Neonatal Alloimmune Thrombocytopenia - NAIT

Diagnosis

Indications for Testing

• Severe thrombocytopenia (platelet count <50,000/µL), bruising or intracranial hemorrhage in a newborn
• Mother with a previously affected pregnancy
• Mother with a sister having a previously affected pregnancy
• Mother with a history of posttransfusion purpura
• Maternal and paternal testing when fetus or neonate suspected of having perinatal alloimmune thrombocytopenia

Laboratory Testing

• CBC with platelet count – testing on infant
  • NAIT does not cause thrombocytopenia in the mother 
  • Platelet count is often <50,000/μL (variable)
• Testing and test interpretation in suspected NAIT should be performed by an experienced platelet immunology reference laboratory
  • A combination of test results are used to determine the likelihood of NAIT
  • Anti-platelet antibody – maternal sample preferred
    • Tests detect maternal antibodies to antigens commonly implicated in NAIT
      • HPA 1, 3, and 5 should be screened in all suspected cases
        • Include HPA 4 if the patient is of Asian descent
      • Identification of a maternal antibody is not diagnostic of NAIT – additional testing needed
      • Tests vary in the antibodies that can be detected
      • Antibodies directed against rare platelet antigens are not detected by most tests
      • Absence of a detectable maternal antibody does not exclude a diagnosis of NAIT
  • Platelet phenotyping or platelet antigen genotyping of mother and father
    • Detect maternal/paternal incompatibilities between HPA antigens
    • Genotyping allows for more accurate risk assessment and better pregnancy management
    • Fetal or neonatal platelet typing is not usually performed
    • For reference laboratories performing followup testing for NAIT, refer to the following
      • Platelet Immunology Laboratory, Puget Sound Blood Center
      • Platelet and Neutrophil Immunology Laboratory, BloodCenter of Wisconsin

Imaging Studies

• CT/MRI – mandatory for thrombocytopenic neonate

Differential Diagnosis of Thrombocytopenia in a Newborn

• Infection/sepsis
  • Congenital TORCH infection
    • Toxoplasma gondii
    • Rubella virus
    • Cytomegalovirus
    • Herpes simplex virus
  • Other infections
    • Hepatitis B
    • Treponema pallidum
    • Varicella-zoster virus
    • HIV
    • Parvovirus B19
  • Perinatal infection with Escherichia coli, Haemophilus influenzae, group B Streptococcus (S. agalactiae)
  • Disseminated intravascular coagulation
• Bone marrow abnormalities or inherited thrombocytopenias
• Maternal autoimmune thrombocytopenia with transplacental passage of antibodies
  • Immune thrombocytopenic purpura
  • Systemic lupus erythematosus
• Maternal exposure to antiplatelet medication

Screening

Monitoring

Clinical Background

Neonatal alloimmune thrombocytopenia (NAIT), also known as fetal and neonatal alloimmune thrombocytopenia, is the most common cause of severe thrombocytopenia (platelet count <50,000/µL) in the first few days of life of an otherwise healthy newborn (also referred to as perinatal alloimmune thrombocytopenia or PAT). It may lead to devastating consequences, including intracranial hemorrhage and death.

Epidemiology

• Incidence – 1/1,000-1/5,000 births
  • Transfusion purpura is less frequent
• Age – affects fetus or neonate only; can occur as early as 18-20 weeks gestation
• Sex – M:F, equal

Inheritance

• ~16 different types of human platelet antigens (HPA) have been identified
• The more common allele is designated “a” and the less common is “b”
• HPA-1a is believed to cause 75% of PAT in Caucasians; HPA-5b causes 20%
• HPA-1a-positive individuals have at least one copy of the “a” allele; HPA-1a-negative individuals are homozygous for the HPA-1b allele
  • 2% of women are homozygous for HPA-1b
    • These women are at risk for alloimmunization during pregnancy if their partner is homozygous HPA-1a or heterozygous HPA1- a/b and contributes the HPA-1a allele to the fetus

Risk Factors

• Previous child with NAIT or family history of NAIT
  • 50% of cases occur during a first pregnancy

Pathophysiology

• Maternal alloimmunization against fetal platelet antigens inherited from the father
  • Sometimes termed the platelet equivalent of Rh disease
• Most commonly occurs in women lacking HPA-1a
  • 2-5% of Caucasians lack HPA-1a
  • 80-90% of cases occur in HPA-1a negative mothers
    • 98% of the U.S. population is HPA-1a positive
  • HPA-1a incompatibility causes the most severe form of the disease; HPA-3a causes the next most severe form
  • HPA-1a and HPA-5b are the most commonly involved HPAs
• IgG antibodies against fetal HPA can cross the placenta, causing fetal platelet destruction

Clinical Presentation

• Otherwise healthy newborn
• Widespread petechiae or purpura
• Visceral hemorrhage – often gastrointestinal or bladder mucosa
• Intracranial hemorrhage – may occur in utero, at birth, or antenatally
  • Fatal in up to one-third of patients
  • Causes neurologic impairment in 20-30% of patients
• Recurrence rate up to 90% in subsequent pregnancies
  • Severity may worsen with subsequent pregnancies

Treatment

• Fetal platelet transfusion with random platelets or antigen-negative platelets
• Intravenous gammaglobulin or steroids

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Platelet Antibodies, Indirect 0051050 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay	Use to detect platelet-specific antibodies in suspected neonatal alloimmune thrombocytopenia, posttransfusion purpura, or multiplatelet transfusion refractoriness Not recommended for the diagnosis of immune thrombocytopenic purpura; preferred test is Platelet Antibodies, Indirect with Reflex to Identification
Platelet Antigen 1 Genotyping (HPA-1) 0051309 Method: Polymerase Chain Reaction/Fluorescence Monitoring
Platelet Antigen 2 Genotyping (HPA-2) 0051310 Method: Polymerase Chain Reaction/Fluorescence Monitoring
Platelet Antigen 3 Genotyping (HPA-3) 0051311 Method: Polymerase Chain Reaction/Fluorescence Monitoring
Platelet Antigen 4 Genotyping (HPA-4) 0051490 Method: Polymerase Chain Reaction/Fluorescence Monitoring
Platelet Antigen 5 Genotyping (HPA-5) 0051312 Method: Polymerase Chain Reaction/Fluorescence Monitoring
Platelet Antigen 6 Genotyping (HPA-6) 0051313 Method: Polymerase Chain Reaction/Fluorescence Monitoring
Platelet Antigen 15 Genotyping (HPA-15) 0051314 Method: Polymerase Chain Reaction/Fluorescence Monitoring
Platelet Antibody (Glycoprotein) Plasma/Eluate 2007237 Method: Qualitative Enzyme-Linked Immunosorbent Assay