Neonatal Thrombocytopenia

Suzanne Reuter MDSDPA 2014Deadwood, SDNeonatal ThrombocytopeniaFinancial Disclosure I have no relevant financial relationships to disclose.ObjectivesDefinition of thrombocytopeniaUnderstand 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 infant3Neonatal Alloimmune Thrombocytopenia (NAIT)*****

Neonatal Alloimmune Thrombocytopenia (NAIT)

MomFetus*****PlacentaNeonatal Alloimmune Thrombocytopenia (NAIT)

MomFetus*****PlacentaWould 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 doWould 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 doBaby Lydia 37 weeksDelivered with spontaneous cry. Apgars 8/9

Dried, suctioned, admitted to NBN

Initial platelet count of 177,000

Nadir 120,000 at 36 hr of age

Bili 5.4 @ 48 hr of ageBaby 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 countsHead Ultrasound Day 1

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 it

Severely low platelet counts in the newborn < 20,000 /microL Normal maternal platelet countNeonatal Alloimmune Thrombocytopenia (NAIT)Most severe complication is intraventricular hemorrhageOccurs in 10-20% of affected newborns - occurs in utero

Neonatal Alloimmune ThrombocytopeniaRate of recurrence in future pregnancies75%-90%

As severe or more severe than previous

Fetal therapiesIn utero platelet transfusions

Maternal therapiesIVIGCorticosteroidsWhich 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 12-24 hours to collect and process. 15Which 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 12-24 hours to collect and process. 16

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/microLWhat is the definition of neonatal thrombocytopenia?Platelet count < 150,000 /microL

Actually, platelet count < 5th percentile

5th percentile decreases with decreasing gestational age34-36 weeks 123, 100 /microL32 weeks 104, 200 /microL

J Perinatol. 2009;29(2):130DefinitionPlatelet count < 150,000/microLEnsure a central sampleClumping with capillary specimens

Mechanisms of ThrombocytopeniaIncreased destruction

Decreased production

The most likely physical symptom of neonatal thrombocytopenia is:

a. Petechiae

b. Bruising

c. Oozing from the umbilical cord

d. No symptomsThe 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

Treatment with which of the following medications increases the risk of thrombocytopenia in premature infants:

a. Quinidine

b. Digoxin

c. Indomethacin

d. Heparin

e. All of the aboveQuinidine antiarrythmic, blocks Na channels

Digoxin cardiac medication used to slow the HR in CHF26Treatment with which of the following medications increases the risk of thrombocytopenia in premature infants:

a. Quinidine

b. Digoxin

c. Indomethacin

d. Heparin

e. 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 mediated27If 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 Thrombocytopenia in a Well, Term NewbornWell, Term Newborn Maternal historyHistory 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 moms platelet count?Decreased -- may be autoimmuneNormal may be autoimmune of alloimmune(Auto)Immune Thrombocytopenia(1st and early 2nd trimester)Antibodies coat platelets

When traversing the spleen, the platelets are eaten by splenic macrophages

At birth, infants have minimal splenic function

After birth, splenic function increases and risk of severe thrombocytopenia .

Splenic Function at BirthNot functional at birth

Howell-Jolly bodies on smear DNA remnants left over in RBC

Usually Howell-Jolly bodies removed on passage of RBC thru spleen

Immune ThrombocytopeniaMust follow neonates platelet levels closely after birthEspecially as splenic function improves

Monitoring the fetus during pregnancy and labor is no longer recommendedWhich immunoglobulin does not cross the placenta?a. IgA

b. IgE

c. IgM

d. IgGWhich 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

35Gestational ThrombocytopeniaMild and asymptomatic thrombocytopeniaNo past history of thrombocytopenia (except possibly during a previous pregnancy)Occurrence during late gestationNo association with fetal thrombocytopeniaSpontaneous resolution after delivery

Gestational ThrombocytopeniaConsidered benignMild and transient ITP?Less antibodies compared to ITPNo thrombocytopenia in neonate

To make the diagnosis:Thrombocytopenia not severeOccurs during last part of pregnancy/termPlatelet count returns to normal after pregnancyInfants platelet count is normal

The PlacentaMay reveal:Congenital infection (CMV, syphilis)Vasculopathy (Preeclampsia)HemorrhageInfarctsThrombiVascular malformations

Placenta with syphilis acute/chronic villitis, spirochetes noted on stainCMV, Herpes viral inclusions noted with special stains38Maternal Pre EclampsiaEstimated 1 in 100 births

Thrombocytopenia, neutropenia in newbornsDecreased productionNeutrophil, platelet inhibitor

Present at birth Nadir is 2-4 days of ageThrombosisIf 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 40Thrombocytopenia in a Sick, Term NewbornBirth AsphyxiaTrue mechanism is unknownMay relate to hypoxia

Bacterial InfectionMechanismDisseminated intravascular coagulation

Platelet aggregation caused by bacterial products on platelet membranes

Injury to megakaryocytes tooMegakaryocyte giant cell in bone marrow which produces plt43Congenital InfectionMost common:Cytomegalovirus (CMV)

Others:ToxoplasmosisHerpesRubella

Disseminated Intravascular CoagulationSystemic process producing:Thrombosis Hemorrhage

Characterized 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 fibrinolysis

Preterm infants have hyporeactive plat compared to term infants.46Disseminated Intravascular CoagulationDue to SepsisAsphyxia (acidosis)Meconium aspirationSevere respiratory distress syndrome

Syndromes with ThrombocytopeniaThrombocytopenia, Absent Radii (TAR)

Kasabach-Merritt SyndromeCapillary Hemangiomas

DIC

ThrombocytopeniaShortened platelet survival Sequestration in vascular malformation

Tx is pred, vincristine, cyclophosphamide

**abnormal endothelium and convoluted architecture of the tumor vasculature promote platelet adhesion and trapping [12]. Platelet aggregation and activation result in thrombocytopenia, consumption of fibrinogen, and ongoing fibrinolysis, leading to intralesional bleeding and tumor enlargement 51Wiskott-Aldrich SyndromeX-linkedMPV (mean platelet volume) 3-5 fL (nl 7-10)

EczemaImmunodeficiencyThrombocytopeniaThrombocytopenia with small plateletsThis condition primarily affects males.WBC are nonfunctionalfL =metric unit of volume equal to 1015 (femtoliter)

52Summary PointsNeonatal Thrombocytopenia Platelet levels < 150,000

Neonatal Alloimmune ThrombocytopeniaSeverely low fetal platelet levelsMaternal platelet value normal

Obtain a good accurate specimenCentral specimen

ReferencesNeoReviews Vol. 14 No. 2 February 1, 2013, pp. e74 -e82

Incidence and Consequences of Neonatal Alloimmune Thrombocytopenia: A Systematic Review. Pediatrics. 2014 Mar 3.

Neonatal Thrombocytopenia, Up to Date 2014.

Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD, SO. J Perinatol. 2009;29(2):130