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


At birth, the girl on physical examination At birth, the girl on physical examination was otherwise normal and in no was otherwise normal and in no distress. A platelet count performed at distress. A platelet count performed at the time of the petechial rash was the time of the petechial rash was 10,000/mL. The infant was transferred 10,000/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 neonatal Discuss the incidence of neonatal

thrombocytopenia.thrombocytopenia.4.4. Develop DD for neonate who have Develop 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 the Platelet 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 the TPO 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, and kidneys, 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 is present The receptor for TPO is c-MPL which is present

on the megakaryocytes and plateletson the megakaryocytes and platelets• TPO rises with platelet fall and declines as the TPO rises with platelet fall and declines as the

megakaryocyte and platelet mass increasemegakaryocyte and platelet mass increase

Definition of Definition of ThrombocytopeniaThrombocytopenia

• The mean fetal platelet count reaches 150 x The 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 normal platelet neonates born to mothers with normal platelet counts have platelets above 150 x 10counts have platelets above 150 x 1099/l at /l at birthbirth1–31–3 Therefore thrombocytopenia in a Therefore thrombocytopenia in a neonate of any viable gestational age can be neonate of any viable gestational age can be defined as a platelet count of <150 x 10defined as a platelet count of <150 x 1099/l /l

Incidence of Incidence of ThrombocytopeniaThrombocytopeniaAt birth:At birth:• 1 – 5 % of healthy term infants 1 – 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 admission 22 – 35 % of all NICU admission 1414

• 70 – 80 % of VLBW 70 – 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 counts Platelet counts 100–150×109/L range 100–150×109/L range are more are more common among healthy common among healthy neonates than adults →neonates than adults →healthy healthy appearing neonate : careful follow-upappearing neonate : careful follow-up

• Worsening of thrombocytopenia, or Worsening of thrombocytopenia, or changes in clinical condition need changes in clinical condition need further evaluation.further evaluation.1212

Incidence of Incidence of ThrombocytopeniaThrombocytopenia

Bleeding in neonates with Bleeding in neonates with severe Thrombocytopeniasevere Thrombocytopenia5 % Intracranial ( usually IVH )5 % Intracranial ( usually IVH )1 – 5 % Gastrointestinal1 – 5 % Gastrointestinal1 – 5 % Pulmonary1 – 5 % Pulmonary1 – 2 % Hematuria 1 – 2 % Hematuria 1515

Stratifying levels of thrombocytopeniaStratifying levels of thrombocytopenia

• The primary reason for evaluating The primary reason for evaluating thrombocytopenia is to assess the risk of bleeding thrombocytopenia is to assess the risk of bleeding and assess the presence of underlying disorders and 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 of spontaneous 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 most spontaneous bleeding and can undergo most proceduresprocedures

Relation of bleeding risk and platelet Relation of bleeding risk and platelet countcount

• Bleeding time increases in a linear fashion Bleeding 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 fecal Slichter 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/l 10 cc/day/l 10 cc/day• < 5 x 10< 5 x 1099/l 50 cc/day/l 50 cc/day

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 neonates The predisposition of sick neonates to develop thrombocytopeniato develop thrombocytopenia

(1) Megakaryocytes in neonates are (1) Megakaryocytes in neonates are smaller and less mature than those smaller 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 during levels of thrombopoietin during thrombocytopeniathrombocytopenia

Classification : according to Classification : 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 infectionAneuploidy

Early onset neonatal(< 72 hours )

Chronic fetal hypoxiaPerinatal asphyxiaPerinatal infection

Late onset neonatal( > 72 hours )

Late onset sepsisNEC

Thrombocytopenia at birthThrombocytopenia at birth

1. Alloimmne1. Alloimmne2. Congenital infection2. Congenital infection CMV, HIV, rubella, toxoplasmaCMV, HIV, rubella, toxoplasma3. Aneuploidy3. Aneuploidy Trisomies 13, 18, 21Trisomies 13, 18, 214. Autoimmune 4. Autoimmune 5. ITP, SLE5. ITP, SLE6. Severe Rheusus hemolytic disease6. Severe Rheusus hemolytic disease7. Inherited7. Inherited

General considerationsGeneral considerations1. Platelet count < 50 at birth1. Platelet count < 50 at birth

Think I → Infection & ImmuneThink I → Infection & Immune

Immune causes account for 15 – 20 % of NT Immune causes account for 15 – 20 % of NT presenting at birthpresenting at birth

2. Any neonate with early- or late-onset 2. Any neonate with early- or late-onset thrombocytopenia, thrombocytopenia, infection has to be infection has to be considered at the top of the differential considered at the top of the differential diagnosis, because delayed diagnosis can diagnosis, because delayed diagnosis can be life-threatening.be life-threatening.

• • MMild to moderate ild to moderate thrombocytopenia at or thrombocytopenia at or shortly after birth in a well-appearing shortly after birth in a well-appearing preterm infant without risk factors for preterm infant without risk factors for infection and with a history of maternal infection and with a history of maternal preeclampsia or IUGR, is most likely preeclampsia or IUGR, is most likely benign.benign.

• • If If clinically stable clinically stable and the platelet count and the platelet count normalizes within ten days, no further normalizes within ten days, no further evaluation is necessary.evaluation is necessary.

An approach for diagnosis of An approach for diagnosis of early onset TPearly onset TP

• • Platelet counts Platelet counts <50×109/L<50×109/L or or

thrombocytopenia in a thrombocytopenia in a clinically ill clinically ill neonate,neonate,

are unlikely related to placental insufficiency,are unlikely related to placental insufficiency,

• • Other diagnoses such as Other diagnoses such as sepsis andsepsis and

neonatal alloimmune thrombocytopenianeonatal alloimmune thrombocytopenia

(NAIT) should be considered.(NAIT) should be considered.


• • In early-onset thrombocytopenia on In early-onset thrombocytopenia on whom sepsis and NAIT has been whom sepsis and NAIT has been excluded a careful family history and excluded a careful family history and physical examphysical exam

• • (1) Maternal platelet count(1) Maternal platelet count

• • (2) Previous (2) Previous siblings or other family siblings or other family members members with thrombocytopeniawith thrombocytopenia


An approach for diagnosis of An approach for diagnosis of early onset TPearly onset TP• • (3) (3) Radial abnormalities Radial abnormalities

(thrombocytopenia absent (thrombocytopenia absent radii radii 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 proximal thrombocytopenia with proximal radio-radio-ulnar synostosis)ulnar synostosis)


• • (5) Features or congenital anomalies (5) Features or congenital anomalies suggestive of suggestive of genetic disorders such as genetic disorders such as trisomies 21, 18, 13, trisomies 21, 18, 13, Turner's syndromeTurner's syndrome

• • (6) Presence of (6) Presence of hepato or splenomegaly hepato or splenomegaly or of or of abdominal massesabdominal masses

An approach for diagnosis of An approach for diagnosis of early onset TPearly onset TP• • In the In the absenceabsence of any obvious of any obvious

diagnostic clues in the history and diagnostic clues in the history and physical exam,physical exam,

the most common cause of the most common cause of isolated isolated severesevere thrombocytopenia in an thrombocytopenia in an well-well-appearingappearing infant infant is is alloimmune alloimmune thrombocytopeniathrombocytopenia

An approach for diagnosis of An approach for diagnosis of early onset TPearly onset TP• • If the If 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

An approach for diagnosis of An approach for diagnosis of early onset TPearly onset TP• • Rarer diagnoses, such as inborn errors Rarer diagnoses, such as inborn errors

of metabolism, or renal vein thrombosis of metabolism, or renal vein thrombosis or Kasabach–Merritt syndrome should or 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, consult consult pediatric hematologistpediatric hematologist

Neonatal Alloimmune TP Neonatal Alloimmune TP (NAIT)(NAIT)• Transplacental passage of maternal Transplacental passage of maternal

alloimmune antibodies directed against alloimmune antibodies directed against fetal platelet antigens inherited from the fetal 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 trimester trimester• Fetal Ab-coated platelets are destroyed Fetal Ab-coated platelets are destroyed

by fetal reticuloendothelial systemby fetal reticuloendothelial system• 50 % of cases occur in 150 % of cases occur in 1stst pregnancy pregnancy

NAIT EpidemiologyNAIT EpidemiologyFetomaternal incompatibility for HPA 1-a accounts for ~75 % Fetomaternal incompatibility for HPA 1-a accounts for ~75 %

of Caucasian causes of Caucasian causes

Other causes: HPA – 5b ( may bleed at higher platelet Other 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 NAIT However , 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 depends Likely 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 / purpura Healthy term neonate with petechae / purpura within 24 – 48 hours of lifewithin 24 – 48 hours of life

Mom with normal platelet countMom with normal platelet countPlatelet count trend:Platelet count trend:Thrombocytopenic at birthThrombocytopenic at birthThrombocytopenia often worsens over the first Thrombocytopenia often worsens over the first

few days ( careful monitoring essential )few days ( careful monitoring essential )Most cases resolve in one week , but Most cases resolve in one week , but

thrombocytopenia may persist up to 8 – 12 thrombocytopenia may persist up to 8 – 12 weeksweeks

NAIT - MorbidityNAIT - Morbidity

• 80 % cutaneous bleeding 80 % cutaneous bleeding • 20 % GI bleeding20 % GI bleeding• 10 – 20 % of untreated pregnancies result in 10 – 20 % of untreated pregnancies result in

intracranial hemorrhage intracranial hemorrhage 1.1.can occur at any time from 20 weeks gestation can occur at any time from 20 weeks gestation

until a few days after birthuntil a few days after birth

2.2.cause of most morbidity / mortalitycause of most morbidity / mortality

very high risk of severe neurodevelopmental very high risk of severe neurodevelopmental problems including cerebral palsyproblems including cerebral 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 initial Important to perform but won’t help with initial management decisionsmanagement decisions

NAIT - ManagementNAIT - Management1.Obtain head U/S if platelet < 501.Obtain head U/S if platelet < 502.Goal for 1 week of life – keep platelets 30-50 if 2.Goal for 1 week of life – keep platelets 30-50 if

asymptomatic, >100 if bleedingasymptomatic, >100 if bleedingTherapeutic options:Therapeutic options:a)a)HPA-1a / HPA- 5b negative plateletsHPA-1a / HPA- 5b negative plateletsb)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 hours response)IVIG 1 gm /kg x 2 days (12-36 hours response)+/- 1 mg methylprednisolone q 8 hours during IVIG+/- 1 mg methylprednisolone q 8 hours during IVIG

Antenatal ManagementAntenatal Management

The 2The 2ndnd affected fetus is more severely affected affected fetus is more severely affected than the first childthan the first child

Management moving towards non invasiveManagement moving towards non invasive

rate of fetal loss and emergency preterm delivery rate of fetal loss and emergency preterm delivery with repeated FBS & IUT was similar to the rate of with repeated FBS & IUT was similar to the rate of ICH in untreated pregnanciesICH 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 HPA regular UVC sampling & transfusion of HPA compatible plateletscompatible platelets

Differences between Rh disease & NAITDifferences between Rh disease & NAIT

Rh NAIT

IncidenceFirst child affectedRoutine screening in placeTesting readily available Prophylaxis available Severe clinical phenotypeManagement of next pregnancy

1/100 (25% severe)No YesYes (any blood bank)YesHydrops, kernicterus In utero RBCs Tx

1/1000YesNoNo (send out)NoICHMaternal IVIG

Neonatal Autoimmune Neonatal Autoimmune thrombocytopenia (NITP)thrombocytopenia (NITP)

Transplacental passage of maternal Transplacental passage of maternal platelet auto antibodies in platelet auto antibodies in mothersmothers with with ITP or SLEITP or SLE

Only 10 – 15 % of babies will have Only 10 – 15 % of babies will have thrombocytopeniathrombocytopenia

In affected cases :In affected cases : typically mild thrombocytopenias in SLE typically mild thrombocytopenias in SLE

infants infants ½ of ITP infants will have platelets < 50 ½ 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

Management Management

All neonates of mothers with ITP &/or SLE All 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 days If 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 maternal in a small number of cases maternal

antibodies persist more than 12 weeks, may antibodies persist more than 12 weeks, may need 2need 2ndnd course of IVIG course of IVIG

Thrombocytopenia in Thrombocytopenia in AneuploidyAneuploidyTrisomy 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 platelet mechanism likely decreased platelet production, similar pathogenesis of chronic production, similar pathogenesis of chronic fetal hypoxiafetal hypoxia

Thrombocytoenia in 1Thrombocytoenia in 1stst 72 72 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 72 72 hours are related to complications of hours are related to complications of pregnancy &/or deliverypregnancy &/or delivery

gestational hypertensiongestational hypertension

gestational diabetesgestational diabetes

IUGRIUGR

TP typically mild to moderate, proportional to TP typically mild to moderate, proportional to severity of PIH/IUGR severity of PIH/IUGR

Early onset ThrombocytopeniaEarly onset ThrombocytopeniaMechanism is decreased megakaryopoiesisMechanism is decreased megakaryopoiesisAffected neonates often have additional Affected 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 hyposplenism d. evidence of hyposplenism (splenocytes, target cells, Howell-Jolly bodies) (splenocytes, target cells, Howell-Jolly bodies)

Early onset NT : Natural Early onset NT : Natural HistoryHistoryPlatelet count falls slowlyPlatelet count falls slowlyNadir DOL ≠ 4-5 typically > 50Nadir DOL ≠ 4-5 typically > 50Recovers to > 150 by DOL ≠ 7-10Recovers to > 150 by DOL ≠ 7-10Very low risk of hemorrhageVery low risk of hemorrhageFurther investigations are unnecessary if Further investigations are unnecessary if

platelet count > 50 & recovers within 2 platelet count > 50 & recovers within 2 weeks weeks

Early onset TP Early onset TP

After chronic fetal hypoxia the next most After chronic fetal hypoxia the next most likely causes are :likely causes are :

Prenatal viral infectionsPrenatal viral infections CMV,rubella,HIV,toxoplasmaCMV,rubella,HIV,toxoplasmaPerinatal bacterial infectionsPerinatal bacterial infections GBS, E.Coli, H.InfluenzaGBS, E.Coli, H.InfluenzaPerinatal asphyxiaPerinatal asphyxiaAneuploidyAneuploidy

Early onset TP rare causesEarly onset TP rare causesA.A. Thrombosis- catheter , renal veinThrombosis- catheter , renal veinB.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 metabolismD. D. Bone marrow replacementBone marrow replacement leukemia, neuroblastoma, osteopetrosisleukemia, neuroblastoma, osteopetrosis

When do you consider When do you consider Inherited TP?Inherited TP?

EarlyEarly onset TP persists onset TP persists > 2 weeks > 2 weeks unusualunusual

Likely causes Likely causes inheritedinherited TP all are rare: TP all are rare:

i.i. congenital amegakaryocytic thrombocytopeniacongenital amegakaryocytic thrombocytopenia

ii.ii. thrombocytopenia absent radii (TAR) syndromethrombocytopenia absent radii (TAR) syndrome

iii.iii. Bernard –Souiler syndromeBernard –Souiler syndrome

iv.iv. Wiskott-Aldrish syndromeWiskott-Aldrish syndrome

v.v. Fanconi anemiaFanconi anemia

Category Subtype Other clinical & labsChromosomal 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 associated Genetic disorders associated with TPwith TP


Category Subtype Other clinical & labs

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



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.



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.

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New Thrombocytopenia > 72 New Thrombocytopenia > 72 hourshours

Late onset sepsisLate onset sepsisNECNECCongenital infectionCongenital infectionAutoimmuneAutoimmuneKasabach-Merritt syndromeKasabach-Merritt syndromeMetabolic diseaseMetabolic diseaseInherited 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 impairs 1. adverse fetal environment impairs production production

2. consumptive stress of sepsis or NEC2. consumptive stress of sepsis or NEC

Infection, NEC & Infection, NEC & thrombocytopeniathrombocytopenia

Infection:Infection:

55 – 70 % of neonates with proven infection 55 – 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 & longer Lower initial count, lower nadir & longer duration of TP than other infectionsduration of TP than other infections

Some authors empiric antifungal in VLBW Some 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, count As sepsis or NEC controlled, count slowly rises over 5 – 7 daysslowly rises over 5 – 7 days

• Clinical bleeding due to late onset TP Clinical bleeding due to late onset TP rarerare

• IVH in premature infants usually almost IVH in premature infants usually almost always occurs before the development always occurs before the development of TP of TP

(exception - severe DIC) (exception - severe DIC)

Late onset NT: managementLate onset NT: management

Closely monitor platelet count at least ( q Closely 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 likelyPlatelets 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

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


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

What is your initial approach?What is your initial approach?


1. 1. Factitious thrombocytopenia should always be Factitious thrombocytopenia should always be considered but is unlikely in this case because considered 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 (TP Determine 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 should If the baby appears ill, a sepsis workup should be performed and parenteral antibiotics should be performed and parenteral antibiotics should be initiated.be initiated.


5. 5. TP from congenital viral infections often TP from congenital viral infections often show microcephaly and show microcephaly and hepatosplenomegaly.hepatosplenomegaly.

6. 6. Radial and thenar hypoplasia suggest a Radial and thenar hypoplasia suggest a primary defect in platelet production 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. Giant blood smear examination eg. Giant platelets → increased rate of peripheral platelets → 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 giant The baby's blood smear reveals giant platelets and marked thrombocytopenia platelets and marked thrombocytopenia but is otherwise normal. The mother's but is otherwise normal. The mother's platelet count is normal and there is no platelet count is normal and there is no history suggesting maternal history suggesting maternal autoimmune disease. autoimmune disease.

• What's the most likely diagnosis and What's the most likely diagnosis and what should be done?what should be done?


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


• While discussing the probable diagnosis While discussing the probable diagnosis with the parents, you are called urgently with the parents, you are called urgently to the nursery because the baby has to the nursery because the baby has developed worsening petechiae and developed worsening petechiae and has gross hematuria. Her vital signs are has gross hematuria. Her vital signs are stable.stable.

• What should be done?What should be done?

Case ScenarioCase Scenario• The baby now has evidence of significant The baby now has evidence of significant

active hemorrhage and should receive a active hemorrhage and should receive a platelet transfusion. platelet transfusion.

• The excellent donor of platelets is to use the The excellent donor of platelets is to use the mother as a pheresis donor for platelets. Her mother as a pheresis donor for platelets. Her PAl-i-negative platelets will not be PAl-i-negative platelets will not be recognized by circulating alloantibody and recognized by circulating alloantibody and will survive normally in the baby. will survive normally in the baby. Alternatively, the blood bank may be able to Alternatively, the blood bank may be able to provide PAl-i-negative platelets from an provide PAl-i-negative platelets from an unrelated donor.unrelated donor.

Case ScenarioCase Scenario• The mother is PAI- negative. The baby's The mother is PAI- negative. The baby's

platelet count increases and she stops platelet count increases and she stops bleeding after she is transfused with bleeding after she is transfused with maternal platelets.maternal platelets.

• The parents are interested in having other The parents are interested in having other children and are concerned about the children and are concerned about the recurrence risk.recurrence risk.

• What do you tell them?What do you tell them?

Case ScenarioCase Scenario• Subsequent pregnancies are at high risk of Subsequent pregnancies are at high risk of

severe neonatal hemorrhage. The mother severe 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 administration Recent data indicate that the administration of intravenous gamma globulin to the mother of intravenous gamma globulin to the mother before delivery decreases the incidence of before 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 weightEarly onset TP in preterm neonates usually 2ry to placental insufficiency rule out infection if no evidence of

insufficiencyLate 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 given Vast majority of neonates are given prophylactic transfusion in the absence prophylactic transfusion in the absence of significant bleedingof significant bleeding

No data exist to demonstrate the benefit No data exist to demonstrate the benefit of maintaining high platelet count in of maintaining high platelet count in preterm to prevent major bleeding preterm 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.

References References 1. Burrows RF, Kelton JG. Incidentally detected thrombocytopenia in healthy mothers and 1. Burrows RF, Kelton JG. Incidentally detected thrombocytopenia in healthy mothers and

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Ahmed elmelhat neonatal thrombocytopenia

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