www.jpnim.

com  Open Access  eISSN: 2281-0692

Journal of Pediatric and Neonatal Individualized Medicine  2017;6(1):e060119
doi: 10.7363/060119 
Received: 2016 Aug 23; accepted: 2016 Oct 19; published online: 2017 Feb 13

Invited review

Immune thrombocytopenia in the

newborn
Murat Yurdakök

Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey

Abstract

The leading cause of moderate or severe thrombocytopenia in otherwise

healthy appearing neonates is immune thrombocytopenia. Immune
thrombocytopenia in the fetus or newborn may result from platelet
alloantibodies against paternal antigens inherited by the fetus (alloimmune
thrombocytopenia) or platelet autoantibodies in the mother with immune
thrombocytopenic purpura (ITP). Only 10% of human platelet antigen
(HPA)-1a negative mothers who are exposed to HPA-1a positive fetal
platelets during pregnancy develop HPA-1a alloantibodies, and 30% of
fetuses/neonates will develop thrombocytopenia and 20% of these cases
being severe. The most serious complication of severe fetal and neonatal
alloimmune thrombocytopenia (FNAIT) is intracranial hemorrhage (ICH),
which is detected in 10-20% of affected fetuses/neonates, with most cases
occurring antenatally. ICH leads to neurological sequelae in 20%, and deaths
in 5-10% cases. There is no evidence-based optimal treatment strategy. Platelet
antibody titration in maternal plasma is not helpful for decision-making. The
best indicator for current pregnancy is the outcome of the previous pregnancy.
The risk of recurrence among subsequent HPA-positive sibling is close to
100% where the previous sibling was affected with antenatal intracranial
ICH. The risk of ICH becomes higher with more severe and earlier onset
in each subsequent pregnancy. Serial platelet counts should be obtained for
the first 5-7 days of delivery to keep the platelet counts higher than 30,000/
µL without active bleeding and higher that 50,000-100,000/µL with active
bleeding. Intravenous immunoglobulin (IVIG) is not alternative to platelet
transfusions, since platelet counts don’t rise before 24-48 h. In platelet-
transfused patients, IVIG can be given to potentially prolong the survival of
the incompatible platelets. ITP during pregnancy is not considered a serious
risk of perinatal bleeding, but may cause a moderate thrombocytopenia in
neonate. In mothers with ITP, the risk of thrombocytopenia is only 10%, with
no more than 1% risk of in utero ICH.

Keywords

Alloimmune, autoimmune, newborn, pathogenesis, thrombocytopenia,

treatment.

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Corresponding author 18-35% of infants admitted to NICUs exhibit

thrombocytopenia at least once. In extremely low
Murat Yurdakök, Department of Pediatrics, Hacettepe Uni- birth weight neonates (< 1,000 g), the incidence of
versity Faculty of Medicine, Ankara 06100, Turkey; email: thrombocytopenia is more than 70%, and severe
muratyurdakok@yahoo.com. thrombocytopenia (< 50,000/µL) is 40% [6].
There are two main causes of neonatal thrombo-
How to cite cytopenia: decreased production and increased
destruction (consumption) of platelets. Specific
Yurdakök M. Immune thrombocytopenia in the newborn. J Pediatr maternal/placental disorders (e.g. preeclampsia
Neonat Individual Med. 2017;6(1):e060119. doi: 10.7363/060119. and gestational diabetes) usually cause mild and
self-limiting neonatal thrombocytopenia. Leading
Introduction causes of moderate or severe thrombocytopenia
are infections (in sick neonates) and immune
Platelets are the second most abundant cell thrombocytopenia (in otherwise healthy appearing
type in circulation after red blood cells. In addition neonates). Immune thrombocytopenia in the fetus
to their vast numbers, the small size of platelets or newborn may result from platelet alloantibodies
(approximately 2-3 µm in diameter) gives them against paternal antigens inherited by the fetus, or
an important role as circulating controllers of the platelet autoantibodies in the mother with immune
integrity of the vessel wall. The fundamental role thrombocytopenic purpura (ITP) or systemic lupus
of platelets in hemostasis and thrombosis was erythematosus.
first described by the Italian pathologist Giulio
Bizzozzero (1846-1901) in 1882 [1]. In mammals, Fetal and neonatal alloimmune thrombocytopenia
the blood pressure is high so that blood loss from
injury is very rapid. Therefore, hemostasis must be Fetal and neonatal alloimmune thrombo-
very rapid, which is met by platelet aggregation cytopenia (FNAIT) is the most common cause of
in less than 100 ms. Platelets serve as the “band- severe thrombocytopenia in the fetus and otherwise
aids” of the blood stream and respond to vessel healthy newborn, and intracranial hemorrhage
injury by aggregating to form a platelet clot (ICH) in term infants. In FNAIT, the mother
(thrombosis). Although platelets lack a nucleus produces IgG antibodies against fetal antigens
and genomic DNA, they contain mRNA required inherited from the father. These antibodies can
for protein synthesis. Therefore, platelets markedly cross the placenta, destroy fetal platelets and may
potentiate thrombin generation (coagulation) after induce severe thrombocytopenia.
thrombosis, and are also involved in vascular
repair, angiogenesis, inflammation, and immune Incidence
responses, with the synthesis of more than 300
proteins [2-5]. FNAIT is a rare disease with the incidence
Platelets are released from bone marrow of one in 1,000-2,000 live births. Severe FNAIT
megakaryocytes with unknown mechanisms. A (platelet count < 25,000/µL) is thought to be much
single megakaryocyte can give 10,000-30,000 more uncommon (1/10,000). It represents 3%
platelets, and circulate for approximately 8-10 of all neonatal thrombocytopenia. It is the most
days. The normal peripheral blood platelet count is common (27%) cause of severe thrombocytopenia
150,000-400,000/µL, which is only two thirds of (< 50,000/µL) in the fetal and neonatal period
all available platelets, as the rest is sequestered by [7-12].
the spleen. Under conditions of hemostatic need,
platelets move from the spleen to the peripheral Clinical findings
blood.
The lower range (5th percentile) for infants Most cases of FNAIT are diagnosed inci-
born < 32 weeks of gestation is 104,000/µL, and dentally. In mild cases of thrombocytopenia it
123,000/µL for late preterm and term neonates. At may be asymptomatic. Petechiae shortly after
birth, the incidence of thrombocytopenia defined birth can be the first finding. Therefore FNAIT
by a platelet count < 150,000/µL is 0.12-0.24% of should be suspected in a thrombocytopenic
all neonates. About 0.1-2% of all infants develop neonate with extensive petechiae after the
thrombocytopenia during the neonatal period. differential diagnosis of more common causes

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of thrombocytopenia, including maternal ITP (integrin αIIbβ3), and GPIbα, GPIbβ, GPIX and
and intrauterine viral infections. Gastrointestinal GPV form GPIb-IX-V complex. These GPs serve
bleeding and hematuria can also be detected. as receptor for specific ligands (e.g. fibrinogen and
After delivery, the greatest risk of bleeding is von Willebrand factor), and play an important role
in the first 96 hours of life. Neonatal deaths can in platelet adhesion and aggregation [10]. Absence
occur up to 5-10% of cases [9]. or dysfunction of GPIIb αIIbβ3/IIIa and GP1b/
The most serious complication of severe IX/V are known as Glanzmann’s thrombasthenia
FNAIT is ICH, which is detected in 10-20% of and Bernard-Soulier disease respectively [9, 10].
affected fetuses/neonates. As many as 75-80% Approximately 80% of pregnancies affected
of cases occur antenatally, with most of them by FNAIT are caused by maternal antibodies
occurring before 28 weeks. ICH may be either against HPA-1a, which is the most common
intraparenchymal or intraventricular, and leads to HPA haplotype in population. 98% of Caucasian
neurological sequelae in 20%, and deaths in 5-10% women express HPA-1a (genotypes HPA-1a/1a
of cases [9]. or HPA-1a/1b). Overall frequency of HPA-1b/1b
genotype in mothers is 2%. HPA-1a is carried on
Diagnosis the β3 component of the αIIbβ3 complex (GPIIb/
GPIIIa complex), also called the fibrinogen
Diagnosis is based on clinical and serological receptor. It is the most abundant molecule on the
findings, including a low platelet count and surface of platelets, and it plays a central role in the
alloimmune antibodies. In addition, determination formation of thrombosis by binding to fibrinogen,
of the human platelet antigen (HPA) genotype von Willebrand factor, fibronectin and vitronectin,
of the mother, father and, if needed, of the child which are all required for hemostasis. The second
(or fetus) is needed to confirm the diagnosis, (10-15%) most common HPA causing FNAIT in
especially in cases without detectable antibodies Caucasians is HPA-5b, which is expressed on the
[7]. Parental genotyping is required: if the father α2 subunit of α2β1 (GPIa/IIa), followed by HPA-
is heterozygous, the risk is 50% in fetus, however 1b and HPA-15 [9].
it is 100% if the father is homozygous. Routine In at risk pregnancies, mothers are commonly
screening for FNAIT in all pregnant women is not HPA-1b/1b, and the genotypes of fathers are
recommended, because of high cost, unavailability either HPA-1a/1a or HPA-1a/1b. After an index
of practical tests, presence of high frequency of pregnancy (alloimmunization occurred), 85%
other HPA-antigens discordancy (20%), and no of couples are at risk for FNAIT in subsequent
available prophylactic treatments [9]. pregnancies. However only 10% of HPA-1a
negative mothers who are exposed to HPA-
Pathogenesis 1a positive platelets during pregnancy become
immunized and develop HPA-1a alloantibodies.
The main contributors to the pathogenesis and Only 30% of fetuses/neonates will develop
factors affecting the severity of FNAIT are (a) feto- thrombocytopenia, with 20% of these cases being
maternal incompatibility, (b) maternal exposure severe. The risk of recurrence among subsequent
to these antigens, (c) maternal alloimmunization HPA-positive sibling is close to 100% where the
with production of IgG antibodies against previous sibling was affected with antenatal ICH.
foreign HPAs, (d) placental transfer of anti- The risk of ICH becomes higher with more severe
HPA antibodies, and (e) destruction of fetal (and and earlier onset in each subsequent pregnancy [7,
neonatal) platelets [9, 10]. 9, 11, 12].
In addition to HPAs, a large number of antigens
Feto-maternal incompatibility present at the cell surface of platelets. Some of
them are shared with other blood cells such as
The platelets carry a still growing number of the human leukocyte class I antigens (HLA class
HPAs, which are further defined according to the I) and red cell AB0 blood group antigens. HLA
frequency in the population as “HPA-a” being high- antibodies are adsorbed by fetal HLA antigens
frequency, and “HPA-b” being low-frequency. in the placenta, and these antibodies do not
HPAs are located on the platelet membrane cause thrombocytopenia. However anti-A or
glycoprotein (GP) structures. GPIIb (integrin anti-B of the IgG class can cause mild neonatal
αIIβ) and GPIIIa (integrin β3) form GPIIb/GPIIIa thrombocytopenia. Interestingly, the presence

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of both anti-HPA-1a antibodies and anti-HLA to HPA-1a antigen presence and the associated
antibodies directed against paternal antigens on immune response. Antibody production depends on
platelets do not intensify thrombocytopenia in T helper cell activation resulting from interaction
FNAIT [13]. between T cell receptor and HLA class II peptide
complex. HLA class II antigen DRB3*01:01
Maternal exposure to these antigens present on T cells provides a binding groove which
shows better avidity for β3 peptides (i.e. HPA-1a)
Fetal platelets express HPA-1a as early as 16 [19]. Therefore 99% of HPA-1b/1b women that
weeks of gestation. However there are no reports produce HPA-1a antibody express DRB3*01:01.
demonstrating the transfer of fetal platelets to In other terms women who are HLA DRB3*01:01
maternal circulation during a normal pregnancy. have a 25 times higher risk of HPA-1a sensitization
Maternal exposure to platelets probably occurs compared to women who lack this allele [20]. HPA-
at delivery, and 0.5-1 ml fetal blood enters the 1a antibody levels in women who are DRB3*01:01
maternal circulation in normal, uncomplicated negative are lower than those in women who are
deliveries. Unlike D sensitization, 40-60% of cases DRB3*01:01 positive [21].
occur in the first pregnancy [7, 9]. This suggests
previous maternal exposure to HPA-1a through Maternal-fetal antibody transfer
blood transfusion, prior undetected pregnancies,
transfer of fetal platelet, trophoblast or trophoblast Fetal rather than maternal Fc receptor plays
particles early in the current pregnancy [10]. a key role in the maternal-fetal transfer of
Platelets, like other cells, generate extracellular immunoglobulin G (IgG) antibody. Placental
vesicles in diameters of 50-150 nm with plasma syncytiotrophoblasts internalize maternal IgG by
membrane budding. These microparticles binding neonatal Fc receptor (FcRn) expressed
participate in all platelet functions, mediate cell- on membrane into endosomes, then transferring
to-cell communication, and express surface them to the fetal circulation. Absence of FcRn
platelet antigens [14]. Hypothetically, platelet or maternal treatment with antibodies blocks IgG
microparticles can pass the placenta and cause transfer [22].
alloimmunization. Each Ig molecule contains two oligosaccharide
GPIbα and GPIIb (the αIIβ subunit of the groups linked to a glycan-bound peptide at the
αIIbβ3 integrin) are expressed only on the Fc domain. Addition of fucose residue to this
platelets and their precursor megakaryocytes. position (core fucosylation) modulates the affinity
However, GPIIIa (the β3 subunit of the αIIbβ3 of IgG-Fc for the FcgRIII receptor expressed on
integrin) may also express αV subunit (i.e. αVβ3 phagocytes. IgG molecules lacking a core-fucose
integrin) on other cells, including trophoblast residue bind more tightly to FcgRIII and exhibit
and endothelial cells and their progenitors, which enhanced cellular immune function. Up to 30%
mediate vascular (angiogenesis) and placental of IgG molecules in normal serum lack a core-
development [15]. In animal studies, anti-GPIαbβ fucose residue. Decrease in core fucosylation is
can induce miscarriage through impairment of more common in women immunized to HPA-1a
angiogenesis, which may be the major cause of positive fetus. Neutrophil phagocytosis of platelets
embryonic hemorrhage, spontaneous miscarriage coated with maternal HPA-1a antibodies increases
due to extensive fibrin deposition, and apoptosis as IgG-Fc core fucosylation decreases, and there
and necrosis in mice with anti-GPIbα antibodies is a significant positive correlation between lower
[16-18]. This finding may increase suspicion in the HPA-1a antibody core fucosylation and lower
real incidence of FNAIT with increased numbers neonatal platelet counts and more severe clinical
of undiagnosed fetal losses. outcome [23].

Maternal immunization Treatment

HPA antigen incompatibility alone is not Antepartum management

sufficient to induce maternal alloimmunization,
since only 10% of HPA-1a incompatible pregnancies Intravenous immunoglobulin (IVIG) is the
result in maternal HPA-1a sensitization. One mainstay of FNAIT management. Animal models
explanation for this unexpected finding is related of thrombocytopenia show that maternal adminis-

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tration of IVIG reduces levels of both β3 and In the high-risk group, treatment is recommended
GPIbα-specific antibodies in maternal and fetal starting at 12 weeks with IVIG 1 g/kg/wk. At 20
blood, and ameliorate FNAIT [24, 25]. weeks IVIG dose is increased to 2 g/kg/wk, and
Prophylactic interventions in pregnant women prednisolone (1 g/kg/day) is added. FBS at 32
or those with a history of FNAIT are only indicated weeks may be performed. Delivery after 32 weeks
if fetal platelets carry the HPA. In approximately is an option if indicated.
30% of cases, the father is heterozygous for the In the very-high-risk group, treatment should start
HPA-1a allele (genotype HPA-1ab), and the at 12 weeks with IVIG (2 g/kg/wk). Prednisolone (1
likelihood that the fetus will inherit the HPA-1b mg/kg/day) is added to this regimen at 20 weeks.
is 50%. In this case, there is no risk of FNAIT, FBS is performed at 32 weeks for additional therapy,
and there is no indication for prophylactic IVIG fetal platelet transfusion or delivery [9].
therapy. The fetal HPA type can be determined Serial FBS to monitor platelet counts with platelet
by amniocentesis or fetal blood sampling (FBS), transfusions and in utero IVIG administration is not
which carries the risk of miscarriage and/or a safe because of high risk of the procedure-related
boosted humoral response in the mother [26]. complications including fetal hemorrhage and fetal
Methods for noninvasive genotyping of HPA death due to severe thrombocytopenia. Serial FBS
alleles with the use of maternal plasma cell-free and weekly intrauterine transfusions of maternal
DNA have been developed to screen HPA status in platelets may not only further sensitize the mother,
suspected cases [27]. but may also aggravate thrombocytopenia in the
Repeated fetal ultrasounds beginning early in fetus through the passage of maternal anti-platelet
the pregnancy are indicated in suspected cases. antibodies during platelet transfusions [13].
There is no evidence-based optimal treatment In practice, IVIG with or without prednisolone
strategy. Platelet antibody titration in maternal is given empirically without knowing fetal status
plasma is not helpful for decision-making. The [19]. Although about 20% of fetuses do not
best indicator for current pregnancy is the outcome respond to IVIG treatment, which exposes them to
of the previous pregnancy, although severe FNAIT the risk of ICH, blind treatment with IVIG without
in a previous child is not always associated with FBS is safe and effective [13].
severe FNAIT in the subsequent child [8]. There is no consensus about the mode of
Presence and time of ICH during previous delivery in women who previously gave birth
pregnancy determine the risk of FNAIT. Standard to a child with FNAIT. In some centers FBS
care is given to pregnant women where a previous is recommended as mentioned above. Vaginal
sibling had no ICH. If a previous sibling had ICH delivery is safe in standard care pregnancies
after 28 weeks of gestation or after birth, the risk is [8]. For those in the high-risk and very-high-
high. Very-high-risk pregnancies are those where risk groups who desire vaginal delivery, FBS
a previous pregnancy had ICH before 28 weeks or is recommended at 32 weeks. If platelet count
complicated with in utero death. is higher than 100,000/µL, the patient should
IgG alloantibodies can cross the placenta as continue therapy, and induction of delivery at
early as 14 weeks of gestation, and fetal platelet 37-38 weeks. If the patient does not accept FBS
membrane glycoproteins are expressed as early as at 32 weeks, FBS is delayed to 36-37 weeks. If
16 weeks of gestation. Therefore treatment should the platelet count is higher than 50,000/µL, a
be initiated early in the pregnancy, especially in vaginal delivery can be performed [26]. For those
high-risk and very-high-risk fetuses. in the very-high-risk group, elective cesarean
In the standard risk group, treatment is initiated section prior to 38 weeks is usually recommended
at 20 weeks of gestation with IVIG (2 g/kg/wk) regardless of platelet count [8, 9].
alone or IVIG (1 g/kg/wk) plus prednisolone (0.5 An estimated rate of effectiveness near to
g/kg/day). FBS is recommended at 32 weeks to 75% when IVIG combined with prednisolone
determine the fetal platelet count. If the platelet [17]. High maternal alloantibody levels before
count is less than 30,000-50,000/µL, prednisolone delivery, and multigravida are predictive of poor
is added to the IVIG regimen, or IVIG dose response to antenatal therapy. HPA-1a negative
increased to 2 g/kg/wk in IVIG plus prednisolone pregnant women carrying both HLA-DB3*01:01
regimen. Another approach is delaying FBS to 36 and HLA-DB4*01:01 shows a reduced response to
weeks without knowledge of fetal platelet counts, IVIG treatment in comparison to women bearing
in order to determine the mode of delivery. HLA-DB3*01:01 only. This may be related to the

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lower binding avidity of HPA-1a epitome of the be given to potentially prolong the survival of the
β3 integrin to HLA-DB3*01:01 [13]. incompatible platelets [7].

Neonatal management Prognosis

Serial platelet counts should be obtained for All thrombocytopenic neonates with FNAIT
the first 5-7 days after delivery to keep the platelet should be monitored until platelet counts reach
counts higher than 30,000/µL without active normal levels [20]. Platelet counts may continue
bleeding and higher than 50,000-100,000/µL with to fall for some days after delivery. But the day
active bleeding [8]. If the neonate presents with of the lowest platelet count differs from patient to
clinical bleeding or the platelet count is less than patient. Platelet counts return to normal after 1-2
30,000/µL, platelet transfusion is indicated. weeks because the half-life of platelets is 8-10 days
Maternal platelets or HPA-compatible donor [7]. The duration of thrombocytopenia in treated
platelets are used. The mother is the best donor, cases ranges between a few days and some weeks
because transfused platelets are not destroyed. [8]. In rare cases, thrombocytopenia may persist
Finding HPA-1a and HPA-5b negative donors is for up to 8-12 weeks. This persistent neonatal
impractical [7]. All platelets should be washed and thrombocytopenia may be related to the transfer
irradiated, however both procedures can reduce of maternal IgA type antiplatelet antibodies by
platelet functions. Washing and irradiation of breastfeeding [28].
platelets also take considerable time, which makes Cranial ultrasonographic examination is
maternal platelets not the best option when an indicated for every newborn with significant
emergency treatment is needed. In addition it is not thrombocytopenia to exclude ICH. In the absence
appropriate to wait for the laboratory confirmation of ICH, prognosis is favorable. Many children
of the diagnosis in suspected cases. with ICH have very low platelet counts, but low
Random donor platelet (AB0 compatible, platelet counts are not a good predictor of ICH
reduced volume, cytomegalovirus negative and [29]. There is no correlation between the severity
irradiated) transfusion is given in a dose of 10 of thrombocytopenia and ICH, and maintaining a
mL/kg where 1 mL platelet suspension usually platelet count greater than 150,000/µL during the
increases platelet count by 5,000/µL at least first week of life does not decrease the incidence
transiently [9]. This increase in platelet count of ICH [2, 7]. Temporal lobe intraparenchymal
reduces the likelihood of bleeding even when they hemorrhage is the most commonly seen location
are incompatible with the maternal antibody [7]. of ICH [30].
Current use of platelet transfusions is Neither thrombocytopenia nor deficiency
heterogeneous and primarily based on expert in blood coagulation (fibrinogen deficiency) is
opinion. Whether more liberal platelets transfusion crucial for the development of ICH, particularly
thresholds prevent hemorrhage is unclear. In in utero in FNAIT animal models, which take
addition, unnecessary platelet transfusion could be into account the contribution of other factors. The
detrimental because of pro-inflammatory factors, integrin αIIbβ3 is the most abundant glycoprotein
which are secreted by the platelets during the on platelets. The β3 subunit is also coexpressed
storage or preparation. Increased inflammatory with the αV subunit (i.e. αVβ3) on proliferating
response may be responsible for an association endothelial cells during angiogenesis. Anti-platelet
between platelet transfusions and increased β3 antibodies inhibit angiogenesis and induce ICH
neonatal mortality [6]. in the brain of murine fetuses and neonates, and
IVIG is not alternative to platelet transfusions, can be prevented with IVIG given to the mother.
since the action of IVIG is observed after 18 Murine anti-platelet β3 integrin antisera and
hours, and platelet counts don’t rise before 24-48 human HPA-1a immunoglobulin purified from
h [8]. During this time severely thrombocytopenic mothers with FNAIT children have similar effects
neonates remain at risk of bleeding. However, on cultured human endothelial cells inhibiting cell
neonates with moderately severe thrombocytopenia proliferation. This study shows that impairment of
(30,000-50,000/µL) without obvious bleeding can angiogenesis rather than thrombocytopenia likely
be treated with IVIG alone in a total dose of 2 g/ causes FNAIT-associated ICH [31].
kg are given over 2-5 days. In platelet-transfused Concentrations of vascular endothelial
patients, IVIG at 0.4-1 g/kg/day for 2-5 days can growth factor, platelet-derived growth factor and

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transforming growth factor β1, which are stored in have been licensed for use in very refractory ITP
α granules, increase in plasma during the platelet or in an inherited thrombocytopenia (e.g. Wiskott-
storage period. Whether these exogenous growth Aldrich syndrome). However both agents would
factors transfused with the platelets have an impact cross the placenta and affect the fetus. The risk
on the vascular stability of cerebral and retinal of thrombosis and induction of malignancies
vessels, which may increase the predisposition for in certain adult patients as well as the lack of
developing ICH and retinopathy of prematurity efficacy data have led to avoidance of these drugs
[2, 11]. during pregnancy [39]. The use of thrombopoietin
mimetics in newborns also seems unlikely.
Future Because serum thrombopoietin levels are not
reduced and both agents take several weeks of
NAITgam treatment to be effective, these drugs are useless
in emergencies [40].
NAITgam (anti-HPA-1a immunoglobulin pre-
pared from the hundreds of women previously Phagocytosis inhibitors
immunized by a FNAIT-affected pregnancy) given
within the first six hours to an HPA-1a negative Fcγ receptors on mononuclear phagocytes
woman who has given birth to an HPA-1a positive recognize autoantibodies, primarily IgG1 subclass,
child is on Phase I/II trials (2011 PROFNAT, a that coat platelets in affected individuals, resulting
European Union Project), and will be on market in in their phagocytosis. Fcγ receptor blockade and
2018. NAITgam is similar to Rh immunoglobulin, inhibition of platelet phagocytosis are the principal
which for almost 50 years has proven safe and mechanisms of IVIG in immune thrombocytopenia.
effective in almost eliminating a related condition, IVIG manufactured from thousands of donors is
hemolytic disease of the fetus and newborn [32]. too expensive and has several side effects. Several
pyrazole-containing derivatives that inhibit
Recombinant monoclonal antibodies phagocytosis by human monocytes have a strong
potential to become first line therapy in immune
Recombinant monoclonal antibodies di- cytopenias [41].
rected against β3 integrin and FcRn are under
development. Since the fetal FcRn is responsible Infants of mothers with immune thrombocy-
for transplacental of maternal IgG, anti-FcRn topenic purpura
monoclonal antibodies was found to be 200-fold
more efficient in comparison to the common IVIG ITP during pregnancy is not considered a serious
in an animal model [33]. Recombinant HPA-1a risk of perinatal bleeding, but may cause moderate
specific antibodies with lower affinity to FcRn are thrombocytopenia in neonate. In mothers with ITP,
also being developed. These antibodies block the the risk of thrombocytopenia is only 10%, with no
binding of maternal HPA-1a antibodies to fetal more than 1% risk of in utero ICH. The incidence
platelets and reduce the clearance of fetal platelets of ITP is estimated at 0.1-1 in 1,000 pregnancies. In
in a mouse model of FNAIT [34-37]. This study one-third of cases, ITP presents during pregnancy.
extended to human volunteers [38], and may be In the majority of patients, asymptomatic
used to reduce the severity of disease. However, thrombocytopenia is detected in tests obtained for
as HPA-1a antibodies also bind to endothelial other reasons. In more severe cases, petechiae and
cells through αVβ3, they may potentially inhibit easy bruising may be noticed [42].
endothelial cell proliferation and cause serious The risk of neonatal thrombocytopenia is
side effects [37]. greater for mothers with higher thrombocytopenia
during pregnancy. The platelet count may
Thrombopoietin mimetics fall during the first 3-5 postnatal days before
recovering spontaneously. IVIG usually corrects
Thrombopoietin is the cytokine that induces severe thrombocytopenia (< 30,000 /µL) [43].
platelet production in the bone marrow. Two ITP is considered to be caused by autoantibodies
thrombopoietin receptor agonists or synthetic against platelet antigens, although these antibodies
thrombopoietin mimetics, eltrombopag (daily cannot be detected in all women with ITP.
orally) and romiplostim (weekly subcutaneously) Therefore, hypothesis on platelet destruction with

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transported maternal antibodies cannot explain rare in infants of mother with ITP compared to
pathophysiology of all cases with fetal/neonatal FNAIT [43]. Maternal splenectomy for resistant
thrombocytopenia [43]. ITP, history of previous siblings with severe
In FNAIT, most cases (75-95%) have maternal thrombocytopenia and maternal platelet counts at
alloantibodies to fetal β3 integrin, and few cases delivery are the main indicators to predict severe
to fetal GPIbα. However, in ITP the prevalence of thrombocytopenia in the newborn infant. Maternal
anti-GPIbα antibodies is 20-40%. Autoantibodies platelet counts during pregnancy and delivery,
against the other antigens may also be determined. presence of detectable antiplatelet antibodies
However, antiplatelet antibodies are not different in maternal serum, and maternal treatment with
between gestational thrombocytopenia and IVIG and/or corticosteroids do not correlate with
ITP, and high levels of antiplatelet antibodies neonatal platelet count at birth [38-40].
may be found in gestational thrombocytopenia. In every baby born to a mother with a pregnancy-
Differential diagnosis can be made with history associated thrombocytopenia, even in the case of
and severity of thrombocytopenia. The presence of confirmed gestational thrombocytopenia, platelet
thrombocytopenia before pregnancy makes the ITP counts in umbilical cord blood should be closely
diagnosis more likely. In the absence of data on the monitored, because platelet counts are not always
platelet count before pregnancy, thrombocytopenia normal in babies born to mothers with incidental
early in the first trimester and continuous decline gestational thrombocytopenia. Since it has been
to severe thrombocytopenia during pregnancy is hypothesized that gestational thrombocytopenia
more consistent with ITP. Mild thrombocytopenia may be a mild form of ITP, follow-up of mothers
developing at the end of the second or in the third long after delivery would be useful [47].
trimester in a healthy pregnant woman will lead to In these infants, platelet counts decline to the
the diagnosis of gestational thrombocytopenia [42]. lowest level at postnatal day 3-5, after then they
The management of ITP during the first and rise spontaneously. Optimal treatment (platelet
second trimesters is the same as that of non-pregnant transfusions, IVIG and/or prednisolone) is not
individuals. Pregnant women with a platelet count evident. The effect of platelet transfusions is often
lower than 30,000/µL, bleeding or with a planned short with frequent recurrence to low platelet
procedure should receive either prednisolone (10 count, requiring additional transfusions and/or
mg daily) and/or IVIG (1 g/kg). Anti-D, which IVIG treatment. When a platelet transfusion fails
is used in refractory ITP, is contraindicated in to result in a stable increase of platelet counts,
pregnancy due to acute hemolysis and anemia in further platelet transfusions are not advised
fetus/neonate [44]. without IVIG [43].
It is unknown whether steroid therapy and IVIG
are equally efficient in titrating anti-GPIbα versus Declaration of interest
anti-αIIbβ3-mediated thrombocytopenia, since
anti-GPIbα may cause platelet destruction through The Author declares that there is no conflict of interest.
an Fc-independent pathway, which is resistant to
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