4  Pediatric Hematology: Selected Topics

Key Points
  • Age-appropriate normal values critical; neonatal values differ markedly from childhood
  • Sick newborns ↑ risk cytopenias from poor marrow reserve
  • Severe neonatal cytopenias: immune-mediated (maternal-fetal Ag mismatch) or inherited
  • Childhood hematologic conditions mostly benign/inherited; malignancy rare
  • ITP in children: usually acute/benign; observation alone for asymptomatic cutaneous disease
  • Neonatal & childhood thrombosis: typically provoked (CVL, infection) or inherited

4.1 Overview

  • Developmental hematology: Distinct etiologies & age-appropriate reference ranges from adults
  • Neonatal & childhood parameters differ substantially from adult norms

4.2 Anemia in Newborns

4.2.1 Etiologies

  • Polycythemia at birth: Hb ↑, Hct ↑, MCV ↑ (fetal RBC production in hypoxic environment)
    • Day 1 normal: Hb 19.3 ± 2.2 g/dL, Hct 61 ± 7.4% (see Table 4-1)
    • Normal childhood Hb = anemia in newborn
    • Physiologic nadir: Hb 10.7 ± 0.9 g/dL at 6-9 wks (earlier/worse in preterm)
  • Hemolytic anemia: Intrinsic (enzyme, membrane, Hgb) or extrinsic (immune, infection)
    • Intrinsic immune → rare in developed countries w/ screening & RhIG
    • Rh-immunization: most common cause neonatal alloimmune HD worldwide
    • Non-immune HD: high morbidity
  • Hypoproliferative anemia: Congenital infections (CMV, HSV, toxo), drug suppression, inherited
    • Diamond-Blackfan anemia (DBA): congenital RBC aplasia, ~1/200,000 births
      • Presents: anemia, anomalies (thumb, cardiac, renal), ↓ retic
      • Steroid responsive; ~5% aplasia at age 1 yr

4.2.2 Management

  • Assess etiology & hemodynamic status
  • Stable mild anemia: observation only
  • Severe anemia or cardiac compromise: packed RBC or exchange transfusion
  • Thresholds vary by center & clinical context

4.3 Anemia in Children

4.3.1 Approach

  • Asymptomatic anemia: often incidental discovery at routine exam
  • Initial labs: CBC w/ reticulocyte, consider Fig 4-1 diagnostic algorithm

4.3.2 Microcytic Anemia

  • Iron deficiency anemia (IDA): most common, diagnosed 1-2 yrs
    • Maternal iron depletes 4-6 mo; child requires dietary iron intake
    • Risk: exclusively breastfed w/o iron supplement, cow’s milk <6 mo, unfortified formula
    • Tx: oral iron (inexpensive, adequate response); dietary counseling
  • Thalassemia trait: microcytic w/ normal/↑ iron stores

4.3.3 Macrocytic Anemia

  • Vitamin B12/folate deficiency: distinguish from trisomy 21 (also macrocytic)
  • Evaluate carefully; marrow failure must be excluded

4.3.4 Hemolytic Anemia

  • Intrinsic causes:
    • Enzyme: G6PD deficiency (precipitants: infection, fava beans, oxidative stress)
    • Membrane: hereditary spherocytosis (HS), MCHC 36 g/dL sensitive/specific
    • Hemoglobinopathy: sickle cell, other (see Ch 11, 13)
  • Extrinsic (immune-mediated):
    • IgG warm-reactive (good prognosis, ~77% self-limited) or IgM cold-reactive
    • Management similar to adults (see Ch 13)
    • All hemolytic anemia: ↑ retic count, review PB smear
  • Transient erythrocytopenia of childhood (TEC):
    • Normocytic anemia from brief illness, ages 9-36 mo
    • Suspect: acute anemia onset in healthy child, normal exam
    • Tx: observe, transfuse symptomatic if needed
    • Follow until resolution w/ PB smear & retic to exclude inherited HA

4.4 Neutropenia in Newborns

4.4.1 Non-immune Mediated

  • Pathophysiology: Underdeveloped marrow (myeloid reserve), sepsis, ↑ consumption
  • Associated w/ in-utero stress (pregnancy-induced HTN)
  • Usually transient; resolves w/ underlying illness

4.4.2 Immune Mediated

  • Neonatal alloimmune neutropenia (NAIN):
    • Maternal IgG cross-placenta → binds paternal Ag on infant neutrophils
    • Antigens: HNA-1, HNA-3 (most common)
    • Diagnosis: confirm Ag difference (maternal vs paternal), maternal IgG to paternal cells
    • Risk: profound neutropenia → sepsis, meningitis, otitis
    • Tx: G-CSF 5 mg/kg/d in severe cases

4.5 Neutropenia in Children

4.5.1 Acquired

  • Autoimmune neutropenia: ANC <1.5 × 10³/μL, primarily <3 yrs
  • Most resolve spontaneously within 2-3 yrs
  • Tx: treat infections; antibody testing low sensitivity (negative ≠ exclude)

4.5.2 Inherited/Benign

  • Duffy-null phenotype [Fy(a-b-)] common in African, Arabian, Yemenite Jewish descent
    • ANC ~1.0 × 10³/μL, stable over time
    • No infections or abnormal exam findings
    • Tx: reassurance only

4.6 Thrombocytopenia in Newborns

4.6.1 Approach

  • Definition: Plt <150 × 10⁹/L; severe <50 × 10⁹/L
  • 25% NICU admissions experience thrombocytopenia from limited marrow capacity
  • Early (≤72 h): antenatal/perinatal events (asphyxia, IUGR, maternal HTN, intrauterine infection, viral)
  • Late (>72 h): postnatal events (NEC, late-onset sepsis)

4.6.2 Immune-Mediated Thrombocytopenia

  • Autoimmune: maternal IgG crosses placenta
    • May be primary or 2° to ITP/SLE
    • Presents days after delivery
    • Risk of bleeding low; many managed w/ observation alone
    • If tx needed: IVIG preferred (limit transfusions)
  • Neonatal alloimmune thrombocytopenia (NAIT):
    • Suspect: severe thrombocytopenia, normal maternal Plt, negative maternal hx
    • Maternal antibodies to paternal HPA on infant Plt (mother lacks Ag)
    • Common: HPA-1a, HPA-1b, HPA-5b
    • Risk: ICH 10-56% depending on severity
    • Tx: maternal platelet transfusions (mother’s Plt compatible w/ infant antibodies)

4.7 Thrombocytopenia in Children

4.7.1 Approach

  • Initial labs: CBC, PT, aPTT, platelet count; assess bleeding
  • Peripheral venipuncture (avoid heparin contamination)
  • Detailed hx & physical exam

4.7.2 Platelet Destruction

  • Immune thrombocytopenic purpura (ITP):

    • Most common cause in children
    • Usually acute, self-limited good prognosis

  • Microangiopathic hemolytic anemia: TTP, HUS, DIC (see Ch 9, 24, 25)

  • Heparin-induced thrombocytopenia (HIT): immune-mediated (see detail elsewhere)

  • Kasabach-Merritt phenomenon:

    • Thrombocytopenia + coagulopathy w/ giant vascular tumor
    • Presents infancy/early childhood
    • Tx: sildenafil, vincristine, corticosteroids
    • Similar coagulopathy seen in complex vascular malformations

4.7.3 Platelet Underproduction

  • Acquired: aplastic anemia, MDS, marrow infiltration
  • Inherited thrombocytopenias: diverse disorders (see Ch 20)
    • Review family hx, physical exam, PB morphology for clues
    • Macrothrombocytopenia:
      • MYH9-related disease (AD)
      • Bernard-Soulier syndrome (AR)
      • GATA1 mutations (X-linked recessive)
      • Gray platelet syndrome (variable)
    • Thrombocytopenia w/ absent radii (TAR)
    • Normocytic thrombocytopenia: congenital marrow abnormalities
    • Wiskott-Aldrich syndrome (X-linked): ↓ Plt, immunodeficiency, eczema
      • Requires immunologist coordination

4.8 Coagulopathy in Newborns

4.8.1 Approach

  • Knowledge of normal range essential (factor levels physiologically ↓)

  • Vitamin K-dependent factors particularly low

  • PT & aPTT physiologically prolonged in term & preterm (compare to refs)

  • Sick neonates: sepsis, asphyxia, DIC → coagulation abnormalities

  • Screening tests: PT, aPTT, Plt; specific factor assays if abnormal

  • Unexpected bleeding (circumcision, birth, not explained by disorder) → investigate

4.8.2 Isolated Prolonged aPTT

  • Most common inherited: Factor XII (Hageman) deficiency, Factor XI deficiency
    • Often benign; diagnose w/ factor assays

4.8.3 Isolated Prolonged PT

  • Vitamin K deficiency (“hemorrhagic disease of newborn”):

    • All hospital births: vitamin K prophylaxis
    • Home deliveries: ↑ incidence; risk of ICH
    • Tx: vitamin K 1-5 mg IV/IM

  • Lupus anticoagulant: rule out if isolated prolonged aPTT, no bleeding

  • Other factor deficiencies: II, V, VII, X (consider if hx of bleeding)

    • Factor VIII, IX: X-linked (hemophilia A/B)
    • VWD: consider if prolonged aPTT

4.8.4 Normal PT & aPTT, Bleeding Hx

  • Factor XIII deficiency: rare, can’t cross-link fibrin
    • Normal PT/aPTT, abnormal bleeding

4.9 Coagulopathy in Children

4.9.1 Approach

  • Hx & screening: CBC, PT, aPTT
  • Additional testing per abnormal findings
  • Labs: collect via peripheral venipuncture (heparin contamination risk)

4.9.2 Isolated Prolonged aPTT

  • Exclude lab error, heparin contamination
  • Rule out lupus anticoagulant if no bleeding
  • If bleeding hx: evaluate for factor deficiency (VIII, IX, XI, XII, XIII)

4.9.3 Table 4-1: Normal Hematologic Values for Newborns

Normal hematologic values for newborns
Parameter Term newborn day 1 ±SD* Healthy preterm newborn (30-38 wk) cord blood*
Hb (g/dL) 19.3 ± 2.2 17.0 ± 2.2
Hct (%) 61 ± 7.4 53.0 (45-59)
MCV (fL) 119 ± 4 120.0 ± 12
RBC (10⁶/μL) 5.8 ± 0.4 —
Reticulocytes (%) 3.2 ± 1.4 Healthy preterm newborn (30-38 wk) cord blood*
Coagulation/inhibitor parameters Healthy term newborn (30-38 wk) cord blood —
PT (s) 16.7 (12.2-23) 12.6 (10-18)
INR 1.2 ± 0.2 1.3 ± 0.5
aPTT (s) 41.3 ± 5.5 104.8 (76-128)
Fibrinogen (mg/dL) 188 (89-295) 138 (125-165)
Vitamin K-dependent factors — —
Factor II activity (%) 43.3 (27-64) 27.9 (15-59)
Factor V activity (%) 89.3 (50-140) 48.9 (23-78)
Factor VII activity (%) 53.2 (25-89) 84.9 (51-162)
Factor VIII:VII (von Fa) 91.4 (38-140) 50 (27-75)
Factor IX activity (%) 31.8 (8-59) 12.3 (5-24)
Factor X activity (%) 49.8 (25-108) 25.8 (11-59)
Factor XI activity (%) 32.6 (24-48) 7.1 (24-53)
Factor XII activity (%) 69.8 (25-108) 25.8 (11-59)
Antithrombin III 57.9 (24-88) 7.1 (24-53)
Protein C (%) 28.2 (14-42) 14.1 (8-48)
Protein S (%) 35.5 (21-47) 15.9 (8-89)
Fibrin prothesis (%) 38.5 (22-53) 23.0 (15-39)
Plasminogen (%) 74.3 (53-67) 27.1 (38-49)

*Abbreviations: aPTT, activated partial thromboplastin time; Hb, hemoglobin; Hct, hematocrit; INR, international normalized ratio; MCV, mean corpuscular volume; PT, prothrombin time; RBC, red blood cell.

Pocket Blood Cell Transfusion Services, selected by donor and upper boundaries, including 10% of populations.

4.10 Thrombosis in Newborns

4.10.1 Approach

  • Prothrombotic state: Balance tilted toward thrombosis (like pregnancy)
    • ATIII mildly ↓, Protein C & S strikingly ↓ (see Table 4-1)
    • Fibrinolytic system activated at birth but plasminogen ↓
    • Physiologic stress (labor, infection) → ↑ risk
  • Uncommon; when occurs: consider DIC, cardiac, infection, familial thrombophilia

4.10.2 Protein C/S Deficiency

  • Purpura fulminans: rare, catastrophic homozygous deficiencies
    • Presents at birth w/ DIC, cutaneous necrosis
    • Tx: FFP urgently + UFH anticoagulation (do not delay)
    • Transition to warfarin once thrombosis resolves
    • Protein C concentrate if available

4.10.3 Management

  • Provoked thrombosis (CVL, sepsis): anticoagulate 3 mo or until risk factor resolved
  • Unprovoked thrombosis: rare; evaluate for inherited prothrombophilia
  • Duration therapy: see Ch 15 for detailed guidance

4.11 Thrombosis in Children

4.11.1 Approach

  • Typically provoked: CVL, infection, cardiac disease (common)
  • Unprovoked rare: when occurs, investigate anatomic/inherited causes
  • Evaluation: hx ± viral illness, trauma, exam for thrombophilia

4.11.2 Arterial Ischemic Stroke

  • Arteriopathies: ~50% of cases (vasculitis, dissection)

    • Dissection: carotid or vertebrobasilar w/ minor trauma
    • Dx: formal angiography ± neck vessel imaging

  • Cardioembolic: cardiac disease (arrhythmia, structural, cardiomyopathy)

  • Clinical presentation (variable):

    • Acute hemiparesis (16-45%), altered mental status (12-24%)
    • Speech disturbance (8-25%), headache (11-85%)
    • Hx: recent viral illness, neck trauma/manipulation

  • Tx: thrombolysis or endovascular therapy if within window

4.11.3 Venous Thromboembolism

  • Provoked VTE (CVL, sepsis, immobility): anticoagulate 3 mo

    • Discontinue when risk factor resolved
    • Some trials support 6 wks if radiologic resolution, no hypercoagulable state

  • Unprovoked VTE: test for inherited thrombophilia; optimal duration unknown

  • Prophylaxis: primary prophylaxis not well-studied; varies by center

    • Cardiac surgical populations: more evidence

4.12 Bibliography

Bizzarro M, Colson E, Ehrenkranz RA. Differential diagnosis and management of anemia in the preterm. Pediatr Clin North Am. 2004;51(4):1087–1107.

Cann C, Mackie J, Monaghan E. Asthma, Rh disease, and Thrombocytopenia: a risk is not in developed. Pediatr Res. 2022;91(4):862–868.

Goldenberg NA, Manco-Johnson MJ, Abshire TC, et al. Effect of anticoagulant therapy for N-S syndrome in pediatric ischemic stroke and late blood event in patients younger than 21 years of age w/ provoked versus thromboembolism: the KIDSTROKE trial. Pediatr Blood Cancer. 2022;172(12):129–137.

Ibanez JK, Bakkalidis CR. Coagulation disorders. Pediatr Rev. 2003;24(3):83–91.

Mitsch V, Zumno R, Vettese J. Postural changes in von red cell distribution: the J Pediatr. 2003;143(1):19–22.

Merz LE, Story CM, Obel MA, et al. Absolute neutrophil count by Duffy status among healthy black and African American adults. Blood. 2003;70(3):317–330.

Neuspiel P, Chan AR, Greenberg NA, et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis. Blood. 2011;118(5):1–14.

Newman CG, Ferrell DJ, Arnold DM, et al. Advances in Hematology. Science Care. 2019;3(23):305–386.

Petterson JA, McKee-Duffy S, Curlì BR, Aimer HB. Neonatal alloimmune neutropenia and immune transfusion in children: incidence and clinical characteristics. J Pediatr. 2014;164(2):323–338.

Taramona MB, Bond JB, Blanchette VS, et al. A Compendium in children w/ immune thrombocytopenia-related platelet count and bleeding complications. Pediatr Blood Cancer. 2014;61(3):478–488.

Valentine SL, Hensley MA, Missmyk JA, et al. Consensus recommendations for RBC transfusion practice in critical children: from the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. Pediatr Crit Care Med. 2016;19(9):884–898.

Vidal E, Santalakamur A, Oliver J, Funtion EV. Central venous catheter-related thrombosis and thromboprophylaxis in children: A systematic review. Thromb Res. 2015;136(1):161–162.

Whyte RK, Jeffries AL, Canadian Paediatric Society, Fetus and Newborn Committee. Red blood cell transfusion in newborn infants. Pediatr Child Health. 2014;19(4):213–222.