I. INTRODUCTION. Neonatal thrombocytopenia is traditionally defined as a platelet count of <150 × 10³/µL and is classified as mild (100 to 149 × 10³/µL), moderate (50 to 99 × 10³/µL), or severe (<50 × 10³/µL). However, platelet counts in the 100 to 149 × 10³/µL range are somewhat more common among neonates than adults. The most recent and largest study on neonatal platelet counts demonstrated that platelet counts at birth increase with advancing gestational age. Importantly, while the mean platelet count was ≥200 × 10³/µL even in the most preterm infants, the 5th percentile was 104 × 10³/µL for those ≤32 weeks’ gestation, and 123 × 10³/µL for late-preterm and term neonates. These findings suggest that different definitions of thrombocytopenia may be applied to preterm infants. For that reason, careful follow-up and expectant management in an otherwise healthy-appearing neonate with mild, transient thrombocytopenia is an acceptable approach, although lack of quick resolution, worsening of thrombocytopenia, or changes in clinical condition should prompt further evaluation.

The incidence of thrombocytopenia in neonates varies significantly, depending on the population studied. Specifically, while the overall incidence of neonatal thrombocytopenia is relatively low (0.7% to 0.9%), the incidence among neonates admitted to the NICU is rather high (18% to 35%). Within the NICU, mean platelet counts are lower among preterm neonates than among neonates born at or near term, and the incidence of thrombocytopenia is inversely correlated to the gestational age, reaching approximately 70% among neonates born with a weight <1,000 g.

II. APPROACH TO THE THROMBOCYTOPENIC NEONATE. When evaluating a thrombocytopenic neonate, the first step to narrow the differential diagnosis is to classify the thrombocytopenia as either early onset (within the first 72 hours of life) or late onset (after 72 hours of life), and to determine whether the infant is clinically ill or well. Importantly, infection/sepsis should always be considered near the top of the differential diagnosis (regardless of the time of presentation and the infant’s appearance) because any delay in diagnosis and treatment can have life-threatening consequences.

A. Early-onset thrombocytopenia (Fig. 47.1). The most frequent cause of early-onset thrombocytopenia in a well-appearing neonate is placental insufficiency, as occurs in infants born to mothers with pregnancy-induced hypertension/preeclampsia or diabetes and in those with intrauterine growth restriction (IUGR). This thrombocytopenia is always mild to moderate, presents immediately or shortly after birth, and resolves within 7 to 10 days. If an infant with a prenatal history consistent with placental insufficiency and mild-to-moderate thrombocytopenia remains clinically stable and the platelet count normalizes within 10 days, no further evaluation is necessary. However, if the thrombocytopenia becomes severe and/or persists >10 days, further investigation is necessary.

Severe early-onset thrombocytopenia in an otherwise healthy infant should trigger suspicion for an immune-mediated thrombocytopenia, either autoimmune (i.e., the mother is also thrombocytopenic) or alloimmune (the mother has a normal platelet count). These varieties of thrombocytopenia
are discussed in detail in the following text. Early-onset thrombocytopenia of any severity in an ill-appearing term or preterm neonate should prompt evaluation for sepsis, congenital viral or parasitic infections, or disseminated intravascular coagulation (DIC). DIC is most frequently associated with sepsis but can also be secondary to birth asphyxia.

In addition to these considerations, the affected neonate should be carefully examined for any radial abnormalities (suggestive of thrombocytopenia-absent radius [TAR] syndrome, amegakaryocytic thrombocytopenia with radioulnar synostosis [ATRUS], or Fanconi anemia). Although
thrombocytopenia associated with Fanconi almost always presents later (during childhood), neonatal cases have been reported. In these patients, thumb abnormalities are frequently found, and chromosomal fragility testing is nearly always diagnostic. If the infant has radial abnormalities with normal-appearing thumbs, TAR syndrome should be considered. The platelet count is usually <50 × 10³/µL, and the white cell count is elevated in >90% of TAR syndrome patients, sometimes exceeding 100 × 10³/µL and mimicking congenital leukemia. Infants that survive the first year of life generally do well because the platelet count then spontaneously improves to low-normal levels that are maintained through life. The inability to rotate the forearm on physical examination, in the presence of severe early-onset thrombocytopenia, suggests the rare diagnosis of congenital amegakaryocytic thrombocytopenia with proximal radioulnar synostosis. Radiologic examination of the upper extremities in these infants confirms the proximal synostosis of the radial and ulnar bones. Other genetic disorders associated with early-onset thrombocytopenia include trisomy 21, trisomy 18, trisomy 13, Turner syndrome, Noonan syndrome, and Jacobsen syndrome. Cases of Noonan syndrome presenting with mild dysmorphic features and very severe neonatal thrombocytopenia (mimicking congenital amegakaryocytic thrombocytopenia) have been recently described. The presence of hepatoor splenomegaly is suggestive of a viral infection, although it can also be seen in hemophagocytic syndrome and liver failure from different etiologies. Other diagnoses, such as renal vein thrombosis, Kasabach-Merritt syndrome, and inborn errors of metabolism (mainly propionic acidemia and methylmalonic acidemia), should be considered and evaluated for based on specific clinical indications (i.e., hematuria in renal vein thrombosis, presence of a vascular tumor in Kasabach-Merritt syndrome).

B. Late-onset thrombocytopenia (Fig. 47.2). The most common causes of thrombocytopenia of any severity presenting after 72 hours of life are sepsis (bacterial or fungal) and necrotizing enterocolitis (NEC). Affected infants are usually ill appearing and have other signs suggestive of sepsis and/or NEC. However, thrombocytopenia can be the first presenting sign of these processes and can precede clinical deterioration. Appropriate treatment (i.e., antibiotics, supportive respiratory and cardiovascular care, bowel rest in case of NEC, and surgery in case of surgical NEC) usually improves the platelet count in 1 to 2 weeks, although in some infants, the thrombocytopenia persists for several weeks. The reasons underlying this prolonged thrombocytopenia are unclear.

If bacterial/fungal sepsis and NEC are ruled out, viral infections such as herpes simplex virus, cytomegalovirus (CMV), or enterovirus should be considered. These are frequently accompanied by abnormal liver enzymes. If the infant has or has recently had a central venous or arterial catheter, thromboses should be part of the differential diagnosis. Finally, drug-induced thrombocytopenia should be considered if the infant is clinically well and is receiving heparin, antibiotics (penicillins, ciprofloxacin, cephalosporins, metronidazole, vancomycin, and rifampin), indomethacin, famotidine, cimetidine, phenobarbital, or phenytoin, among others. Other less common causes of late-onset thrombocytopenia include inborn errors of metabolism and Fanconi anemia (rare).