Neonatal Alloimmune Thrombocytopenia - NAIT

Medical Experts

Contributors critically edit at least some content for accuracy and integrity, and approve any content they edit for publication.
Authors frame content, identify key sources of information, draft and/or critically edit and revise content to ensure medical accuracy and integrity, and review and approve content for publication.

Contributor

Ji

Yuan Ji, PhD, DABCP, FACMG

Associate Professor of Pathology (Clinical), University of Utah

Section Chief, Molecular Genetics and Genomics, ARUP Laboratories

Contributor

Moser

Karen A. Moser, MD

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Hemostasis/Thrombosis, ARUP Laboratories

Contributor

Smock

Kristi J. Smock, MD

Professor of Pathology (Clinical), University of Utah

Chief Medical Director, ARUP Institute for Clinical and Experimental Pathology

Medical Director, Hemostasis/Thrombosis, ARUP Laboratories

Neonatal alloimmune thrombocytopenia (NAIT), also referred to as fetal and neonatal alloimmune thrombocytopenia or perinatal alloimmune thrombocytopenia, is the most common cause of thrombocytopenia in an otherwise healthy newborn.¹

Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017;10(8):729-737.

NAIT is caused by alloantibodies formed by the mother in response to a paternally inherited human platelet antigen (HPA) on the surface of fetal platelets. These maternal alloantibodies pass through the placenta to the fetus, attack the fetal platelets, and cause fetal platelet destruction.^{1

Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017;10(8):729-737.} Many cases of NAIT are mild, resulting in only skin manifestations. Left untreated, mild cases may resolve within 2 weeks of birth.^{1

Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017;10(8):729-737.}^{2

Peterson JA, McFarland JG, Curtis BR, et al. Neonatal alloimmune thrombocytopenia: pathogenesis, diagnosis and management. Br J Haematol. 2013;161(1):3-14.} NAIT can also cause severe thrombocytopenia (platelet count <50,000/µL), which can result in intracranial hemorrhage (ICH) and even infant death, although severe hemorrhages are uncommon.^{1

Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017;10(8):729-737.}^{3

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.} Laboratory testing is used to diagnose NAIT in an affected infant and to determine the risk of NAIT in future pregnancies.^{4

Petermann R, Bakchoul T, Curtis BR, et al. Investigations for fetal and neonatal alloimmune thrombocytopenia: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(12):2526-2529.} Testing involves evaluation of maternal serum for platelet alloantibodies and genotyping or phenotyping of the maternal, paternal, and/or neonatal platelets.^{4

Petermann R, Bakchoul T, Curtis BR, et al. Investigations for fetal and neonatal alloimmune thrombocytopenia: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(12):2526-2529.}^{5

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013;88(9):818-821.}^{6

Smock KJ, Perkins SL. Thrombocytopenia: an update. Int J Lab Hematol. 2014;36(3):269-278.} NAIT can occur in first pregnancies. After diagnosis, subsequent pregnancies should be monitored and antenatal therapy can be used to avoid bleeding complications.^{1

Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017;10(8):729-737.}

Quick Answers for Clinicians

When should neonatal alloimmune thrombocytopenia be suspected?

Neonatal alloimmune thrombocytopenia (NAIT) should be suspected in newborns with incidentally detected thrombocytopenia or manifestations of a bleeding complication (eg, ultrasound anomalies in utero that may suggest intracranial hemorrhage [ICH],¹

Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017;10(8):729-737.

petechiae, bruising, or purpura shortly after birth, hematomas that develop at sites of injection, or bleeding following circumcision), and in all pregnancies of women who have had a previously affected infant.^{3

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.}

What are the primary laboratory tests used to investigate neonatal alloimmune thrombocytopenia?

The primary tests for neonatal alloimmune thrombocytopenia (NAIT) are an initial CBC with platelet count to confirm thrombocytopenia, followed by a maternal serum test for platelet alloantibodies. (Neonatal samples are discouraged for circulating antibody testing due to insensitivity.⁵

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013;88(9):818-821.

) Platelet genotyping is performed to assess maternal, paternal, and/or neonatal human platelet antigen (HPA) incompatibilities. The identification of an HPA incompatibility along with the presence of a corresponding maternal alloantibody establishes a diagnosis of NAIT.^{1

Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017;10(8):729-737.}^{3

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.}^{4

Petermann R, Bakchoul T, Curtis BR, et al. Investigations for fetal and neonatal alloimmune thrombocytopenia: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(12):2526-2529.}

What is the role of screening for neonatal alloimmune thrombocytopenia?

Broad screening in first pregnancies is not currently recommended,³

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.

^{7

Regan F, Lees CC, Jones B, et al. Prenatal management of pregnancies at risk of fetal neonatal alloimmune thrombocytopenia (FNAIT): Scientific Impact Paper No. 61. BJOG. 2019;126(10):e173‐e185.} although groups such as the International Collaboration for Transfusion Medicine have proposed that universal screening of first pregnancies be considered.^{8

Lieberman L, Greinacher A, Murphy MF, et al. Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach. Br J Haematol. 2019;185(3):549‐562.} Currently, testing for neonatal alloimmune thrombocytopenia (NAIT) is recommended during pregnancy in women with at-risk pregnancies (eg, women with a previously affected child), and antenatal therapy is recommended in such pregnancies to avoid bleeding complications.^{3

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.} See Antenatal Testing below.

What are some of the challenges of diagnostic testing for neonatal alloimmune thrombocytopenia?

Diagnosis of neonatal alloimmune thrombocytopenia (NAIT) can be challenging when rare antiplatelet antibodies are involved. Cross-matching between maternal serum and paternal platelets can be performed in specialized laboratories and may detect less common or unique antigen incompatibilities.³

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.

Delayed, low-titer, or low-affinity alloantibodies can also present diagnostic challenges.^{3

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.}^{4

Petermann R, Bakchoul T, Curtis BR, et al. Investigations for fetal and neonatal alloimmune thrombocytopenia: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(12):2526-2529.}

Indications for Testing

Laboratory testing for NAIT is appropriate for:

Diagnosis of a fetus with bleeding on ultrasound (especially if suggestive of ICH) or a neonate with bleeding symptoms or early-onset, severe thrombocytopenia^{1

Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017;10(8):729-737.}^{5

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013;88(9):818-821.}
Diagnosis of a fetus of a woman with a previously affected child^{3

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.}
Risk assessment in women planning a pregnancy who have a history of an affected pregnancy or posttransfusion purpura,^{5

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013;88(9):818-821.}^{6

Smock KJ, Perkins SL. Thrombocytopenia: an update. Int J Lab Hematol. 2014;36(3):269-278.} or who have a sister or another relative with a previously affected pregnancy^{1

Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017;10(8):729-737.}

Laboratory Testing

Diagnosis

Antenatal Testing

If NAIT is suspected during pregnancy, the mother can be tested regularly for the development of alloantibodies; however, alloantibody levels can fluctuate and have not been demonstrated to correlate with NAIT severity.³

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.

Platelet genotyping is used to identify potential genetic incompatibilities. See Platelet Antigen Genotyping and Phenotyping below.

Postnatal Testing

Initial Testing

A CBC with platelet count is an initial test for infants suspected of having NAIT; in addition, a maternal CBC with platelet count should be performed to rule out low platelets in the mother, which might indicate autoimmune thrombocytopenia.³

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.

The International Society on Thrombosis and Haemostasis (ISTH) considers a platelet count <100,000/μL at birth or within 7 days after birth, with no other cause, as diagnostic for NAIT in the first affected pregnancy.^{4

Petermann R, Bakchoul T, Curtis BR, et al. Investigations for fetal and neonatal alloimmune thrombocytopenia: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(12):2526-2529.} However, there are often many potential causes of neonatal thrombocytopenia. Thrombocytopenia with a platelet count of <50,000/μL is considered severe^{3

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.}; in some cases the count may be as low as <20,000/μL.^{6

Smock KJ, Perkins SL. Thrombocytopenia: an update. Int J Lab Hematol. 2014;36(3):269-278.} Platelet counts continue to decline after birth in infants with NAIT but often recover and become normal within a couple of weeks.^{2

Peterson JA, McFarland JG, Curtis BR, et al. Neonatal alloimmune thrombocytopenia: pathogenesis, diagnosis and management. Br J Haematol. 2013;161(1):3-14.}^{5

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013;88(9):818-821.} A CBC with platelet count that confirms thrombocytopenia should be followed by specific tests to establish a diagnosis of NAIT (ie, antiplatelet antibody tests and platelet antigen genotyping) if there is clinical suspicion.

Antiplatelet Antibody Tests

Antiplatelet antibody tests and test interpretation should be performed by an experienced platelet immunology reference laboratory (see specific laboratories listed below). Definitive diagnosis of NAIT requires a combination of tests because laboratory diagnosis of NAIT is based on both detection of anti-HPA alloantibodies and determination of the causative antigen.⁹

Bertrand G, Kaplan C. How do we treat fetal and neonatal alloimmune thrombocytopenia? Transfusion. 2014;54(7):1698-1703.

It is important to note that false-negative antibody test results can occur due to delayed, low-titer, or low-affinity antibodies, so the absence of a detectable maternal antibody does not rule out NAIT.^{4

Petermann R, Bakchoul T, Curtis BR, et al. Investigations for fetal and neonatal alloimmune thrombocytopenia: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(12):2526-2529.}

A maternal sample is preferred for evaluation of the presence of anti-HPA antibodies; neonatal serum/plasma samples are considered less sensitive when testing for circulating antibodies and are not recommended.⁵

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013;88(9):818-821.

Antiplatelet antibody tests are designed to detect maternal alloantibodies to antigens associated with NAIT, for example, anti-HPA-1, anti-HPA-3, and anti-HPA-5.^{5

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013;88(9):818-821.} More rare HPAs also have been implicated in NAIT, but antibodies targeting these less common HPAs are not detected by tests that use commercial kits and require testing by a specialized laboratory.

Reference laboratories that perform comprehensive testing for NAIT include the following:

Platelet Immunology Laboratory, Bloodworks Northwest
BloodCenter of Wisconsin (part of Versiti)

Platelet Antigen Genotyping and Phenotyping

Testing for NAIT also involves genotyping or phenotyping of the mother’s and father’s and/or neonatal platelets.⁵

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013;88(9):818-821.

The paternal platelet genotype is often used as a surrogate for the fetal or neonatal genotype, but typing paternal platelets may be uninformative in some cases. A physician experienced in the diagnosis and treatment of NAIT should provide guidance regarding the testing (whom to test and which tests to use). Genotyping enables detection of incompatibilities between HPAs. Ideally, genotyping involves both parents and the neonate to obtain comprehensive information.^{3

Espinoza JP, Caradeux J, Norwitz ER, et al. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.} Genotyping also enables more accurate risk assessment for future pregnancies because paternal zygosity for the specific HPA in question will affect risk.^{4

Petermann R, Bakchoul T, Curtis BR, et al. Investigations for fetal and neonatal alloimmune thrombocytopenia: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(12):2526-2529.} Platelet antigen incompatibility is necessary but not sufficient for NAIT (in many cases, genetic incompatibilities do not result in antibody formation). Close correlation between clinical information and the results of platelet antibody testing is necessary for definitive diagnosis.

If the father is heterozygous for the relevant HPA, the genotype of the fetus in future pregnancies will be indeterminate. Fetal samples may be tested, if testing is indicated, or treatment may be administered empirically if clinically warranted.⁵

Heikal NM, Smock KJ. Laboratory testing for platelet antibodies. Am J Hematol. 2013;88(9):818-821.

Platelet phenotyping is now used less frequently than molecular genotyping, but phenotyping may be helpful to resolve discrepant or inconclusive genotyping results. It is available in specialized laboratories.⁴

Petermann R, Bakchoul T, Curtis BR, et al. Investigations for fetal and neonatal alloimmune thrombocytopenia: communication from the SSC of the ISTH. J Thromb Haemost. 2018;16(12):2526-2529.

ARUP Laboratory Tests

Platelet Antigen Genotyping

3000193

Platelet Antigen Genotyping Panel 3000193

Method

Polymerase Chain Reaction (PCR)/Fluorescence Monitoring

3016673

Platelet Antigen Genotyping Panel, Fetal 3016673

Method

Polymerase Chain Reaction (PCR)/Fluorescence Monitoring/Fragment Analysis

Neonatal Alloimmune Thrombocytopenia - NAIT

Medical Experts

Ji

Moser

Smock

Quick Answers for Clinicians

Indications for Testing

Laboratory Testing

Diagnosis

Antenatal Testing

Postnatal Testing

Initial Testing

Antiplatelet Antibody Tests

Platelet Antigen Genotyping and Phenotyping

ARUP Laboratory Tests

References

28644735

23384054

23687553

30382606

23757218

24750673

30968555

30828796

24773309

About

Testing

Education Center

Contact Us

Cite this page

Feedback

Neonatal Alloimmune Thrombocytopenia - NAIT

Medical Experts

Quick Answers for Clinicians

Indications for Testing

Laboratory Testing

Diagnosis

Antenatal Testing

Postnatal Testing

Initial Testing

Antiplatelet Antibody Tests

Platelet Antigen Genotyping and Phenotyping​

ARUP Laboratory Tests

References

Related Information From ARUP Laboratories

Topics From ARUP Consult

Test Fact Sheets From ARUP Consult

Platelet Antigen Genotyping and Phenotyping