Neonatal Hematology for the Primary Care Physician

1. Neonatal Hematology for the Primary Care Physician Vlad C. Radulescu, M.D. University of Kentucky

2. 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

3. 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

4. Normal Newborn CBC • Hemoglobin • Red blood cell indices : Mean Corpuscular Volume • Peripheral smear

5. 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

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

7. Hemoglobin Full term Premature 1200 -2350 g Premature <1200 g Adapted from: Nathan and Oski Hematology of Infancy and childhood, 7th ed.

8. Mean Corpuscular Volume Data extracted from: The Harriet Lane Handbook, 19th edition, table 14-1

9. Normal Adult Blood Smear

10. Neonatal Blood Smear

11. 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 newborn • 2/3 had Bart’s Hemoglobin • Suggestive of alpha thalassemia

12. Case #1 : 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

13. Anemia in the Newborn

14. Anemia in the Newborn

15. Anemia in the Newborn • 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?

16. Evaluation of Anemia in the Newborn • 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

17. Anemia through blood loss • Fetal- maternal transfusion • Rupture of the cord • Laceration of the placenta • Internal hemorrhage • Intracranial • Retroperitoneal • Intrathoracic • Intraabdominal

18. Anemia due to hemolysis • Immune hemolysis • Maternal alloimmunization to fetal RBC antigens • Maternal auto-antibodies ( Lupus) • Non-Immune Hemolysis • Enzymes • G6PD • RBC membrane • spherocytosis • Hemoglobin • Thalassemia, Hgb. SS

19. 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

20. 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 hemolysisif • they can activate complement • promote cell mediated cytotoxicity

21. 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

22. Hemolytic Disease of the Newborn • 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

23. Anemia through decreased production • 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

24. Anemia of prematurity • 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

25. Hemoglobin Screening in Newborns

26. 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 sepsis • Splenic sequestration

27. 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.

28. Normal variants 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

29. Hemoglobin Switching during development

30. Normal newborn • Screening test: FA • Hemoglobin electrophoresis: • Hgb F 60-90% • Hgb A1 10-40% • Hgb A2 < 1 %

31. Sickle Cell Syndromes

32. Sickle Cell Syndromes: Interventions • 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

33. Thalassemia Syndromes

34. Globin Genes

35. Alpha Thalassemia

36. Alpha Thalassemia • 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

37. Non- Sickle Hemoglobinopathies

38. Carriers of Hemoglobin Variants

39. 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

40. Hemostatic abnormalities in the newborn

41. 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

42. Hemostatic abnormalities: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

43. Laboratory evaluation • CBC • PT • PTT • Fibrinogen • Platelet Function Analysis • Normal values*

44. Neonatal Thrombocytopenia

45. 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

46. 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

47. Thrombocytopenia in the well -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)

48. Thrombocytopenia in the well -looking newborn • Newborn exam • Normal • NAIT • Maternal ITP • Maternal drug exposure • Congenital abnormalities • Thrombocytopenia absent radii syndrome (TAR) • Fanconi anemia • Hepatosplenomegaly • Infection • Leukemia

49. 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

50. 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