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Neonatal Hematology for the Primary Care Physician. Vlad C. Radulescu, M.D. University of Kentucky. Topics. Normal newborn hematologic parameters Common causes of anemia in the newborn Neonatal screening for abnormal hemoglobins Hemostatic abnormalities

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Neonatal hematology for the primary care physician

Neonatal Hematology for the Primary Care Physician

Vlad C. Radulescu, M.D.

University of Kentucky


Topics
Topics

  • Normal newborn hematologic parameters

  • Common causes of anemia in the newborn

  • Neonatal screening for abnormal hemoglobins

  • Hemostatic abnormalities

  • Current use of umbilical cord blood stem cells


Case 1
Case #1

  • 3 months old infant

  • 32 weeks gestation, birth weight : 2100 g

  • Spent two weeks in NICU for respiratory distress, feeding difficulties

  • Feeding well, thriving, appropriate growth

  • CBC:

    • WBC 10,500 / fl,

    • Hgb 9.5g /dl, MCV 95fl,

    • platelet count 245,000 / fl


Normal newborn cbc
Normal Newborn CBC

  • Hemoglobin

  • Red blood cell indices : Mean Corpuscular Volume

  • Peripheral smear


Neonatal changes that impact the red blood cell indices
Neonatal changes that impact thered blood cell indices

  • Sudden increase in tissue oxygenation after birth

    • Decrease erythropoietin levels

    • Decreased hemoglobin production

  • Transition from fetal hemoglobin to adult hemoglobin

  • Rapid growth


Hemoglobin
Hemoglobin

Data extracted from:

The Harriet Lane Handbook,

19th edition,

table 14-1


Hemoglobin1
Hemoglobin

Full term

Premature

1200 -2350 g

Premature

<1200 g

Adapted from:

Nathan and Oski

Hematology of Infancy and childhood, 7th ed.


Mean corpuscular volume
Mean Corpuscular Volume

Data extracted from:

The Harriet Lane Handbook,

19th edition,

table 14-1





Case 1 normal infant
Case # first few months of life, more dramatically for the pre-term infant1 : normal infant

  • 3 months old infant

  • 32 weeks gestation, birth weight : 2100 g

  • Spent two weeks in NICU for respiratory distress, feeding difficulties

  • Feeding well, thriving, appropriate growth

  • CBC:

    • WBC 10,500 / fl,

    • Hgb 9.5g /dl, MCV 95fl,

    • platelet count 245,000 / fl


Anemia in the newborn
Anemia in the Newborn first few months of life, more dramatically for the pre-term infant


Anemia in the newborn1
Anemia in the Newborn first few months of life, more dramatically for the pre-term infant


Anemia in the newborn2
Anemia in the Newborn first few months of life, more dramatically for the pre-term infant

  • Presentation

    • 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 newborn
Evaluation of Anemia in the Newborn first few months of life, more dramatically for the pre-term infant

  • CBC

  • 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
Anemia through blood loss first few months of life, more dramatically for the pre-term infant

  • Fetal- maternal transfusion

  • Rupture of the cord

  • Laceration of the placenta

  • Internal hemorrhage

    • Intracranial

    • Retroperitoneal

    • Intrathoracic

    • Intraabdominal


Anemia due to hemolysis
Anemia due to hemolysis first few months of life, more dramatically for the pre-term infant

  • Immune hemolysis

    • Maternal alloimmunization to fetal RBC antigens

    • Maternal auto-antibodies ( Lupus)

  • Non-Immune Hemolysis

    • Enzymes

      • G6PD

    • RBC membrane

      • spherocytosis

    • Hemoglobin

      • Thalassemia, Hgb. SS


Hemolytic disease of the newborn
Hemolytic Disease of the Newborn first few months of life, more dramatically for the pre-term infant

  • 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 newborn1
Hemolytic Disease of the Newborn first few months of life, more dramatically for the pre-term infant

  • 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 hemolysisif

    • they can activate complement

    • promote cell mediated cytotoxicity


Hemolytic disease of the newborn2
Hemolytic Disease of the Newborn first few months of life, more dramatically for the pre-term infant

  • 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 newborn3
Hemolytic Disease of the Newborn first few months of life, more dramatically for the pre-term infant

  • Diagnosis:

    • 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
Anemia through decreased production first few months of life, more dramatically for the pre-term infant

  • Physiologic anemia

  • Anemia of prematurity

  • Late anemia of the hemolytic disease of the newborn

  • Bone marrow failure syndromes

    • Diamond Blackfansdr.

    • Fanconisdr.

  • Nutritional deficiencies

  • Infections

  • Infiltrative processes

    • Leukemia

    • Neuroblastoma


Anemia of prematurity
Anemia of prematurity first few months of life, more dramatically for the pre-term infant

  • Causes

    • Low erythropoietin levels

    • Small circulating blood volumes

    • Blood loss

    • Hemolysis

  • Minimize blood loss

  • PRBC 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 first few months of life, more dramatically for the pre-term infant


Hemoglobin screening in newborns1
Hemoglobin Screening in Newborns first few months of life, more dramatically for the pre-term infant

  • Goal: early diagnosis of sickle cell disease

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

    • Pneumococcal sepsis

    • Splenic sequestration


M ethodology
M first few months of life, more dramatically for the pre-term infantethodology

  • 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.


Hemoglobin2

Normal variants first few months of life, more dramatically for the pre-term infant

Embrionic

Fetal a2 g2

Adult 1 a2 b2

Adult 2 a2 d2

Abnormal variants

S, D, C, E : abn. bchain

Barts: g4

H: b4

Hemoglobin


Hemoglobin switching during development
Hemoglobin Switching during development first few months of life, more dramatically for the pre-term infant


Normal newborn
Normal newborn first few months of life, more dramatically for the pre-term infant

  • Screening test: FA

  • Hemoglobin electrophoresis:

    • Hgb F 60-90%

    • Hgb A1 10-40%

    • Hgb A2 < 1 %


Sickle cell syndromes
Sickle Cell Syndromes first few months of life, more dramatically for the pre-term infant


Sickle cell syndromes interventions
Sickle Cell Syndromes: Interventions first few months of life, more dramatically for the pre-term infant

  • Refer to Pediatric Hematology/ repeat testing

  • Evaluate 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
Thalassemia first few months of life, more dramatically for the pre-term infant Syndromes


Globin genes
Globin Genes first few months of life, more dramatically for the pre-term infant


Alpha thalassemia
Alpha Thalassemia first few months of life, more dramatically for the pre-term infant


Alpha thalassemia1
Alpha first few months of life, more dramatically for the pre-term infantThalassemia

  • Follow-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 hemoglobinopathies
Non- Sickle Hemoglobinopathies first few months of life, more dramatically for the pre-term infant


Carriers of hemoglobin variants
Carriers of Hemoglobin Variants first few months of life, more dramatically for the pre-term infant


Carriers of hemoglobin variants1
Carriers of Hemoglobin Variants first few months of life, more dramatically for the pre-term infant

  • 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
Hemostatic first few months of life, more dramatically for the pre-term infant abnormalities in the newborn


  • Case # 2 first few months of life, more dramatically for the pre-term infant

  • 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
Hemostatic first few months of life, more dramatically for the pre-term infantabnormalities:presentation

  • Petechial rash

  • Ecchymoses

  • Cephalohematoma

  • Small but prolonged bleeding at the heel-stick site

  • Hematoma at the IM injection site

  • Oozing form the umbilicus

  • Bleeding with circumcision

  • Intracranial bleeding


Laboratory evaluation
Laboratory evaluation first few months of life, more dramatically for the pre-term infant

  • CBC

  • PT

  • PTT

  • Fibrinogen

  • Platelet Function Analysis

  • Normal values*


Neonatal thrombocytopenia
Neonatal Thrombocytopenia first few months of life, more dramatically for the pre-term infant


Neonatal thrombocytopenia1
Neonatal Thrombocytopenia first few months of life, more dramatically for the pre-term infant

  • 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
Thrombocytopenia in the sick newborn first few months of life, more dramatically for the pre-term infant

  • 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
Thrombocytopenia in the first few months of life, more dramatically for the pre-term infantwell -looking newborn

  • Maternal history

    • Drug 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 newborn1
Thrombocytopenia in the first few months of life, more dramatically for the pre-term infantwell -looking newborn

  • Newborn 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
Neonatal first few months of life, more dramatically for the pre-term infantAllo-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 nait1
Neonatal first few months of life, more dramatically for the pre-term infantAllo-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
Case # 2 first few months of life, more dramatically for the pre-term infant

  • 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 ptt coagulation abnormalities
Abnormal PT and or PTT first few months of life, more dramatically for the pre-term infantCoagulation abnormalities:

  • History

    • Did the child receive the Vitamin K injection at birth?

    • Any family history of bleeding disorders?

      • Von Willebrand disease

      • Factor VIII or factor IX deficiency


Hemophilia a and b
Hemophilia A and B first few months of life, more dramatically for the pre-term infant

  • 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 b1
Hemophilia A and B first few months of life, more dramatically for the pre-term infant

  • Manifestations

    • Prolonged bleeding at the heel-stick site

    • Cephalhematoma

    • Excessive or prolonged bleeding with circumcision

    • Hematomas at the IM injection sites


Hemophilia a and b2
Hemophilia A and B first few months of life, more dramatically for the pre-term infant

  • 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
Case # 3 first few months of life, more dramatically for the pre-term infant

  • 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

  • PT 60 s , corrects to 29 s on mixing studies

  • Maternal great-uncle was a “free bleeder”

  • Fct. VIII level 4%


Umbilical cord blood stem cell transplantation
Umbilical Cord first few months of life, more dramatically for the pre-term infantBlood Stem Cell Transplantation

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

    • Less likely to cause graft versus host disease

    • Does not need to be fully HLA matched for a successful transplant

    • Can be collected without any risk for the donor


Private cord blood banking
Private Cord Blood Banking first few months of life, more dramatically for the pre-term infant

  • 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 first few months of life, more dramatically for the pre-term infant

    • Blood count values

    • Hemostatic parameters

  • Differential diagnosis

    • Disorders of the feto-maternal unit

    • Immunologic responses of the mother to fetal antigens

    • Congenital / genetic abnormalities


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