Ahmed elmelhat neonatal thrombocytopenia

Neonatal ThrombocytopeniaNeonatal Thrombocytopenia
Dr. Ahmed El MelhatDr. Ahmed El Melhat
Registrar NICURegistrar NICU
Under Supervision of
Dr. Mohamed El Sunni
Consultant NICU

Case ScenarioCase Scenario
• You are called to the L & D ward toYou are called to the L & D ward to
evaluate a 6-hour-old baby was foundevaluate a 6-hour-old baby was found
to have diffuse petechiae by the nurseto have diffuse petechiae by the nurse
while changing the diaper. Thiswhile changing the diaper. This
apparently healthy infant girl was bornapparently healthy infant girl was born
to a healthy 38 years-old motherto a healthy 38 years-old mother
(gravida 3, para 3) who had a(gravida 3, para 3) who had a
spontaneous vaginal delivery withoutspontaneous vaginal delivery without
complications.complications.

At birth, the girl on physical examinationAt birth, the girl on physical examination
was otherwise normal and in nowas otherwise normal and in no
distress. A platelet count performed atdistress. A platelet count performed at
the time of the petechial rash wasthe time of the petechial rash was
10,000/mL. The infant was transferred10,000/mL. The infant was transferred
to the neonatal tertiary care facility.to the neonatal tertiary care facility.

Objectives
1. To identify formation & functions of the platelets.
2. Define thrombocytopenia.
3.3. Discuss the incidence of neonatalDiscuss the incidence of neonatal
thrombocytopenia.thrombocytopenia.
4.4. Develop DD for neonate who haveDevelop DD for neonate who have
thrombocytopenia based on time of presentation,thrombocytopenia based on time of presentation,
risk factors , signs and symptoms .risk factors , signs and symptoms .
5. Develop guidelines in the management of
thrombocytopenia.

Platelet KineticsPlatelet Kinetics
• Normal circulating platelet countNormal circulating platelet count
• 150 to 450 x 10150 to 450 x 1099
/l in Northern Europeans/l in Northern Europeans
• 90 to 300 x 1090 to 300 x 1099
/l in people of Mediterranean/l in people of Mediterranean
descentdescent
• 1/3 of platelets are sequestered in the spleen1/3 of platelets are sequestered in the spleen
• Half life of a platelet is 9 to 10 daysHalf life of a platelet is 9 to 10 days
• Platelet production is the function of thePlatelet production is the function of the
multinucleated megakaryocytemultinucleated megakaryocyte
• 15 to 45 x 1015 to 45 x 1099
/l platelets are produced daily to/l platelets are produced daily to
maintain steady statemaintain steady state

Thrombopoietin (TPO)Thrombopoietin (TPO)
• TPO is the primary regulatory protein in theTPO is the primary regulatory protein in the
production of plateletsproduction of platelets
• TPO gene is on chromosome 3TPO gene is on chromosome 3
• TPO is expressed in the liver,TPO is expressed in the liver, kidneys, andkidneys, and
smooth muscle cellssmooth muscle cells
• Has a plasma half life of 30 hoursHas a plasma half life of 30 hours
• The receptor for TPO is c-MPL which isThe receptor for TPO is c-MPL which is
present on the megakaryocytes and plateletspresent on the megakaryocytes and platelets
• TPO rises with platelet fall and declines asTPO rises with platelet fall and declines as
the megakaryocyte and platelet massthe megakaryocyte and platelet mass
increaseincrease

Definition ofDefinition of
ThrombocytopeniaThrombocytopenia
• The mean fetal platelet count reaches 150 xThe mean fetal platelet count reaches 150 x
101099
/l by the end of the first trimester of/l by the end of the first trimester of
pregnancypregnancy1313, and rises to 175–250 x 10, and rises to 175–250 x 1099
/l by/l by
end of the second trimesterend of the second trimester7,8,107,8,10 .Term.Term
neonates born to mothers with normalneonates born to mothers with normal
platelet counts have platelets above 150 xplatelet counts have platelets above 150 x
101099
/l at birth/l at birth1–31–3 Therefore thrombocytopenia inTherefore thrombocytopenia in
a neonate of any viable gestational age cana neonate of any viable gestational age can
be defined as a platelet count of <150 x 10be defined as a platelet count of <150 x 1099
/l/l

Incidence ofIncidence of
At birth:At birth:
• 1 – 5 % of healthy term infants1 – 5 % of healthy term infants 99
• Severe TP (count < 50) 0.1 – 0.5 %Severe TP (count < 50) 0.1 – 0.5 % 99
Neonatal intensive care unit:Neonatal intensive care unit:
• 22 – 35 % of all NICU admission22 – 35 % of all NICU admission 1414
• 70 – 80 % of VLBW70 – 80 % of VLBW 1515
• 2 – 10 % (8% of preterm & 6% of all neonates)2 – 10 % (8% of preterm & 6% of all neonates)
with severe TP (count< 50)with severe TP (count< 50) 1414

• Platelet countsPlatelet counts 100–150×109/L range100–150×109/L range
are moreare more common among healthycommon among healthy
neonates than adults →neonates than adults →healthyhealthy
appearing neonate : careful follow-upappearing neonate : careful follow-up
• Worsening of thrombocytopenia, orWorsening of thrombocytopenia, or
changes in clinical condition needchanges in clinical condition need
further evaluation.further evaluation.1212
Incidence ofIncidence of

Bleeding in neonates withBleeding in neonates with
severe Thrombocytopeniasevere Thrombocytopenia
5 % Intracranial ( usually IVH )5 % Intracranial ( usually IVH )
1 – 5 % Gastrointestinal1 – 5 % Gastrointestinal
1 – 5 % Pulmonary1 – 5 % Pulmonary
1 – 2 % Hematuria1 – 2 % Hematuria 1515

Stratifying levels of thrombocytopeniaStratifying levels of thrombocytopenia
• The primary reason for evaluatingThe primary reason for evaluating
thrombocytopenia is to assess the risk of bleedingthrombocytopenia is to assess the risk of bleeding
and assess the presence of underlying disordersand assess the presence of underlying disorders
(TTP, HIT etc.)(TTP, HIT etc.)
• < 20 x 10< 20 x 1099
/l increased risk of bleeding/l increased risk of bleeding
• 20 to 50 x 1020 to 50 x 1099
/l rarely have increase risk of/l rarely have increase risk of
spontaneous bleeding but increase risk ofspontaneous bleeding but increase risk of
bleeding from proceduresbleeding from procedures
• 50 to 100 x 1050 to 100 x 1099
/l no increased risk of/l no increased risk of
spontaneous bleeding and can undergo mostspontaneous bleeding and can undergo most
proceduresprocedures

Relation of bleeding risk and plateletRelation of bleeding risk and platelet
countcount
• Bleeding time increases in a linear fashionBleeding time increases in a linear fashion
below a platelet count of 100 Kbelow a platelet count of 100 K
• Slichter et al tagged RBC and found fecalSlichter et al tagged RBC and found fecal
blood lossblood loss
• 10 x 1010 x 1099
/l 5 cc/day/l 5 cc/day
• 5 to 10 x 105 to 10 x 1099
• < 5 x 10< 5 x 1099

Mechanism of TP in neonatesMechanism of TP in neonates
(1) Increased platelet consumption(1) Increased platelet consumption
(sepsis or NEC)(sepsis or NEC)
(2) Decreased platelet production (mother(2) Decreased platelet production (mother
with severe placental insufficiency)with severe placental insufficiency)
(3) Hypersplenism, or a combination of(3) Hypersplenism, or a combination of
these.these.

The predisposition of sick neonatesThe predisposition of sick neonates
to develop thrombocytopeniato develop thrombocytopenia
(1) Megakaryocytes in neonates are(1) Megakaryocytes in neonates are
smaller and less mature than thosesmaller and less mature than those
in adults,in adults, produce less plateletsproduce less platelets
(2) Preterm neonates : relatively low(2) Preterm neonates : relatively low
levels of thrombopoietin duringlevels of thrombopoietin during
thrombocytopeniathrombocytopenia

Classification : according toClassification : according to
platelet countplatelet count
mild 100 - 150
moderate 50 - 99
severe < 50

Common Causes of TPCommon Causes of TP
Fetal
( at birth )
Alloimmune
Congenital infection
Aneuploidy
Early onset neonatal
(< 72 hours )
Chronic fetal hypoxia
Perinatal asphyxia
Perinatal infection
Late onset neonatal
( > 72 hours )
Late onset sepsis
NEC

Thrombocytopenia at birthThrombocytopenia at birth
1. Alloimmne1. Alloimmne
2. Congenital infection2. Congenital infection
CMV, HIV, rubella, toxoplasmaCMV, HIV, rubella, toxoplasma
3. Aneuploidy3. Aneuploidy
Trisomies 13, 18, 21Trisomies 13, 18, 21
4. Autoimmune4. Autoimmune
5. ITP, SLE5. ITP, SLE
6. Severe Rheusus hemolytic disease6. Severe Rheusus hemolytic disease
7. Inherited7. Inherited

General considerationsGeneral considerations
1. Platelet count < 50 at birth1. Platelet count < 50 at birth
Think I → Infection & ImmuneThink I → Infection & Immune
Immune causes account for 15 – 20 % of NTImmune causes account for 15 – 20 % of NT
presenting at birthpresenting at birth
2. Any neonate with early- or late-onset2. Any neonate with early- or late-onset
thrombocytopenia,thrombocytopenia, infection has to beinfection has to be
considered at the top of the differentialconsidered at the top of the differential
diagnosis, because delayed diagnosis candiagnosis, because delayed diagnosis can
be life-threatening.be life-threatening.

•• MMild to moderateild to moderate thrombocytopenia at orthrombocytopenia at or
shortly after birth in a well-appearingshortly after birth in a well-appearing
preterm infant without risk factors forpreterm infant without risk factors for
infection and with a history of maternalinfection and with a history of maternal
preeclampsia or IUGR, is most likelypreeclampsia or IUGR, is most likely
benign.benign.
•• IfIf clinically stableclinically stable and the platelet countand the platelet count
normalizes within ten days, no furthernormalizes within ten days, no further
evaluation is necessary.evaluation is necessary.
An approach for diagnosis ofAn approach for diagnosis of
early onset TPearly onset TP

•• Platelet countsPlatelet counts <50×109/L<50×109/L oror
thrombocytopenia in athrombocytopenia in a clinically illclinically ill neonate,neonate,
are unlikely related to placental insufficiency,are unlikely related to placental insufficiency,
•• Other diagnoses such asOther diagnoses such as sepsis andsepsis and
neonatal alloimmune thrombocytopenianeonatal alloimmune thrombocytopenia
(NAIT) should be considered.(NAIT) should be considered.

•• In early-onset thrombocytopenia onIn early-onset thrombocytopenia on
whom sepsis and NAIT has beenwhom sepsis and NAIT has been
excluded a careful family history andexcluded a careful family history and
physical examphysical exam
•• (1) Maternal platelet count(1) Maternal platelet count
•• (2) Previous(2) Previous siblings or other familysiblings or other family
membersmembers with thrombocytopeniawith thrombocytopenia

•• (3)(3) Radial abnormalitiesRadial abnormalities
(thrombocytopenia absent(thrombocytopenia absent radiiradii
syndrome or Fanconi anemia)syndrome or Fanconi anemia)
•• (4) Inability to rotate the forearm(4) Inability to rotate the forearm
(congenital amegakaryocytic(congenital amegakaryocytic
thrombocytopenia with proximalthrombocytopenia with proximal radio-radio-
ulnar synostosis)ulnar synostosis)

•• (5) Features or congenital anomalies(5) Features or congenital anomalies
suggestive ofsuggestive of genetic disorders such asgenetic disorders such as
trisomies 21, 18, 13,trisomies 21, 18, 13, Turner's syndromeTurner's syndrome
•• (6) Presence of(6) Presence of hepato or splenomegalyhepato or splenomegaly
or ofor of abdominal massesabdominal masses

•• In theIn the absenceabsence of any obviousof any obvious
diagnostic clues in the history anddiagnostic clues in the history and
physical exam,physical exam,
the most common cause ofthe most common cause of isolatedisolated
severesevere thrombocytopenia in anthrombocytopenia in an well-well-
appearingappearing infantinfant isis alloimmunealloimmune

•• If theIf the alloimmune work-up is negative,alloimmune work-up is negative,
then:then:
(1)testing for(1)testing for viral infectionsviral infections
(2)and(2)and chromosome analysischromosome analysis

•• Rarer diagnoses, such as inborn errorsRarer diagnoses, such as inborn errors
of metabolism, or renal vein thrombosisof metabolism, or renal vein thrombosis
or Kasabach–Merritt syndrome shouldor Kasabach–Merritt syndrome should
be consideredbe considered
•• If the diagnosis is still unclear and theIf the diagnosis is still unclear and the
thrombocytopenia persists,thrombocytopenia persists, consultconsult
pediatric hematologistpediatric hematologist

Neonatal Alloimmune TPNeonatal Alloimmune TP
(NAIT)(NAIT)
• Transplacental passage of maternalTransplacental passage of maternal
alloimmune antibodies directed againstalloimmune antibodies directed against
fetal platelet antigens inherited from thefetal platelet antigens inherited from the
father , but absent on maternal plateletsfather , but absent on maternal platelets
• Sensitization begins early in 2Sensitization begins early in 2ndnd
trimestertrimester
• Fetal Ab-coated platelets are destroyedFetal Ab-coated platelets are destroyed
by fetal reticuloendothelial systemby fetal reticuloendothelial system
• 50 % of cases occur in 150 % of cases occur in 1stst
pregnancypregnancy

NAIT EpidemiologyNAIT Epidemiology
Fetomaternal incompatibility for HPA 1-a accounts for ~75 %Fetomaternal incompatibility for HPA 1-a accounts for ~75 %
of Caucasian causesof Caucasian causes
Other causes: HPA – 5b ( may bleed at higher plateletOther causes: HPA – 5b ( may bleed at higher platelet
account) , HPA – 15b, HPA – 3a ( more severe ), HPA –account) , HPA – 15b, HPA – 3a ( more severe ), HPA –
4a ( most common cause in Asians)4a ( most common cause in Asians)
However , HPA 1-a occurs in 1: 350 pregnancies but NAITHowever , HPA 1-a occurs in 1: 350 pregnancies but NAIT
occurs in only 1 : 1000 – 1500 of pregnancies.occurs in only 1 : 1000 – 1500 of pregnancies.
Likely underestimate due to wide range of severity dependsLikely underestimate due to wide range of severity depends
on the specific HPA – 1b that Mom hason the specific HPA – 1b that Mom has

NAIT – Natural HistoryNAIT – Natural History
Healthy term neonate with petechae / purpuraHealthy term neonate with petechae / purpura
within 24 – 48 hours of lifewithin 24 – 48 hours of life
Mom with normal platelet countMom with normal platelet count
Platelet count trend:Platelet count trend:
Thrombocytopenic at birthThrombocytopenic at birth
Thrombocytopenia often worsens over the firstThrombocytopenia often worsens over the first
few days ( careful monitoring essential )few days ( careful monitoring essential )
Most cases resolve in one week , butMost cases resolve in one week , but
thrombocytopenia may persist up to 8 – 12thrombocytopenia may persist up to 8 – 12
weeksweeks

NAIT - MorbidityNAIT - Morbidity
• 80 % cutaneous bleeding80 % cutaneous bleeding
• 20 % GI bleeding20 % GI bleeding
• 10 – 20 % of untreated pregnancies10 – 20 % of untreated pregnancies
result in intracranial hemorrhageresult in intracranial hemorrhage
1.1.can occur at any time from 20 weekscan occur at any time from 20 weeks
gestation until a few days after birthgestation until a few days after birth
2.2.cause of most morbidity / mortalitycause of most morbidity / mortality
very high risk of severevery high risk of severe
neurodevelopmental problems includingneurodevelopmental problems including
cerebral palsycerebral palsy

Diagnosis of NAITDiagnosis of NAIT
Ideally, HPA type Mom, Dad & babyIdeally, HPA type Mom, Dad & baby
Maternal platelet antibody screenMaternal platelet antibody screen
Important to perform but won’t help with initialImportant to perform but won’t help with initial
management decisionsmanagement decisions

NAIT - ManagementNAIT - Management
1.Obtain head U/S if platelet < 501.Obtain head U/S if platelet < 50
2.Goal for 1 week of life – keep platelets 30-50 if2.Goal for 1 week of life – keep platelets 30-50 if
asymptomatic, >100 if bleedingasymptomatic, >100 if bleeding
Therapeutic options:Therapeutic options:
a)a)HPA-1a / HPA- 5b negative plateletsHPA-1a / HPA- 5b negative platelets
b)b)Random donor platelets (quick response)Random donor platelets (quick response)
c)c)Maternal washed platelets (emergency only)Maternal washed platelets (emergency only)
d)d)IVIG 1 gm /kg x 2 days (12-36 hoursIVIG 1 gm /kg x 2 days (12-36 hours
response)response)
+/- 1 mg methylprednisolone q 8 hours during+/- 1 mg methylprednisolone q 8 hours during
IVIGIVIG

Antenatal ManagementAntenatal Management
 The 2The 2ndnd
affected fetus is more severelyaffected fetus is more severely
affected than the first childaffected than the first child
 Management moving towards non invasiveManagement moving towards non invasive
rate of fetal loss and emergency pretermrate of fetal loss and emergency preterm
delivery with repeated FBS & IUT was similardelivery with repeated FBS & IUT was similar
to the rate of ICH in untreated pregnanciesto the rate of ICH in untreated pregnancies
 Maternal IVIG 1g/kg weekly for low risk casesMaternal IVIG 1g/kg weekly for low risk cases
 For high risk cases (previous child with ICH)For high risk cases (previous child with ICH)
regular UVC sampling & transfusion of HPAregular UVC sampling & transfusion of HPA
compatible plateletscompatible platelets

Differences between Rh disease & NAITDifferences between Rh disease & NAIT
Rh NAIT
Incidence
First child affected
Routine screening in place
Testing readily available
Prophylaxis available
Severe clinical phenotype
Management of next
pregnancy
1/100 (25% severe)
No
Yes
Yes (any blood bank)
Yes
Hydrops, kernicterus
In utero RBCs Tx
1/1000
Yes
No
No (send out)
No
ICH
Maternal IVIG

Neonatal AutoimmuneNeonatal Autoimmune
thrombocytopenia (NITP)thrombocytopenia (NITP)
 Transplacental passage of maternalTransplacental passage of maternal
platelet auto antibodies inplatelet auto antibodies in mothersmothers withwith
ITP or SLEITP or SLE
 Only 10 – 15 % of babies will haveOnly 10 – 15 % of babies will have
 In affected cases :In affected cases :
typically mild thrombocytopenias in SLEtypically mild thrombocytopenias in SLE
infantsinfants
½ of ITP infants will have platelets < 50½ of ITP infants will have platelets < 50

NITP : Natural HistoryNITP : Natural History
Counts of nadir by DOL ≠2-5, rise by ≠ 7Counts of nadir by DOL ≠2-5, rise by ≠ 7
Very low fetal morbidityVery low fetal morbidity
severe bleeding in < 1%severe bleeding in < 1%
some patient series report 0 % ICHsome patient series report 0 % ICH

ManagementManagement
 All neonates of mothers with ITP &/or SLEAll neonates of mothers with ITP &/or SLE
should have CBC at birthshould have CBC at birth
 If normal no action necessaryIf normal no action necessary
 If thrombocytopenic , daily CBC for 3 daysIf thrombocytopenic , daily CBC for 3 days
a.a. if platelets < 50 obtain head U/Sif platelets < 50 obtain head U/S
b.b. if platelets < 30 treat with IVIGif platelets < 30 treat with IVIG
c.c. in a small number of cases maternalin a small number of cases maternal
antibodies persist more than 12 weeks, mayantibodies persist more than 12 weeks, may
need 2need 2ndnd
course of IVIGcourse of IVIG

Thrombocytopenia inThrombocytopenia in
AneuploidyAneuploidy
Trisomy 18 86%Trisomy 18 86%
Triploidy 75%Triploidy 75%
Turner 31%Turner 31%
Trisomy 13 31%Trisomy 13 31%
Trisomy 21 6% ( but mild TP)Trisomy 21 6% ( but mild TP)
mechanism likely decreased plateletmechanism likely decreased platelet
production, similar pathogenesis ofproduction, similar pathogenesis of
chronic fetal hypoxiachronic fetal hypoxia

Thrombocytoenia in 1Thrombocytoenia in 1stst
7272
hours of lifehours of life
Chronic fetal hypoxiaChronic fetal hypoxia
Perinatal asphexiaPerinatal asphexia
Perinatal infectionPerinatal infection
D|CD|C
AlloimmuneAlloimmune
AutoimmuneAutoimmune
Congenital infectionCongenital infection
ThrombosisThrombosis
Bone marrow replacementBone marrow replacement
Kasabach-Merrit syndromeKasabach-Merrit syndrome
Metabolic diseaseMetabolic disease
Inherited thrombocytopeniaInherited thrombocytopenia

Early onset ThrombocytopeniaEarly onset Thrombocytopenia
Most common causes of TP presenting in 1Most common causes of TP presenting in 1stst
7272
hours are related to complications ofhours are related to complications of
pregnancy &/or deliverypregnancy &/or delivery
gestational hypertensiongestational hypertension
gestational diabetesgestational diabetes
IUGRIUGR
TP typically mild to moderate, proportional toTP typically mild to moderate, proportional to
severity of PIH/IUGRseverity of PIH/IUGR

Early onset ThrombocytopeniaEarly onset Thrombocytopenia
Mechanism is decreased megakaryopoiesisMechanism is decreased megakaryopoiesis
Affected neonates often have additionalAffected neonates often have additional
hemorrhagic abnormalitieshemorrhagic abnormalities
a. transient neutropeniaa. transient neutropenia
b. increased nucleated red blood cellsb. increased nucleated red blood cells
c. increased erythropoietin levelc. increased erythropoietin level
d. evidence of hyposplenismd. evidence of hyposplenism
(splenocytes, target cells, Howell-Jolly(splenocytes, target cells, Howell-Jolly
bodies)bodies)

Early onset NT : NaturalEarly onset NT : Natural
HistoryHistory
Platelet count falls slowlyPlatelet count falls slowly
Nadir DOL ≠ 4-5 typically > 50Nadir DOL ≠ 4-5 typically > 50
Recovers to > 150 by DOL ≠ 7-10Recovers to > 150 by DOL ≠ 7-10
Very low risk of hemorrhageVery low risk of hemorrhage
Further investigations are unnecessary ifFurther investigations are unnecessary if
platelet count > 50 & recovers within 2platelet count > 50 & recovers within 2
weeksweeks

Early onset TPEarly onset TP
After chronic fetal hypoxia the next mostAfter chronic fetal hypoxia the next most
likely causes are :likely causes are :
Prenatal viral infectionsPrenatal viral infections
CMV,rubella,HIV,toxoplasmaCMV,rubella,HIV,toxoplasma
Perinatal bacterial infectionsPerinatal bacterial infections
GBS, E.Coli, H.InfluenzaGBS, E.Coli, H.Influenza
Perinatal asphyxiaPerinatal asphyxia
AneuploidyAneuploidy

Early onset TP rare causesEarly onset TP rare causes
A.A. Thrombosis- catheter , renal veinThrombosis- catheter , renal vein
B.B. Kasbach-Merritt syndromeKasbach-Merritt syndrome
enlarging vascular lesionenlarging vascular lesion
usually with microangiopathic anemia & DICusually with microangiopathic anemia & DIC
20 % of cases non cutaneous ( liver )20 % of cases non cutaneous ( liver )
C.C. Inborn errors of metabolismInborn errors of metabolism
D.D. Bone marrow replacementBone marrow replacement
leukemia, neuroblastoma, osteopetrosisleukemia, neuroblastoma, osteopetrosis

When do you considerWhen do you consider
Inherited TP?Inherited TP?
EarlyEarly onset TP persistsonset TP persists > 2 weeks> 2 weeks unusualunusual
Likely causesLikely causes inheritedinherited TP all are rare:TP all are rare:
i.i. congenital amegakaryocyticcongenital amegakaryocytic
ii.ii. thrombocytopenia absent radii (TAR)thrombocytopenia absent radii (TAR)
syndromesyndrome
iii.iii. Bernard –Souiler syndromeBernard –Souiler syndrome
iv.iv. Wiskott-Aldrish syndromeWiskott-Aldrish syndrome
v.v. Fanconi anemiaFanconi anemia

Category Subtype Other clinical & labs
Chromosomal Trisomy13 Aplasia cutis , CHD, Cleft lip and palate ,
polydactly
Trisomy18 IUGR, CHD, rocker-bottom feet ,
overlapping digits, hypertelorism , small
mouth , clinodactyly.
Trisomy21 CHD , transverse palmar crease ,
hypotonia , short neck with redundant
posterior folds.
Turner S. CHD, Cutis vulgus ,webbed posterior
neck, broad chest with wide spaced
nipples , Lower extremity edema
11 q terminal disorder
( Jacobsen S, Paris
Trousseau
Thrombocytopenia)
CHD, genitourinary anomalies, abnormal
brain imaging , Limb anomalies
Genetic disorders associatedGenetic disorders associated
with TPwith TP

with TPwith TP
familial May- Hegglin anomaly,Sebastian
syndrome
Giant platelets , Neutrophilic inclusions
Fetcher syndrome Giant platelets , sensorineural hearing loss,
cataracts, nephritis, neutrophilic inclusions.
Bernard- soulier Syndrome Giant platelets
X-linked macro thrombocytopenia due
to GATA-1 mutation
Anemia, genitourinary abnormalities
( Cryptorchiadism)
Congenital amegakaryocytic
thrombocytopenia
Abnormalities of head size and shape.
Developmental delay ,CHD,cleft and high arched
palate , Abnormal kidneys, optic atrophy, vulgus and
varus deformities, Vertebral anomalies ,
Coloboma,Scoliosis,absent BM,megakaryocytes

with TPwith TP
familial Wiscott -Aldrich syndrome Immunodeficiency , small palates,
eczema
Amegakaryocytic
Thrombocytopenia and radioulnar
synostosis
Restricted forearm pronation,
proximal radioulnar synostosis in
forearm, absent BM
megakaryocytes
Fanconi anemia Hypopigmeted and
hyperpigmented skin lesions. UT
abnormalities , microcephaly ,
upper extermity radial side
abnormalities involving the thumb ,
pancytopenia ( usually with onset in
childhood)
Thrombocytopenia and absent radii Shortened/absent radii bilaterally ,
normal thumbs, ulnar and hand
abnormalities , abnormalities of the
humerous.CH defects ,
Eosinophilia, leukemoid reaction
Neonatal primary hemophagocytic
lymphohistiocytosis
Fever, HSM , Hyperferritemia ,
hypertriglyceridemia,
hypofibrogenemia.

with TPwith TP
Metabolic Propionic acidemia ,
methylmalonic acidemia
FTT, developmental delay, Ketoacidosis ,
hyperglycinemia, hyperammonemia
Isovaleric acidemia Odor of sweaty feet, poor feeing,
hypotonia , hyperammonemia, metabolic
acidosis
Gausher disease HSM, Gausher cells in BM.

New Thrombocytopenia > 72New Thrombocytopenia > 72
hourshours
Late onset sepsisLate onset sepsis
NECNEC
Congenital infectionCongenital infection
AutoimmuneAutoimmune
Kasabach-Merritt syndromeKasabach-Merritt syndrome
Metabolic diseaseMetabolic disease
Inherited thrombocytopeniaInherited thrombocytopenia

Late onset thrombocytopeniaLate onset thrombocytopenia
Almost always due to sepsis or NECAlmost always due to sepsis or NEC
77% sepsis & 11% NEC77% sepsis & 11% NEC
Combined mechanism:Combined mechanism:
1. adverse fetal environment impairs1. adverse fetal environment impairs
productionproduction
2. consumptive stress of sepsis or NEC2. consumptive stress of sepsis or NEC

Infection, NEC &Infection, NEC &
Infection:Infection:
55 – 70 % of neonates with proven infection55 – 70 % of neonates with proven infection
have TPhave TP
50 % of these have count < 10050 % of these have count < 100
Gram +ve < Gram –ve < fugalGram +ve < Gram –ve < fugal
NEC:NEC:
80 – 90 % neonates with NEC have TP80 – 90 % neonates with NEC have TP
platelet count typically ranges from 30 - 60platelet count typically ranges from 30 - 60

Fungal infection & TPFungal infection & TP
TP seen in > 80 % of fugal infectionsTP seen in > 80 % of fugal infections
Platelet count typically < 50Platelet count typically < 50
Lower initial count, lower nadir & longerLower initial count, lower nadir & longer
duration of TP than other infectionsduration of TP than other infections
Some authors empiric antifungal in VLBWSome authors empiric antifungal in VLBW
infants with clinical sepsis & severe TPinfants with clinical sepsis & severe TP

Late onset TP: Natural HistoryLate onset TP: Natural History
• Progresses rapidly, nadir (usually < 50)Progresses rapidly, nadir (usually < 50)
reached within 24 – 48 hoursreached within 24 – 48 hours
• As sepsis or NEC controlled, countAs sepsis or NEC controlled, count
slowly rises over 5 – 7 daysslowly rises over 5 – 7 days
• Clinical bleeding due to late onset TPClinical bleeding due to late onset TP
rarerare
• IVH in premature infants usually almostIVH in premature infants usually almost
always occurs before the developmentalways occurs before the development
of TPof TP
(exception - severe DIC)(exception - severe DIC)

Late onset NT: managementLate onset NT: management
Closely monitor platelet count at least ( qClosely monitor platelet count at least ( q
12 hours) because of rapidity of decline12 hours) because of rapidity of decline

Evaluate for bacterial/fugal
sepsis & NEC
• Evaluate for DIC
• Evaluate for viral infections (HSV &
acquired CMV)
• Evaluate for thrombosis especially if
there is central line
• Consider ITP
• Consider drug induced TP
• Consider IEM
• Consider Fanconi anemia
NO further
evaluation for
thrombocytopenia
bacterial/fugal sepsis
& NEC likely
Platelets normalizes
with treatment
No evidence of bacterial/fugal
sepsis & NEC
Late onset sepsis > 72 hours
If yes If No
• Appropriate therapy
• Follow platelet count
Consult pediatric
hematologist
12

Platelets transfusion in the NICUPlatelets transfusion in the NICU
 A very high proportion of neonates
receive platelet transfusions
69% in one recent study 4
 Repeated transfusions are often given

Transfusion : current
recommendations
There have been no trials demonstrating
whether or not transfusion reduces bleeding
or improves outcomes in neonates with
severe TP
Only one RCT was published in 1993
(Andrews):
no difference in incidence of extent of ICH
confined to neonates with count > 50 aimed
to increase count to normal

Retrospective review (Murray et al.2002)
• Plt transfusions with plt <50×109/L in NICU (n=53
over 3 years).
• 51% of these neonates were transfused:
those with a platelet count <30×109/L, and
those with a platelet count 30~50×109/L who had a
previous ICH or were clinically unstable.
• No major hemorrhage, whether plt transfusions
were given or not
• A prophylactic platelet transfusion trigger of
<30×109/L probably represents a safe practice for
clinically stable NICU patients
(limitations of retrospective study).

In the NICU at the University of
Florida
• Usually transfuse clinically stable, non-bleeding
neonates for platelet counts <25×109/L.
• Recommend using a platelet transfusion trigger of
<50×109/L :
(1) for clinically unstable neonates of any gestational
and post-conceptional age,
(2) for all neonates <1500 g during the first week of
life (because of the high risk of IVH),
(3) for neonates with coagulopathy, and before and
after invasive procedures.

In the NICU at the University of
Florida
• Recommend transfusion for platelet counts
<100×109/L in cases of active bleeding, or
with the concurrent use of medications
that interfere with platelet function (i.e.
indomethacin) or increased risk of
bleeding.
• Not evidence based, and has never been
tested in clinical studies.

Bleeding in severe TP
Recent prospective study(Starwarth,2009)
91 % of neonates whose platelet count fells
below 20 did not develop major bleeding
of those who did:
vast majority were VLBW < 28 weeks plus 2
term neonates with DIC
Several studies have found no correlation
between severity of TP & incidence of
clinically bleeding

Tendencies from these
recommendations
• Awareness of platelet transfusion- associated
risks.
• Over the last decade there has been a trend
toward accepting lower platelet counts in
neonates, particularly if they are clinically
stable and not bleeding

BCSH guidelines for platelets Tx12
Platelet count
< 20
< 30
< 50
All neonates
< 1 kg & < 1 week of age
Clinically unstable
Previous major bleeding (grade III- IV
IVH)
Active minor bleeding
Coagulopathy
Upcoming surgery or exchange
transfusion
Major bleeding

Thrombopoietic growth factors
• The risks associated with blood products,
use thrombopoietic growth factors
• IL-3, IL-6, IL-11, Stem Cell Factor (SCF), and
Thrombopoietin (Tpo) all support
megakaryocyte
development in vitro,
--limited platelet recovery in the adult
--No trials in neonates

Recombinant IL-11 (rhIL-11)
• the only thrombopoietic growth factor approved in
the USA for the prevention of severe
chemotherapy induced thrombocytopenia.
(1)significant side effects (such as fluid retention
and atrial arrythmias),
(2)lack of efficacy in certain varieties of
thrombocytopenia
(3)never investigated in NICU patients,

The cloning of thrombopoietin (Tpo, the most
potent known stimulator of platelet production)
• several subjects treated with recombinant
Tpo (PEG-rHMGDG) developed neutralizing
antibodies against endogenous Tpo, which
resulted in severe thrombocytopenia and
aplastic anemia.
• Ultimately, these complications led to the
discontinuation of clinical trials involving Tpo.

Thrombopoietin-mimetic molecules
• Small molecules that have no sequence
homology to Tpo, but bind to the Tpo
receptor and have biologically comparable
effects.
• AMG-531 (Amgen, Inc.) is currently being
evaluated in clinical trials.
• No in vitro or in vivo studies evaluating the
potential use of these compounds in
neonates.

• You are called to the L & D ward toYou are called to the L & D ward to
evaluate a 6-hour-old baby was foundevaluate a 6-hour-old baby was found
to have diffuse petechiae by the nurseto have diffuse petechiae by the nurse
while changing the diaper. Thiswhile changing the diaper. This
apparently healthy infant girl was bornapparently healthy infant girl was born
to a healthy 38 year-old womanto a healthy 38 year-old woman
(gravida 3, para 3) who had a(gravida 3, para 3) who had a
spontaneous vaginal delivery withoutspontaneous vaginal delivery without
complications.complications.

At birth, the girl on physical examinationAt birth, the girl on physical examination
was otherwise normal and in nowas otherwise normal and in no
distress. A platelet count performed atdistress. A platelet count performed at
the time of the petechial rash wasthe time of the petechial rash was
10,000/mL. The infant was transferred10,000/mL. The infant was transferred
to the neonatal tertiary care facility.to the neonatal tertiary care facility.
What is your initial approach?What is your initial approach?

1.1. Factitious thrombocytopenia should always beFactitious thrombocytopenia should always be
considered but is unlikely in this case becauseconsidered but is unlikely in this case because
of the presence of clinical signs.of the presence of clinical signs.
2.2. The baby should be examined.The baby should be examined.
3.3. Determine whether the baby is sick or not (TPDetermine whether the baby is sick or not (TP
may be first sign of sepsis or NEC)may be first sign of sepsis or NEC)
4.4. If the baby appears ill, a sepsis workup shouldIf the baby appears ill, a sepsis workup should
be performed and parenteral antibiotics shouldbe performed and parenteral antibiotics should
be initiated.be initiated.

5.5. TP from congenital viral infections oftenTP from congenital viral infections often
show microcephaly andshow microcephaly and
hepatosplenomegaly.hepatosplenomegaly.
6.6. Radial and thenar hypoplasia suggestRadial and thenar hypoplasia suggest
a primary defect in platelet productiona primary defect in platelet production
(e.g., Fanconi anemia or TAR(e.g., Fanconi anemia or TAR
syndrome).syndrome).

7.7. blood smear examination eg. Giantblood smear examination eg. Giant
platelets → increased rate of peripheralplatelets → increased rate of peripheral
platelet destructionplatelet destruction
8.8. Maternal history:Maternal history:
(platelet count – medications – SLE &(platelet count – medications – SLE &
other collagen vascular diseases )other collagen vascular diseases )

• The baby's blood smear reveals giantThe baby's blood smear reveals giant
platelets and marked thrombocytopeniaplatelets and marked thrombocytopenia
but is otherwise normal. The mother'sbut is otherwise normal. The mother's
platelet count is normal and there is noplatelet count is normal and there is no
history suggesting maternalhistory suggesting maternal
autoimmune disease.autoimmune disease.
• What's the most likely diagnosis andWhat's the most likely diagnosis and
what should be done?what should be done?

• The most likely diagnosis is alloimmuneThe most likely diagnosis is alloimmune
thrombocytopenia from transplacentalthrombocytopenia from transplacental
passage of a maternal antibody thatpassage of a maternal antibody that
specifically recognizes an antigen thatspecifically recognizes an antigen that
the infant inherited from her father.the infant inherited from her father.

• While discussing the probableWhile discussing the probable
diagnosis with the parents, you arediagnosis with the parents, you are
called urgently to the nursery becausecalled urgently to the nursery because
the baby has developed worseningthe baby has developed worsening
petechiae and has gross hematuria.petechiae and has gross hematuria.
Her vital signs are stable.Her vital signs are stable.
• What should be done?What should be done?

• The baby now has evidence of significantThe baby now has evidence of significant
active hemorrhage and should receive aactive hemorrhage and should receive a
platelet transfusion.platelet transfusion.
• The excellent donor of platelets is to use theThe excellent donor of platelets is to use the
mother as a pheresis donor for platelets. Hermother as a pheresis donor for platelets. Her
PAl-i-negative platelets will not bePAl-i-negative platelets will not be
recognized by circulating alloantibody andrecognized by circulating alloantibody and
will survive normally in the baby.will survive normally in the baby.
Alternatively, the blood bank may be able toAlternatively, the blood bank may be able to
provide PAl-i-negative platelets from anprovide PAl-i-negative platelets from an
unrelated donor.unrelated donor.

• The mother is PAI- negative. The baby'sThe mother is PAI- negative. The baby's
platelet count increases and she stopsplatelet count increases and she stops
bleeding after she is transfused withbleeding after she is transfused with
maternal platelets.maternal platelets.
• The parents are interested in having otherThe parents are interested in having other
children and are concerned about thechildren and are concerned about the
recurrence risk.recurrence risk.
• What do you tell them?What do you tell them?

• Subsequent pregnancies are at high risk ofSubsequent pregnancies are at high risk of
severe neonatal hemorrhage. The mothersevere neonatal hemorrhage. The mother
should be followed up as a "high-risk"should be followed up as a "high-risk"
patient.patient.
• Recent data indicate that the administrationRecent data indicate that the administration
of intravenous gamma globulin to the motherof intravenous gamma globulin to the mother
before delivery decreases the incidence ofbefore delivery decreases the incidence of
neonatal thrombocytopenia.neonatal thrombocytopenia.

Take home message
TP is a common finding in the NICU
Incidence inversely proportional to gestational
age & birth weight
Early onset TP in preterm neonates
usually 2ry to placental insufficiency
rule out infection if no evidence of
insufficiency
Late onset TP
usually due to sepsis or NEC

Take home message
Most cases of thrombocytopenia are
not severe enough to warrant
treatment.
In approximately 20–25% of patients,
however, the thrombocytopenia is
severe (<50×109/L) and therapy with
platelet transfusions might be
considered.

Take home message
In term babies with severe TP who are
otherwise well:
NAIT should be excluded
prompt treatment should be
instituled

Take home message
Platelet transfusion decisions in neonates is
very limited, but it suggests that transfusing
non-bleeding infants <1500 g during the
first week of life for platelet counts
>50×109/L does not reduce the incidence of
intraventricular hemorrhage, and that
30×109/L might be a safe transfusion
threshold for clinically stable neonates.

Take home message
Wide variations in transfusion triggers &Wide variations in transfusion triggers &
transfusion practices among NICUstransfusion practices among NICUs
Vast majority of neonates are givenVast majority of neonates are given
prophylactic transfusion in the absenceprophylactic transfusion in the absence
of significant bleedingof significant bleeding
No data exist to demonstrate the benefitNo data exist to demonstrate the benefit
of maintaining high platelet count inof maintaining high platelet count in
preterm to prevent major bleedingpreterm to prevent major bleeding

Take home message
Additional studies are necessary to
establish the safety of any set of guidelines
for nonbleeding neonates.
Bleeding neonates: platelet transfusions
administered for platelet counts
<100×109/L.

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