Transfusion medicine
Transfusion reactions & complications
Fetal / neonatal alloimmune thrombocytopenia


Minor changes: 28 April 2021

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PubMed Search: Fetal / neonatal alloimmune thrombocytopenia [TIAB]

Evelyn M. Potochny, D.O.
Melissa R. George, D.O.
Page views in 2021 to date: 65
Cite this page: Potochny EM, Arbogast BD, George MR. Fetal / neonatal alloimmune thrombocytopenia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedFNAIT.html. Accessed May 7th, 2021.
Definition / general
  • Rare, potentially life threatening bleeding disorder affecting the fetus / neonate
  • Caused by maternal IgG antibodies targeting fetal / neonatal platelet antigens inherited from the father
Essential features
  • Thrombocytopenia in neonate with or without associated fetal / neonatal bleeding
  • Confirmation of maternal platelet antibody(ies) directed at paternally inherited platelet antigen(s)
  • May affect fetus / neonate in first pregnancy
  • May see increasing severity in subsequent pregnancies
  • References: Cohn: AABB Technical Manual, 20th Edition, 2020, Br J Haematol 2013;161:3
Terminology
  • Fetal neonatal alloimmune thrombocytopenia (FNAIT)
  • Neonatal alloimmune thrombocytopenia (NAIT)
  • Fetomaternal alloimmune thrombocytopenia (FMAIT)
  • Neonatal alloimmune thrombocytopenic purpura (NATP)
Pathophysiology
  • Platelet antigen nomenclature defined by the International Society for Blood Transfusion, Platelet Immunobiology Working Group (ISBT: Platelet Immunobiology [Accessed 22 March 2021])
  • Human platelet antigens (HPA) named in chronological order of discovery with numerical nomenclature
  • Human platelet antigen systems are biallelic
    • High incidence allele designated as "a"
    • Low incidence allele or polymorphism designated as "b"
    • Molecular testing (e.g. PCR) can distinguish the antigens
  • Human platelet antigens are located on platelet membrane glycoproteins or glycoprotein complexes
  • Fetal neonatal alloimmune thrombocytopenia results from maternal alloimmunization during pregnancy or transfusion
  • IgG antibodies cross the placenta and destroy corresponding platelets
    • Antibodies against the antigens below are most commonly implicated (Transfusion 2004;44:1220):
    • HPA1a ≈ 80% (Caucasian population) (i.e. mother homozygous for HPA1b develops anti-HPA1a antibodies against the paternally derived HPA1a allele on her offspring’s platelets)
    • HPA5b ≈ 10% (Caucasian population)
    • HPA4a more common in Asians (Transfus Med Rev 2008;22:255)
  • Antibodies against human leukocyte antigens not known to cause fetal neonatal alloimmune thrombocytopenia
  • Affected infants are thrombocytopenic and at risk of major bleeding complications, including intracranial hemorrhage
  • References: Cohn: AABB Technical Manual, 20th Edition, 2020, Br J Haematol 2013;161:3
Clinical features
  • Severe fetal / neonatal thrombocytopenia is most commonly caused by fetal neonatal alloimmune thrombocytopenia
  • Affected infant may present with petechial hemorrhages, purpura and an extremely low platelet count
  • Pregnant women not routinely screened for platelet antibodies
  • Might not be known until birth of affected neonate
  • References: Cohn: AABB Technical Manual, 20th Edition, 2020, Br J Haematol 2013;161:3
Symptoms
  • Asymptomatic fetus
  • Symptomatic fetus with:
    • Intracranial hemorrhage, identified by ultrasound
  • Asymptomatic neonate
  • Neonate with:
    • Bleeding
    • Genitourinary hemorrhage
    • Ocular hemorrhage
    • Intraabdominal hemorrhage
    • Pulmonary hemorrhage
    • Spinal cord hemorrhage
    • Intracranial hemorrhage
    • Petechiae
    • Purpura
  • Reference: Transfusion 2016;56:1230
Screening
  • Consider if neonate born with low platelet count
  • When fetal neonatal alloimmune thrombocytopenia is considered in the differential diagnosis, testing may include:
    • Maternal serum HPA antibody testing
    • Maternal platelet genotyping
    • Paternal platelet genotyping
  • May monitor pregnancy if sibling with:
    • History of fetal neonatal alloimmune thrombocytopenia
    • Antenatal intracranial hemorrhage
  • Unclear if screening more effective than simply treating mother and neonate when symptoms develop (BJOG 2019;126:e173)
Laboratory
  • Diagnosis made when:
    • HPA antibodies detected in maternal serum
    • Corresponding antigen detected from paternal testing via HPA genotyping
    • Less often, corresponding antigen detected by HPA genotyping of fetus
      • Via chorionic villus sampling after 11 weeks gestational age
      • Via amniocentesis after 16 weeks gestational age (BJOG 2019;126:e173)
  • Maternal platelet count is normal, as opposed to immune thrombocytopenic purpura, where maternal count is also low
Case reports
  • Neonates with fetal neonatal alloimmune thrombocytopenia with severe bleeding complications other than intracerebral hemorrhage (Transfusion 2016;56:1230)
  • Newborn twin girls with fetal neonatal alloimmune thrombocytopenia, presumably from passive human leukocyte antigen antibodies (BMJ Case Rep 2017;2017:bcr2016218269)
  • Term infant with fetal neonatal alloimmune thrombocytopenia secondary to maternal antibodies to HPA15 (Pediatrics 2018;141:S506)
  • 27 year old pregnant woman with antenatal diagnosis of intracranial hemorrhage from fetal neonatal alloimmune thrombocytopenia (BMJ Case Rep 2015;2015:bcr2014209130)
  • 43 year old woman with first pregnancy complicated by fetal neonatal alloimmune thrombocytopenia due to HPA5a antibodies (Transfus Apher Sci 2020;59:102880)
Treatment
  • Prevention not possible at present
  • Antenatal management:
    • Intravenous immune globulin (IVIG) offered to at risk women
      • Some offer to mother starting at 18 weeks gestation
      • Others risk stratify mother based on prior pregnancy history:
        • Very high risk: intracranial hemorrhage or platelets < 20 x 109/L in prior pregnancy
        • Extremely high risk: thrombocytopenia and intracranial hemorrhage prior to 28 weeks gestation in prior pregnancy
        • High risk: thrombocytopenia only in prior pregnancy
        • No difference if IVIG alone or in combination with corticosteroids (Obstet Gynecol 2006;107:91)
  • Postnatal treatment of symptomatic neonates
    • Thrombocytopenic neonates with or without bleeding
      • Platelet threshold for transfusion varies by study:
        • < 35 x 109/L or < 50 x 109/L
        • Majority of intracranial hemorrhage occurs < 30 x 109/L
    • Platelet transfusions
      • If the HPA antigen is known, HPA antigen negative platelets
        • Both washed, irradiated platelets or HPA selected platelets effective (led to higher posttransfusion platelet counts)
        • HPA selected more effective than unselected
      • Random platelets
        • Safe option; should not delay transfusion to infant trying to obtain HPA selected or washed maternal platelets (Br J Haematol 2019;185:549)
      • Washed, irradiated maternal platelets
        • May be difficult to obtain due to timing, ability to perform plateletpheresis collection on the mother
      • Platelet transfusion plus IVIG but no clear benefit of adding IVIG (J Perinatol 2019;39:1329)
    • Washed, irradiated platelets or HPA selected platelets led to higher posttransfusion platelet counts
    • However, platelet transfusion of any kind resulted in clinical hemostasis
    • More studies required to assess benefit of platelet transfusion with intravenous immune globulin in neonate
  • References: Transfus Apher Sci 2020;59:102704, BJOG 2019;126:e173
Sample assessment & plan
  • Assessment:
    • Patient is a 25 year old gravida 2, para 1 (G2P1) who previously delivered a neonate affected by fetal neonatal alloimmune thrombocytopenia without intracerebral hemorrhage
    • Father in the previous pregnancy is heterozygous for the incompatible platelet antigen and is the father of the current pregnancy
    • Mother is currently at 10 weeks gestation and given her history is being evaluated for a second pregnancy potentially affected by fetal neonatal alloimmune thrombocytopenia
  • Plan:
    • Close monitoring and management by maternal fetal medicine
    • Start intravenous immunoglobulin at approximately 12 - 16 weeks gestation
    • Fetal blood sampling may occur during the pregnancy but should not be automatic in all cases due to the risks associated with this invasive procedure
    • Fetal HPA status can be determined by typing fetal DNA for platelet antigens, amniocentesis at 15 - 16 weeks of gestation, fetal blood is not necessary
    • Ultrasound examinations to look for fetal intracranial hemorrhage beginning at 16 to 20 weeks and occurring every 4 - 6 weeks until delivery
    • In viable pregnancies, early delivery or C section may be necessary to allow treatment of fetal / neonatal thrombocytopenia
Differential diagnosis
Board review style question #1
26 year old gravida 1, para 1 (G1P1) patient gives birth to a neonate born with petechiae and a platelet count of 15 K/uL. Fetal neonatal alloimmune thrombocytopenia is suspected and paternal platelet antigen genotyping is performed, as is maternal HPA antibody testing and maternal platelet antigen genotyping. The 2 most common HPA antigens associated with this diagnosis are

  1. HPA1a and HPA1b
  2. HPA1a and HPA3b
  3. HPA1a and HPA5b
  4. HPA3a and HPA5b
  5. HPA5a and HPA5b
Board review style answer #1
C. HPA1a and HPA5b are the 2 most common antigens to which maternal antibody is directed. However, fetal neonatal alloimmune thrombocytopenia can be linked to any HPA antigen.

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Reference: Fetal / neonatal alloimmune thrombocytopenia
Board review style question #2
35 year old gravida 3, para 2 (G3P2) patient has a history of a severely fetal neonatal alloimmune thrombocytopenia affected neonate born with intracranial hemorrhage, followed by a subsequent pregnancy managed with intrauterine fetal transfusion. She is currently at 10 weeks gestation. What would be the most appropriate management for this pregnancy?

  1. Automatic intrauterine fetal transfusion of washed maternal platelets at 28 weeks, regardless of fetal platelet count
  2. High dose maternal corticosteroids, starting now until delivery
  3. Intrauterine fetal transfusion of washed maternal platelets to keep fetal platelet count > 100 x 109/L; delivery by Cesarian section only
  4. IVIG starting between 12 - 16 weeks gestation, with fetal monitoring / blood sampling and delivery near term at about 36 weeks
  5. Routine prenatal care, no additional interventions
Board review style answer #2
D. Recent articles show that IVIG started at about 12 - 16 weeks gestation is appropriate management for women with a history of fetal neonatal alloimmune thrombocytopenia affected pregnancy. Close monitoring is necessary. Most studies have not demonstrated definitive benefit for maternal corticosteroids and may show adverse outcomes (maternal gestational diabetes, etc). Fetal blood sampling may occur at intervals and governs the need for fetal intrauterine transfusion. It should not be considered automatic during the course of pregnancies. Fetal platelet transfusion thresholds are suggested to be between 25 - 50 x 109/L. Keeping fetal platelet count > 100 x 109/L would be an unnecessarily high threshold and may pose risk as percutaneous umbilical vein blood sampling and transfusions are not without risk.

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Reference: Fetal / neonatal alloimmune thrombocytopenia
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