Final Diagnosis -- Fetal/Neonatal Alloimmune Thrombocytopenia


Fetal/Neonatal Alloimmune Thrombocytopenia


Fetal/neonatal alloimmune thrombocytopenia (FNAIT), a common cause of severe isolated thrombocytopenia in the fetus and the newborn, occurs in 1 in 500 to 1 in 5000 live births (1). There is an increased incidence of FNAIT in patients with HLA-DRB3*01:01 (1). At the core of the pathophysiology of FNAIT is the destruction of the fetal platelets by maternal IgG antibodies during pregnancy. These antibodies are directed against fetal-specific platelet antigens that are inherited from the father and differ from those present in the mother (2). FNAIT may be seen as the platelet counterpart to Rh hemolytic disease of the newborn (RHD) as both processes stem from alloimmunization due to antigens present on fetal cells (RBC's or platelets) that are lacking in the mother. Important differences exist between the two entities though (Table 1).

There are several important contributors to the pathogenesis of FNAIT, including: (a)Feto-maternal HPA incompatibility, (b) Maternal exposure to incompatible fetal HPA (c)Maternal alloimmunization and maternal-fetal antibody transfer (3).

(A)FETO-MATERNAL INCOMPATIBILITY- The process of FNAIT is initiated by feto-maternal incompatibility with respect to human platelet antigens (HPA). HPAs are glycoproteins found on the surface of platelets (see Figure 6). They are named using the HPA system by number in the order in which they were first described with "a" designating the high-frequency alloantigen and "b" designating the low-frequency alloantigen. HPA-1a is most often implicated in causing FNAIT, accounting for approximately 80% of the cases in Caucasian populations (3).

(B)MATERNAL EXPOSURE TO INCOMPATIBLE FETAL HPA- Despite close interaction between fetal and maternal circulation, under normal circumstances there is no actual exchange of blood (4). It is however likely that maternal sensitization to HPA by fetal platelets, if it does occur, most often results from obstetrical or trauma related complications or occurs at parturition. So then how is alloimmunization and FNAIT possible in first pregnancy? Studies indicate that fetal trophoblasts are probably the major contributors of both fetal cells and DNA detected in maternal blood (5,6). The presence of GPIIIa on circulating syncytiotrophoblast cellular material could be the source of HPA-1a alloantigen causing primary immunization of susceptible primigravidae early enough for anti-HPA-1a to cause fetal thrombocytopenia during a first pregnancy(3).

(C)MATERNAL ALLOIMMUNIZATION and MATERNAL-FETAL ANTIBODY TRANSFER- Whatever the mechanism and source of maternal exposure to fetal platelet antigens during pregnancy, exposure to incompatible HPA can elicit production of HPA-specific antibodies that cause FNAIT.

The culmination of this entire process is thrombocytopenia, which may be asymptomatic or manifested clinically in a variety of different ways. The most frequently observed signs of thrombocytopenia are: petechiae (90%), hematomas (66%), melena (30%), hemoptysis (8%), retinal bleeding (7%) and hematuria (3%) (7). Additionally, the birth weight is often below average in neonates with FNAIT (7). The laboratory evaluation of FNAIT is summarized in Table 2.

TABLE 2. Laboratory evaluation of FNAIT (8)

The management of FNAIT cases may be approached during either the antenatal or postnatal period depending on the clinical scenario. During the antenatal period, the mother may be treated with IVIG and/or corticosteroids, with recent studies reporting that IVIG with steroids was a more effective therapy than IVIG alone (9). Unfortunately, IVIG therapy may not be enough in some cases, necessitating weekly in-utero platelet transfusions (10,11). Elective caesarian section may also be helpful in preventing intracranial hemorrhage during delivery. In the postnatal period, IVIG therapy as well as platelet transfusions may be employed. Currently, transfusion of donor-matched, antigen-negative platelets is the best treatment of choice for neonates born with FNAIT who exhibit signs of bleeding (12). If compatible platelets are not available, and if the mother is suitable for platelet apheresis, it is possible to transfuse the newborn with washed, irradiated and leukoreduced platelets harvested from the mother or random platelets may also be used. IVIG and random donor platelets have about 90% treatment response (13); this is what was used in our patient. Importantly, whether or not FNAIT is treated, anti-HPA disappears within 2-3 weeks of birth.


  1. Strong NK, Eddleman KA. "Diagnosis and management of neonatal alloimmune thrombocytopenia in pregnancy." Clin Lab Med. 2013 Jun;33(2):311-25.
  2. Peterson JA et al. "Neonatal alloimmune thrombocytopenia: pathogenesis, diagnosis and management." Br J Haematol. 2013 Apr;161(1):3-14.
  3. Brian R. Curtis. "Recent progress in understanding the pathogenesis of fetal and neonatal alloimmune thrombocytopenia." Br J Haematol. 2015 Sep;171:671-682.
  4. Kumpel, B.M. & Manoussaka, M.S. (2012) Placental immunology and maternal alloimmune responses. Vox Sanguinis, 102, 2-12.
  5. Bianchi, D.W. (2004) Circulating fetal DNA: its origin and diagnostic potential-a review. Placenta, 25(Suppl. A), S93-S101.
  6. Alberry, M., Maddocks, D., Jones, M., Abdel Hadi, M., Abdel-Fattah, S., Avent, N. & Soothill, P.W. (2007) Free fetal DNA in maternal plasma in anembryonic pregnancies: confirmation that the origin is the trophoblast. Prenatal Diagnosis, 27, 415-418.
  7. Sachs UJ. Fetal/neonatal alloimmune thrombocytopenia. Thromb Res. 2013 Jan;131 Suppl 1:S42-6.
  8. Michael Laposata. The diagnosis of disease in the Clinical Laboratory. Second Edition, 2014
  9. Bertrand G, Drame M, Martageix C, Kaplan C. Prediction of the fetal status in non-invasive management of alloimmune thrombocytopenia. Blood 2011;117:3209e13.
  10. Kaplan C, Murphy MF, Kroll H, Waters AH. Feto-maternal alloimmune thrombocytopenia: antenatal therapy with IvIgG and steroids e more questions than answers. European Working Group on FMAIT. Br J Haematol 1998;100:62e5.
  11. Letsky EA, Greaves M. Guidelines on the investigation and management of thrombocytopenia in pregnancy and neonatal alloimmune thrombocytopenia. Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task Force of the British Society for Haematology. Br J Haematol 1996;95:21e6.
  12. Darko Zdravic et al. "Fetal and neonatal alloimmune thrombocytopenia." Seminars in Fetal and Neonatal Medicine. 2016;21:19-27.
  13. Kiefel V et al., Antigen-positive platelet transfusion in neonatal alloimmune thrombocytopenia (NAIT), Blood, 2006; 107; 3761-3763

Contributed by Dayne Ashman, MD and Alesia Kaplan, MD

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