ORIGINAL ARTICLE
Thrombocytopenia in late preterm and term neonates after
perinatal asphyxia
Robert D. Christensen,1 Vickie L. Baer 1 and Hassan M. Yaish2
BACKGROUND: A recent NHLBI conference concluded
that platelet (PLT) transfusions of neonates must
become more evidence based. One neonatal disorder
for which transfusions are given is a poorly defined
entity, the thrombocytopenia of perinatal asphyxia. To
expand the evidence base for this entity, we performed
a multicentered, retrospective analysis of neonates with
perinatal asphyxia.
STUDY DESIGN AND METHODS: We analyzed
records of term and late preterm neonates with perina-
tal asphyxia defined by a cord blood pH of not more
than 6.99 and/or base deficit of at least 16 mmol/L.
From these we identified neonates with at least two
PLT counts of fewer than 150 109/L in the first week
of life and described the severity, nadir, and duration of
the thrombocytopenia.
RESULTS: Thrombocytopenia occurred in 31% (117/
375) of neonates with asphyxia versus 5% of matched
nonasphyxiated controls admitted to a neonatal inten-
sive care unit (p < 0.0001). Twenty-one of the 117
asphyxiated neonates were excluded from the remain-
ing analysis due to disseminated intravascular coagula-
tion or extracorporeal membrane oxygenation. Nadir
PLT counts of the remaining 96 were on Day 3
(75 109/L; 90% confidence interval, 35.7 109-
128.6 109/L) and normalized by Days 19 to 21. PLT
counts after asphyxia roughly correlated inversely with
elevated nucleated red blood cell count (NRBC) counts
at birth. Thirty of the 96 received at least one PLT
transfusion, all given prophylactically, none for bleeding.
CONCLUSIONS: We maintain that the thrombocytope-
nia of perinatal asphyxia is an authentic entity. Its asso-
ciation with elevated NRBC counts suggests that
hypoxia is involved in the pathogenesis. Because PLT
counts are only moderately low, the condition is tran-
sient, and bleeding problems seem rare, we speculate
that PLT transfusions should not be needed for most
neonates with this condition.
P
latelet (PLT) transfusions can be lifesaving for
certain thrombocytopenic neonates.1 However,
a recent multidisciplinary NHLBI think tank
expressed the concern that some neonates may
be receiving PLT transfusions unnecessarily, thereby con-
veying little or no benefit with an unfavorable benefit-to-
risk ratio.2
One neonatal condition for which PLT transfusions
are sometimes given, yet the supporting evidence is
meager, is an entity termed the thrombocytopenia of
perinatal asphyxia. Although this condition has been the
subject of previous reports, many aspects are unclear.
Sola-Visner and Saxonhouse3 recently commented that
for this condition the causative mechanism, the usual
range of severity, the typical duration, and the role of PLT
transfusions are all relatively unknown.
As a step toward enhancing the knowledge base of the
thrombocytopenia of perinatal asphyxia, we conducted a
retrospective analysis of all neonates in the past 9 years
who met the definition of perinatal asphyxia. This was
done to find the incidence, severity, and usual duration of
this variety of thrombocytopenia. Next we sought to
understand the value of PLT transfusions in these patients
by examining, among those where a PLT transfusion was
ABBREVIATIONS: DIC = disseminated intravascular
coagulation; ECMO = extracorporeal membrane oxygenation;
MPV = mean platelet volume; NRBC = nucleated red blood cell
count; TPO = thrombopoietin.
From the 1Women and Newborns Clinical Program,
Intermountain Healthcare, and the 2Department of Pediatrics,
Division of Hematology/Oncology, University of Utah School of
Medicine, Salt Lake City, Utah.
Address reprint requests to: Robert D. Christensen, MD,
Women and Newborns Clinical Program, Intermountain
Healthcare, 4403 Harrison Boulevard, Ogden, UT 84403; e-mail:
robert.christensen@imail.org.
Received for publication March 10, 2014; revision received
May 28, 2014, and accepted May 30, 2014.
doi: 10.1111/trf.12777
2014 AABB
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CHRISTENSEN ET AL.
given, the reasons for and response to transfusion. We
then attempted to identify the underlying cause of this
variety of thrombocytopenia and to assess whether thera-
peutic hypothermia (cooling) used in the treatment of
neonates with perinatal asphyxia played a role in the
pathogenesis of the thrombocytopenia. Last, we sought to
determine the implication of finding thrombocytopenia
after perinatal asphyxia on the mortality rate.
MATERIALS AND METHODS
Patient information
Data were collected retrospectively as deidentified limited
data sets from archived Intermountain Healthcare
records. Intermountain Healthcare is a not-for-profit
health care system that owns and operates 19 hospitals
with labor and delivery units in Utah and Idaho. The infor-
mation collected was limited to the complete blood
counts and the information displayed in tables and figures
of this report. Patient records were accessed if the neonate
had a date of birth from June 1, 2004, through May 31,
2013. The Intermountain Healthcare Institutional Review
Board approved this as a deidentified data-only study, not
requiring the consent of individual subjects.
A standard operating procedure was in place at all
Intermountain Healthcare hospitals during all study
years, guiding the delivering physician (obstetrician or
family physician) on collecting umbilical cord blood for
blood gas determination of any birth for which the meta-
bolic status is in question.4 After the neonate is delivered
and the umbilical cord clamped and cut, the umbilical
artery (and sometimes the umbilical vein also), on the side
of the cord still attached to the placenta, is punctured with
a needle attached to a 1-mL syringe and 0.2 mL of blood
is withdrawn for immediate blood gas determination. The
cord blood gas findings defining perinatal asphyxia were
pH of not more than 6.99 and/or base deficit of at least
16.0 mm/L, because these were suggested in the Ameri-
can College of Obstetricians and Gynecologists Commit-
tee Opinion on cord blood gas analysis4 and were used by
two large studies of therapeutic hypothermia5,6 and are
consistent with the 2003 report of the American College of
Obstetricians and Gynecologists Task Force on Neonatal
Encephalopathy and Cerebral Palsy.7
Blood cell counting and PLT transfusions
PLT counts and mean PLT volumes (MPVs) were deter-
mined in all hospitals with a hematology analyzer (Model
LH750, Beckman Coulter, Fullerton, CA) from 2004
through mid-2012. After mid-2012 the PLT counts and
MPVs were determined using counters (Sysmex America,
Inc., Lincolnshire, IL). All blood tests were performed in
accordance with Intermountain Healthcare Laboratory
Services standard operating procedures. Nucleated red
2 TRANSFUSION Volume **, ** **
blood cells (NRBCs) were quantified using either auto-
mated cell counts, performed in accordance with the
hematology analyzer manufacturers instructions, or
manual enumeration, performed by certified medical
technologists on Wright-stained blood smears enumerat-
ing a minimum of 100 white blood cells per test. The ref-
erence intervals for complete blood cell count variables
are those we previously published from Intermountain
Healthcare data bases.8
Guidelines for administering PLT transfusions in the
Intermountain Healthcare neonatal intensive care units
(NICUs) during this period have been previously pub-
lished.9 All PLT transfusions were type specific or AB (D+
or D), and were derived from apheresis. They were not
pooled or volume-reduced but were all subjected to
leukofiltration and irradiation, and administered in a
volume of 10 to 15 mL/kg body weight. Gestational age
was determined by obstetric assignment unless this was
changed by the neonatologist on the basis of gestational
age assessment (physical examination and neurological-
neurodevelopmental findings).
Neonates meeting the definition of perinatal
asphyxia, and found to have thrombocytopenia (2 PLT
counts <150 109/L), were matched 1:1 with neonates
from the same hospitals born during the same period of
time who had cord gasses that did not meet either defi-
nition (pH or BE) of perinatal asphyxia. Matching was
performed on the basis of gestational age (1 week), sex,
and birth weight (250 g). Patients whose data would
otherwise qualify for inclusion in the study were
excluded if they were treated with extracorporeal mem-
brane oxygenation (ECMO) or had a confirmed diagnosis
of disseminated intravascular coagulation (DIC). This
was done because of the confounding effect of PLT con-
sumption caused by ECMO or DIC on the issues relating
to thrombocytopenia. DIC was diagnosed by the combi-
nation of hypofibrinogenemia for age,10 schistocytosis,11
prolongation of the prothrombin time and activated
partial thromboplastin time for age,12 and elevated
D-dimers.
Data collection and statistical analysis
The program used for data collection was a modified sub-
system of clinical workstation. The 3 M Company (Minne-
apolis, MN) approved the structure and definitions of all
data points for use within the program. Data were
managed and accessed by authorized data analysts.
Means and standard deviations (SDs) were used to express
values in groups that were normally distributed and
medians and ranges to express values in groups that were
not. Differences in categorical variables were assessed
using the Fisher exact test or chi square. A nonpaired t test
was used to assess continuous variables. Significance was
set as a p value of less than 0.05.

RESULTS
Incidence, severity, and duration
of thrombocytopenia
Of 24,351 neonates born at at least 35 weeks gestation
during the period studied and admitted to an Intermoun-
tain Healthcare Hospital NICU, 439 met the criteria for
perinatal asphyxia (Fig. 1). Of these, 375 had at least two
PLT counts in the first week and 64 did not. Of the 375
where thrombocytopenia could be assessed, 117 (31.2%)
had at least two PLT counts of fewer than 150 109/L
during the first week, thereby qualifying for the definition
of first-week thrombocytopenia. The 117 who developed
thrombocytopenia differed from the 257 who did not by
having a lower 5-minute Apgar score (4 2 vs. 5 2,
p < 0.0001). However, groups that did versus did not
develop thrombocytopenia did not differ in sex (54% vs.
56% male, p = 0.671), birthweight (3097 625 g vs.
3223 558 g, p = 0.059), or delivery type (57% vs. 54%
cesarean delivery, p = 0.615). The incidence of thrombo-
cytopenia in those with perinatal asphyxia (31.2%) was far
greater than the 5% incidence among 375 matched control
Admissions 35 weeks gestation during the
9-year period studied (n = 24,351)
Did not have a blood gas definition of perinatal asphyxia
(n = 23,912)
Controls matched 1:1 with the 375 with perinatal
asphyxia who had 2 PLT counts in the first week
Thrombocytopenic ( 2 counts <150 109/L)
(n = 18)
5%
Excluded from further analysis (n=21)
ECMO (n=16)
DIC not treated with ECMO (n=5)
Fig. 1. Study flow diagram to identify neonates with the thrombocytopenia of perinatal asphyxia.
THROMBOCYTOPENIA AFTER ASPHYXIA
neonates admitted to a NICU who did not have perinatal
asphyxia but had at least two PLT counts obtained in the
first week (p < 0.0001).
Twenty-one of the 117 with thrombocytopenia were
excluded from the analysis because they had a known
cause of thrombocytopenia separate from the thrombocy-
topenia of perinatal asphyxia. These included ECMO
(n = 16), excluded because of consumption of PLTs in the
circuit, and DIC (n = 5), excluded because of generalized
PLT consumption (Fig. 1). The five with DIC were all born
by emergent cesarean section for placental abruption and
absent or low fetal heart rate. Additional information
about these five is provided in Table 1. PLT counts in the
group with thrombocytopenia after perinatal asphyxia are
shown in Fig. 2. The reference interval for PLT counts of
neonates, not transfused with PLTs, during their first 3
weeks (5th to 95th percentile limits), which we published
previously,13 is shown by the shaded area. The lowest
PLT counts were typically on Day 3, with a nadir of
75 109/L (90% confidence interval [CI], 35.7 109-
128.6 109/L) and a return to within the reference interval
by 3 weeks.
Had a blood gas definition of perinatal asphyxia
(n = 439)
Had 2 platelet counts obtained during the first
week (n = 375)
Thrombocytopenic ( 2 counts <150 109/L)
(n = 117)
31.2%
Included as thrombocytopenia of
perinatal asphyxia
(n = 96)
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CHRISTENSEN ET AL.

TABLE 1. Five neonates with perinatal asphyxia and DIC*

Initial
Initial PLT count Fibrinogen PT aPTT D-dimers
condition (109/L) Blood smear (mg/dL) (sec) (sec) (ng FEU/mL) DIC treatment Outcome
Abruption 9 Marked schistocytosis 84 19.4 57 >8,463 Multiple FFP, multiple PLTs Lived
Abruption 17 Marked schistocytosis 102 30 >150 >50,000 Multiple FFP, Cryo, multiple PLTs Died
Abruption 15 Marked schistocytosis <30 >100 >150 >20,000 Multiple FFP, Cryo, multiple PLTs Died
Abruption 81 Marked schistocytosis 58 36.7 >150 >20,000 Multiple FFP, Cryo, multiple PLTs Died
Abruption 47 Marked schistocytosis 64 21.6 53 >20000 Multiple FFP, Cryo, multiple PLTs Died
* All were delivered by emergent cesarean section with absent fetal heart rate or severe bradycardia. All had blood gasses qualifying for the
definition of perinatal asphyxia. All had at least two PLT counts of fewer than 150 109/L, low fibrinogen for age, schistocytosis, prolonged
clotting times for age, and elevated D-dimers. All had hypotension and oozing at venipuncture or catheter-insertion sites and were treated
with dopamine, fluid boluses, FFP, and PLT transfusions.
aPTT = activated partial thromboplastin time; FEU = fibrinogen equivalent units; PT = prothrombin time.

Fig. 2. All PLT counts of 96 neonates with the thrombocytopenia of perinatal asphyxia during their first 3 weeks are included in the
figure. Patients were at least 35 weeks gestation at birth, met a cord blood gas definition of perinatal asphyxia, and in the first week
had at least two PLT counts of less than 150 109/L. The median values, first and third interquartile ranges (box), and 90% CIs
(whiskers) are shown. The shaded area represents the normal reference interval for PLT counts of neonates of at least 35 weeks
gestation during the first 21 days after birth (modified from Wiedmeier et al., J Perinatol 2009;29:130-136).13

Response to transfusion and MPV comparing the pretransfusion count to a count 1 to 24

Thirty of the 96 neonates received 56 apheresis PLT trans-
fusions. Chart reviews indicated that all 56 transfusions
were given prophylactically, meaning that the patient did
not have active bleeding. PLT counts before the transfu-
sions ranged from 24 109 to 108 109/L (median count,
44 109/L). The increase in PLT count after transfusion,
hours after the transfusions, was 86 109 50 109/L.
Figure 3 shows the increase and subsequent decrease in
PLT counts over the days after PLT transfusion. For ease of
comparison, all PLT counts were normalized to percent-
age of the pretransfusion PLT count. Next, to try to reduce
confounding variables that can occur during the 24-hour

4 TRANSFUSION Volume **, ** **

 THROMBOCYTOPENIA AFTER ASPHYXIA

Fig. 3. PLT counts after 56 apheresis PLT transfusions to 30 neonates are included in the figure. All values are normalized to per-
centage of the pretransfusion PLT count (all pretransfusion counts are shown as 100%). The median values, first and third
interquartile ranges (box), and 90% CIs (whiskers) are shown. The peak and characteristics of the subsequent fall are used to infer
the kinetic mechanism responsible for the thrombocytopenia (reduced PLT production vs. accelerated PLT destruction).

period after transfusion, we conducted a subgroup analy-
sis including only the PLT counts performed in the 6-hour
period after completing the transfusions. This showed an
average 6-hour increase to 287 109 143 109 PLTs/L.
We next compared PLT counts after apheresis PLT
transfusion of six nonasphyxiated neonates during this
time period that had a diagnosis of alloimmune thrombo-
cytopenia (immune-mediated PLT destruction). Their
counts increased by only 5.7 109 4.5 109 PLTs/L.
MPV measurements accompanying the PLT counts of
the 96 thrombocytopenic neonates over their first week
after birth are displayed in Figure 4. Overlying the values
in the shaded area is the MPV reference interval (5th to
95th percentile limits) that we published previously.12
Relationships with hypoxia and
therapeutic hypothermia
An elevated NRBC count at birth has been used as a
marker for prolonged (exceeding 24 hr) hypoxia in
utero.14,15 Figure 5 includes data of all 375 neonates with
perinatal asphyxia and shows their NRBC count at birth
and their lowest PLT count during the first 3 days. A weak
relationship (R2 = 0.107) was seen between high NRBCs at
birth and low PLT counts.
Table 2 shows data from the neonates with perinatal
asphyxia divided into two groups: 1) acute hypoxia,
defined as having a normal NRBC count on the day of
birth (50th percentile reference range, n = 172), and 2)
chronic hypoxia, defined as having an elevated NRBC
count on the day of birth (>95th percentile reference range
limit, 3.0 109 NRBCs/L, n = 167).15 Many characteristics
of neonates in the two groups were similar; however,
thrombocytopenia was much more common (52% vs.
15%, p < 0.0001) in the chronic hypoxia group.
Therapeutic hypothermia was administered to 91 of
the 375 neonates with perinatal asphyxia. All of these were
during the period 2008 to 2013, because the Intermoun-
tain Healthcare NICUs began offering this treatment in
2008.13 The 91 with therapeutic hypothermia had slightly
lower PLT counts at birth (168.7 109 75.9 109/L,
mean SD) than did those not treated with hypothermia
(195.5 109 68.6 109/L, p < 0.0001). However, both
groups had a decrease in PLT count over the first 3 to
4 days (nadir counts, 108.9 109 65.2 109/L in those on
hypothermia vs. 142.5 109 78.2 109/L in those not

Volume **, ** ** TRANSFUSION 5

CHRISTENSEN ET AL.
Fig. 4. MPV measured in fL. Values are shown from 96 neonates who met a definition of thrombocytopenia of perinatal asphyxia.
The median values, first and third interquartile ranges (box), and 90% CIs (whiskers) are shown. The shaded area represents the
normal reference interval for MPV (modified from Wiedmeier et al., J Perinatol 2009;29:130-136).13
treated with hypothermia, p = 0.012). The proportion of
fall in PLT count was the same among those treated versus
not treated with hypothermia; therefore, it appeared to us
that therapeutic hypothermia did not independently
cause thrombocytopenia.
Outcomes
Of the 258 neonates who did not develop thrombocytope-
nia after asphyxia (Fig. 1), 13 died (5%). In contrast, of the
117 neonates who developed thrombocytopenia after
asphyxia, 17 died (14.5%, p < 0.002). Two of the 16 treated
with ECMO, four of the five with DIC, and 11 of the 96 with
the thrombocytopenia of perinatal asphyxia died. None of
the 11 deaths among those with the thrombocytopenia of
perinatal asphyxia involved active bleeding or hemor-
rhagic complications. Rather, all 11 deaths involved with-
drawal of respiratory support when the family and
caregivers concluded the situation was futile, because
hypoxic-ischemic encephalopathy resulted in severe
central nervous system damage. In contrast, three of the
four who died with DIC, and one who died with ECMO,
had bleeding problems unresolved and complicating care
at the time of death (Table 3).
6 TRANSFUSION Volume **, ** **
DISCUSSION
Thrombocytopenia is a relatively common problem
among patients in NICUs.16,17 The majority of neonates
with thrombocytopenia are small and ill and have an
acquired variety of consumptive thrombocytopenia
accompanying bacterial or fungal sepsis or necrotizing
enterocolitis.3,16 A different variety of thrombocytopenia
has been described among neonates after perinatal
asphyxia.3,18 Although DIC can occur in such patients, and
can cause thrombocytopenia from PLT consumption, the
majority of neonates reported with thrombocytopenia
after birth asphyxia do not have evidence of consumptive
coagulopathy.3 This study was an attempt to better define
the thrombocytopenia of perinatal asphyxia as a needed
step toward evidence-based NICU PLT transfusion
practices.
We began our study by identifying all patients in the
past 9 years at least 35 weeks gestation who met a cord
blood gas definition of perinatal asphyxia7 and had at least
two PLT counts drawn during their first week. Among 375
such neonates we sought the incidence of thrombocyto-
penia, and among those we sought information on the
severity and duration of the thrombocytopenia and its

Fig. 5. Among 375 neonates meeting the cord blood gas definition of perinatal
asphyxia, their NRBC count (109/L) at birth is compared with their lowest PLT count environments (1, 5, and 20%). Although
recorded in the first week after birth.
underlying mechanism. Our findings led us to speculate
that the thrombocytopenia of perinatal asphyxia is most
likely: 1) an authentic entity, although the condition can
cooccur with DIC; 2) probably a hyporegenerative condi-
tion, as opposed to being due entirely to accelerated PLT
consumption and/or destruction; 3) associated with intra-
uterine hypoxemia; 4) only moderately severe (mean
nadir count, 75 109/L); and 5) self-limited, typically with
a nadir count on Day 3 and a duration of about 3 weeks.
This was a retrospective study, and we acknowledge
significant problems with that approach. For instance,
PLT counts after PLT transfusions were not obtained on a
standard schedule, PLT transfusions were given to some
and not to others with no clear explanation, surely some
relevant data were sometimes missing from the charts or
electronic databases, and bias may have been uninten-
tionally introduced. Also, changes in obstetric and neona-
tology practices occurred during the 9 years of study.
Examples of practice changes we recognize include the
marked overall reduction in NICU transfusion during this
period9 and the specific reduction in PLT transfusions on
the basis of a change from PLT countbased guidelines to
PLT massbased guidelines.19 Also, therapeutic hypother-
mia was introduced in 2008. These flaws limit the confi-
dence in our conclusions, but the data do provide, in our
opinion, reasonable hypotheses for future observational
and prospective testing.
The molecular mechanisms resulting in the thrombo-
cytopenia of perinatal asphyxia are obscure, but several
THROMBOCYTOPENIA AFTER ASPHYXIA
experiments have generated potential
explanations. For instance, McDonald
and colleagues20 subjected adult mice to
hypoxia and found a decrease in the size
of individual megakaryocytes in the
marrow and an overall reduction in
marrow megakaryocyte mass, suggest-
ing that the primary kinetic mecha-
nism was reduced PLT production.
Saxonhouse and coworkers21 evaluated
whether megakaryocyte progenitors are
damaged directly by hypoxia. He found
no evidence for this by culturing
CD34(+) hematopoietic progenitor cells
obtained from umbilical cord blood in
0% versus 20% oxygen environments.
The anoxic environment did not result
in CD34(+) cell death or diminished
megakaryocyte clonogenic potential. In
a follow-up study Saxonhouse and
coworkers22 cocultured CD34(+) pro-
genitors with or without mononuclear
(accessory) cells under various oxygen
the progenitors themselves were unaf-
fected by the ambient oxygen concen-
tration, the cocultures with accessory cells showed a
progressive reduction in megakaryocytic clones with
decreasing O2 concentrations. The conclusion was that
nonprogenitor cells in the hematopoietic microenviron-
ment were likely damaged by hypoxia resulting in
impaired megakaryocytopoiesis. This conclusion is con-
sistent with the in vitro experiments of LaIuppa and col-
leagues23 showing that hypoxia alters the effects of
cytokines on megakaryocytic progenitors.
We suspect that the new thrombopoietin (TPO)
receptor agonists romiplostim and eltrombopag will not
be of value in treating the thrombocytopenia of perinatal
asphyxia.24 Three reasons form the basis of our
assumption: 1) These medications require approximately
14 days between commencement of dosing and a signifi-
cant increase in PLT count, and the duration of this variety
of thrombocytopenia is generally only 3 weeks. 2) Ninety
percent of neonates with this disorder will not decrease
their PLT count below approximately 40 109/L and thus
may not need any specific treatment. 3) We suspect that
impaired TPO production is not a pathogenic component
of this disorder, because McDonald and coworkers
reported that, in mice, hypoxia does not reduce TPO
production.20
One treatment option for neonates with the throm-
bocytopenia of perinatal asphyxia is PLT transfusion, but
much investigation is needed to determine the risks and
benefits of transfusions for neonates with this condition
and to establish transfusion guidelines for this group. As
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TABLE 2. Characteristics of neonates at least 35 weeks gestation meeting a definition of perinatal asphyxia and
grouped according to whether their NRBC count on the day of birth was normal (Group 1) or elevated
(Group 2)*
Thrombocytopenia
Apgar Initial PLT count diagnosed
Gestational Birthweight score base deficit at birth during the
Group age (weeks) (g) (5 min) Initial pH (mmol/L) (109/L) first week
1: normal NRBC count at birth 39 1 3172 535 5.5 2.2 6.89 0.09 18 3 220 67 26/172 (15%)
(acute hypoxia) (n = 172)
2: elevated NRBC count at birth 38 1 3228 645 4.8 2.5 6.87 0.12 18 3 183 75 87/167 (52%)
(chronic hypoxia) (n = 167)
p value 0.229 0.379 0.009 0.223 0.762 <0.0001 <0.0001
* A normal NRBC count at birth was used as a marker of acute perinatal hypoxia. An elevated NRBC count at birth (>95th% upper reference
interval) was used as a marker of hypoxia with a duration of more than 24 to 36 hours before birth.14,15
Two or more PLT counts of fewer than 150 109/L.

TABLE 3. Causes of, and associations with, death among neonates with thrombocytopenia after
Category of thrombocytopenia
Thrombocytopenia of perinatal
asphyxia (n = 96)
ECMO after perinatal asphyxia
(n = 16)
DIC after perinatal asphyxia
(n = 5)
CDH = congenital diaphragmatic hernia; HIE = hypoxemic-ischemic encephalopathy; SVC = superior vena cava.
perinatal asphyxia
Death caused by or associated with Withdrawal of respiratory support because
Death bleeding problems of futility
11 (11.5%) 0 Eleven all had severe HIE. None were
recorded to have died because of or in
association with bleeding problems.
2 (12.5%) One developed a large subdural The patient with a large subdural
hemorrhage on ECMO with a marked hemorrhage had multiple other
midline brain shift unresolvable medical problems and
support was withdrawn.
One had CDH and developed an
occlusive SVC thrombus on ECMO, in
addition to multiple other problems, and
support was withdrawn.
4 (80%) Three had bleeding and oozing requiring One patient had support withdrawn for
dressings on multiple body parts up to severe HIE. At the time of death
the time of death abnormal bleeding/oozing was no longer
present.

highlighted by Josephson and colleagues2 in a recent sym-
posium, PLT transfusion strategies for neonates currently
lack a strong evidence base, yet this is needed as a high
priority. From our present findings we conclude that most
neonates with this variety of thrombocytopenia will have
nadir PLT counts of higher than 40 109/L (the mean
nadir count was 75 109/L; 90% CI, 35.7 109-128.6 109/
L). Surveys of neonatologists in Central Europe25 and
North America26 agree that PLT transfusions are recom-
mended when PLT counts fall below 20 109/L, but
counts that low should be quite rare in the thrombocyto-
penia of perinatal asphyxia. Whether transfusions should
be recommended when the counts are in the 40 109 to
60 109/L range is not clear.2,27 Stanworth and coworkers28
reported a prospective observational study of 194 neo-
nates with thrombocytopenia, where a subgroup of 47 had
their lowest count in the 40 109 to 60 109/L range. Only
two of those who were at least 35 weeks gestation had a
major hemorrhage and both of those had DIC. Thus we
judge it is very likely that late preterm and term neonates
with this variety of thrombocytopenia, with PLT counts in
the 40 109 to 60 109/L and free of other complications,
should do well without PLT transfusions. Thirty of the 96
neonates in this analysis with this variety of thrombocy-
topenia received one or more PLT transfusions. In retro-
spect, we question how many of these, if any, were
beneficial. None of the 30 had a PLT count of fewer than
20 109/L, almost half had a pretransfusion PLT count of
more than 50 109/L, and all 30 were transfused prophy-
lactically with no bleeding.
Our data suggest that therapeutic hypothermia does
not independently cause neonatal thrombocytopenia.
Hypothermia for 72 hours has recently become a common
and effective means of improving neurodevelopment of
term neonates after perinatal asphyxia.29,30 Hypothermia
does adversely affect PLT function, as manifested by pro-
longation of the bleeding time and lengthening of the
PFA100 closure time.13 Once rewarming has occurred,
PLT function rapidly normalizes.13 Additional study is
needed to determine whether PLT dysfunction during

8 TRANSFUSION Volume **, ** **


therapeutic hypothermia warrants giving PLT transfu-
sions at higher PLT counts than for neonates not on thera-
peutic hypothermia.
Taken together our study results suggest that
approximately 30% of term and late preterm neonates
with a cord pH of not more than 6.99 and/or a base deficit
of at least 16 mmol/L will have a condition that can be
called the thrombocytopenia of perinatal asphyxia. A
minority of these neonates will have coexisting severe
DIC. Likely those will be the most ill patients, with
elevated coagulation times and D-dimers,31 very low and
rapidly decreasing PLT counts, persistent hypotension
and acidosis, and a poor prognosis for survival. However,
we speculate that the great majority of neonates with
thrombocytopenia after perinatal asphyxia will have a
much more benign condition, with PLT counts that do not
fall below 40 109/L. We maintain that these should not
need treatment with either PLT transfusions or TPO ago-
nists and that their PLT counts will gradually increase
from a nadir on approximately Day 3 to the normal range
over about 3 weeks without any specific intervention.
ACKNOWLEDGMENT
The authors thank Martha C. Sola-Visner, Harvard University and
Boston Childrens Hospital, for helpful discussions about this
topic and for suggestions in manuscript editing. We also thank
Erick Henry, MPH, Intermountain Healthcare, for assistance with
the graphics.
CONFLICT OF INTEREST
The authors have disclosed no conflicts of interest.
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