Neonatal Hematology for the Primary Care PhysicianVlad C. Radulescu, M.D.

University of Kentucky

TopicsNormal newborn hematologic parametersCommon causes of anemia in the newbornNeonatal screening for abnormal hemoglobins

Hemostatic abnormalitiesCurrent use of umbilical cord blood stem cells

Case #13 months old infant32 weeks gestation, birth weight : 2100 gSpent two weeks in NICU for respiratory distress, feeding difficulties

Feeding well, thriving, appropriate growthCBC: WBC 10,500 / fl, Hgb 9.5g /dl, MCV 95fl, platelet count 245,000 / fl

Normal Newborn CBC

HemoglobinRed blood cell indices : Mean Corpuscular VolumePeripheral smear

Neonatal changes that impact thered blood cell indices

Sudden increase in tissue oxygenation after birthDecrease erythropoietin levelsDecreased hemoglobin production

Transition from fetal hemoglobin to adult hemoglobin

Rapid growth

Hemoglobin

28 wks

32 wks

term 2 wks

1mo. 2mo. 6mo 1yr 6yrs 12 yrs

02468

101214161820

Hemoglobin

Data extracted from: The Harriet Lane Handbook, 19th edition, table 14-1

Hemoglobin

Full term

Premature 1200 -2350 gPremature

<1200 g Adapted from:

Nathan and OskiHematology of Infancy and childhood, 7th ed.

Mean Corpuscular Volume

30 w

ks

32 w

kste

rm2

wks

1 m

onth

2mon

ths

6 m

onth

s1

yr6

yrs

12 y

rs0

20

40

60

80

100

120

140

MCV

Data extracted from: The Harriet Lane Handbook, 19th edition, table 14-1

Normal Adult Blood Smear

Neonatal Blood Smear

Hemoglobin, MCV are high at birth and decrease over the first few months of life, more dramatically for the pre-term infant

MCV < 94fl in newborn2/3 had Bart’s HemoglobinSuggestive of alpha thalassemia

Case #1 : normal infant3 months old infant32 weeks gestation, birth weight : 2100 gSpent two weeks in NICU for respiratory distress, feeding difficulties

Feeding well, thriving, appropriate growthCBC: WBC 10,500 / fl, Hgb 9.5g /dl, MCV 95fl, platelet count 245,000 / fl

Anemia in the Newborn

Anemia in the Newborn

Hgb. < 13.5 g/dl

Blood Loss

Hemolysis

Failure of production

Anemia in the NewbornPresentation

Life threatening event Pallor, difficulty feeding, poor weight gain, tachycardia Incidental finding

Does it require immediate intervention? If a transfusion is indicated should any tests be done prior

to transfusion

Does the newborn have to be referred to a hematologist?

Evaluation of Anemia in the NewbornCBC

RBC indices – MCV (Mean Corpuscular Volume)

Reticulocyte count Elevated – RBC destruction ( hemolysis) or bleed Decreased – decreased RBC production

Coombs ( direct anti-globulin test) Positive in immune hemolysis

Maternal and fetal blood type Identifies mismatched in the ABO and Rh blood types that may

represent set-ups for allo-immunization

Anemia through blood loss

Fetal- maternal transfusion

Rupture of the cord

Laceration of the placenta

Internal hemorrhage Intracranial Retroperitoneal Intrathoracic Intraabdominal

Anemia due to hemolysis

Immune hemolysisMaternal

alloimmunization to fetal RBC antigens

Maternal auto-antibodies ( Lupus)

Non-Immune HemolysisEnzymesG6PD

RBC membrane spherocytosis

HemoglobinThalassemia, Hgb.

SS

Hemolytic Disease of the Newborn

The mother becomes sensitized to antigens present on fetal red blood cells Fetal- maternal hemorrhage Prior maternal transfusion

Antigens Rh ABO Kell, Duffy, Kidd

Maternal antibodies cross the placenta IgG can cross, IgM, IgA can not cross Transport increases in the 3rd trimester

Hemolytic Disease of the Newborn

Maternal antibodies bind to fetal RBC and sometimes other tissues

AB, Duffy, Kidd, Kell antigens are expressed on erythroid and non erythroid tissues

Rh, MN, SS antigens expressed only on erythroid tissues

Antibodies bound to RBC induce hemolysis if they can activate complement promote cell mediated cytotoxicity

Hemolytic Disease of the Newborn

RhD Most commonly identified antigenic stimulus Mother is Rh negative, fetus Rh positive The incidence has dropped with the use of anti-D

antibodies to decrease maternal sensitization

ABO Mother is type O, fetus is type A, B

Kell, Duffy, Kidd Maternal sensitization may be due to prior maternal blood

transfusions mismatched in the minor blood types

Hemolytic Disease of the NewbornDiagnosis:

Mismatch between maternal and newborn blood types

History of prior maternal transfusions

Combs ( Direct Antiglobulin Test) positive

Neonatal Hyperbilirubinemia

Managemnt

Anemia simple or exchange

transfusion

Hyperbilirubinemia Phototherapy Exchange transfusions

Anemia through decreased production

Physiologic anemia

Anemia of prematurity

Late anemia of the hemolytic disease of the newborn

Bone marrow failure syndromes Diamond Blackfan sdr. Fanconi sdr.

Nutritional deficiencies

Infections

Infiltrative processes Leukemia Neuroblastoma

Anemia of prematurity

Causes Low erythropoietin levels Small circulating blood

volumes Blood loss Hemolysis

Minimize blood lossPRBC transfusions

Hgb < 7 g/dl Apnea & bradycardia Tachycardia Tachypnea Poor weight gain Respiratory distress

Erythropoietin Iron supplements

Hemoglobin Screening in Newborns

Hemoglobin Screening in Newborns

Goal: early diagnosis of sickle cell disease

The first manifestations of sickle cell disease in infants may be life-threatening complications:Pneumococcal sepsisSplenic sequestration

Methodology

High performance liquid chromatography

Identifies different types of hemoglobin

Relevant for sickle cell disease: Hgb S , Hgb C

Incidental findings: Hgb H , Hgb Bart’s, Hgb E, D, etc.

HemoglobinNormal variants

Embrionic Fetal a2 g2 Adult 1 a2 b2 Adult 2 a2 d2

Abnormal variants S, D, C, E : abn. b chain Barts: 4g H: 4b

Hemoglobin Switching during development

Normal newborn

Screening test: FA

Hemoglobin electrophoresis: Hgb F 60-90% Hgb A1 10-40% Hgb A2 < 1 %

Sickle Cell SyndromesScreening test

Diagnostic possibilities

FS Hgb SSHgb S B0 thalassemia

FSCFSD

Hgb SCHgb SD

FSA Hgb S B+ thal.

Sickle Cell Trait

Sickle Cell Syndromes: Interventions

Refer to Pediatric Hematology/ repeat testingEvaluate infant for splenomegaly.Educate parents/caregivers regarding

risk of sepsis , aggressive management of fevers splenic sequestration in Sickle Cell disease

Pen V K 125 mg po bid until repeat testing confirms or rules out a sickle cell syndrome

Thalassemia Syndromes

Screening test

Diagnosis Implications

F bThalasemia majorPremature infant

Severe anemia, may need transfusionsRepeat screening

FAB aThallsemia

Variable manifestations depending on the number of affected genes

Genetic implications

Globin Genes

Alpha Thalassemia

Alpha ThalassemiaFollow-up tests:

CBC, Hemoglobin electrophoresis Consider alpha globin gene mutation analysis

Family history Ethnic origin: common in SE Asia History of anemia or microcytosis

Genetic counseling

Consider Pediatric Hematology referral

Non- Sickle HemoglobinopathiesScreening test

Diagnosis Implications

FE Hemoglobin EEHgb E b0 Thal.

Mild anemiaModerate to severe anemia

FC Hemoglobin CCHgb C b0 Thal.

Mild anemiaMild Anemia

Carriers of Hemoglobin VariantsScreening test

Diagnostic possibilities

Implications

FAS Sickle Cell Trait

Generally AsymptomaticGenetic implications

FAC Hemoglobin C trait

AsymptomaticGenetic implications

FAE Hemoglobin E trait

Asymptomatic / mild anemiaGenetic implications

FAV Variant Hemoglobin

Most likely clinically insignificant

Carriers of Hemoglobin Variants In general, no medical intervention is needed for

the patient

Genetic counseling : asses the risk of having a child with sickle cell disease or thalassemia major

For the patient future children

For the patient’s parents Evaluation of the carrier state : CBC, Hgb electrophoresis

Hemostatic abnormalities in the newborn

Case # 2

FT newborn Covered in petechiae at

birth Birthweight : 3.4kg Apgar scores: 9, 9

Case # 3

FT male newborn Birthweight : 3.5kg Apgar scores: 8, 9 Oozing for 4 hrs. at the site

of the heel-stick Develops unexpected

bleeding after circumcision

Hemostatic abnormalities:presentation

Petechial rash EcchymosesCephalohematomaSmall but prolonged bleeding at the heel-stick siteHematoma at the IM injection siteOozing form the umbilicus Bleeding with circumcision Intracranial bleeding

Laboratory evaluation

CBCPTPTTFibrinogen

Platelet Function Analysis

Normal values*

1 day 1 month

1 year

PT 14-16s 11-15s 11-14s

PTT 34-44s 35-46s 28-38s

Neonatal Thrombocytopenia

Neonatal Thrombocytopenia

Prevalence Common in the sick newborn 20-40% of NICU admissions 70-80% of very low birth weight premature newborns

Uncommon in the healthy newborn (1-2%)

Timing <72 hrs – due to prenatal or perinatal factors >72 hrs - due to postnatal factors Sepsis Necrotizing enterocolitis

Thrombocytopenia in the sick newborn

Frequently associated with: Infection Asphyxia Meconium aspiration Respiratory distress syndrome Necrotizing enterocolitis Presence of indwelling catheters

Predictor of poor prognosis Mortality Intestinal gangrene in NEC

Frequently leads to bleeding complications

Thrombocytopenia in the well -looking newborn

Maternal historyDrug ingestion Sulphonamides, valproic acid, carbamazepine, quinindine

Hypertension / Pre-eclampsia

Infections during pregnancy

Maternal ITP/ low maternal platelet count

Previous newborn with thrombocytopenia Neonatal Allo-immune Thrombocytopenia (NAIT)

Thrombocytopenia in the well -looking newbornNewborn exam

Normal NAIT Maternal ITP Maternal drug exposure

Congenital abnormalities Thrombocytopenia absent radii syndrome (TAR) Fanconi anemia

Hepatosplenomegaly Infection Leukemia

Neonatal Allo-Immune Thrombocytopenia ( NAIT)Mechanism

The mother is exposed to a Platelet antigen they do not posses The mother produces an IgG. antibody that crosses the placenta Induces thrombocytopenia in the newborn

Incidence 1:5000- 10,000 birth

May occur with the first pregnancy, more severe with subsequent pregnancies

Manifestations Thrombocytopenia Purpura Internal hemorrhage including intracranial hemorrhage

Neonatal Allo-Immune Thrombocytopenia ( NAIT)Diagnosis

Identification of maternal and paternal platelet antigens Maternal and paternal genotyping

Management Platelet transfusions IV Immunoglobulins

Subsequent pregnancies Close monitoring IV Ig. Steroids Cord blood sampling and in utero platelet transfusions

Case # 2

FT newborn Covered in petechiae at birth Birthweight : 3.4kg Apgar scores: 9, 9 Platelet count 10,000 Older brother had thrombocytopenia Maternal CBC is normal

Abnormal PT and or PTTCoagulation abnormalities:

History

Did the child receive the Vitamin K injection at birth?

Any family history of bleeding disorders?Von Willebrand diseaseFactor VIII or factor IX deficiency

Hemophilia A and B

X linked disorders Females are carriers Males have the bleeding

disorder

1/3 of cases of Factor VIII deficiency are due to new mutations, thus no family history

Hemophilia A and B

ManifestationsProlonged bleeding at the heel-stick siteCephalhematomaExcessive or prolonged bleeding with

circumcisionHematomas at the IM injection sites

Hemophilia A and B

Laboratory PT- normal PTT- prolonged Mixing studies PTT corrects with

addition of normal plasma

Factor VIII or IX level is low

Management No arterial sticks No IM injections No procedures Pressure at the site of

bleeding

Hematology consult ASAP

Factor concentrates

Case # 3

FT male newbornBirthweight : 3.5kgApgar scores: 8, 9Oozing for 4 hrs. at the site of the heel-stickDevelops unexpected bleeding after circumcisionPT 60 s , corrects to 29 s on mixing studiesMaternal great-uncle was a “free bleeder”Fct. VIII level 4%

Umbilical Cord Blood Stem Cell Transplantation

Cord blood stem cells may be used for a bone marrow transplant

Less likely to cause graft versus host diseaseDoes not need to be fully HLA matched for a

successful transplantCan be collected without any risk for the donor

Private Cord Blood Banking Service offered to parents by several for profit companies

Autologous transplant Malignant disorders rare in children no graft vs. leukemia/ tumor effect

Allogeneic transplant First degree relatives with Malignancies treatable with stem cell transplant Hemoglobinopathies ( Sickle Cell Disease, Thalassemia) Congenital Immunodeficiency Disorders Bone marrow Failure Disorders

Newborns have distinct Blood count values Hemostatic parameters

Differential diagnosis Disorders of the feto-maternal unit Immunologic responses of the mother to fetal antigens Congenital / genetic abnormalities