Thrombocytopenia in neonates

Adapted from a presentation by Bronwyn Waddell, MS 4

NICU Sub-internship

9-17-04

Definition

Thrombocytopenia < 150,000/µL (150 x 109/L)– Rare in general population (<1%); 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 (<50,000/µL) and/or persistent thrombocytopenia can result in bleeding.

– Severe and/or persistent thrombocytopenia requires evaluation, even in an asymptomatic infant.

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

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

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

Evaluation in early thrombocytopenia:

Mild to Moderate

Neonate with early thrombocytopenia (<72 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

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

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/Fanconi’s)

– Decreased pronation/supination of forearm (congenital amegakaryocytic TCP w/proximal radial-ulnar synostosis)

Increased destruction Immune thrombocytopenia (0.3%)

– Neonatal alloimmune thrombocytopenia (NAIT) • Mom forms IgG class antiplatelet Ab against the "foreign" antigen (dad’s)

• Clinical features: mom asx, baby may have petechiae, ecchymosis• Labs: plts (often < 10,000/µL), antigen testing of parents’ plts,

mother's serum for antiplatelet alloantibody• Management: well, term infants transfused if plt <20,000/µL or if bld

– Transfusion threshold higher (<50,000/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

Increased Destruction:Immune 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 < 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

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

(<20,000/µL) or for bleeding. – If an immune-mediated condition is suspected, IVIG can be used

while awaiting confirmation.

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

Peripheral Consumption Disseminated intravascular coagulationthrombosis 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

>50,000/µL and PT time within physiologic range. Fibrinogen concentration is maintained >100 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

Peripheral Consumption Necrotizing enterocolitis: GI necrosis in 2-10% of infants <1500 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.

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 <10,000 - 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

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 <20,000– Infant w/hemorrhage and plt <50,000– Consider w/bld and plt <100,000, esp ICH risk– Consider trx at predetermined value (20-100)

depending on infant’s status (d/w attending)

Transfusion precautions

Neonates should receive 10-15 ml/kg of CMV-safe (CMV Ab-) or leukoreduced plts– Increases count by >50 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

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

Sources/References Sola M. Evaluation and treatment of severe and prolonged

thrombocytopenia in neonates. Clin Perinatol; 2004:31(1) Saxonhouse M, Sola M. Platelet function in term and preterm

neonates. Clin Perinatol 2004;31(1) Andrew et al. A randomized, controlled trial of platelet transfusions in

thrombocytopenic premature infants. J Pediatr 1993;123:285-91. Murray NA. Evaluation and treatment of thrombocytopenia in the

neonatal intensive care unit. Acta Paediatr Suppl 2002;91:74-81. Sola, MC, Del Vecchio, A, Rimsza, LM. Evaluation and treatment of

thrombocytopenia in the neonatal intensive care unit. Clin Perinatol 2000; 27:655.

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 1991;118:546-54.

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