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Ahmed elmelhat neonatal thrombocytopenia
 

Ahmed elmelhat neonatal thrombocytopenia

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this lecture was created totally by dr Ahmed El melhat, pediatrician & neonatologist, from Port said Egypt, El Nasr hospital Port said, now in Saudia Arabia

this lecture was created totally by dr Ahmed El melhat, pediatrician & neonatologist, from Port said Egypt, El Nasr hospital Port said, now in Saudia Arabia

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    Ahmed elmelhat neonatal thrombocytopenia Ahmed elmelhat neonatal thrombocytopenia Presentation Transcript

    • 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.
    • Case ScenarioCase Scenario 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 ThrombocytopeniaThrombocytopenia 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 ThrombocytopeniaThrombocytopenia
    • 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 /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 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. An approach for diagnosis ofAn approach for diagnosis of early onset TPearly onset TP
    • •• 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 An approach for diagnosis ofAn approach for diagnosis of early onset TPearly onset TP
    • An approach for diagnosis ofAn approach for diagnosis of early onset TPearly onset TP •• (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)
    • An approach for diagnosis ofAn approach for diagnosis of early onset TPearly onset TP •• (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
    • An approach for diagnosis ofAn approach for diagnosis of early onset TPearly onset TP •• 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 thrombocytopeniathrombocytopenia
    • An approach for diagnosis ofAn approach for diagnosis of early onset TPearly onset TP •• 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
    • An approach for diagnosis ofAn approach for diagnosis of early onset TPearly onset TP •• 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 thrombocytopeniathrombocytopenia  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 thrombocytopeniathrombocytopenia 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
    • Genetic disorders associatedGenetic 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
    • Genetic disorders associatedGenetic disorders associated with TPwith TP Category Subtype Other clinical & labs 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.
    • Genetic disorders associatedGenetic disorders associated with TPwith TP Category Subtype Other clinical & labs 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.
    • 12
    • 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 & thrombocytopeniathrombocytopenia 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.
    • 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 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.
    • Case ScenarioCase Scenario 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?
    • Case ScenarioCase Scenario 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.
    • Case ScenarioCase Scenario 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).
    • Case ScenarioCase Scenario 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 )
    • Case ScenarioCase Scenario • 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?
    • Case ScenarioCase Scenario • 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.
    • Case ScenarioCase Scenario • 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?
    • Case ScenarioCase Scenario • 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.
    • Case ScenarioCase Scenario • 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?
    • Case ScenarioCase Scenario • 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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