Thrombocytopenia in neonates

1
Thrombocytopenia in neonates

• Adapted from a presentation by Bronwyn Waddell,
  MS 4
• NICU Sub-internship
• 9-17-04

2
Definition

• Thrombocytopenia lt 150,000/µL (150 x 109/L)
• Rare in general population (lt1) 22 in NICU
• Many healthy newborns b/w 100,000 - 150,000/µL.
• Average platelet counts lower in preterm infants
• Reflects increase during gestation, from 187,000
  to 274,000/µL at 15 and 40 weeks
• Severe reductions (lt50,000/µL) and/or persistent
  thrombocytopenia can result in bleeding.
• Severe and/or persistent thrombocytopenia
  requires evaluation, even in an asymptomatic
  infant.

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Evaluation of the thrombocytopenic neonate

• Based on recognizing typical patterns
• 1) Immune
• 2) Infectious
• 3) Genetic
• 4) Drug-induced
• 5) Disseminated intravascular coagulation
• 6) Placental insufficiency
• 7) Miscellaneous

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Algorithm in Evaluation

• Does thrombocytopenia fit pattern of
  pathophysiologic process? (Table 1)
• Proceed to confirmatory testing
• Further evaluation is indicated if
• It does not fit one of these patterns
• The dx is not confirmed by appropriate testing
• It is more severe/prolonged than fits dx
• It does not respond to appropriate tx

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Category Subtype Severity Onset Resolution Mechanism
Immune Alloimmune Autoimmune Severe Moderate Early Early Days - wks Wks - mos Incr. consumption
Infection Bacterial Viral Fungal Variable Variable Severe Variable Early Late 1-7 days Variable 2-7 days Mixed
Genetic disorder Chromosomal Bone marrow failures Familial TCP Moderate Severe Mild-mod Early Early Early Days - wks Variable Never Decreased production
Drugs Mod-severe Late 8 days (med) Variable
DIC Severe Variable Variable Inc consump
PIH/ IUGR Mild-mod Early 7-10 days Dec prodxn
NEC Mod-sev Late 7-10 days Inc consump
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Evaluation in early thrombocytopenia Mild to
Moderate

• Neonate with early thrombocytopenia (lt72 hrs)
• First distinguish b/w mild-mod and severe
• Mild (100-150 x 109/L) or moderate (50-100 x
  109/L).
• PIH and IUGR are common causes of early
  thrombocytopenia among premature infants
• Generally, resolves spontaneously by day 7-10 of
  life
• Other labs include PT, PTT, D-dimers, cx

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Evaluation in early severe thrombocytopenia

• Severe/prolonged should trigger evaluation for
  other disease processes
• Well-appearing infant most common cause in
  immediate post-natal period is immune
  thrombocytopenia from anti-plt Ab across placenta
• Ill-appearing infant consider other causes
• Sepsis, DIC (freq post severe perinatal asphyxia)
• Viral infections and congenital toxoplasmosis
• If tests fail to confirm dx, base further w/u on
  PE, response to plt transfusion, and mechanistic
  eval

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Physical Examination

• Dysmorphic features suggestive of chromosomal
  disorders provide dx clues
• Trisomy 21, 13, 18, Turner, Noonan syndrome,
  DiGeorge/velocardiofacial syndrome
• HSM, abd masses (renal v thrombosis),
  forearm/thumb abnormalities (TAR/Fanconis)
• Decreased pronation/supination of forearm
  (congenital amegakaryocytic TCP w/proximal
  radial-ulnar synostosis)

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Increased destruction

• Immune thrombocytopenia (0.3)
• Neonatal alloimmune thrombocytopenia (NAIT)
• Mom forms IgG class antiplatelet Ab against the
  "foreign" antigen (dads)
• Clinical features mom asx, baby may have
  petechiae, ecchymosis
• Labs plts (often lt 10,000/µL), antigen testing
  of parents plts, mother's serum for antiplatelet
  alloantibody
• Management well, term infants transfused if plt
  lt20,000/µL or if bld
• Transfusion threshold higher (lt50,000/µL) in
  preterm/term infants who are ill or have risk
  factors.
• Initial evaluation head CT to r/o hemorrhage
  (10-20)
• Adequate plt counts maintained during 1st 72-96
  hrs (highest bld risk)
• Tx with high-dose intravenous gamma-globulin
  (IVIG) may be effective

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Increased DestructionImmune Thrombocytopenia

• Autoimmune thrombocytopenia
• Mediated by maternal Ab that react with maternal
  and infant platelets.
• Occurs in maternal autoimmune disorders,
  including ITP and SLE
• Dx apparent from mother's PMH and maternal
  thrombocytopenia
• Mothers of infants with unexplained neonatal
  thrombocytopenia? autoimmune disorder?
• Healthy women w/o hx of autoimmune d/o sometimes
  develop gestational thrombocytopenia that usually
  is mild, transient, and benign.
•  Clinical features Petechiae, bruising, and
  bleeding.
• 90 infants have moderately severe
  thrombocytopenia in range of 20,000 to 50,000/µL
• Risk in infant correlates with severity of ITP in
  the mother
• Mother s/p splenectomy, plts lt 50 in preg, or
  older sibling w/neonatal affects
• Plts decrease sharply during the several days
  after birth nadir at 2-5 days
• Management transfusion, IVIG, or prednisone for
  severe TCP or clinical bleeding
• Plt trx may not be as effective as in NAIT
  autoAb usually react w/donor platelets

11
Drug related thrombocytopenia

• Drug-related thrombocytopenia
• Mechanism is accelerated plt destruction caused
  by drug-dependent Abs.
• BM suppression may occur post chemo to mom or
  newborn infant
• Maternal thrombocytopenia post drug exposure
  mediated by IgG
• Infant's platelet count should be monitored if
  exposed to quinidine, penicillins, digoxin, and
  antiepileptic drugs indomethacin,
  heparin-induced thrombocytopenia less common
•   Management If drug-associated
  thrombocytopenia is suspected, the offending
  agent should be withdrawn.
• Transfusions should be given for low platelet
  counts (lt20,000/µL) or for bleeding.
• If an immune-mediated condition is suspected,
  IVIG can be used while awaiting confirmation.

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Peripheral Consumption

• Hypersplenism thrombocytopenia may be associated
  with an enlarged spleen.
• Underlying disorders hemolytic anemia,
  congenital hepatitis, congenital viral infection,
  and portal vein thrombosis
• Management Dx and tx of underlying cause.
• Plt transfusions PRN. Splenectomy if bleeding
  uncontrollable.
• Kasabach-Merritt DIC, hemangiomas (kaposiform
  hemangioendotheliomas)
• shortened platelet survival caused by
  sequestration of plts in AVM.
• Lesions noted at birth in approximately 50 of
  patients
• Trunk (including retroperitoneum), arms and
  shoulder, lower extremity, and cervicofacial
• Severe thrombocytopenia, hypofibrinogenemia,
  elevated fibrin degradation products, and
  fragmentation of red blood cells
• Management resolution of hemangioma, support
  hemostasis w/trx
• Tx prednisone, interferon alpha, surgery,
  embolization, vincristine, cyclophosphamide,
  actinomycin D

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Peripheral Consumption

• Disseminated intravascular coagulation?thrombosis
  and hemorrhage.
• Complication of underlying illness, typically
  sepsis, asphyxia, MAS, severe RDS.
• Dx suggested by associated illness, clinical
  presentation, and presence of microangiopathic
  changes on the peripheral blood smear.
• Confirming labs prolonged PT and PTT, decreased
  fibrinogen, increased D-dimer
• Tx directed at the underlying cause of DIC
  platelets and FFP to maintain plt gt50,000/µL and
  PT time within physiologic range. Fibrinogen
  concentration is maintained gt100 mg/dL with
  infusion of cryoprecipitate.
• Infection bacterial, viral, and fungal
  organisms.
• Bacterial mechanisms for thrombocytopenia include
  DIC, endothelial damage, antibody-mediated, and
  platelet aggregation caused by adherence of
  bacterial products to platelet membranes.
• Decreased plt production due to injury to
  megakaryocytes in BM also possible
• Viral congenital rubella and cytomegalovirus.
• Mechanisms include platelet aggregation, loss of
  sialic acid from the platelet membrane caused by
  viral neuraminidase, and megakaryocyte
  degeneration.
• Splenomegaly and reticuloendothelial
  hyperactivity may play a role.
• Management tx underlying infection, platelet
  transfusions if associated bld

14
Peripheral Consumption

• Necrotizing enterocolitis GI necrosis in 2-10
  of infants lt1500 g.
• thrombocytopenia from platelet destruction
• In early stages, declining plts correlate with
  necrotic bowel and worsening disease.
• Levels of cytokines, including platelet
  activating factor (PAF), are increased in
  premature infants with NEC and correlate w/
  disease severity
• Intestinal damage and inflammatory cell
  recruitment result from a cascade of cellular
  events that may be mediated at least in part by
  PAF
• Thrombosis low plts often accompanies thrombosis
  in newborns.
• Patients should be evaluated for a thromboembolic
  disorder if thrombocytopenia cannot be explained
  by other conditions.

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Decreased platelet production

• Often associated with genetic disorders result
  in isolated thrombocytopenia or syndrome
• Thrombocytopenia-absent radius syndrome severe
  thrombocytopenia and bilateral absent radii
  thumbs are always present
• Also hypoplasia or absence of the ulna, or
  abnormal or absent humerus.
• Congenital heart disease, usually ASD or TOF,
  occurs in 1/3 of pts
• plt lt10,000 - 30,000/µL at birth-1st postnatal
  week in 59
• Mortality is significant in neonate and early
  infancy, primarily due to ICH.
• If pt survives this period, spontaneous
  resolution usually occurs after 1st year
• Tx supportive with platelet transfusions given
  when needed.
•   Fanconi anemia thrombocytopenia from FA is
  rare in the neonatal period.
• Pancytopenia typically diagnosed at six to nine
  years old
• Condition recognized in newborn by characteristic
  congenital malformations in 60-70
• Hypopigmented spots, abnormality of thumbs,
  microcephaly, café-au-lait spots, and urogenital
  abnormalities short stature of prenatal onset

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Our DNCC Guidelines for platelet transfusion

• Transfuse 10-15 mL/kg leukoreduced, irradiated
  platelets over 0.5-1 hour for
• Infants w/o signs of acute bld, but plt lt20,000
• Infant w/hemorrhage and plt lt50,000
• Consider w/bld and plt lt100,000, esp ICH risk
• Consider trx at predetermined value (20-100)
  depending on infants status (d/w attending)

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Transfusion precautions

• Neonates should receive 10-15 ml/kg of CMV-safe
  (CMV Ab-) or leukoreduced plts
• Increases count by gt50 x 109
• Neonates are at increased risk for
  transfusion-associated GVHD
• Irradiated bld products for immunodeficiency,
  intrauterine or exchange transfusions, or blood
  trx from relative or HLA-selected donor

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Conclusion Neonatal Thrombocytopenia

• Common in NICU (sick and premature)
• Differentiate and tx based on severity
• Recognition of etiology based on typical patterns
  associated with specific pathophysiologic
  processes
• Work up and treat per algorithm and current
  clinical guidelines
• Pursue immune etiology in infant w/persistent
  thrombocytopenia

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Sources/References

• Sola M. Evaluation and treatment of severe and
  prolonged thrombocytopenia in neonates. Clin
  Perinatol 200431(1)
• Saxonhouse M, Sola M. Platelet function in term
  and preterm neonates. Clin Perinatol 200431(1)
• Andrew et al. A randomized, controlled trial of
  platelet transfusions in thrombocytopenic
  premature infants. J Pediatr 1993123285-91.
• Murray NA. Evaluation and treatment of
  thrombocytopenia in the neonatal intensive care
  unit. Acta Paediatr Suppl 20029174-81.
• Sola, MC, Del Vecchio, A, Rimsza, LM. Evaluation
  and treatment of thrombocytopenia in the neonatal
  intensive care unit. Clin Perinatol 2000 27655.
  
• Jones, KL. Smith's Recognizable Patterns of Human
  Malformations, 5th ed. WB Saunders, Philadelphia
  1997
• Tomer et al. Autologous platelet kinetics in
  patients with severe thrombocytopenia. J Lab Clin
  Med 1991118546-54.
• UpToDate Version 12.1 search term neonatal
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