Article disorders of blood

Neonatal Thrombocytopenia
Karen S. Fernández, MD,* Educational Gaps
Pedro de Alarcón, MD†
1. Knowing the differential diagnosis and most likely etiologies of thrombocytopenia in
the neonate will lead to more appropriate diagnostic evaluations and treatments.
Author Disclosure 2. Thrombocytopenia may be a symptom of a variety of congenital or acquired conditions
Drs Fernández and de in the neonatal period and prompt further diagnostic evaluations.
Alarcón have disclosed
no financial
relationships relevant Abstract
to this article. This Thrombocytopenia is one of the most common hematologic problems in the neonate.
It affects up to 30% of all patients admitted to the neonatal intensive care unit (NICU).
commentary does
The causes of thrombocytopenia in neonates are diverse and include immune, in-
contain a discussion of herited, and acquired disorders. The evaluation of the neonate with thrombocytopenia
an unapproved/ may be challenging. Developing a diagnostic strategy to evaluate the neonate with
investigative use of thrombocytopenia is key for the practicing clinician. Here, we provide a practical ap-
a commercial product/ proach to the evaluation of the neonate with thrombocytopenia and an overview of its
device. most common etiologies.

Objectives
1. Describe the differences between neonatal and adult thrombopoiesis.
2. Provide a differential diagnosis of neonatal thrombocytopenia.
3. Describe the clinical presentation and management of the most common forms of
thrombocytopenia during the neonatal period.
4. Explain and contrast the pathophysiology of neonatal autoimmune thrombocytopenia
and alloimmune thrombocytopenia.
5. Describe the most common inherited causes of
thrombocytopenia in the newborn.
Abbreviations: 6. Discuss the approach to treatment for the neonate with
thrombocytopenia according to the etiology.
BSS: Bernard Soulier syndrome
CAMT: congenital amegakaryocytic thrombocytopenia
DIC: disseminated intravascular coagulation Definition and Incidence
FA: Fanconi anemia Thrombocytopenia is defined as a platelet count under
GP: glycoprotein 150,000/mL. However, healthy neonates tend to have
HPA: human platelet antigen platelet counts in the range of 100 to 150,000/mL. Throm-
ICH: intracranial hemorrhage bocytopenia occurs in less than 1% of all neonates, but is one
IVIG: intravenous immunoglobulin of the most common hematological problems in neonates,
NAIT: neonatal alloimmune thrombocytopenia affecting 25% to 30% of all admissions to the neonatal inten-
NEC: necrotizing enterocolitis sive care unit (NICU). The evaluation and management of
NICU: neonatal intensive care unit thrombocytopenia is a challenge for the neonatologist and
TAR: thrombocytopenia absent radii hematologist, because it can be caused by multiple disease
Tpo: thrombopoietin processes. Therefore, a review of the differential diagnosis,
WAS: Wiskott-Aldrich syndrome the pathophysiology, and the management of the newborn
with thrombocytopenia is important.

*Assistant Professor of Pediatrics, University of Illinois College of Medicine at Peoria and Children’s Hospital of Illinois, Peoria, IL.
†
William H. Albers Professor and Chair Department of Pediatrics, University of Illinois College of Medicine at Peoria and Children’s
Hospital of Illinois, Peoria, IL.

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 disorders of blood thrombocytopenia

Platelets Production in the Newborn maintain the integrity of the vascular endothelium and
Platelets are tiny cellular fragments produced by mega- to control hemorrhage from small-vessel injury through
karyocytes. Platelet production, or thrombopoiesis, is the formation of small aggregates or plugs in the micro-
a complex process that consists of four main steps: circulation. Bleeding tendency results when platelets are
deficient in number or function.
1. Production of thrombopoietin (Tpo) as the thrombo-
The normal platelet count in newborns and infants is
poietic stimulus.
considered to be between 150,000 and 450,000/mL.
2. Generation and proliferation of megakaryocyte
However, this range of platelet count comes from a lim-
progenitors.
ited number of small sample studies of healthy newborns.
3. Maturation of megakaryocytes characterized by a pro-
A study from 18 hospitals in the United States using data
gressive increase in nuclear ploidy (the number of sets
from more than 47,000 neonates reported lower limit of
of chromosomes in a given cell) and cytoplasmic ma-
platelet ranges from neonates at various gestational ages
turity that leads to the generation of large polyploid
during their first 90 days after birth of 123,000/mL in
(8N–64N) megakaryocytes.
late preterm and term neonates and 104,000/mL in in-
4. Platelet formation and release of new platelets into the
fants of less than 32 weeks’ gestation. Whether or not
circulation.
a platelet count below 150,000/mL is considered abnor-
These mechanisms are significantly different between mal, it should always be interpreted within the context of
neonates and adults with thrombocytopenia. In neonates the clinical situation.
Tpo levels are not as high in thrombocytopenic neonates, The tendency to bleed is proportional to the number
particularly in the small for gestational age infants, as of platelets within the circulation. As such, there is no risk
those found in children or adults. The number of mega- of bleeding with platelet counts greater than 100,000/
karyocyte progenitors circulating in the peripheral blood mL, minimal or mild risk of bleeding occurs with platelet
of neonates is higher than in children and adults. They counts between 20,000 and 100,000/mL, the risk is
give rise to colonies with a greater number of megakar- moderate with platelet counts below 20,000/mL, and
yocytes, and may be more sensitive to Tpo stimulation the risk is severe and/or there is spontaneous bleeding
in comparison with those of children or adults. Megakar- with platelets below 5,000/mL. In the neonate, the cor-
yocytes in the neonate are smaller and have lower ploidy, relation of platelet count with bleeding has not been
but their cytoplasm reflects that of a mature cell. Last, established. The trauma and the stress of birth can precip-
Tpo effect inhibits megakaryocyte polyploidization in itate, although rarely, intracranial or internal bleeding
the neonate. Neonates maintain normal platelet counts when platelets are below 30,000/mL, and, therefore,
on the basis of the increased proliferative potential of clinicians act upon this platelet count to prevent bleeding
their megakaryocyte progenitors. in the NICU setting. This threshold seems to be higher
Most cases of thrombocytopenia encountered in the for preterm infants. Many centers will use a platelet count
NICU are nonimmune and associated with several com- of 50,000/mL to transfuse preterm infants. However,
mon neonatal conditions, such as chronic intrauterine there is little evidence that this approach will prevent in-
hypoxia, sepsis, necrotizing enterocolitis (NEC), and vi- tracranial hemorrhage (ICH). Prospective studies are
ral infections. Although an in-depth review of the partic- warranted to establish the most safe and cost-effective
ular mechanism underlying the etiology of these threshold at which to transfuse premature infants.
nonimmune causes of thrombocytopenia in the neonate The bleeding pattern in the presence of moderate to
is beyond the scope of this review, understanding the dif- severe thrombocytopenia is mucocutaneous. The pres-
ferences between neonatal and adult megakaryopoiesis ence of petechiae, bruises, or bleeding from the mucous
helps us see what predisposes the neonate to develop membranes is characteristic of low platelet counts. In
thrombocytopenia and the potential utility of thrombo- the neonate, intraventricular hemorrhage or intracranial
poietic growth factors as potential therapeutic interven- bleed are also possible in the setting of thrombocytopenia.
tions in selected neonates.
Diagnostic Approach to Neonatal
Platelet Count and Risk of Bleeding Thrombocytopenia
Circulating platelets are about one fifth of the diameter of Multiple disease processes can cause thrombocytopenia.
a red blood cell, with a mean volume between 7 and 9 fL. A practical approach to the diagnosis and management
Platelets live for a very short time in the circulation with of thrombocytopenia in the neonate can be based on
a half-life of 7 to 10 days. Their primary function is to the time of onset of thrombocytopenia (early £72 hours

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disorders of blood thrombocytopenia

after birth or late ‡72 hours after birth), gestational age of a healthy newborn that occurs in the first 72 hours after
the patient (term versus preterm), on the underlying birth is associated with a maternal history of placental in-
mechanism (consumption, increased destruction, de- sufficiency. These infants will recover a normal platelet
creased production), or on whether the thrombocytope- count within 10 days and require only close observation.
nia is due to maternal or infant factors or individualized In sick newborns without evidence of placental insuffi-
to the particular infant. Critical parameters that are com- ciency, evaluation for sepsis is warranted in addition to
mon to all these approaches include the severity of initiation of broad spectrum antibiotics.
thrombocytopenia, the maternal history, the health sta- When the newborn’s underlying condition improves,
tus of the infant, and the presence or absence of congen- the thrombocytopenia should also improve, usually
ital malformations. within 5 to 7 days. Persistent thrombocytopenia should
A simplified approach to the diagnosis of thrombocy- alert the physician to look for other causes.
topenia in the newborn is presented here. It is based on Patients with severe thrombocytopenia or a platelet
an algorithm (see Figure) and a table (see Table) that count lower than 50,000/mL should be evaluated for
takes the above factors into account, especially the sever- sepsis, disseminated intravascular coagulation (DIC),
ity of thrombocytopenia and the level of illness of the or neonatal alloimmune thrombocytopenia (NAIT).
neonate. If any of those are present no additional evaluation is
The sick newborn may become thrombocytopenic required.
from a variety of neonatal complications such as infection, In newborns without signs of sepsis, additional evalu-
asphyxia, meconium aspiration, respiratory distress syn- ation must be pursued and must include: (1) maternal
drome, polycythemia, NEC, and the presence of an in- history of thrombocytopenia, (2) detailed familial history
dwelling umbilical catheter. In the sick newborn who of thrombocytopenia, (3) detailed physical examination
has severe thrombocytopenia, specific treatment for the with special attention to the upper extremities, dysmor-
underlying condition should be provided and the throm- phic features suggestive of a congenital anomaly or a par-
bocytopenia treated symptomatically. ticular syndrome, such as thrombocytopenia-absent radii
In general, mild to moderate thrombocytopenia with syndrome, Fanconi anemia, trisomy 13, 18, 21, or
a platelet count between 50,000 and 149,000/mL in Turner syndrome.

Figure. Diagnostic approach to an infant with thrombocytopenia. NAIT=Neonatal alloimmune thrombocytopenia.

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 disorders of blood thrombocytopenia

Specific Illnesses and Patterns Associated With Neonatal

Table.

Thrombocytopenia
Categories Subtypes Differential Diagnoses (Where Applicable) Severity Onset
Immune Alloimmune Neonatal alloimmune thrombocytopenia Severe Early
Autoimmune Maternal ITP, lupus, other collagen Severe-moderate Early
vascular disorder
Infectious Bacterial GBS, Gram-negative rods, Variable Variable
Staphylococcus, etc.
Viral CMV, HSV, HIV, enteroviruses Variable Usually early
Fungal Candida, other Severe Usually early
Parasite Toxoplasmosis Variable Early
Placental Preeclampsia, eclampsia, chronic Mild-moderate Early
insufficiency hypertension
Intrauterine growth restriction due Mild-moderate Early
to placental insufficiency
DIC Asphyxia Severe Early
Sepsis Severe Variable
Congenital TTP (rare) Severe Variable
Genetic Chromosomal Trisomy 13, Trisomy 18, Trisomy 21, Variable Early
disorders Turner syndrome, Jacobsen syndrome
Familial Macrothrombocytopenias, Wiskott-Aldrich Variable Early*
syndrome, X-linked thrombocytopenias,
Amegakaryocytic thrombocytopenia,
TAR, Fanconi anemiaa
Metabolic Proprionic acidemia, methylmalonic Mild-moderate Variable
acidemia, etc.
Medication Antibiotics Penicillin and derivatives, vancomycin, Variable Late
induced metronidazole, etc.
Heparin Variable Late
Anticonvulsants Phenytoin, phenobarbital Variable Late
H-2 receptor Variable Late
antagonists
Miscellaneous Thrombosis RVT, line-associated thrombosis, Moderate Variable
sagittal sinus thrombosis
Vascular tumor Kasabach Kasabach-Merritt, hepatic Moderate Variable
hemangioendothelioma
NEC Severe-moderate Usually late
ECMO Variable Variable
Most familial thrombocytopenias are present at birth except for Fanconi anemia, which usually does not appear until childhood. GBS¼Group B
streptococcus; ITP¼immune thrombocytopenic purpura; CMV¼cytomegalovirus; HSV¼herpes simplex virus; HIV¼human immunodeficiency virus;
TTP¼thrombotic thrombocytopenic purpura; TAR¼thrombocytopenia-absent radii syndrome; RVT¼renal vein thrombosis; NEC¼necrotizing
enterocolitis; ECMO¼extra corporeal membrane oxygenation.
a
Reproduced with permission from Fernández KS, de Alarcón PA. Congenital thrombocytopenias and thrombocytopathies. In: de Alarcón PA, Christensen
RD, Werner EJ, eds. Neonatal Hematology: Pathogenesis, Diagnosis, and Management of Hematologic Problems. 2nd ed. Cambridge, United Kingdom:
Cambridge University Press; 2013, p. 174.

In newborns with a negative maternal or familial history The most common etiology of severe thrombocytope-
and an unrevealing physical examination, other infections, nia in an otherwise healthy-looking newborn is immune-
such as toxoplasmosis, other viruses and syphilis, rubella, mediated thrombocytopenia in which there is passage
cytomegalovirus, and human immunodeficiency virus com- of maternal antibodies from the mother to the fetus.
plex; human immunodeficiency virus infection; or enterovi- Other rarer disorders, such as vascular tumors or heman-
ruses, should be considered. In addition, catheter-related giomas with Kasabach-Merritt phenomenon and renal
thrombosis, chromosomal anomalies, and inborn errors vein thrombosis, should be investigated.
of metabolism, especially propionic acidemia and methyl- When thrombocytopenia occurs more than 72 hours
malonic acidemia, should be considered. after birth, it is more likely to be due to bacterial or fungal

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disorders of blood thrombocytopenia

sepsis and/or NEC. For patients in whom a bacterial or couple. The most serious complication of NAIT is ICH.
fungal process is excluded as etiology of thrombocytopenia, This may occur in as many as 10% of the cases, and up to
viral infections such as herpes simplex virus and cytomeg- 50% of the time it happens before birth. All infants with
alovirus, DIC, catheter-related thrombosis, drug-induced severe thrombocytopenia due to NAIT should have a cra-
thrombocytopenia, heparin-induced thrombocytopenia, nial ultrasound to look for evidence of ICH.
or other inherited disorders should be considered. This If available, the best alternative to treat these patients
group of patients constitutes the most common reason is the use of HPA-1a–negative platelets from the blood
for consultation to the hematology team. Immune- bank. Random donor platelets, even though they are
mediated thrombocytopenias should also be considered likely to have the target antigen, are effective in treating
in this group, in particular, because they tend to worsen the infant with severe thrombocytopenia. Platelets ob-
in the first few days after birth. The differential diagnosis tained from the mother are also effective, but these pla-
of immune-mediated thrombocytopenias is between telets need to be washed to minimize the presence of the
NAIT, maternal autoimmune disorders, or, rarely, mater- circulating anti-HPA-1a antibodies. Specific platelet anti-
nal drug-induced immune thrombocytopenia. gen and antibody testing are not readily available at all
In the following sections we will highlight some of the centers but can be requested at major referral laborato-
features of the most common causes of thrombocytope- ries. The administration of intravenous immunoglobulin
nia in newborns in the three major categories of destruc- (IVIG) may be helpful and represents another alternative
tion of platelets by immune mediated process, decreased treatment but less effective than platelet transfusions.
or abnormal production of platelets owing to inherited Once an infant is diagnosed with NAIT, it is important
disorders, and consumption of platelets related to some to carry out a complete diagnostic plan with genotyping
acquired disorders. of mother and father to be able to provide genetic coun-
seling. In subsequent pregnancies, if the father is a homo-
zygote for the affected antigen, therapy should be started
Immune-Mediated Causes of Neonatal as early as the 13th week of pregnancy with weekly
Thrombocytopenia IVIG with or without prednisone, depending on the se-
Neonatal Alloimmune Thrombocytopenia verity of the previously affected infant or if there was
NAIT is a rare disorder that presents in an otherwise well- a history of ICH. If the father is a heterozygote for
appearing newborn with moderate to severe thrombocy- the antigen, the risk of the infant must be determined
topenia. NAIT occurs when fetal platelets contain an by molecular analysis of fetal cells circulating in the ma-
antigen inherited from the father, a human platelet anti- ternal blood, if available, or by invasive procedures:
gen (HPA) that the mother lacks. Fetal platelets that cross chorionic villi biopsy or amniocentesis, which both carry
the placenta into the maternal circulation trigger the pro- significant risks to the pregnancies, to establish if the fetus
duction of maternal antiplatelet antibodies against the is affected.
foreign antigen. These antibodies cross the placenta into
the fetal circulation and destroy platelets resulting in fetal Neonatal Autoimmune Thrombocytopenia
and neonatal thrombocytopenia. There are sixteen HPAs Neonatal autoimmune thrombocytopenia, in contrast to
identified but only three cause 95% of the NAIT cases NAIT, is caused by the passage of maternal antibodies
(HPA-1a, HPA-5b, and HPA-15b). Feto-maternal in- that react with both maternal and infant platelets, and
compatibility for HPA-1a is responsible for 75% of cases therefore both mother and infant are affected. This dis-
in whites. HPA-1a incompatibility occurs in 1:350 preg- order occurs in maternal autoimmune disorders such
nancies, although thrombocytopenia develops in only as immune thrombocytopenic purpura or systemic lupus
1:1,000 to 1,500 pregnancies. erythematosus. It occurs in 1 to 2:1,000 pregnancies.
Infants with NAIT will have symptoms of mucocuta- The diagnosis becomes obvious from a maternal history
neous bleeding but will look otherwise healthy. Typically, of thrombocytopenia. Transplacental passage of maternal
platelet count falls below 50,000 in the first few days after autoantibodies in this setting is much less of a clinical
birth, but then rises as the alloantibody concentration problem than NAIT. It is important to note that the ma-
declines, which usually happens in 1 to 4 weeks, the ternal history is not always positive, because there are
expected half-life of immunoglobulin G. This immune- many thrombocytopenic mothers who would be asymp-
mediated platelet disorder is the equivalent to Rh sensi- tomatic and therefore unaware of their own disorder. All
tization of red blood cells with the only difference that neonates of mothers with autoimmune diseases should
NAIT often develops in the first pregnancy of an at-risk have their platelet count determined at birth. In most

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 disorders of blood thrombocytopenia

cases, the platelet count rises spontaneously by day 7. In eczema, and recurrent bacterial and viral infections. Most
cases of severe thrombocytopenia, treatment with IVIG is cases will not present during the neonatal period unless
recommended. The presence of unexplained thrombocy- there is a known family history. The disorder usually
topenia in a newborn that is suggestive of autoimmune presents in the first year after birth with bleeding symp-
destruction and in whom NAIT has been excluded toms. Bleeding is due to abnormal platelet function, re-
should trigger evaluation for the presence of an autoim- duced platelet survival, and thrombocytopenia. X-linked
mune disorder in the mother, because neonatal throm- thrombocytopenia is a part of the spectrum of WAS.
bocytopenia can sometimes be the presenting sign of These patients have thrombocytopenia and small platelets
maternal disease. as the major manifestations of their disease. However, the
difference is in the variable and less severe degrees of ec-
zema and immunodeficiency.
Inherited Thrombocytopenias
Aneuploidies Fanconi Anemia
Thrombocytopenia is seen in neonates with trisomy 13, Fanconi anemia (FA) can present in the newborn with
18, and 21, and also with Turner syndrome. The exact persistent thrombocytopenia. It is, in most cases, an au-
mechanism of thrombocytopenia is unknown, but may tosomal recessive disorder. The infant may present with
be due to reduced platelet production and the pathogen- thrombocytopenia alone, pancytopenia, or with dysmor-
esis may be similar to that seen in chronic fetal hypoxia. phic features only. The associated congenital abnormali-
ties of hypopigmented and hyperpigmented skin lesions,
Bernard-Soulier Syndrome microcephaly, small size, urinary-tract abnormalities,
Bernard-Soulier syndrome (BSS) is a moderate to severe and upper-extremity radial-side abnormalities involving
platelet function defect characterized by mild thrombo- the thumb, should alert the physician to the possibility
cytopenia, giant platelets, and mucosal type bleeding. of FA. The cross-linking agent diepoxybutane has been
It is a very rare disorder with an incidence of 1:1,000,000. used effectively to diagnose FA and is the standard diag-
It may present in the neonatal period, although bleeding nostic test. Treatment is rarely necessary in the neonatal
is not usually severe. It is a qualitative platelet disorder with period.
a defect in the von Willebrand factor receptor, the glyco-
protein (GP) complex GP Ib–IX–V. Thrombocytopenia Absent Radii Syndrome
The defect in BSS is in the GPIba gene, and also in This syndrome is characterized by the bilateral absence of
the GPIbb and GPIX genes, mapped to chromosome the radii and thrombocytopenia. The inheritance pattern
17, chromosome 22, and chromosome 3, respectively. of the thrombocytopenia absent radii (TAR) syndrome is
Defect in chromosome 22 and abnormality in GPIbb autosomal recessive. Both boys and girls are affected, but
explains why infants with DiGeorge syndrome and there is a predominance of girls. The onset of symptoms
cardiac disease may develop severe bleeding due to a usually occurs very early in life. Half of the patients have
coexisting BSS. onset of hemorrhagic manifestations in the first week
The diagnosis of BSS is confirmed by the absence of after birth, and most develop thrombocytopenia by 4
CD41a or PGPIb–IX–V by flow cytometry. Treatment months of age. In contrast to infants with FA, in patients
for BSS is mostly supportive and with platelet transfusion with TAR syndrome both thumbs are present. The prog-
for life-threatening bleeding. Mothers with BSS may de- nosis in the TAR syndrome is dependent on the severity
velop alloantibodies against GPIb–IX–V that can cross of the hemorrhagic manifestations. If the patient survives
the placenta, and, therefore, their offspring can develop the first year after birth, the hemorrhagic manifestations
NAIT due to the passage of alloantibodies against resolve, because the platelet count spontaneously im-
GPIb–IX–V antigens. proves to low normal levels which are then maintained.
Treatment is supportive with platelet transfusions indi-
Wiskott-Aldrich Syndrome cated only in the event of active bleeding.
Small platelets on peripheral blood film and/or a low
mean platelet volume may indicate Wiskott–Aldrich syn- Congenital Amegakaryocytic Thrombocytopenia
drome (WAS). WAS is due to mutations in the WAS pro- Congenital amegakaryocytic thrombocytopenia (CAMT)
tein gene on the short arm of the X chromosome. is a rare recessive autosomal disorder presenting during
Mutations in this gene have been isolated to Xp11.23. the neonatal period with thrombocytopenia. Most af-
WAS is characterized by microthrombocytopenia, fected infants have petechiae or other evidence of

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disorders of blood thrombocytopenia

bleeding. Physical anomalies are present in approxi- anomalies with visceral involvement. The thrombocyto-
mately 50% of the patients. CAMT typically presents with penia is due to the trapping and consumption of platelets
isolated thrombocytopenia; however, 50% of the patients in the endothelium of the abnormal blood vessels. The
will later progress to aplastic anemia during infancy or treatment of these lesions requires supportive treatment
early childhood. The bone marrow shows decreased with plasma and platelet transfusion if DIC is present.
to absent megakaryocytes with normal erythroid and Some of these vascular malformations with aggressive
myeloid precursors. Bleeding episodes in neonates with behavior may need treatment with steroids, interferon,
CAMT are treated by platelets transfusions, but stem vincristine, and other chemotherapy agents. More re-
cell transplantation is the definitive form of therapy for cently, the use of the angiogenesis inhibitor bevacizumab
this disorder. There is another variant of amegakaryocytic and the use of the mTOR inhibitor, rapamycin, have
thrombocytopenia with radioulnar synostosis. Patients shown some activity; however, further studies are
with amegakaryocytic thrombocytopenia with radioulnar necessary before recommending therapy with these
synostosis have a mutation in the HOXA11 gene that dis- agents.
tinguishes them from TAR syndrome, and from CAMT in
which the mutation is located in the cMPL gene. Thrombotic Disorders
Acquired thrombotic events in the NICU have increased
Giant Platelet Syndromes over the past several years, mainly because of the high
Giant platelet syndromes may present in the neonatal complexity of the patients cared for in the NICU requir-
period. The characteristic of these disorders is not only ing indwelling catheters and being at risk for several fac-
a reduced platelet count, but the appearance of large tors that predispose them to secondary thrombotic
platelets on the peripheral smear. Several of the rare events. The use of heparin flushes to maintain the patency
giant platelet syndromes present in the fetus, including of indwelling catheters is also a risk for the develop-
the May-Hegglin anomaly, which is characterized by ment of heparin-induced thrombocytopenia that is as-
the presence of leukocyte Dohle-like inclusion bodies. sociated with arterial thrombosis. Inherited deficiency
This could be a rare cause of fetal or neonatal ICH. of ADAMTS13, the cleaving protease of von Wille-
The defect in May-Hegglin anomaly is in the MY-H9 brand factor, that causes thrombotic thrombocytopenic
gene on chromosome 22q. This mutation is also found purpura may present in the newborn period. Renal vein
in other giant platelet syndromes such as Fletcher syn- thrombosis should also be considered in the differential
drome, where leukocyte inclusions are absent and diagnosis of patients with thrombocytopenia and renal
there is association of sensorial hearing loss, nephritis failure. Thrombocytopenia is part of the clinical presen-
and cataracts, and Epstein syndrome, in which there tation of anticoagulant factor deficiencies, and these
are no leukocyte inclusions but there is association to deficiencies should be considered in the differential di-
hearing loss and nephritis without cataracts. Other mac- agnosis of thrombocytopenia. However, the severe
rothrombocytopenias are a group of heterogeneous dis- form of these deficiencies presents with purpura ful-
orders that include functional platelet disorders like minans and diffuse thromboses and not just isolated
Bernard-Soulier syndrome that was previously de- thrombocytopenia.
scribed, gray platelet syndrome in which there is lack
of platelet granules, and Jacobsen-Paris-Trousseau syn-
drome that is associated with psychiatric problems or Conclusions
mental retardation. Thrombocytopenia is a common problem in the new-
born. The differential diagnosis of thrombocytopenia
in the neonate can be simplified when taking into ac-
Consumptive Causes of Thrombocytopenia in count the severity of the thrombocytopenia and the
the Neonatal Period clinical appearance of the neonate. Most episodes of
Kasabach-Merritt Phenomenon thrombocytopenia in the newborn occur after the first
This is an important cause of thrombocytopenia in the 72 hours after birth and are most commonly caused
newborn. It typically presents with profound thrombocy- by infectious process. Persistent thrombocytopenia, or
topenia, microangiopathic anemia, and DIC in associa- thrombocytopenia that does not respond to adequate
tion with a vascular malformation. The diagnosis is treatment of the presumed etiology of the low platelet
obvious when the vascular anomaly is cutaneous, but it count, deserves further investigation to look for some
may be more challenging with the presence of vascular of the rare causes of thrombocytopenia in neonates

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 disorders of blood thrombocytopenia

including immune-related disorders, inherited throm- Suggested Reading

bocytopathies and other acquired causes of platelet Chakravorty S, Roberts I. How I manage neonatal thrombocyto-
consumption. penia. Br J Haematol. 2012;156(2):155–162
Drachman JG. Inherited thrombocytopenia: when a low platelet
count does not mean ITP. Blood. 2004;103(2):390–398
Ferrer-Marin F, Liu ZJ, Gutti R, Sola-Visner M. Neonatal
thrombocytopenia and megakaryocytopoiesis. Semin Hematol.
American Board of Pediatrics Neonatal-Perinatal 2010;47(3):281–288
Hammill AM, Wentzel M, Gupta A, et al. Sirolimus for the
Content Specifications treatment of complicated vascular anomalies in children. Pediatr
• Know the normal pattern of platelet Blood Cancer. 2011;57(6):1018–1024
production and maturation. Nurden P, Nurden AT. Congenital disorders associated with
• Know the causes and pathophysiology platelet dysfunctions. Thromb Haemost. 2008;99(2):253–263
of neonatal thrombocytopenia and Risson DC, Davies MW, Williams BA. Review of neonatal
thrombocytosis. alloimmune thrombocytopenia. J Paediatr Child Health.
• Know the clinical and laboratory 2012;48(9):816–822
manifestations and management of neonatal Sola-Visner M, Sallmon H, Brown R. New insights into the
thrombocytopenia and thrombocytosis. mechanisms of nonimmune thrombocytopenia in neonates.
Semin Perinatol. 2009;33(1):43–51

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1. Which of the following distinguishes thrombopoiesis in neonates from adults?

a. Megakaryocytes in neonates are larger than those found in adults.
b. The mechanisms of neonatal response and physiology of thrombocytopenia are essentially identical to
adults.
c. The number of megakaryocyte progenitors circulating in peripheral blood of neonates is lower than in
adults.
d. Thrombopoietin does not stimulate thrombopoiesis in neonates.
e. Thrombopoietin levels are not as high in thrombocytopenic neonates, particularly small for gestational age
infants, compared with adults.

2. The laboratory calls you regarding a patient in the NICU to note an abnormal platelet count of 105,000/mL.
This patient is a 2-day-old 33-weeks’-gestational-age female. Which of the following is the most appropriate
management decision?
a. A platelet level and antibody tests should be ordered for the mother.
b. A platelet transfusion of 10 mL/kg should be given.
c. The patient can be monitored clinically, and a platelet count can be repeated the next morning.
d. This patient is at high risk of bleeding, particularly intracranial hemorrhage.
e. The patient should undergo metabolic and genetic screening, including chromosomal disorders.

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disorders of blood thrombocytopenia

3. A 38-weeks’-gestational-age newborn male has a complete blood count drawn several hours after birth
because of being small for gestational age, and thrombocytopenia is noted, with other parameters of the blood
count being in normal ranges. In regard to the possibility of sepsis, which of the following factors would lead
you to consider close observation and not giving antibiotics at this time?
a. The platelet count is 25,000/mL, and the patient has no evidence of bleeding.
b. The platelet count is 95,000/mL, and the patient has hypotension and capillary refill greater than 3
seconds.
c. The platelet count is 85,000/mL, and the patient’s mother has a known history of placental insufficiency.
d. The platelet count is 50,000/mL, the patient has no bleeding symptoms but has respiratory distress
requiring oxygen.
e. Platelet count should not be considered in the evaluation for sepsis.

4. A 38-weeks’-gestational-age male presents in the well infant nursery at 2 days after delivery with
mucocutaneous bleeding, and a complete blood count reveals platelet count of 25,000/mL. He appears well
otherwise. He is admitted to the NICU and a cranial ultrasound reveals bilateral grade I intraventricular
hemorrhage. His mother’s platelet count is 175,000/mL. What is the most likely diagnosis?
a. Bernard-Soulier syndrome.
b. Laboratory error.
c. Neonatal alloimmune thrombocytopenia.
d. Neonatal autoimmune thrombocytopenia.
e. Wiskott-Aldrich syndrome.

5. A 1-kg, 29-weeks’-gestational-age female is now 2 weeks old. She is on nasal cannula oxygen and parental
nutrition via a peripherally inserted central line, and she is receiving gavage feedings of both maternal breast
milk and premature infant formula. There have been increased apnea and bradycardia events over the past 24
hours with an increased need for oxygen concentration. A complete blood count reveals hematocrit of 26%,
white blood cell count of 6,000/mL, and platelet count of 65,000/mL. The platelet count 1 day after delivery
was noted to be 125,000/mL. What is the most appropriate next step in management of this patient?
a. Avoid giving any medications for the next 48 hours in case thrombocytopenia may be drug-related.
b. Give 10 mL of packed platelet transfusion over the next hour.
c. Obtain platelet counts from the mother and father.
d. Perform sepsis evaluation and start antibiotics while awaiting cultures.
e. Stop giving maternal breast milk for 48 hours in case there may be passage of maternal drugs via breast
milk, and instead use formula only.

e82 NeoReviews Vol.14 No.2 February 2013