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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Conflict of Interest
  8. References

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 perinatal 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 intensive care unit (p < 0.0001). Twenty-one of the 117 asphyxiated neonates were excluded from the remaining analysis due to disseminated intravascular coagulation 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 thrombocytopenia of perinatal asphyxia is an authentic entity. Its association with elevated NRBC counts suggests that hypoxia is involved in the pathogenesis. Because PLT counts are only moderately low, the condition is transient, and bleeding problems seem rare, we speculate that PLT transfusions should not be needed for most neonates with this condition.

Abbreviations
DIC

disseminated intravascular coagulation

ECMO

extracorporeal membrane oxygenation

MPV

mean platelet volume

NRBC

nucleated red blood cell count

TPO

thrombopoietin

Platelet (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 conveying 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 Saxonhouse[3] 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 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 therapeutic 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

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Conflict of Interest
  8. References

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 information 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 metabolic 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 American College of Obstetricians and Gynecologists Committee Opinion on cord blood gas analysis[4] and were used by two large studies of therapeutic hypothermia[5, 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 determined 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 blood cells (NRBCs) were quantified using either automated cell counts, performed in accordance with the hematology analyzer manufacturer's instructions, or manual enumeration, performed by certified medical technologists on Wright-stained blood smears enumerating a minimum of 100 white blood cells per test. The reference 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 published.[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 definition (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 membrane oxygenation (ECMO) or had a confirmed diagnosis of disseminated intravascular coagulation (DIC). This was done because of the confounding effect of PLT consumption caused by ECMO or DIC on the issues relating to thrombocytopenia. DIC was diagnosed by the combination 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 subsystem of clinical workstation. The 3 M Company (Minneapolis, 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

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Conflict of Interest
  8. References

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 Intermountain 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 thrombocytopenia in those with perinatal asphyxia (31.2%) was far greater than the 5% incidence among 375 matched control 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).

figure

Figure 1. Study flow diagram to identify neonates with the thrombocytopenia of perinatal asphyxia.

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Twenty-one of the 117 with thrombocytopenia were excluded from the analysis because they had a known cause of thrombocytopenia separate from the thrombocytopenia 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.

Table 1. Five neonates with perinatal asphyxia and DICa
Initial conditionInitial PLT count (×109/L)Blood smearFibrinogen (mg/dL)PT (sec)aPTT (sec)D-dimers (ng FEU/mL)DIC treatmentOutcome
  1. a

    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.

  2. aPTT = activated partial thromboplastin time; FEU = fibrinogen equivalent units; PT = prothrombin time.

Abruption9Marked schistocytosis8419.457>8,463Multiple FFP, multiple PLTsLived
Abruption17Marked schistocytosis10230>150>50,000Multiple FFP, Cryo, multiple PLTsDied
Abruption15Marked schistocytosis<30>100>150>20,000Multiple FFP, Cryo, multiple PLTsDied
Abruption81Marked schistocytosis5836.7>150>20,000Multiple FFP, Cryo, multiple PLTsDied
Abruption47Marked schistocytosis6421.653>20000Multiple FFP, Cryo, multiple PLTsDied
figure

Figure 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]

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Response to transfusion and MPV

Thirty of the 96 neonates received 56 apheresis PLT transfusions. Chart reviews indicated that all 56 transfusions were given prophylactically, meaning that the patient did not have active bleeding. PLT counts before the transfusions ranged from 24 × 109 to 108 × 109/L (median count, 44 × 109/L). The increase in PLT count after transfusion, comparing the pretransfusion count to a count 1 to 24 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 “percentage of the pretransfusion PLT count.” Next, to try to reduce confounding variables that can occur during the 24-hour period after transfusion, we conducted a subgroup analysis 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.

figure

Figure 3. PLT counts after 56 apheresis PLT transfusions to 30 neonates are included in the figure. All values are normalized to percentage 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).

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We next compared PLT counts after apheresis PLT transfusion of six nonasphyxiated neonates during this time period that had a diagnosis of alloimmune thrombocytopenia (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]

figure

Figure 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]

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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.

figure

Figure 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 recorded in the first week after birth.

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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.

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)a
GroupGestational age (weeks)Birthweight (g)Apgar score (5 min)Initial pHInitial base deficit (mmol/L)PLT count at birth (×109/L)Thrombocytopenia diagnosed during the first weekb
  1. a

    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]

  2. b

    Two or more PLT counts of fewer than 150 × 109/L.

1: normal NRBC count at birth (acute hypoxia) (n = 172)39 ± 13172 ± 5355.5 ± 2.26.89 ± 0.0918 ± 3220 ± 6726/172 (15%)
2: elevated NRBC count at birth (chronic hypoxia) (n = 167)38 ± 13228 ± 6454.8 ± 2.56.87 ± 0.1218 ± 3183 ± 7587/167 (52%)
p value0.2290.3790.0090.2230.762<0.0001<0.0001

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 Intermountain 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 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 thrombocytopenia 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 hemorrhagic complications. Rather, all 11 deaths involved withdrawal 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).

Table 3. Causes of, and associations with, death among neonates with thrombocytopenia after perinatal asphyxia
Category of thrombocytopeniaDeathDeath caused by or associated with bleeding problemsWithdrawal of respiratory support because of futility
  1. CDH = congenital diaphragmatic hernia; HIE = hypoxemic-ischemic encephalopathy; SVC = superior vena cava.

Thrombocytopenia of perinatal asphyxia (n = 96)11 (11.5%)0Eleven all had severe HIE. None were recorded to have died because of or in association with bleeding problems.
ECMO after perinatal asphyxia (n = 16)2 (12.5%)One developed a large subdural hemorrhage on ECMO with a marked midline brain shift

The patient with a large subdural hemorrhage had multiple other 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.

DIC after perinatal asphyxia (n = 5)4 (80%)Three had bleeding and oozing requiring dressings on multiple body parts up to the time of deathOne patient had support withdrawn for severe HIE. At the time of death abnormal bleeding/oozing was no longer present.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Conflict of Interest
  8. References

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 asphyxia[7] and had at least two PLT counts drawn during their first week. Among 375 such neonates we sought the incidence of thrombocytopenia, and among those we sought information on the severity and duration of the thrombocytopenia and its 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 condition, as opposed to being due entirely to accelerated PLT consumption and/or destruction; 3) associated with intrauterine 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 unintentionally introduced. Also, changes in obstetric and neonatology practices occurred during the 9 years of study. Examples of practice changes we recognize include the marked overall reduction in NICU transfusion during this period[9] and the specific reduction in PLT transfusions on the basis of a change from PLT count–based guidelines to PLT mass–based guidelines.[19] Also, therapeutic hypothermia was introduced in 2008. These flaws limit the confidence 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 thrombocytopenia of perinatal asphyxia are obscure, but several experiments have generated potential explanations. For instance, McDonald and colleagues[20] 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, suggesting that the primary kinetic mechanism was reduced PLT production. Saxonhouse and coworkers[21] 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 coworkers[22] cocultured CD34(+) progenitors with or without mononuclear (accessory) cells under various oxygen environments (1, 5, and 20%). Although the progenitors themselves were unaffected by the ambient oxygen concentration, 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 microenvironment were likely damaged by hypoxia resulting in impaired megakaryocytopoiesis. This conclusion is consistent with the in vitro experiments of LaIuppa and colleagues[23] 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 significant 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 thrombocytopenia 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 highlighted by Josephson and colleagues[2] in a recent symposium, 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 Europe[25] and North America[26] agree that PLT transfusions are recommended when PLT counts fall below 20 × 109/L, but counts that low should be quite rare in the thrombocytopenia 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 coworkers[28] reported a prospective observational study of 194 neonates 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 thrombocytopenia received one or more PLT transfusions. In retrospect, 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 prophylactically 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 prolongation 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 therapeutic hypothermia warrants giving PLT transfusions at higher PLT counts than for neonates not on therapeutic 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 agonists 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

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Conflict of Interest
  8. References

The authors thank Martha C. Sola-Visner, Harvard University and Boston Children's 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

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Conflict of Interest
  8. References

The authors have disclosed no conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Conflict of Interest
  8. References
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  • 2
    Josephson CD, Glynn SA, Kleinman SH, et al.; State-of-the Science Symposium Transfusion Medicine Committee. A multidisciplinary “think tank”: the top 10 clinical trial opportunities in transfusion medicine from the National Heart, Lung, and Blood Institute-sponsored 2009 state-of-the-science symposium. Transfusion 2011;51:828-841.
  • 3
    Sola-Visner MC, Saxonhouse MA. Acquired thrombocytopenia. In: de Alarcón PA, Werner EJ, Christensen RD, editors. 2nd ed. Neonatal hematology. Cambridge: Cambridge University Press; 2013. p. 162-164.
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    American Academy of Pediatrics, American College of Obstetricians and Gynecologists. Neonatal encephalopathy and cerebral palsy: defining the pathogenesis and pathophysiology. Elk Grove Village, IL, AAP; Washington, DC, ACOG, 2003.
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    Christensen RD. Reference ranges in neonatal hematology. In: de Alarcón PA, Werner EJ, Christensen RD, editors. 2nd ed. Neonatal hematology. Cambridge: Cambridge University Press; 2013. p. 385-408.
  • 9
    Baer VL, Henry E, Lambert DK, et al. Implementing a program to improve compliance with neonatal intensive care unit transfusion guidelines was accompanied by a reduction in transfusion rate: a pre-post analysis within a multihospital health care system. Transfusion 2011;51:264-269.
  • 10
    Christensen RD, Baer VL, Lambert DK, et al. Reference intervals for common coagulation tests of preterm infants. Transfusion 2014;54:627-632.
  • 11
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