Indirect (Unconjugated) Hyperbilirubinemia


  • See Chapter 35 (Gastroenterology).



  • Occurs in 1%–5% of newborns (platelet count <150,000/mm3); severe thrombocytopenia (<50,000/mm3) occurs in 0.1%–0.5%.
  • Sick newborns have an incidence as high as 22%–50%.

eFigure 37-1

Brief differential diagnosis for thrombocytopenia in neonates.

*One of the most common causes of thrombocytopenia is improper specimen collection; confi rm with peripheral smear to exclude laboratory error

Immune Thrombocytopenias: Decreased Platelet Survival

Comparison of Immune-Mediated Causes of Thrombocytopenia in Neonates


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Autoimmune Thrombocytopenia

Alloimmune Thrombocytopenia


  • Antibody made against maternal platelet antigen; antigen is also found on fetal platelets

  • Antibody made against paternal platelet antigen; antigen is also found on fetal platelets

Clinical findings

  • Mild to moderate thrombocytopenia (20,000–50,000/mm3)
  • Petechiae and bruising are common
  • Mother usually has thrombocytopenia or history of ITP
  • Maternal platelets may be normal because she may have adequate production of platelets to compensate for increased destruction

  • May lead to severe thrombocytopenia (<20,000/mm3) and in utero hemorrhagic complications (∼20% of infants with NAIT have intracranial hemorrhages)
  • Infant appears healthy but may have petechiae and bruising
  • Maternal platelet count is usually normal
  • Most common antigen is HPA-1


  • Maternal autoantibodies cross the placenta and bind to neonatal platelets, causing increased destruction

  • Maternal alloantibodies cross the placenta and bind to neonatal platelets, causing increased destruction


  • Identification of autoantibody in maternal serum against antigens on her own platelets

  • Identification of alloantibody using paternal platelets and maternal serum

Prenatal management

  • Use of steroids to prevent fetal thrombocytopenia is controversial; not shown to be of benefit
  • Use of immune globulin to prevent fetal thrombocytopenia is controversial; not shown to be of benefit
  • PUBS (Percutaneous Umbilical cord Blood Sampling) seems to be safe but is invasive, and its use is controversial; not shown to be of benefit
  • Mode of delivery (cesarean section vs vaginal) does not change maternal or fetal outcomes; cesarean section is not shown to be of benefit

  • Use of steroids, immune globulin, PUBS, fetal scalp platelet counts during labor, and elective cesarean delivery can be used on a case-by-case basis

Postnatal management

  • May include platelet transfusions (pooled donor), steroids, immune globulin or exchange transfusion
  • Transfuse platelets for levels <20,000/mm3 or for clinical bleeding

  • If diagnosis is made before delivery, maternal platelets are collected 24 h before delivery
  • If infant requires platelet transfusions postnatally, use collected maternal platelets that have been washed and resuspended in plasma

If emergent transfusion is required and maternal platelets are not available, either maternal whole blood or HPA-1–negative donor platelets may be used

Immune globulin at a dose of 1–2 g/kg total given over 2–3 h for 2–5 d has been reported with some success

Steroids can be considered for persistent thrombocytopenia

Other Causes of Thrombocytopenia with Decreased Platelet Survival

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Platelet consumption

  • DIC

  • Treat underlying disorder (remember that DIC is a secondary phenomenon)
  • Replenish clotting factors and supplement with vitamin K as needed

  • Giant hemangioma (Kasabach-Merritt syndrome)

  • Transfuse platelets as necessary
  • Replenish clotting factors as needed
  • Treatment of hemangioma may involve corticosteroid administration, surgical removal, or embolization of hemangioma

  • NEC

  • Treatment of underlying disease
  • Transfuse platelets and replenish clotting factors as needed
Platelet destruction

  • Immune thrombocytopenias

  • See table immediately prior
  • Drug-induced thrombocytopenia is treated with removal of the offending agent

  • Hypersplenism

  • Associated with viremic illnesses, portal hypertension
  • Transfuse platelets as needed
  • Splenectomy in severe cases
Intrinsic platelet dysfunction

  • Wiskott-Aldrich syndrome

  • Transfuse platelets as needed

  • May-Hegglin anomaly

  • Bernard-Soulier syndrome

Thrombocytopenia with Decreased Production

  • Injury to megakaryocytes
  • Marrow failure or infiltration
  • Congenital thrombocytopenia

    • Thrombocytopenia-absent radii (TAR) syndrome
    • Fanconi anemia
    • Familial thrombocytopenia

  • Recall that thrombocytopenia may also be seen in infants with erythroblastosis fetalis (likely caused by hepatic and splenic platelet trapping or consumption caused by DIC) and after exchange transfusion with platelet-poor blood.



  • Defined as a central hematrocrit >65% (free-flowing venous or arterial hematocrit)

    • Heelstick hematocrit can be as much as 5%–20% above the true, central hematocrit.
    • Warming the heel before specimen collection decreases this discrepancy.

  • Pathologic symptoms of polycythemia are attributable to hyperviscosity (locally, tissue hypoxia, acidosis, hypoglycemia, and microvascular thrombosis). Hyperviscosity may be caused by conditions other than polycythemia.
  • Blood viscosity increases exponentially with hematocrit >65%.

Brief Differential Diagnosis of Polycythemia in Neonates


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Possible Mechanism



Increased transfer of RBC mass from placenta to infant at the time of delivery

Delayed cord clamping

Cord stripping

Positioning the infant below the placental vascular bed

Maternal–fetal hemorrhage

Intrapartum asphyxia or acidosis

Twin-to-twin transfusion

Forceful uterine contractions

Increased fetal erythropoiesis

Stimulus for increased fetal erythropoiesis from fetal hypoxia

Placental insufficiency related:

  • Maternal hypertension
  • Chronic placental abruption
  • Postmaturity
  • Cyanotic heart disease
  • IUGR
  • Maternal cigarette smoking

Stimulus for increased fetal erythropoiesis from increased oxygen consumption

Infant of a diabetic (chronic or gestational) mother

Congenital hyperthyroidism

Beckwith-Wiedemann syndrome

Congenital adrenal hyperplasia


Trisomies 13, 18 and 21

Decreased relative plasma volume

Concentration of RBC mass in smaller volume of plasma (hemoconcentration)


Clinical Presentation

  • Multiple organ systems may be affected.
  • The clinical presentation depends on the extent of involvement of each system.

Possible Manifestations of Polycythemia in Neonates by Organ System


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Organ System





Venous thrombosis

Poor feeding


Cerebral infarction


Tremors or jitteriness

Vasomotor instability



Respiratory distress



Pulmonary hypertension


Feeding intolerance

NEC (association)


Decreased GFR




Renal vein thrombosis









Other thromboses


  • Partial exchange transfusion (see below) can be done to lower hematocrit and decrease blood viscosity, but this treatment is controversial because data do not suggest an improvement in long-term neurologic outcomes over infants not subjected to partial exchange transfusion.
  • Use of partial exchange transfusion should be done in accordance with the institution’s guidelines and policies.

Management of Polycythemia


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Central Hematocrit 65%–70%

Central Hematocrit >70%


Expectant management

Increase fluid administration by 20–30 mL/kg/day and repeat HCT within 4–6 h

Partial exchange transfusion


Partial exchange transfusion

Partial exchange transfusion

  • To calculate the volume of blood to be exchanged to bring the hematocrit to 50%–60%, the following equation may be used:

Neonatal Thrombosis



  • Main procoagulant protein: Thrombin (both intrinsic and extrinsic pathways result in formation of thrombin from prothrombin) converts fibrinogen to a fibrin clot.
  • Inhibitors of coagulation: Antithrombin, heparin cofactor I, protein C, protein S, TFPI. Remember that antithrombin activity is potentiated by heparin.
  • Main fibrinolytic protein: Plasmin converts fibrin to fibrin degradation products and D-dimers.
  • Proteins are synthesized by the fetus. Maternal and fetal coagulant proteins do not cross the placenta.
  • In neonates, there are decreased concentrations of both procoagulant and anticoagulant proteins.
  • Tendency toward prolonged PT and aPTT, but healthy neonates do not show a tendency toward bleeding or thrombosis.
  • Thrombin inhibition by plasmin is diminished compared with adults.
  • Platelet number and lifespan are the same as in adults, but it is normal to have a shortened bleeding time.

Risk Factors

  • Thrombosis occurs in neonates with the highest frequency compared with any other time in childhood.
  • Indwelling vascular catheters are the single largest risk factor for developing thrombotic disease and are associated with >80% venous and 90% arterial thrombotic complications.
  • Renal vein thrombosis is the most common non–catheter-associated pathologic thrombosis.

    • Risk factors
    • Infection
    • Increased blood viscosity (ie, polycythemia, extreme leukocytosis)
    • Dehydration
    • Asphyxia
    • Infant of a diabetic mother
    • Intrauterine growth restriction
    • Infants undergoing vascular surgery of any kind
    • Inherited defects in coagulation proteins or genes (see table below)

      • Consider if FHx, early age of onset, recurrent disease, or unusual or multiple locations of disease
      • Highest likelihood of pathologic thrombosis occurs in infants who are homozygous for one defect or double heterozygotes for different defects

        • Thrombotic illness may occur within hours or days of birth
        • Often have evidence of in utero cerebral injury
        • Classic presentation is purpura fulminans

    • Acquired thrombophilic disorders include placental transfer of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody)

Examples and Relative Risks of Various Thrombotic Disorders in Neonates


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  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin deficiency

  • Activated protein C resistance:
  • Factor V Leiden mutation G169A
  • Prothrombin gene mutation G20210A

  • Hyperhomocysteinemia
  • ↑ Lipoprotein (a) levels
  • Methyltetrahydrofolate reductase polymorphism (C677T)





Relative risk for neonatal thrombotic disease




Comparison of Arterial versus Venous Thromboses


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Major Venous Thrombosis

Major Arterial Thrombosis

Renal Vein Thrombosis

General Considerations

  • Majority caused by CVLs
  • <1% of significant venous thromboembolism is idiopathic
  • Dural sinus thrombosis may cause neonatal cerebral infarction
  • Short-term consequences of catheter-associated thrombosis include pulmonary embolism and SVC syndrome
  • Long-term consequences are poorly understood

  • Majority caused by vascular access
  • Short-term consequences are related to impaired blood flow to end organs
  • Long-term consequences are poorly understood

  • Occurs primarily in neonates and young infants
  • Affected infants are usually term, LGA, with a male predominance
  • Disease is often bilateral

Signs and Symptoms

  • Difficulty infusing through catheter
  • Signs of venous obstruction
  • Swelling of affected extremity or head or neck
  • Superficial vein distention
  • Thrombocytopenia

  • Initial sign is dysfunction of UAC
  • Hematuria (gross or micro)
  • Hypertension
  • Decreased perfusion of lower extremities (poor pulses, pallor)

  • Flank mass
  • Hematuria (gross or micro)
  • Proteinuria
  • Thrombocytopenia
  • Renal dysfunction
  • Abnormal coagulation studies


  • US with Doppler flow is excellent for major thrombosis but may be inconclusive in smaller infants or low-flow states
  • Contrast studies (ie, venography)

  • US with Doppler flow is usually diagnostic, but the false-negative rate is significant
  • Contrast studies (ie, arteriography)

  • US with Doppler flow
  • Adjunct studies (urine analysis)


  • Heparin added to all fluids being infused through catheter (as per individual NICU protocol)
  • Removal of central venous access as soon as clinically feasible

  • Heparin added to all fluids being infused through catheter (as per individual NICU protocol)
  • Removal of arterial access as soon as clinically feasible
  • Correct positioning of umbilical arterial catheter (between T6 and T10 on chest or abdominal film)


  • For nonfunctional CVLs, remove line; if clinically vital to maintain line, use of thrombolytic agents (tPA) or hydrochloric acid in-line may be considered
  • Thrombolytic agents can be considered for extensive venous thrombosis with the line in situ for site-directed therapy
  • Alternatively remove the line and begin heparin therapy

  • For nonfunctional arterial catheters, remove line
  • For large, nonocclusive thrombus (as determined by US or contrast study), remove line and consider heparin therapy
  • For occlusive clots with significant clinical signs of end-organ compromise, consider aggressive thrombolytic therapy (local vs systemic thrombolytic therapy)
  • Surgical thrombectomy is not indicated because of significant morbidity and mortality

  • Unilateral without renal dysfunction or extension into IVC: Provide supportive care
  • Unilateral with renal dysfunction or extension into IVC or bilateral disease without renal compromise: Consider heparin therapy
  • Bilateral with significant renal dysfunction: Consider thrombolytic therapy

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Jan 9, 2019 | Posted by in PEDIATRICS | Comments Off on Hematology
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