reference ranges for both citrate-modified and
heparinase-modified TEG values, given the frequency of these
modifications in neonatal blood samples.
While TEG has been studied more extensively in neonates,
ROTEM has only recently begun to be used in this population.
One study described ROTEM references ranges in a pediatric
cohort from 0 months to 16 years and found differences among
all age groups (
83). The most striking differences were with
infants 0–3 months of age, who exhibited accelerated initiation
and propagation of coagulation and increased clot firmness
despite prolonged standard plasma coagulation tests (PT/PTT)
(83). As reference ranges have become published, investigators
have started assessing the utility of the ROTEM to evaluate
coagulation in common neonatal clinical conditions, such as
sepsis and congenital heart disease (CHD). Initially, one group
found that a hypercoagulable ROTEM profile on the first day
of neonatal sepsis was associated with disease severity (
88). In a
more re cent study, the same group found that septic neonates
were more likely to show fibrinolysis shutdown on ROTEM
than non-septic neonates, but the test could not discriminate
septic from non-septic neonates and could not predict clinical
outcomes (89). It has also been well-described that neonates
with CHD often have coagulation abnormalities that result in
an increased incidence of bleeding (90, 91). One study evaluated
hemostasis in these infants with ROTEM and found that neonates
with cyanosis secondary to CHD had inferior clot formation
as well as a higher incidence of abnormal parameters when
compared to non-cyanotic CHD patients and healthy controls
(92), suggesting that cyanosis and/or polycythemia may have an
impact on hemostasis.
INTERVENTIONS TO MANAGE AND
PREVENT BLEEDING IN NEONATES
Platelet Transfusions
Platelets are essential for hemostasis and contribute substantially
to clot formation. For that re ason, in the setting of acute bleeding,
neonates are frequently transfused platelets if the platelet count is
<100 × 10
9
/L, or empirically in cases of life-t h reatening acute
hemorrhage (i.e., as part of a massive transfusion protocol).
However, the majority of platelet transfusions in the NICU are
given to non-bleeding neonates, when the platelet count falls
below an arbitrary level below which the risk of bleeding is
thought to increase.
Historically, it has been widely accepted that
thrombocytopenic pre-term neonates should receive platelet
transfusions at higher platelet count (PC) thresholds than older
children and adults due to their high incidence of spontaneous
intracranial bleeding, particularly intraventricular hemorrhage
(IVH). Over the last decade, several sur vey s and observational
studies revealed a striking world-wide variability in neonatal
platelet transfusion thresholds, and an overall more liberal
approach to platelet transfusions in U.S. compared to European
NICUs (
93, 94). This variability was at le ast in part due to the
paucity of high-level evidence in the field. Until recently, there
was only one randomized trial of platelet transfusion thresholds
in pre-term neonates, published 25 years ago (
95). That study
randomized 152 Very-Low-Birth-Weight (VLBW, <1,500 g at
birth) neonates to receive platelet transfusions for platelet counts
<150 × 10
9
/L or <50 × 10
9
/L in the first week of life, and
found no differences in the incidence of new IVH or extension
of existing IVH (the primary outcome) between the two groups
(
95). These results likely formed the basis for the use of 50 ×
10
9
/L as the most frequent threshold for platelet transfusions in
pre-term neonates.
The recently published much larger PlaNeT-2 multicenter
trial randomized 660 thrombocytopenic neonates with a median
gestational age of 26.6 weeks and a median birth weight of 740
grams to receive platelet transfusions at platelet count thresholds
of <50 × 10
9
/L (<50 group) or <25 × 10
9
/L (<25 group).
Unlike in the prior study, infants were randomized at any time
during their NICU hospitalization when the platelet count fell
below 50 × 1 0
9
/L, and the primary outcome was a composite of
death or new major bleeding within 28 days of randomization
(96). Ninety percent of infants in the <50 group and 53%
in the <25 group received at le ast one platelet transfusion.
Unexpectedly, infants in the <50 group had a significantly
higher rate of mortality or major bleeding within 28 days of
randomization compared to t hose in the <25 group (26 vs. 19%,
respectively; odds ratio 1.57, 95%CI 1.06–2.32). In a subgroup
analysis, findings were similar for neonates <28 weeks’ gestation,
the group at highest risk of bleeding and death (53, 55).
While these findings might have seemed surprising at
first, they were in fact consistent with a number of prior
obser vational studies describing a poor association between
severity of thrombocytopenia and bleeding risk (
51, 53–55), a
lack of effe c tiveness of platelet transfusions to prevent bleeding in
neonates (5 1, 97), and an association between number of platelet
transfusions and neonatal mortality and morbidity (98–101).
The results of PlaNeT-2 provided high-level evidence in
support of these concepts, although the possibility that the
benefits of the lower transfusion threshold would be limited to
clinically stable infants with a low risk of bleeding and/or death
led to initial skepticism. This question was largely addressed in
a follow-up study in which a multivariable logistic regression
model was developed (as des cribed above) (
60) and used to
predict the baseline bleeding/mortality risk of neonates enrolled
in PlaNeT-2 (102). Based on their model-predicted b aseline risk,
653 neonates in PlaNeT-2 were divided into four quartiles (very
low, low, moderate, and high risk) and the absolute risk difference
between the <50 group and the <25 group was assessed within
each quartile. Interestingly, the lower transfusion threshold was
associated with an absolute risk reduction i n all four groups,
varying from 4 .9% in the lowest to 12.3% in the highest risk
group. These results suggested that using a lower (<25 × 10
9
/L)
prophylactic platelet transfusion threshold is beneficial even in
high risk neonates (Table 1).
Although these studies provided strong support for the use
of lower platelet transfusion thresholds in non-bleeding pre-term
infants, some uncertainties remain. First, only 37% of infants in
the study were randomized by day of life 5 and 59% by day 10,
the period when most clinically significant hemorrhages occur in
Frontiers in Pediatrics | www.frontiersin.org 9 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
pre-term neonates (66). While this might have simply reflected
the time of onset of thrombocytopenia in the study population,
39% of infants in PlaNeT-2 received one or more platelet
transfusions prior to randomization, for unknown reasons and at
non-specified platelet counts. This raises the question of whether
these transfusions were given during the first few days of life, the
highest risk period for IVH in pre-term neonates.
Nevertheless, th e results of PlaNeT-2 provided strong support
for the hypothesis that platelet transfusions may have deleterious
effects in neonates, which could be mediated by various potential
mechanisms. Neonates in PlaNeT-2, consistent with routine
neonatal practices, were transfused with 15 mL/Kg of a platelet
suspension. This is a substantia lly higher volume than that
used in older children or adults, who usually receive ∼5
mL/Kg of a standard platelet suspension. This high transfusion
volume, combined with the fragile vasculature of pre-term
neonates (see Intraventricular Hemorrhage above) and a rapid
rate of transfusion, raises the possibility that the platelet
transfusion itself could have caused or extended intraventricular
hemorrhages through rapid volume expansion, thus providing a
potential explanation for the higher incidence of major bleeding
in the <50 compared to the <25 group. It has also been
hypothesized that a “developmental mismatch” occurs when
adult platelets are given to neonates. As reviewed above, adult
platelets are functionally hyperreactive compared to neonatal
platelets, and in vitro mixing studies found that adult platelets
added to neonatal thrombocytopenic blood (with its higher
hematocrit, MCV, and vWF levels) can induce a prothrombotic
phenotype (
103). Finally, it has become increasingly clear over
the last decade that platelets have important functions beyond
hemostasis, including as central mediators and modulators of
inflammation (104, 105). Thus, it is plausible that some of the
pathogenic effects of platelet transfusions on neonates could
be mediated through inflammatory pathways. Additional work
is needed to elucidate which of these potential mechanisms
contribute to the increased mortality and morbidity associated
with the liberal use of platelet transfusions in neonates, but
in the meantime the data suggest that non-bleeding neonates
(regardless of severity of illness) benefit from a restrictive platelet
transfusion threshold.
Fresh Frozen Plasma
Fresh frozen plasma (FFP) contains all of the clotting factors,
fibrinogen, plasma proteins, electrolytes, protein C, protein S,
antithrombin, and tissue factor pathway inhibitor. It is used
primarily to replenish coagulation factors and is clinically
indicated in the setting of hemorrhage, bleeding or severe
coagulopathy due to multiple coagulation factor deficiencies
secondary to liver disease, DIC, or congenital factor deficiencies
for which there is no concentrate available (i.e., Factor V or XI
deficiencies). While these are clear indications, for which FFP
administration can be life-saving, FFP is most frequently given
to non-bleeding neonates, especially those who are critically
ill, either with the goal of preventing bleeding and/or for
non-hematological indications (i.e., volume expansion in an
infant with massive capillary leak). It has been estimated
that 6–12% of all NICU admissions receive at least one
FFP transfusion (
106, 107), and in a study by Stanworth
and colleagues 62% of infants who received FFP did not
have signs of clinical bleeding at the time of transfusion,
and 14% did not even have coagulation tests prior to FFP
administration (108). Studies examining the success rate of
FFP transfusion normalizing neonatal clotting times found
success rates ranging from 40 to 60%, depending on the
dose administered (107–109). The success rate of clotting time
correction increased to 59–68% if neonatal reference ranges
for coagulation factors were used (42). Howe ver, multiple
studies have shown that, regardless of clotting time correction,
administration of FFP does not change clinical outcomes.
One study looking at FFP administration in the setting of
DIC found no improvement in coagulation tests or in overall
survival (110). Four studies have investigated the use of
prophylactic FFP transfusion in pre-term neonates to decrease
the incidence of IVH: O ne found a decrease in IVH with FFP
administration, but the other three reported similar IVH rates
in their control and treatment arms (
111–114) and a meta-
analysis found no differences in grade of IVH or mortality (115)
(Table 3). Additional controlled studies have found no benefit
of FFP administration to non-bleeding neonates with sepsis,
respiratory distress syndrome, hypotension, or hypoxic ischemic
encephalopathy (116–120). Despite this growing evidence, FFP
continues to be administered to non-bleeding neonates outside
of the evidence-based recommendations, in many instances
in response to “prolonged” coagulation tests that might be
developmentally appropriate.
Recombinant FVIIa and Prothrombin
Complex Concentrate
Recombinant Factor VIIa (rFVIIa) is a genetically engineered
coagulation protein initially created for the treatment of
bleeding in patients with he mophilia and antibodies against
standard coagulation factor replacements. It is extremely
effective in activating the final pathway of the coagulation
cascade and has been perceived by some as a “universal
hemostatic agent,” prompting its frequent off-label use in
bleeding patients without hemophilia. Since bleeding and
coagulation disorders are common in neonates, rFVIIa is
an attractive solution to an unsolved problem. Several case
reports have described the successful administrati on of rFVIIa
to pre-term and term neonates with intractable hemorrhage
and/or severe coagulopathy (
121). One retrospective report
of 29 neonates found that earlier rFVIIa administration
(<24 h from beginning of bleeding) was associated with a
statistically significant improvement in survival (121) and with
a decreased need for subsequent blood products. However,
concerns have been raised regarding the safety profile of
rFVIIa, specifically a potential increase in thrombotic events
(122). A systematic review of neonates re ceiving rFVIIa or
FFP found no difference in the occurrence of thrombotic
events in neonates with bleeding or coagulopathy (
123).
However, while multiple randomized controlled trials of rFVIIa
administration have been per formed in adults, only three
studies have included children with a total of 11 neonates,
Frontiers in Pediatrics | www.frontiersin.org 10 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
and so high-quality data is lacking to guide the safe use of
rFVIIa in this population and concerns over increased risk of
thrombosis remain.
Prothrombin complex concentrate (PCC) is a human plasma-
derived product containing the vitamin K-dependent coagulation
factors and the vitamin K-dependent clotting inhibitor proteins.
The current indications for PCC are the treatment and
perioperative prophylaxis of bleeding in congenital or acquired
deficiency of prothrombin complex coagulati on factors.
Increasingly, it has been used off-label in hopes of preventing
and treating severe bleeding in neonates. In 2002, The Guideline
for the I nvestigation and Management of Neonatal Hemostasis
and Thrombosis recommended considering PCC when hig h
volume products (such as FFP) need to be avoided or in the
presence of hemorrhage due to depleted factors (
124). Due
to its smaller volume, PCC can be infused quicker than, and
corrects the INR faster than FFP (41 vs. 115 min) (
124, 125).
As with rFVIIa, there are no randomized controlled studies
to guide the safe use of PCC in the neonatal population, but a
recent retrospective study examined 37 neonates with intractable
bleeding or severe coagulopathy who received PCC as a rescue
intervention. In this study, hemostasis was achieved in the
majority of infants and there was a statistically signific ant
improvement in PT, INR, and PTT. Thirteen out of 24 neonates
survived. PCC had been administered to t he neonates who
survived within 24 h of bleeding initiation and no thrombotic
events were observed (126). As with rFVIIa, randomized
controlled trials or prospective controlled studies are needed
to determine the efficacy and safety of PCC in the neonatal
population before it can become part of the stand ard care of a
bleeding neonate.
CONCLUSIONS
The neonat al hemostatic system is strikingly different from that
of adults in that neonates exhibit comparatively hyporeactive
platelets and decreased levels of coagulation f actors, the latter
translating into prolonged clotting times (PT and PTT). Since
pre-term neonates have a high incidence of bleeding, particularly
IVH, neonatologists frequently administer blood products (i.e.,
platelets and FFP) based on arbitrary laboratory thresholds in an
attempt to overcome these “deficiencies” and reduce the bleeding
risk. However, it has become increasingly clear that bot h the
platelet hyporeactivity as well as the decreased coagulation f actor
levels a re effectively counteracted by other factors in neonatal
blood that promote hemostasis (i.e., high levels of vWF, high
hematocrit and MCV, reduced levels of natural anticoagulants),
resulting in a well-balanced neonatal hemostatic system, perhaps
slightly tilted toward a prothrombotic phenotype (Figure 1).
While life-saving in the presence of active major bleeding, the
administration of platelets and/or FFP to non-bleeding neonates
based on laboratory tests has not only failed to decrease bleeding,
but has been associated with increased neonatal bleeding and
mortality in the case of platelets. Given the unique features
of neonat al hemostasis, there has been interest in exploring
the potential use of new tests of whole blood hemostasis (i.e.,
TEG or ROTEM) or primary hemostasis (i.e., PFA-100 CT-
ADP) to predict and/or manage bleeding in neonates. However,
more studies are needed to establish the potential value of these
tests in the management of neonates of different gestational
ages a nd with different clinical conditions. With an increased
understanding of neonatal hemostasis and in vivo factors that
increase a neonate’s bleeding risk, it might be possible to develop
novel and more accurate approaches to manage the hemostatic
challenges of critically ill neonates.
AUTHOR CONTRIBUTIONS
PD and MS-V reviewed the literature, wrote, and edited the
manuscript. Both authors contributed to the article and approved
the submitted version.
FUNDING
MS-V work was funded by P01HL046925 and PD was supported
by T32HL0079172.
REFERENCES
1. Venkatesh V, Curley A, Khan R, Clarke P, Watts T, Josephson C, et al.
A novel approach to standardised recording of bleeding in a high risk
neonatal population. Arch Dis Child Fetal Neonatal Ed. (2013) 98:F260–
3. doi: 10.1136/archdischild-2012-302443
2. Poryo M, Boeckh JC, Gortner L, Zemlin M, Duppre P, Ebrahimi-Fakhari
D, et al. Ante-, peri- and postnatal factors associated with intraventricular
hemorrhage in very premature infants. Early Hum Dev. (2018) 116:1–
8. doi: 10.1016/j.earlhumdev.2017.08010
3. Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of
disease. Pediatric Res. (2010) 67:1–8. doi: 10.1203/PDR0b013e3181c1b176
4. Handley SC, Passarella M, Lee HC, Lorch SA. Incidence Trends and Risk
Factor Variation in Severe Intraventricular Hemorrhage across a Population
Based Cohort. J Pediatr. (2018) 200:24–9. e3. doi: 10 .10 16 /j .jpeds.2018.040 2 0
5. Ahmad KA, Bennett MM, Ahmad SF, Clark RH, Tolia VN.
Morbidity and mortality with early pulmonary haemorrhage
in preterm neonates. Arch Dis Child Fetal Neonatal
Ed. (2019) 104:F63–F8. doi: 10.1136/archdischild-2017-3
14172
6. Aziz A, Ohlsson A. Surfactant for pulmonary haemorrhage
in neonates. Cochrane Database Syst Rev. (2020)
2:CD005254. doi: 10.1002/14651858.CD005254pub4
7. Suryawanshi P, Nagpal R, Meshram V, Malshe N, Kalrao V. Pulmonary
hemorrhage (PH) in extremely low birth weight (ELBW) infants:
successful treatment with surfactant. J Clin Diagn Res. (2015) 9:SD03–
4. doi: 10.7860/JCDR/2015/85965691
8. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. (2011) 364:255–
64. doi: 10.1056/NEJMra1005408
9. Fitzgibbons SC, Ching Y, Yu D, Carpenter J, Kenny M, Weldon C, et al.
Mortality of necrotizing enterocolitis expressed by birth weight categories.
J Pediatric Surg. (2009) 44:1072–5. doi: 10.1016/j.jpedsurg.2009.02013
10. Namachivayam K, MohanKumar K, Shores DR, Jain SK, Fundora J, Everett
AD, et al. Targeted inhibition of thrombin attenuates murine neonatal
necrotizing enterocolitis. Proc Natl Acad Sci USA. (2020) 117:10958–
69. doi: 10.1073/pnas1912357117
11. Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD. Platelet
reference ranges for neonates, defined using data from over 47,000
patients in a multihospital healthcare system. J Perinatol. (2009) 29:130–
6. doi: 10.1038/jp.2008141
Frontiers in Pediatrics | www.frontiersin.org 11 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
12. Israels SJ, Cheang T, Robertson C, McMillan-Ward EM, McNicol A.
Impaired signal transduction in neonatal platelets. Pediatr Res. (1999)
45:687–91. doi: 10.1203/00006450-199905010-00014
13. Sitaru AG, Holzhauer S, Speer CP, Singer D, Obergfell A, Walter U, et al.
Neonatal platelets from cord blood and peripheral blood. Platelets. (2005)
16:203–10. doi: 10.1080/09537100400016862
14. Hardy AT, Palma-Barqueros V, Watson SK, Malcor JD, Eble JA,
Gardiner EE, et al. Significant hypo-responsiveness to GPVI and
CLEC-2 agonists in pre-term and full-term neonatal platelets and
following immune thrombocytopenia. Thromb Haemost. (2018)
118:1009–20. doi: 10.1055/s-0038-1646924
15. Bednarek FJ, Bean S, Barnard MR, Frelinger AL, Michelson AD. The platelet
hyporeactivity of extremely low birth weight neonates is age-dependent.
Thromb Res. (2009) 124:42–5. doi: 10.1016/j.thromres.2008.10004
16. Schlagenhauf A, Schweintzger S, Birner-Grunberger R, Leschnik B, Muntean
W. Comparative evaluation of PAR1, GPIb-IX-V, and integrin alphaIIbbeta3
levels in cord and adult platelets. Hamostaseologie. (2010) 30(Suppl. 1):S164–
7. doi: 10.1055/s-0037-1619105
17. Israels SJ, Odaibo FS, Robertson C, McMillan EM, McNicol A. Deficient
thromboxane synthesis and response in platelets from premature infants.
Pediatr Res. (1997) 41:218–23. doi: 10.1203/00006450-199702000-00011
18. Palma-Barqueros V, Torregrosa JM, Caparros-Perez E, Mota-Perez N,
Bohdan N, Llanos MDC, et al. Developmental differences in platelet
inhibition response to prostaglandin E1. Neonatology. (2019) 117:15–
23. doi: 10.1159/000504173
19. Urban D, Pluthero FG, Christensen H, Baidya S, Rand ML, Das A, et
al. Decreased numbers of dense granules in fetal and neonatal platelets.
Haematologica. (2017) 102:e36–e8. doi: 10.3324/haematol.2016152421
20. Ts’ao CH, Green D, Schultz K. Function and ultrastructure of platelets
of neonates: enhanced ristocetin aggregation of neonatal platelets. Br J
Haematol. (1976) 32:225–33. doi: 10.1111/j.1365-2141.1976.tb00925x
21. Whaun JM. Platelet function in the neonate: including qualitative platelet
abnormalities associated with bleeding. New York, NY: Raven Press (1988).
22. Suarez CR, Gonzalez J, Menendez C, Fareed J, Fresco R, Walenga J. Neonatal
and maternal platelets: activation at time of birth. Am J Hematol. (1988)
29:18–21. doi: 10.1002/ajh2830290105
23. Caparros-Perez E, Teruel-Montoya R, Palma-Barquero V, Torregrosa JM,
Blanco JE, Delgado JL, et al. Down regulation of the Munc18b-syntaxin-
11 complex and beta1-tubulin Impairs secretion and spreading in neonatal
platelets. Thromb Haemost. (2017) 117:2079–91. doi: 10.1160/TH17-04-0241
24. Whaun JM. The platelet of the newborn infant. 5-hydroxytryptamine
uptake and release. Thromb Diath Haemorrh. (1973) 30:327–
33. doi: 10.1055/s-0038-1649081
25. Andrew M, Paes B, Bowker J, Vegh P. Evaluation of an automated
bleeding time device in the newborn. Am J Hematol. (1990) 35:275–
7. doi: 10.1002/ajh2830350411
26. Carcao MD, Blanchette VS, Dean JA, He L, Kern MA, Stain AM, et
al. The platelet function analyzer (PFA-100): a novel in-vitro system for
evaluation of primary haemostasis in children. Br J Haematol. (1998) 101:70–
3. doi: 10.1046/j.1365-2141.1998.00656x
27. Israels SJ, Cheang T, McMillan-Ward EM, Cheang M. Evaluation of primary
hemostasis in neonates with a new in vitro platelet function analyzer. J
Pediatrics. (2001) 138:116–9. doi: 10.1067/mpd.2001109794
28. Roschitz B, Sudi K, Kostenberger M, Muntean W. Shorter PFA-100
closure times in neonates than in adults: role of red cells, white
cells, platelets and von Willebrand factor. Acta Paediatr. (2001) 90:664–
70. doi: 10.1080/08035250119138
29. Boudewijns M, Raes M, Peeters V, Mewis A, Cartuyvels R, Magerman K,
et al. Evaluation of platelet function on cord blood in 80 healthy term
neonates using the Platelet Function Analyser (PFA-100); shorter in vitro
bleeding times in neonates than adults. Eur J Pediatr. (2003) 162:212–
3. doi: 10.1007/s00431-002-1093-7
30. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al.
Development of the human coagulation system in the full-term infant. Blood.
(1987) 70:165–72. doi: 10.1182/blood.V70.1.165bloodjournal701165
31. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al.
Development of the human coagulation system in the healthy premature
infant. Blood. (1988) 72:1651–7. doi: 10.1182/blood.V72.5.16511651
32. Katz JA, Moake JL, McPherson PD, Weinstein MJ, Moise KJ, Carpenter
RJ, et al. Relationship between human development and disappearance of
unusually large von Willebrand factor multimers from plasma. Blood. (1989)
73:1851–8. doi: 10.1182/blood.V73.7.18511851
33. Weinstein MJ, Blanchard R , Moake JL, Vosburgh E, Moise K. Fetal and
neonatal von willebrand factor (vWF) is unusually large and similar to the
vWF in patients with thrombotic thrombocytopenic purpura. Br J Haematol.
(1989) 72:68–72. doi: 10.1111/j.1365-2141.198 9 .tb07654 x
34. Gerrard JM, Docherty JC, Israels SJ, Cheang MS, Bishop AJ, Kobrinsky NL,
et al. A reassessment of the bleeding time: association of age, hematocrit,
platelet function, von Willebrand factor, and bleeding time thromboxane B2
with the length of the bleeding time. Clin Invest Med. (1989) 12 :16 5–7 1 .
35. Sola MC, del Vecchio A, Edwards TJ, Su ttner D, Hutson AD, Christensen
RD. The relationship between hematocrit and bleeding time in very low
birth weight infants during the first week of life. J Perinatol. (2001) 21:368–
71. doi: 10.1038/sj.jp7210546
36. Del V.ecchio A, Latini G, Henry E, Christensen RD. Template bleeding
times of 240 neonates born at 24 to 41 weeks gestation. J Perinatol. (2008)
28:427–31. doi: 10.1038/jp.200810
37. Saxonhouse MA, Garner R, Mammel L, Li Q, Muller KE, Greywoode J, et al.
Closure times measured by the platelet function analyzer PFA-100 are longer
in neonatal blood compared to cord blood samples. Neonatology. (2010)
97:242–9. doi: 10.1159/000253755
38. Pal S, Curley A, Stanworth SJ. Interpretation of clotting tests in
the neonate. Arch Dis Child Fetal Neonatal Ed. (2015) 100:F270–
4. doi: 10.1136/archdischild-2014-306196
39. Achey MA, Nag UP, Robinson VL, Reed CR, Arepally GM,
Levy JH, et al. The developing balance of thrombosis and
hemorrhage in pediatric surgery: clinical implications of age-
related changes in hemostasis. Clin Appl. Thromb. Hemost. (2020)
26:1076029620929092. doi: 10.1177/1076029620929092
40. Pichler E, Pichler L. The neonat al coagulation system and the vitamin K
deficiency bleeding - a mini review. Wien Med Wochenschr. (2008) 158:385–
95. doi: 10.1007/s10354-008-0538-7
41. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation
of the hemostatic system during childhood. Blood. (1992) 80:199 8–
2005. doi: 10.1182/blood.V80.8.19981998
42. Christensen RD, Baer VL, Lambert DK, Henry E, Ilstrup SJ, Bennett ST.
Reference intervals for common coagulation tests of preterm infants (CME).
Transfusion. (2014) 54:627–32. doi: 10.1111/trf12322
43. Neary E, Okafor I, Al-Awaysheh F, Kirkham C, Sheehan K, Mooney C, et
al. Laboratory coagulation parameters in extremely premature infants born
earlier than 27 gestational weeks upon admission to a neonatal intensive care
unit. Neonatology. (2013) 104:222–7. doi: 10.1159/000353366
44. Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, et al.
Developmental haemostasis. Impact for clinical haemostasis laboratories.
Thromb Haemost. (2006) 95:362–72. doi: 10.1160/TH05-01-0047
45. Neary E, McCallion N, Kevane B, Cotter M, Egan K , Regan I, et al.
Coagulation indices in very preterm infants from cord blood and postnatal
samples. J Thromb Haemost. (2015) 13:2021–30. doi: 10.1111/jth13130
46. Monagle P, Massicotte P. Developmental haemostasis: secondary
haemostasis. Semin Fetal Neonatal Med. (2011) 16:294–
300. doi: 10.1016/j.siny.2011.07007
47. Catford K, Muthukumar P, Reddy C, Al Atrash H, Clarke P, Venkatesh V, et
al. Routine neonatal coagulation testing increases use of fresh-frozen plasma.
Transfusion. (2014) 54:1444–5. doi: 10.1111/trf12610
48. Cvirn G, Gallistl S, Rehak T, Jurgens G, Muntean W. Elevated thrombin-
forming capacity of tissue factor-activated cord compared with adult plasma.
J Thromb Haemost. (2003) 1:1785–90. doi: 10.1046/j.1538-7836 .20 03 .
00320x
49. Blanchette VS, Chen L, de Friedberg ZS, Hogan VA, Trudel E, Decary F.
Alloimmunization to the PlA1 platelet antigen: results of a prospective study.
Br J Haematol. (1990) 74:209–15. doi: 10.1111/j.1365-2141.1990.tb02567x
50. Johnson JA, Ryan G, al-Musa A, Farkas S, Blanchette VS. Prenatal diagnosis
and management of neonatal alloimmune thrombocytopenia. Seminars
Perinatol. (1997) 21:45–52. doi: 10.1016/S0146-0005(97)80019-5
51. Sparger KA, Assmann SF, Granger S, Winston A, Christensen RD, Widness
JA, et al. Platelet transfusion practices among very-low-birth-weight infants.
JAMA Pediatrics. (2016) 170:687–94. doi: 10.1001/jamapediatrics.20160507
52. Muthukumar P, Venkatesh V, Curley A, Kahan BC, Choo L,
Ballard S, et al. Severe thrombocytopenia and patterns of bleeding
in neonates: results from a prospective observational study and
Frontiers in Pediatrics | www.frontiersin.org 12 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
implications for use of platelet transfusions. Transfus Med. (2012)
22:338–43. doi: 10.1111/j.1365-3148.2012.01171x
53. Stanworth SJ, Clarke P, Watts T, Ballard S, Choo L, Morris
T, et al. Prospective, observational study of outcomes in
neonates with severe thrombocytopenia. Pediatrics. (2009)
124:e826–34. doi: 10.1542/peds2009-0332
54. von Lindern JS, van den Bruele T, Lopriore E, Walther FJ. Thrombocytopenia
in neonates and the risk of intraventricular hemorrhage: a retrospective
cohort study. BMC Pediatr. (2011) 11:16 . doi: 10.1186/1471-24 31 -1 1 -1 6
55. Deschmann E, Saxonhouse MA, Feldman HA, Norman M, Barbian M,
Sola-Visner M. Association between in vitro bleeding time and bleeding in
preterm infants with thrombocytopenia. JAMA Pediatrics. (2019) 173:393–
4. doi: 10.1001/jamapediatrics.20190008
56. Baer VL, L ambert DK, Henry E, Christensen RD. Severe thrombocytopenia
in the NICU. Pediatrics. (2009) 124:e1095–100. doi: 10.1542/peds2009-0582
57. Josephson CD, Granger S, Assmann SF, Castillejo MI, Strauss
RG, Slichter SJ, et al. Bleeding risks are higher in children versus
adults given prophylactic platelet transfusions for treatment-
induced hypoproliferative thrombocytopenia. Blood. (2012)
120:748–60. doi: 10.1182/blood-2011-11-389569
58. Waller AK, Lantos L, Sammut A, Salgin B, McKinney H, Foster HR, et
al. Flow cytometry for near-patient testing in premature neonates reveals
variation in platelet function: a novel approach to guide platelet transfusion.
Pediatric Res. (2019) 85:874–84. doi: 10.1038/s41390-019-0316-9
59. Deschmann E, Saxonhouse MA, Feldman HA, Norman M, Barbian M,
Sola-Visner M. Association of bleeding scores and platelet transfusions with
platelet counts and closure times in response to adenosine diphosphate (CT-
ADPs) among preterm neonates with thrombocytopenia. JAMA Netw Open.
(2020) 3:e203394. doi: 10.1001/jamanetworkopen.20203394
60. Fustolo-Gunnink SF, Fijnvandraat K, Putter H, Ree IM, Caram-
Deelder C, Andriessen P, et al. Dynamic prediction of bleeding
risk in thrombocytopenic preterm neonates. Haematologica. (2019)
104:2300–6. doi: 10.3324/haematol.2018208595
61. Sutor AH. Vitamin K deficiency bleeding in infants and children. Semin
Thromb Hemost. (1995) 21:317–29. doi: 10.1055/s-2007-1000653
62. Shearer MJ. Vitamin K deficiency bleeding (VKDB) in early infancy. Blood
Rev. (200 9 ) 23:49–59. doi: 10.1016/j.blre.2008.06001
63. Loughnan PM, McDougall PN. Epidemiology of late onset haemorrhagic
disease: a pooled data analysis. J Paediatr Child Health. (1993) 29:177–
81. doi: 10.1111/j.1440-1754.1993.tb00480x
64. Shearer MJ. Vitamin K metabolism and nutriture. Blood Rev. (1992) 6:9 2–
104. doi: 10.1016/0268-960X(92)90011-E
65. Kenet G, Chan AK, Soucie JM, Kulkarni R. Bleeding
disorders in neonates. Haemophilia. (2010) 16(Suppl. 5):168–
75. doi: 10.1111/j.1365-2516.2010.02316x
66. Kulkarni R, Lusher J. Perinatal management of newborns with haemophilia.
Br J Haematol. (2001) 112:264–74. doi: 10.1046/j.1365-2141.2001.02362x
67. Chambost H, Gaboulaud V, Coatmelec B, Rafowicz A, Schneider P, Calvez
T, et al. What factors influence the age at diagnosis of hemophilia?
Results of the French hemophilia cohort. J Pediatrics. (2002) 1 41 :54 8–
52. doi: 10.1067/mpd.2002128115
68. Chalmers EA. Haemophilia and the newborn. Blood Rev. (2004) 18:85–
92. doi: 10.1016/S0268-960X(03)00062-6
69. Kulkarni R, Lusher JM. Intracranial and extracranial hemorrhages in
newborns with hemophilia: a review of the literature. J Pediatr Hematol
Oncol. (1999) 21:289–95. doi: 10.1097/00043426-199907000-00009
70. Conway JH, Hilgartner MW. Initial presentations of pediatric
hemophiliacs. Arch Pediatr Adolesc Med. (1994) 148:589–
94. doi: 10.1001/archpedi.199402170060043007
71. Ljung R, Lindgren AC, Petrini P, Tengborn L. Normal vaginal delivery is
to be recommended for haemophilia carrier gravidae. Acta Paediatr. (1994 )
83:609–11. doi: 10.1111/j.1651-2227.1994.tb13090x
72. Klinge J, Auberger K, Auerswald G, Brackmann HH, Mauz-Korholz
C, Kreuz W. Prevalence and outcome of intracranial haemorrhage in
haemophiliacs–a survey of the paediatric group of the German Society
of Thrombosis and Haemostasis (GTH). Eur J Pediatr. (1999) 158 (Suppl.
3):S162–5. doi: 10.1007/PL00014346
73. Walker ID, Walker JJ, Colvin BT, Letsky EA, Rivers R, Stevens R.
Investigation and management of haemorrhagic disorders in pregnancy.
Haemostasis and Thrombosis Task Force. J Clin Pathol. (1994) 47:100–
8. doi: 10.1136/jcp.47.2100
74. Kulkarni R, Lusher JM, Henry RC, Kallen DJ. Current practices regarding
newborn intracranial haemorrhage and obstetrical care and mode of
delivery of pregnant Haemophilia carriers: a survey of obstetricians,
neonatologists and haematologists in the United States, on behalf of the
National Hemophilia Foundation’s Medical and Scientific Advisory Council.
Haemophilia. (1999) 5:410–5. doi: 10.1046/j.1365-2516.1999.00357x
75. Cattivelli K, Distefano C, Bonetti L, Testa S, Siboni SM, Plebani A, et al.
Recurrent bleedings in newborn: a factor VII deficiency case report. Transfus
Med Hemother. (2018) 45:104–6. doi: 10.1159/000481993
76. Khair K, Liesner R. Bruising and bleeding in infants and
children–a practical approach. Br J Haematol. (2006) 1 3 3:2 21 –
31. doi: 10.1111/j.1365-2141.2006.06016x
77. Jaffray J, Young G, Ko RH. The bleeding newborn: a review of present ation,
diagnosis, and management. Semin Fetal Neonatal Med. (2016) 21:44–
9. doi: 10.1016/j.siny.2015.12002
78. Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and
treatment. Blood. (2015) 125:2052–61. doi: 10.1182/blood-2014-08-532820
79. Herrmann FH, Wulff K, Auerswald G, Schulman S, Astermark J, Batorova
A, et al. Factor VII deficiency: clinical manifestation of 717 subjects from
Europe and Latin America with mutations in the factor 7 gene. Haemophilia.
(2009) 15:267–80. doi: 10.1111/j.1365-2516.20 0 8.01 9 10 x
80. Di Minno MN, Dolce A, Mariani G, Group SS. Bleeding symptoms at disease
presentation and prediction of ensuing bleeding in inherited FVII deficiency.
Thromb Haemost. (2013) 109:1051–9. doi: 10.1160/TH12-10-0740
81. Miller BE, Bailey JM, Mancuso TJ, Weinstein MS, Holbrook GW, Silvey
EM, et al. Functional maturity of the coagulation system in children:
an evaluation using thrombelastography. Anesth Analg. (1997) 84:745–
8. doi: 10.1097/00000539-199704000-00008
82. Kettner SC, Pollak A, Zimpfer M, Seybold T, Prusa AR, Herkner
K, et al. Heparinase-modified thrombelastography in term and
preterm neonates. Anesth Analg. (2004) 98:1650–2, table of
contents. doi: 10.1213/01.ANE.0000115149.25496DD
83. Oswald E, Stalzer B, Heitz E, Weiss M, Schmugge M, Strasak A, et al.
Thromboelastometry (ROTEM) in children: age-related reference ranges
and correlations with standard coagulation tests. Br J Anaesth. (2010)
105:827–35. doi: 10.1093/bja/aeq258
84. R adicioni M, Bruni A, Bini V, Villa A, Ferri C. Thromboelastographic
profiles of the premature infants with and without intracranial hemorrhage
at birth: a pilot study. J Matern Fetal Neonatal Med. (2015) 28:1779–
83. doi: 10.3109/14767058.2014968773
85. Edwards RM, Naik-Mathuria BJ, Gay AN, Olutoye OO, Teruya J. Parameters
of thromboelastography in healthy newborns. Am J Clin Pathol. (2008)
130:99–102. doi: 10.1309/LABNMY41RUD099J2
86. Sewell EK, Forman KR, Wong EC, Gallagher M, Luban NL, Massaro
AN. Thromboelastography in term neonates: an alternative approach to
evaluating coagulopathy. Arch Dis Child Fetal Neonatal Ed. (2017) 102:F79–
F84. doi: 10.1136/archdischild-2016-310545
87. Strauss T, Levy-Shraga Y, Ravid B, Schushan-Eisen I, Maayan-
Metzger A, Kuint J, et al. Clot formation of neonates tested by
thromboelastography correlates with gestational age. Thromb Haemost.
(2010) 103:344–50. doi: 10.1160/TH09-05-0282
88. Sokou R, Giallouros G, Konstantinidi A, Pantavou K, Nikolopoulos G,
Bonovas S, et al. Thromboelastometry for diagnosis of neonatal sepsis-
associated coagulopathy: an observational study. Eur J Pediatr. (2018)
177:355–62. doi: 10.1007/s00431-017-3072-z
89. Lampridou M, Sokou R, Tsantes AG, Theodoraki M, Konstantinidi
A, Ioakeimidis G, et al. ROTEM diagnostic capacity for
measuring fibrinolysis in neonatal sepsis. Thromb Res. (2020)
192:103–8. doi: 10.1016/j.thromres.2020.05028
90. Rudolph AM, Nadas AS, Borges WH. Hematologic adjustments to cyanotic
congenital heart disease. Pediatrics. (1953) 11:454–65.
91. Bahnson HT, Ziegler RF. A consideration of the causes of death following
operation for congenital heart disease of the cyanotic type. Surg Gynecol
Obstet. (1950) 90:6 0– 76 .
92. Osthaus WA, Boethig D, Johanning K, Rahe-Meyer N, Theilmeier
G, Breymann T, et al. Whole blood coagulation measured by
modified thrombelastography (ROTEM) is impaired in infants
Frontiers in Pediatrics | www.frontiersin.org 13 March 2021 | Volume 9 | Article 627715
Davenport and Sola-Visner Hemostatic Challenges in Neonates
with congenital heart diseases. Blood Coagul Fibrinolysis. (2008)
19:220–5. doi: 10.1097/MBC0b013e3282f54532
93. Cremer M, Sola-Visner M, Roll S, Josephson CD, Yilmaz Z, Buhrer C, et
al. Platelet transfusions in neonates: practices in the United States vary
significantly from those in Austria, Germany, and Switzerland. Transfusion.
(2011) 51:2634–41. doi: 10.1111/j.1537-2995.2011.0 32 08 x
94. Josephson CD, Su LL, Christensen RD, Hillyer CD, Castillejo MI, Emory
MR, et al. Platelet transfusion practices among neonatologists in the
United States and Canada: results of a survey. Pediatrics. (2009) 123:278–
85. doi: 10.1542/peds2007-2850
95. Andrew M, Vegh P, Caco C, Kirpalani H, Jefferies A, Ohlsson
A, et al. A randomized, controlled trial of platelet transfusions
in thrombocytopenic premature infants. J Pediatrics. (1993)
123:285–91. doi: 10.1016/S0022-3476(05)81705-6
96. Curley A, Stanworth SJ, Willoughby K, Fustolo-Gunnink SF, Venkatesh
V, Hudson C, et al. Randomized trial of platelet-transfusion thresholds in
neonates. N Engl J Med. (2019) 380:242–51. doi: 10.1056/NEJMoa1807320
97. von Lindern JS, Hulzebos CV, Bos AF, Brand A, Walther FJ, Lopriore E.
Thrombocytopaenia and intraventricular haemorrhage in very premature
infants: a tale of two cities. Arch Dis Child Fetal Neonatal Ed. (2012)
97:F348–52. doi: 10.1136/fetalneonatal-2011-300763
98. Baer VL, Lambert DK, Henry E, Snow GL, Sola-Visner MC, Christensen
RD. Do platelet transfusions in the NICU adversely affect survival? Analysis
of 1600 thrombocytopenic neonates in a multihospital healthcare system. J
Perinatol. (2007) 27:790–6. doi: 10.1038/sj.jp7211833
99. Del Vecchio A, Sola MC, Theriaque DW, Hutson AD, Kao KJ, Wright
D, et al. Platelet transfusions in the neonatal intensive care unit:factors
predicting which patients will require multiple transfusions. Transfusion.
(2001) 41:803–8. doi: 10.1046/j.1537-2995.2001.4 10 60 8 03 x
100. Patel RM, Josephson CD, Shenvi N, Maheshwari A, Easley KA, Stowell
S, et al. Platelet transfusions and mortality in necrotizing enterocolitis.
Transfusion. (2018) 59:981–8. doi: 10.1111/trf15112
101. Kenton AB, He g emier S, Smit h EO, O’Donovan DJ, Brandt ML, Cass DL,
et al. Platelet transfusions in infants with necrotizing enterocolitis do not
lower mortality but may increase morbidity. J Perinatol. (2005) 25:173–
7. doi: 10.1038/sj.jp7211237
102. Fustolo-Gunnink SF, Fijnvandraat K, van Klaveren D, Stanworth S, Curley
AE, Onland W, et al. Preterm neonates benefit from low prophylactic platelet
transfusion threshold despite varying risk of bleeding or de ath. Blood. (2019)
134:2354–60. doi: 10.1182/blood2019000899
103. Ferrer-Marin F, Chavda C, Lampa M, Michelson AD, Frelinger
AL, 3rd, Sola-Visner M. Effects of in vitro adult platelet
transfusions on neonatal hemostasis. J Thromb Haemost. (2011)
9:1020–8. doi: 10.1111/j.1538-7836.2011.04233x
104. Smith TL, Weyrich AS. Platelets as central mediators of
systemic inflammatory responses. Thromb Res. (2011) 127:391–
4. doi: 10.1016/j.thromres.2010.10013
105. Weyrich AS. Platelets: more than a sack of glue. Hematology. (2014)
2014:400–3. doi: 10.1182/asheducation-2014.1400
106. Baer VL, Lambert DK, Schmutz N, Henry E, Stoddard RA, Miner C, et
al. Adherence to NICU transfusion guidelines: data from a multihospital
healthcare system. J Perinatol. (2008) 28:492–7. doi: 10.1038/jp.200823
107. Puetz J, Darling G, McCormick KA, Wofford JD. Fresh frozen plasma and
recombinant factor VIIa use in neonates. J Pediatr Hematol Oncol. (2009)
31:901–6. doi: 10.1097/MPH0b013e3181c29c25
108. Stanworth SJ, Grant-Casey J, Lowe D, Laffan M, New H, Murphy
MF, et al. The use of fresh-frozen plasma in England: high levels of
inappropriate use in adults and children. Transfusion. (2011) 51:62–
70. doi: 10.1111/j.1537-2995.2010.02798x
109. Altuntas N, Yenicesu I, Beken S, Kulali F, Burcu B.elen F, Hirfanoglu
IM, et al. Clinic al use of fresh-frozen plasma in neonatal intensive
care unit. Transfus Apher Sci. (2012) 47:91–4. doi: 10.1016/j.transci.2012.
05007
110. Gross SJ, Filston HC, Anderson JC. Controlled study of treatment for
disseminated intravascular coagulation in the neonate. J Pediatr. (1982)
100:445–8. doi: 10.1016/S0022-3476(82)80457-5
111. Hambleton G, Appleyard WJ. Controlled trial of fresh frozen plasma
in asphyxiated low birthweight infants. Arch Dis Child. (1973) 48 :31 –
5. doi: 10.1136/adc.48.131
112. Beverley DW, Pitts-Tucker TJ, Congdon PJ, Arthur RJ, Tate G. Prevention of
intraventricular haemorrhage by fresh frozen plasma. Arch Dis Child. (1985)
60:710–3. doi: 10.1136/adc.60.8710
113. Ekblad H, Kero P, Shaffer SG, Korvenranta H. Extracellular volume in
preterm infants: influence of gestational age and colloids. Early Hum Dev.
(1991) 27:1–7. doi: 10.1016/0378-3782(91)90 0 22 -U
114. A randomized trial comparing the effect of prophylactic intravenous fresh
frozen plasma, gelatin or glucose on early mortality and morbidity in preterm
babies. The Northern neonat al nursing initiative [NNNI] trial group. Eur J
Pediatr. (1996) 155:580–8. doi: 10.1007/BF01957909
115. Osborn DA, Evans N. Early volume expansion for prevention of morbidity
and mortality in very preterm infants. Cochrane Database Syst Rev. (200 4)
2:CD002055. doi: 10.1002/14651858.CD002055pub2
116. Acunas BA, Peakman M, Liossis G, Davies ET, Bakoleas B, Costalos C, et
al. Effect of fresh frozen plasma and gammaglobulin on humoral immunity
in neonatal sepsis. Arch Dis Child Fetal Neonatal Ed. (1994) 70:F182–
7. doi: 10.1136/fn.70.3F182
117. Krediet TG, Beurskens FJ, van Dijk H, Gerards LJ, Fleer A. Antibody
responses and opsonic activity in sera of preterm neonates with
coagulase-negative staphylococcal septicemia and the effect of
the administration of fresh frozen plasma. Pediatric Res. (1998)
43:645–51. doi: 10.1203/00006450-199805000-00013
118. Gottuso MA, Williams ML, Oski FA. The role of exchange transfusions in the
management of low-birth-weight infants with and without severe respiratory
distress syndrome. II. Further observations and studies of mechanisms of
action. J Pediatr. (1976) 89:279–85. doi: 10.1016/S0022-3476(76)8046 8- 4
119. Emery EF, Greenoug h A, Gamsu HR. Randomised controlled trial of colloid
infusions in hypotensive preterm infants. Arch Dis Child. (1992) 67:1185–
8. doi: 10.1136/adc.67.10_Spec_No1185
120. Forman KR, Diab Y, Wong EC, Baumgart S, Luban NL, Massaro AN.
Coagulopathy in newborns with hypoxic ischemic encephalopathy (HIE)
treated with therapeutic hypot hermia: a retrospective case-control study.
BMC Pediatr. (2014) 14:277. doi: 10.1 18 6/ 14 71 - 24 31 -1 4 -2 77
121. Gkiougki E, Mitsiakos G, Chatziioannidis E, Papadakis E, Nikolaidis N.
Predicting response to rFVIIa in neonates with intractable bleeding or
severe coagulation disturbances. J Pediatr Hematol Oncol. (2013) 35 :221 –
6. doi: 10.1097/MPH0b013e318286d27e
122. Young G, Wicklund B, Neff P, Johnson C, Nugent DJ. Off-label use
of rFVIIa in children with excessive bleeding: a consecutive study of
153 off-label uses in 139 children. Pediatr Blood Cancer. (2009) 53:17 9 –
83. doi: 10.1002/pbc22053
123. Puetz J, Darling G, Brabec P, Blatny J, Mathew P. Thrombotic events in
neonates receiving recombinant factor VIIa or fresh frozen plasma. Pediatr
Blood Cancer. (2009) 53:1074–8. doi: 10.1002/pbc22160
124. Rech MA, Wittekindt L, Friedman SD, Kling K, Ubogy D. Prothrombin
complex concentrate for intracerebral hemorrhage secondary to vitamin
K deficiency bleeding in a 6-week-old child. J Pediatr. (2015) 167:1443–
4. doi: 10.1016/j.jpeds.2015.09030
125. Ashikhmina E, Said S, Smith MM, Rodriguez V, Oliver WC, Jr, Nuttall
GA, et al. Prothrombin complex concentrates in pediatric cardiac surgery:
the current state and the future. Ann Thorac Surg. (2017) 104:1423–
31. doi: 10.1016/j.athoracsur.2017.04009
126. Mitsiakos G, Karametou M, Gkampeta A, Karali C, Papathanasiou AE,
Papacharalambous E, et al. Effectiveness and safety of 4-factor prothrombin
complex concentrate (4PCC) in neonates with intractable bleeding or severe
coagulation disturbances: a retrospective study of 37 cases. J Pediatric
Hematol Oncol. (2019) 41:e135–e40. doi: 10.1097/MPH0000000000001397
Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2021 Davenport and Sola-Visner. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other forums is permitted, provided the
original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these
terms.
Frontiers in Pediatrics | www.frontiersin.org 14 March 2021 | Volume 9 | Article 627715
