Indications for Testing

• Severe thrombocytopenia (<50,000/µL), bruising or intracranial hemorrhage in a newborn
• Mother with history of a previously affected pregnancy
• Mother with a sister having a previously affected pregnancy
• Mother with a history of post-transfusion purpura

Laboratory Testing

• CBC with platelet count – testing on infant
  • Platelet count is often <50,000/μL (variable)
  • FNAIT does not cause thrombocytopenia in the mother
• Testing and test interpretation should be performed by an experienced platelet immunology reference laboratory
  • A combination of test results are used to determine the likelihood of FNAIT
  • Anti-platelet antibody – maternal sample preferred
    • Tests detect maternal antibodies to antigens commonly implicated in FNAIT (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 FNAIT; additional testing is 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 FNAIT
  • Platelet phenotyping or platelet antigen genotyping of mother and father
    • Used to detect maternal/paternal incompatibilities between HPA antigens
    • Fetal or neonatal platelet typing is not usually performed
    • For reference laboratories performing followup testing for FNAIT, refer to the following
      • Platelet Immunology Laboratory, Puget Sound
      • Platelet and Neutrophil Immunology Laboratory, Blood Center 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

• Generalized screening is not recommended; however, several prospective studies involving >100,000 pregnancies suggest there may be a role for screening and intervention (Skogen, et al)

• Routine monitoring for intracranial hemorrhage (ICH) not recommended in general population
• Monitoring recommended in mother with previous infant with FNAIT or ICH
  • Fetal blood sampling may be performed but is not recommended due to bleeding
  • Institution of intravenous immunoglobulin early in pregnancy (as early as 12 weeks, depending on when gestational date ICH was noted in previous neonate)

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) 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
• 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 FNAIT or family history of FNAIT
  • 50% of cases occur during a first pregnancy

Pathophysiology

• Maternal alloimmunization against fetal platelet antigens inherited from the father
• 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 is up to 90% in subsequent pregnancies; severity may worsen with subsequent pregnancies
  • May include in utero intracranial hemorrhage

Treatment

• Fetal platelet transfusion with random platelets or antigen-negative platelets
• Intravenous immune globulin or glucocorticosteroids

Tests generally appear in the order most useful for common clinical situations

General

• Arnold DM, Smith JW, Kelton JG. Diagnosis and management of neonatal alloimmune thrombocytopenia. Transfus Med Rev. 2008; 22 (4) :255-267.PubMed
• Bassler D, Greinacher A, Okascharoen C, Klenner A, Ditomasso J, Kiefel V, Chan A, Paes B. A systematic review and survey of the management of unexpected neonatal alloimmune thrombocytopenia. Transfusion. 2007; :-.PubMed
• Bessos H, Killie MK, Seghatchian J, Skogen B, Urbaniak SJ. The relationship of anti-HPA-1a amount to severity of neonatal alloimmune thrombocytopenia - Where does it stand?. Transfus Apher Sci. 2009; 40 (2) :75-78.PubMed
• Bussel J. Diagnosis and management of the fetus and neonate with alloimmune thrombocytopenia. J Thromb Haemost. 2009; 7 Suppl 1 :253-257.PubMed
• Bussel JB, Sola-Visner M. Current approaches to the evaluation and management of the fetus and neonate with immune thrombocytopenia. Semin Perinatol. 2009; 33 (1) :35-42.PubMed
• Curtis BR. Genotyping for human platelet alloantigen polymorphisms: applications in the diagnosis of alloimmune platelet disorders. Semin Thromb Hemost. 2008; 34 (6) :539-548.PubMed
• Kamphuis MM, Paridaans N, Porcelijn L, De Haas M, Van Der Schoot CE, Brand A, Bonsel GJ, Oepkes D. Screening in pregnancy for fetal or neonatal alloimmune thrombocytopenia: systematic review. BJOG. 2010; 117 (11) :1335-1343.PubMed
• Kaplan C. Foetal and neonatal alloimmune thrombocytopaenia. Orphanet J Rare Dis. 2006; 1 :39-.PubMed
• Killie MK, Kjeldsen-Kragh J, Husebekk A, Skogen B, Olsen JA, Kristiansen IS. Cost-effectiveness of antenatal screening for neonatal alloimmune thrombocytopenia. BJOG. 2007; 114 (5) :588-595.PubMed
• Kjeldsen-Kragh J, Killie MK, Tomter G, Golebiowska E, Randen I, Hauge R, Aune B, Oian P, Dahl LB, Pirhonen J, Lindeman R, Husby H, Haugen G, Gronn M, Skogen B, Husebekk A. A screening and intervention program aimed to reduce mortality and serious morbidity associated with severe neonatal alloimmune thrombocytopenia. Blood. 2007; 110 (3) :833-839.PubMed
• Roberts I, Murray NA. Neonatal thrombocytopenia. Semin Fetal Neonatal Med. 2008; 13 (4) :256-264.PubMed
• Skogen B, Husebekk A, Killie MK, Kjeldsen-Kragh J. Neonatal alloimmune thrombocytopenia is not what it was: a lesson learned from a large prospective screening and intervention program. Scand J Immunol. 2009; 70 (6) :531-534.PubMed
• Skogen B, Killie MK, Kjeldsen-Kragh J, Ahlen MT, Tiller H, Stuge TB, Husebekk A. Reconsidering fetal and neonatal alloimmune thrombocytopenia with a focus on screening and prevention. Expert Rev Hematol. 2010; 3 (5) :559-566.PubMed
• van den Akker ES, Oepkes D. Fetal and neonatal alloimmune thrombocytopenia. Best Pract Res Clin Obstet Gynaecol. 2007; :-.PubMed

Disseminated Intravascular Coagulation
Functional Platelet Disorders