1. Dr Varsha Atul Shah

2. Objectives
 Definitions
 Epidemiology
 Etiological classifications
 History and physical exam findings
 Laboratory investigations
 Neonatal alloimmune thrombocytopenia (NAIT)
 Neonatal autoimmune thrombocytopenia
 General treatment issues

3. Definitions
 Normal platelet count 150,000 - 450,000/mcL
MILD
100,000-150,
000
MODERATE
50,000-100,0
00
SEVERE
<50,000

4. Types of classification
Etiological classification based on clinical features
PATHOLOGICA CLINICAL
L MECHANISMS FEATURES
TIMING OF
THROMBOCYT
OPEIA

5. Epidemiology
 General neonatal population:
Incidence of thrombocytopenia 1%
 Severe thrombocytopenia (< 50,000 ) 8% of preterm & 6
0.12% ( Hamilton data) % all neonates
0.24% ( Finnish data) admitted to ICU
have severe
 NICU population: thrombocytopenia
Incidence of thrombocytopenia 22 –35 %
< 100,000 > 50% of affected newborns
<50, 000 20% of affected newborns
 Premature newborns
Incidence of severe thrombocytopenia 8%

6. Etiology classification according to
pathological mechanisms
Impaired production Increased consumption
 Immune mediated (15-20%):
autoimmune, alloimmune, drug
 Placental insufficiency(eg.IUGR,
induced
Maternal PIH)
 Peripheral consumption:
 Infections: bacterial, viral,
hypersplenism ( eg. congenital
fungal
infections); Kassabach- Merritt
 Infiltrative disorders (eg.
syndrome; DIC; infection;
congenital leukemia)
NEC; drug toxicity, thrombus
 Congenital thrombocytopenia  Procedure related : eg.
eg. TAR, hereditary
postexchange transfusion
macrothrombocytopenias)  Miscellaneous: neonatal cold
 Drug toxicity injury

7. Combined mechanisms
 Some neonates develop thrombocytopenia
secondary to combined mechanisms: i.e. a
premature infant born to a mother with PIH who
develops sepsis or an IUGR infant who develops
NEC
 Also some etiologies like sepsis can cause
thrombocytopenia due to impaired production in
the marrow as well as increased destruction from
DIC, endothelial damage and platelet aggregation
due to bacterial products adhering to platelet
membranes

8. Impaired procuction
 Accounts for 75 % of cases
 Have impaired megakaryoctyopoiesis and platelet
production
 Megakaryocytes and their precursor and progenitor
cells are considerably reduced at birth
 Levels of the megakaryocytopoietic
cytokine thrombopoietin (Tpo) are therefore
elevated.

9. Consumption and sequestration
 25–35% of episodes of neonatal thrombocytopenia
 15–20% of neonatal thrombocytopenias present at
birth result from transplacental passage of maternal
platelet alloantibodies and autoantibodies
 disseminated intravascular coagulation is responsible
for a further 10–15% of cases, nearly always in babies
who are very ill, particularly in association with
perinatal asphyxia and infection

10. Etiological classification based
on clinical features
Sick neonates,
Normal appearing preterm and those
neonates with other medical
conditions
Neonates with
physical
abnormalities and
dimorphic features

11. Healthy neonates
 Maternal autoimmune thrombocytopenia
( eg. ITP or SLE), maternal drug
 Neonatal alloimmune thrombocytopenia
(NAIT)
 Occult infection
 Amegakaryocytic thrombocytopenia
 Hereditary macrothrombocytopenias
 Wiskott- Aldrich syndrome

12. Neonates preterm/assoc medical
conditions
 Hypoxia +/- acidosis after  RDS
birth trauma  PPHN
 Chronic hypoxia from  NEC
placental insufficiency  Thrombosis ( indwelling
 Cold injury vascular catheters,ECMO)
 Maternal pre-eclampsia  Exchange transfusions
 Bacterial infection/sepsis  Bone marrow disorders
 Congenital viral infection (leukeumia,
(CMV, rubella) neuroblastoma, other
 DIC solid
tumours)

13. Neonates who have physical
abnormalities or dysmorphic features
 Thrombocytopenia with absent radius
(TAR) syndrome
 Fanconi anemia( can present with mild
thrombocytopenia alone)
 Chromosomal abnormalities due to trisomy
21, 13, 18 or Turner’s syndrome
 Kasabach- Merritt syndrome

14. Thrombocytopenia with absent
radius (TAR) syndrome

15. FANCONI ANAEMIA

16. Fetal
Early Neonatal
<72 hrs
Late Neonatal
>72 hrs

17. Fetal onset
 Alloimmune
 Autoimmune (maternal ITP, SLE)
 Congenital infections (CMV, toxoplasma,
rubella, HIV)
 Aneuploidy ( trisomy 21, 13, 18), or triploidy
 Severe Rh hemolytic disease
 Congenital/ inherited ( eg Wiskott- Aldrich
syndrome)

18. Early onset Late onset
-usually secondary to
-usually secondary to
placental insufficiency
sepsis or necrotising
and caused by
enterocolitis
reduced platelet
production;
-usually more severe
and prolonged.
-fortunately most
episodes are mild or
-Platelet
moderate
transfusion remains
- resolve
the only treatment.
spontaneously.

19. Early onset neonatal
 Placental insufficiency  Congenital infection
eg PIH, IUGR, diabetes)  Thrombosis ( eg. aortic,
 Perinatal asphyxia renal vein)
 Perinatal infection  Bone marrow replacement
( eg. E. coli, GBS) (eg. Congenital leukemia)
 DIC  Kasabach- Merritt
 Allommune syndrome
 Autoimmune(eg ITP, SLE)  Metabolic disease ( eg.
 Congenital / inherited Propionic or
( eg. methylmalonic acidemia)
TAR, congenital
amegakaryocytic
thrombocytopenia)

20. Late onset neonatal
 Late onset sepsis
 NEC
 Congenital infection
 Autoimmune
 Kasabach- Merritt syndrome
 Metabolic disease
 Congenital/ inherited

21. Congenital and inherited thrombocytopenias
that may present in the fetus or neonate
With thrombocytopathy Without thrombocytopathy
 Bernard-Soulier syndrome  Fanconi’s anaemia
 Wiskott-Aldrich syndrome  TAR syndrome
 X-linked thrombocytopenia  Amegakaryocytic
 Chediak-Higashi syndrome thrombocytopenia
 Quebec platelet disorder  Giant platelet syndromes
 Some giant platelet (e.g.
syndromes (e.g. Montreal May-Hegglin anomaly,
syndrome) Sebastian syndrome,
Fechtner syndrome)
 Autosomal dominant
thrombocytopenia

22. Kasabach -
Merritt
syndrome

23. Approach to neonate with
thrombocytopenia: Maternal history
 History or ITP,SLE or splenectomy
 Previous infant with thrombocytopenia or family
history of neonate with thrombocytopenia
 Pre or perinatal infections
 Drug use ( eg.quinine, thiazides, hydralazine)
 PIH
 Abnormal placenta ( infarction, congenital infection,
chorioamnionitis)
 Maternal platelet count: decreased suggests
autoimmune; normal may be autoimmune or alloimmune
in well appearing neonate
 Prior pregnancy : ? Same partner

24. Approach to neonate with
thrombocytopenia: neonatal history
 History of perinatal asphyxia
 Meconium aspiration or RDS
 Infection
 NEC
 DIC
 IUGR
 Thrombus or indwelling catheters
 Intracranial hemorrhage or other severe bleeding

25. Approach to neonate with thrombocytopenia: neonatal
physical exam
 Head circumference and weight percentile
 Signs of thrombocytopenia: bruising , oozing from
puncture sites, petechiae
 Sick vs. well : signs of sepsis, RDS, asphyxia
 Hepatosplenomegaly, blueberry muffin rash
( congenital infections)
 Dysmorphic features: trisomy 13, 18, 21 or certain
syndromes: eg TAR , Fanconi
 Large hemangioma

26. Approach to neonate with thrombocytopenia:
laboratory investigations
 Confirm that thrombocytopenia is not factitious
 Abnormalities in WBCs ( sepsis, congenital leukemia),
hemoglobin ( bleeding, aplasia)
 Evidence of co-existing coagulopathy ( INR, PTT, d-dimers,
FDP, fibrinogen)
 LFTs
 MPV: large platelets often indicate increased production in
response to increased consumption ( though can rarely see
giant
platelets related to congenital platelet disorders)
 Other investigations tailored to the cause: ie platelet antibodies
and antigen typing in NAIT, septic workup, viral studies looking
for congenital viral infections, chromosomal studies
 Bone marrow in persistent or unusual cases

27. MICROSCOPIC SLIDES

28. Normal
Platelets

29. Thrombocytopenia

30. Large platelets

31. Wiskott Aldrich syndrome: small
platelets

32. Caused by maternal
platelet specific
antibodies against
paternally
inherited platelet
antigens

33. Neonatal alloimmune thrombocytopenia
(NAIT)
 Incidence 1/1000-1/3000 pregnancies
 Anti – HPA-1a accounts for 80-90% of cases in
Caucasians; 10 - 15% of cases are associated with anti -
HPA- 5b
 In the Caucasian population 2% of women are HPA-1a
negative and about 10% of these women develop anti-
HPA-1a ( influenced by certain HLA classes)
 In Asians NAIT occurs secondary to anti-HPA-4

34. NAIT: morbidity
 10 – 20% of affected newborns develop an intracranial
hemorrhage (ICH) with about a 7% mortality
 20% of survivors of ICH develop long term
neurodevelopmental sequelae
 ¼- ½ of ICH occur in utero
 severe NAIT occurs during the first pregnancy in 40-50%
of cases
 The recurrence rate of NAIT is greater than 75% for
subsequent pregnancies and generally follows a more
severe course: therefore need referral to high risk
obstetrics
for subsequent pregnancies

35. NAIT: diagnostic workup
 Presumptive diagnosis in otherwise well infant with severe
thrombocytopenia +/- unexplained ICH and no history of
maternal ITP, SLE or drugs that can cause
thrombocytopenia
 In suspected cases need to send maternal blood for HPA
antibody and genotyping and paternal blood for
genotyping, can also send sample on subsequent fetuses
for genotyping when the father is heterozygous for HPA
1a/1b ( can be done by amnio or CVS)
At present there is no routine prenatal screening

36. Affected neonate
Confirm
thrombocytopenia on a
repeat blood sample
If Plt count
<100000
Neonatal studies Maternal studies
Suspect
alloimmune Careful
Careful history & exam antenatal
thrombocytopenia
Test for DIC history for PIH
if cause uncertain
Consider Kassabach Maternal FBC
merritt syndrome, TAR, Urgent studies
TORCH Maternal & paternal
Perform head USG to r/ blood samples for
o ICH rapid HPA1a
alloantibodies

37. Plt count <30000 Plt count >30000 with
and/or clinically no evidence of
significant bleeding bleeding
Transfuse platelet
10-20ml/kg Observe, follow the
Obtain post platlet count daily
transfusion plt count Await results of initial
serological studies and
do not transfuse
>30000 <30000
Follow plt daily Consider 2nd dose random donor plt,
Transfuse irradiated, single dose of IVIG(1gm/kg/d)
washed or plasma If Plt <10000 and/or clinical bleeding,
depleted maternal transfuse irradiated, washed or plasma
platelets or antigen neg depleted maternal platelets or
platelets if clinically compatible antigen negative donor
indicated platlets asap.

38. NAIT: antenatal treatment
 Subsequent pregnancies should be managed
by maternal-fetal medicine
 Risk stratification can be based on presence
and timing ( prenatal vs postnatal) ICH in a
previous infant +/- platelet count obtained
from fetal blood sampling of index
pregnancy(increased risk if platelets <20,000)

39. NAIT : antenatal treatment
 Treatments include IVIG to mum, po steroids for
mum and fetal platelet transfusions
 Fetal blood sampling (FBS) entails risk with as
much as an 8% fetal loss/pregnancy in cases of
NAIT: in utero transfusion of HPA-1a and 5b
negative platelets should be given at time of
sampling if the fetal platelet count is <50,000

40. NAIT: antenatal treatment: risk
stratification approach
 Standard risk : no ICH in previously affected child: IVIG
1g/kg/wk OR prednisone 0.5 mg/kg/ day starting at 20 wks
gestation
 High risk : peripartum ICH in previously affected child:
IVIG 1g/kg/wk AND prednisone 1 mg/kg/d starting at 20
wks; response monitored by FBS
 Very high risk : antenatal ICH in previously affected child:
IVIG 2g/kg/wk starting at 12 wks with FBS at 20 wks and
the addition of prednisone 1 mg/kg/d for poor responders
 If persistent poor response can give weekly in utero
platelet transfusion
 C/section if fetal platelet count is <50,000

41. NAIT : neonatal management
 Need to monitor platelets closely particularly in the first 72- 96
hrs of life since the risk of ICH is highest during that time
 Need baseline cranial US to detect ICH
 Should transfuse with platelets for all infants with platelets
< 30,000 and for premature, sick or infants with ICH at < 50,000
 Traditionally initial treatment was washed maternal platelets or
HPA –1a and 5b negative platelets
 More recent studies ( Kiefel et al, 2006, Bussel et al, 2005)
show that random donor platelets can be effective( may adsorb
circulating alloantibodies): this depends on availability of
maternal platelets or Ag negative platelets
 IVIG can be used as additional therapy in cases of suboptimal
response

42. NAIT : natural history
 Thrombocytopenia usually resolves by 2 weeks
although can last for up to 6 weeks

43. Neonatal autoimmune
thrombocytopenia
 Due to antibody directed against maternal and
fetal platelets ( eg. Maternal ITP or lupus)
 Antenatally may be difficult to distinguish
between this and gestational thrombocytopenia
which has an extremely low risk of neonatal
thrombocytopenia
 Mothers may have a normal platelet count if they
have had a splenectomy or if there is enough
compensatory thrombocytosis

44. Infants of mothers with ITP : risk for
thrombocytopenia
 10% risk overall of developing severe
thrombocytopenia ( platelets <50,000) in infants
of mums with ITP
 May be increased if the mother has had a
splenectomy, if her platelet count has been
< 50,000 at some point during her pregnancy or if
there has been a previously affected sibling
 Risk of ICH is 1% or less
 Subsequent pregnancies do not have a risk of a
more severely affected infant

45. Neonatal Autoimmune thrombocytopenia: antenatal
management
 IVIG can be used for severely affected women
 Prednisone has also been used early in pregnancy in
selected patients
 C/section should only be performed for obstetrical
indications

46. Neonatal autoimmune
thrombocytopenia: neonatal management
 Cord platelets should be obtained and serial platelet
counts should be monitored every 8- 24 hrs for the first
few days of life since the nadir typically occurs at 2 – 5
days of age
 Should perform cranial US if significant thrombocytopenia
( platelets< 100,000)
 Treat with IVIG 1g/kg/d X 2 days if platelets < 30,000
 May give IVIG at higher threshold +/- platelets if
significant bleeding
 Antibodies may persist for a while and may need a second
course of IVIG even a 2-3 weeks later

47. Treatment of other causes of
neonatal thrombocytopenia
 Treat underlying cause if possible: ie sepsis,RDS
 Platelet transfusions as indicated

48. Transfusion thresholds
(Murray, NA, 2002)
<30,000 Consider transfusion for all
30,000-49,000 Do not transfuse if clinically stable
Consider transfusion if:
< 1000 g and < 1 wk of age
Clinically unstable
Previous major bleeding (GR 3-4 IVH or
pulmonary hemorrhage)
Current minor bleeding
Concurrent coagulopathy
Requires surgery or exchange transfusion
50,000-99,000 Do not transfuse
>99,000
Transfuse if bleeding

49. Summary
 Neonatal thrombocytopenia is a relatively common
problem especially in the NICU setting
 Etiologies are diverse and differ in sick and well infants
clinical features and timing of presentation can help sort out the
causes
 Immune mediated thrombocytopenia requires specific
investigations and management strategies
 NAIT conveys a greater risk for significant bleeding
( including antenatal ICH) compared to autoimmune
thrombocytopenia
 Random donor platelets have been shown to be effective in
many cases of NAIT contrary to previously held beliefs