What non‑splenic causes can contribute to thrombocytopenia in a newborn?

Non-Splenic Causes of Neonatal Thrombocytopenia

The most common non-splenic causes of neonatal thrombocytopenia are sepsis, necrotizing enterocolitis, birth asphyxia, neonatal alloimmune thrombocytopenia (NAIT), maternal immune thrombocytopenia (ITP), disseminated intravascular coagulation, and congenital infections. 1, 2, 3

Infectious and Inflammatory Causes

Sepsis and necrotizing enterocolitis are the leading causes of late-onset thrombocytopenia in neonates, particularly in the intensive care setting. 1, 2 These conditions trigger increased platelet destruction through inflammatory mechanisms and should be excluded first with blood cultures (bacterial and fungal) and appropriate imaging before pursuing other diagnoses 1.

• Viral infections (including congenital infections) represent another important infectious etiology that can cause thrombocytopenia through direct bone marrow suppression or increased peripheral destruction 2.

Immune-Mediated Causes

Neonatal alloimmune thrombocytopenia (NAIT) is the most common cause of severe thrombocytopenia in term newborns, occurring in approximately 1 in 1,000 live births. 4

• NAIT typically presents at birth or within the first 7 days with platelet counts below 100 × 10⁹/L, though most affected infants have counts less than 50 × 10⁹/L 5, 6, 4.
• The diagnosis requires HPA genotyping of mother, infant, and father, along with maternal serum alloantibody testing and crossmatch with paternal platelets 5, 4, 1.
• Before investigating for NAIT, more common causes such as hypoxia and infection must be excluded 5.

Maternal autoimmune disorders including ITP and systemic lupus erythematosus (SLE) can cause transplacental passage of maternal antibodies, resulting in neonatal thrombocytopenia. 1

• Check maternal platelet count and inquire about maternal autoimmune history 1.
• If maternal SLE is present, obtain maternal and neonatal anti-Ro/SSA and anti-La/SSB antibody titers 1.
• This form of thrombocytopenia may persist for months and requires close follow-up 1.

Perinatal Hypoxia and Asphyxia

Birth asphyxia is an important risk factor for thrombocytopenia, causing increased platelet destruction through mechanisms related to chronic intrauterine hypoxia. 2, 3

• In a prospective study of 807 NICU admissions, birth asphyxia was identified as a significant associated risk factor for developing thrombocytopenia 3.
• The thrombocytopenia from hypoxia is typically destructive in nature, with short platelet survival and normal megakaryocyte numbers 3.

Disseminated Intravascular Coagulation (DIC)

DIC frequently accompanies sepsis-related thrombocytopenia and can be identified through coagulation studies. 1

• Order PT, INR, aPTT, and fibrinogen to assess for DIC 1.
• In one study, 21% of thrombocytopenic neonates had laboratory evidence of DIC 3.
• Normal coagulation studies in the setting of isolated severe thrombocytopenia effectively exclude vitamin K deficiency and hemophilia A, directing the work-up toward immune-mediated or consumptive etiologies 6, 4.

Increased Platelet Destruction (Non-Immune)

Approximately 22% of infants admitted to neonatal intensive care units develop thrombocytopenia, with the majority caused by increased platelet destruction rather than decreased production. 3

• The platelet count nadir usually occurs by day 4 and resolves by day 10 3.
• Studies using 111In-labeled-platelet survival demonstrate shortened platelet lifespan (12 to 128 hours), rising mean platelet volume, and normal megakaryocyte numbers, confirming a destructive mechanism 3.
• In thrombocytopenic infants, 52% had elevated platelet-associated IgG levels, suggesting immune-mediated destruction 3.

Iatrogenic Causes

Exchange transfusions can precipitate thrombocytopenia, accounting for 12% of cases in one large prospective study. 3

Congenital/Genetic Causes

Rare inherited thrombocytopenias such as Wiskott-Aldrich syndrome should be considered in well-appearing infants with severe isolated thrombocytopenia and no other identifiable cause. 7

• A high index of suspicion for unusual causes allows early diagnosis and prompt curative therapy 7.

Critical Diagnostic Pitfalls to Avoid

• Verify platelet count using clean venipuncture rather than heel-stick sampling to ensure accurate diagnosis 1.
• Perform urgent transcranial ultrasonography when platelet count is < 50,000/µL to screen for intracranial hemorrhage, which occurs in up to 1.5% of thrombocytopenic neonates 1.
• Do not give intramuscular vitamin K or any intramuscular injections until platelet count is confirmed and corrected 4, 1.