2 Financial DisclosureI have no relevant financial relationships to disclose.
3 Objectives Definition of thrombocytopenia Understand the pathophysiology of neonatal alloimmune thrombocytopeniaReview bone marrow function as it relates to platelet production and releaseDifferential Diagnosis in a well, term infantDifferential Diagnosis in a sick, term infant
7 Would you treat the severe thrombocytopenia in NAIT? a. Yes, the risk of bleeding is really high b. No, this condition will spontaneously resolve and the risk of bleeding is only a threat in premature infants. c. Depends on what the doctor wants to do
8 Would you treat the severe thrombocytopenia in NAIT? a. Yes, the risk of bleeding is really high b. No, this condition will spontaneously resolve and the risk of bleeding is only a threat in the fetus and premature infants. c. Depends on what the doctor wants to do
9 Baby Lydia – 37 weeks Delivered with spontaneous cry. Apgars 8/9 Dried, suctioned, admitted to NBNInitial platelet count of 177,000Nadir 120,000 at 36 hr of ageBili 48 hr of age
10 Baby ‘Lila’ – 37 weeks (No Tx) Delivered with spontaneous cry. Apgars 8/9Dried, suctioned, admitted to NICUInitial platelet count of 8,000PE: diffuse petechiae, bruising over lower extremitiesPlatelet transfusion 15 ml/kgAdministered intravenous immunoglobulin 1 gm/kgRepeat platelet count 4 hours later 94,000Platelet f/u 31,000IVIG repeated x2 – normalization of platelet counts
12 Neonatal Alloimmune Thrombocytopenia (NAIT) Develops in first pregnancy (unlike Rh sensitization)Fetal platelet antigens form early in gestationMaternal antibodies cross early 2nd trimesterThrombopoietin level is normalMegakaryocytes and platelets produced bind to itSeverely low platelet counts in the newborn< 20,000 /microLNormal maternal platelet count
13 Neonatal Alloimmune Thrombocytopenia (NAIT) Most severe complication is intraventricular hemorrhageOccurs in 10-20% of affected newborns¼ - ½ occurs in utero
14 Neonatal Alloimmune Thrombocytopenia Rate of recurrence in future pregnancies75%-90%As severe or more severe than previousFetal therapiesIn utero platelet transfusionsMaternal therapiesIVIGCorticosteroids
15 Which is the best treatment for thrombocytopenia in NAIT in the first 48 hr of life in an infant with a platelet count of 6,000 /microL?a. Random donor platelet transfusion b. Washed maternal platelets c. Intravenous Immunoglobulin d. Methylprednisolone**Remember 98% of Caucasians have HPA-1a on their platelets.Washing maternal platelets takes hours to collect and process.
16 Which is the best treatment for thrombocytopenia in NAIT in the first 48 hr of life in an infant with a platelet count of 6,000 /microL?a. Random donor platelet transfusion b. Washed maternal platelets c. Intravenous Immunoglobulin d. Methylprednisolone**Remember 98% of Caucasians have HPA-1a on their platelets.Washing maternal platelets takes hours to collect and process.
17 What is the definition of neonatal thrombocytopenia? a. Platelet count < 100, 000/microL b. Platelet count < 50,000/microL c. Platelet count < 25, 000/microL d. Platelet count < 150, 000/microL
18 What is the definition of neonatal thrombocytopenia? Platelet count < 150,000 /microLActually, platelet count < 5th percentile5th percentile decreases with decreasing gestational age34-36 weeks – 123, 100 /microL32 weeks – 104, 200 /microLJ Perinatol. 2009;29(2):130
19 Definition Platelet count < 150,000/microL Ensure a central sample Clumping with capillary specimens
20 Mechanisms of Thrombocytopenia Increased destructionDecreased production
23 The most likely physical symptom of neonatal thrombocytopenia is: a. Petechiaeb. Bruisingc. Oozing from the umbilical cordd. No symptoms
24 The most likely physical symptom of neonatal thrombocytopenia is: No physical sign or symptom is the most likely presentation of isolated thrombocytopenia.Petechiae, bruising, bleeding can be appreciated on physical exam
26 Treatment with which of the following medications increases the risk of thrombocytopenia in premature infants:a. Quinidineb. Digoxinc. Indomethacind. Heparine. All of the aboveQuinidine – antiarrythmic, blocks Na channelsDigoxin – cardiac medication used to slow the HR in CHF
27 Treatment with which of the following medications increases the risk of thrombocytopenia in premature infants:a. Quinidineb. Digoxinc. Indomethacind. Heparine. All of the aboveQuinidine – antiarrythmic, blocks Na channelsHeparin – immune and non immune mediated (nonimmune due to direct effect on plt activation) abnormal ab that activate platelets to clots and low pltsDigoxin – immune mediated
28 If maternal thrombocytopenia follows drug exposure and is mediated by IgG antibody, the Ab may cross the placenta and affect fetal platelets.Indomethacin and Heparin have been implicated in neonatal thrombocytopenia.Indomethacin – platelet dysfunctionHeparin – development of platelet antibodies
30 Well, Term Newborn Maternal history History of immune thrombocytopenic purpura (ITP) or systemic lupus erythematosus (SLE)?Previous infant with thrombocytopenia or family history?Any infections during pregnancy?Drug/medication use during pregnancy?History of HELLP, preeclampsiaWhat is mom’s platelet count?Decreased -- may be autoimmuneNormal – may be autoimmune of alloimmune
31 (Auto)Immune Thrombocytopenia (1st and early 2nd trimester) Antibodies coat plateletsWhen traversing the spleen, the platelets are “eaten” by splenic macrophagesAt birth, infants have minimal splenic functionAfter birth, splenic function increases and risk of severe thrombocytopenia .
32 Splenic Function at Birth Not functional at birthHowell-Jolly bodies on smear – DNA remnants left over in RBCUsually Howell-Jolly bodies removed on passage of RBC thru spleen
33 Immune Thrombocytopenia Must follow neonate’s platelet levels closely after birthEspecially as splenic function improvesMonitoring the fetus during pregnancy and labor is no longer recommended
34 Which immunoglobulin does not cross the placenta? a. IgA b. IgE c. IgM d. IgG
35 Which immunoglobulin does not cross the placenta? a. IgA (300,000 D) b. IgE (190,000 D) c. IgM (900,000 D) d. IgG (150,000 D)Which immunoglobulin will not cross the placenta due to size? IgMIgE 190,000 MWIgA 300,000IgM 900,000IgG 150,000
36 Gestational Thrombocytopenia Mild and asymptomatic thrombocytopeniaNo past history of thrombocytopenia (except possibly during a previous pregnancy)Occurrence during late gestationNo association with fetal thrombocytopeniaSpontaneous resolution after delivery
37 Gestational Thrombocytopenia Considered benignMild and transient ITP?Less antibodies compared to ITPNo thrombocytopenia in neonateTo make the diagnosis:Thrombocytopenia not severeOccurs during last part of pregnancy/termPlatelet count returns to normal after pregnancyInfant’s platelet count is normal
38 The Placenta May reveal: Congenital infection (CMV, syphilis) Vasculopathy (Preeclampsia)HemorrhageInfarctsThrombiVascular malformationsPlacenta with syphilis – acute/chronic villitis, spirochetes noted on stainCMV, Herpes – viral inclusions noted with special stains
39 Maternal Pre Eclampsia Estimated 1 in 100 birthsThrombocytopenia, neutropenia in newbornsDecreased productionNeutrophil, platelet inhibitorPresent at birthNadir is 2-4 days of age
40 Thrombosis If you cannot explain thrombocytopenia, evaluate for clot Infants with RVT , more likely to have inherited prothrombotic condition like: factor V Leiden mutation, protein C and S deficiency, methylenetetrahydrofolate reductase (MTHFR) mutation, and elevation of lipoprotein
42 Birth AsphyxiaTrue mechanism is unknownMay relate to hypoxia
43 Bacterial Infection Mechanism Disseminated intravascular coagulation Platelet aggregation caused by bacterial products on platelet membranesInjury to megakaryocytes tooMegakaryocyte – giant cell in bone marrow which produces plt
44 Congenital Infection Most common: Others: Cytomegalovirus (CMV) ToxoplasmosisHerpesRubella
46 Disseminated Intravascular Coagulation Systemic process producing:ThrombosisHemorrhageCharacterized by:Prolonged protime (PT)Prolonged activated partial thromboplastin time (PTT)Decrease in fibrinogenIncrease in fibrin split products or D-DimersDecreased plateletsProlonged PT and this INRFibrinogen – Factor 1 (fibrinogen to fibrin which is a clot)FSP/Ddimer : a small protein fragment present in the blood after a blood clot is degraded by fibrinolysisPreterm infants have hyporeactive plat compared to term infants.
51 Kasabach-Merritt Syndrome Capillary HemangiomasDICThrombocytopeniaShortened platelet survivalSequestration in vascular malformationTx is pred, vincristine, cyclophosphamide**abnormal endothelium and convoluted architecture of the tumor vasculature promote platelet adhesion and trapping . Platelet aggregation and activation result in thrombocytopenia, consumption of fibrinogen, and ongoing fibrinolysis, leading to intralesional bleeding and tumor enlargement
52 Wiskott-Aldrich Syndrome X-linkedMPV (mean platelet volume) 3-5 fL (nl 7-10)ImmunodeficiencyThrombocytopeniaEczemaThrombocytopenia with small plateletsThis condition primarily affects males.WBC are nonfunctionalfL =metric unit of volume equal to 10−15 (femtoliter)
53 Summary Points Neonatal Thrombocytopenia Platelet levels < 150,000Neonatal Alloimmune ThrombocytopeniaSeverely low fetal platelet levelsMaternal platelet value – normalObtain a good accurate specimenCentral specimen
55 References NeoReviews Vol. 14 No. 2 February 1, 2013, pp. e74 -e82 Incidence and Consequences of Neonatal Alloimmune Thrombocytopenia: A Systematic Review. Pediatrics Mar 3.Neonatal Thrombocytopenia, Up to Date 2014.Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD, SO. J Perinatol. 2009;29(2):130