1. Thrombocytopenia in neonates Adapted from a presentation by Bronwyn Waddell, MS 4 NICU Sub-internship 9-17-04

2. Definition  Thrombocytopenia < 150,000/µL (150 x 10 9 /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.

3. 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

4. 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

5. Category SubtypeSeverityOnsetResolutionMechanism Immune Alloimmune Autoimmune Severe Moderate Early Days - wks Wks - mos Incr. consumption Infection Bacterial Viral Fungal 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 Days - wks Variable Never Decreased production DrugsMod- severe Late8 days (med) Variable DICSevereVariable Inc consump PIH/ IUGR Mild-modEarly7-10 daysDec prodxn NECMod-sevLate7-10 daysInc consump

6. 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 10 9 /L) or moderate (50-100 x 10 9 /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

7. 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

8. 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)

9. 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/ µ L), antigen testing of parents ’ plts, mother's serum for antiplatelet alloantibody Management: well, term infants transfused if plt <20,000/ µ L or if bld – Transfusion threshold higher (<50,000/ µ L) 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

10. 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/ µ L – 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

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

12. 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

13. 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 >50,000/ µ L 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

14. 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.

15. 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/ µ L at birth-1 st 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, caf é -au-lait spots, and urogenital abnormalities; short stature of prenatal onset

16. 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)

17. Transfusion precautions  Neonates should receive 10-15 ml/kg of CMV-safe (CMV Ab-) or leukoreduced plts –Increases count by >50 x 10 9  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

18. 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

19. 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.  UpToDate Version 12.1: search term neonatal thrombocytopenia