Fetal Neonatal Alloimmune Thrombocytopenia
Victoria Lindstrom Chase
Michael J. Paidas
Introduction
Fetal and neonatal thrombocytopenia is defined by a platelet count less than 150,000/µL. Thrombocytopenia can be the result of a variety of different etiologies ranging from immunologic disorders, to antenatal infections, to genetic conditions. Platelet counts above 50,000/µL are unlikely to cause significant sequelae. However, when the fetal platelet count drops below this threshold, significant sequela may arise, with the most serious being spontaneous intracranial bleeding. Of fetuses and neonates with severe thrombocytopenia, defined by a platelet count less than 50,000/µL, fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause.
Etiology
FNAIT is a pregnancy complication that affects a fetus or baby’s platelets and can lead to serious fetal or neonatal morbidity and mortality. Platelets have protein on their surface called human platelet antigens (HPAs) that are both maternally and paternally inherited in an autosomal codominant fashion. In pregnancy and at the time of delivery, fetal platelets enter maternal circulation. If the maternal immune system identifies foreign, paternally inherited HPAs, maternal alloantibodies against the fetal HPAs may occur. The maternal immunoglobulin (Ig) G antibodies produced then cross the placenta and invoke fetal platelet destruction (Figure 23.1).
FNAIT is considered the platelet equivalent of hemolytic disease of the fetus and newborn (HDFN; and see Chapter 22). However, there are important differences between the two diseases. Approximately 2% of women are HPA-1-negative, as compared to approximately 10% of Rh-negative women. FNAIT frequently occurs in the first pregnancy, in contrast to HDFN, in which clinically affected fetuses and newborns rarely occur in the first pregnancy, but disease is manifested in the second and subsequent pregnancies. Sensitization following an incompatible transfusion rarely occurs with the HPA-1a antigen, whereas anti-D is the most common antibody response during incompatible transfusions. Routine antenatal screening for FNAIT does not exist but does for Rh phenotyping. Prevention does not exist for FNAIT but does for HDFN related to anti-D, namely antenatal and postnatal RhIG (anti-D).
The incidence of FNAIT is 1 in 1000 to 1 in 2000 live births.1,2 Severity of thrombocytopenia ranges from clinically asymptomatic neonates to fetuses or neonates with intracranial hemorrhage (ICH) and/or death.3 Death or long-term neurological damage resulting from ICH that occurs at or soon after delivery is historically quoted at 25%4 with in utero spontaneous ICH occurring in 5% to 10% of pregnancies.5 In more contemporary literature of pregnancies affected by FNAIT, the rate of ICH has been reported as 8.9% and mortality approximately as 1%.6
As mentioned, FNAIT may occur in the first pregnancy of an at-risk couple. The fetal bleeding risk is a result of thrombocytopenia and, in mouse studies, maternal alloantibody mediated damage to vascular integrity and angiogenesis.7,8,9 The severity of thrombocytopenia differs depending on the platelet antigen involved,10 may worsen with increasing gestation,3 and is more severe if prior pregnancies have been affected.
Biologic Activity of Human Platelet Antigens
Over 30 HPAs have been identified (Table 23.1). They are carried on platelet membrane glycoproteins (GP) 1a-V-IX, more commonly known as the
von Willebrand receptor; GPIIb/IIIa, an αIIb/β3 integrin and fibrinogen receptor; heparin platelet (HP) Ia/IIa, a collagen receptor; and cluster of differentiation (CD) 109, a glycosylphosphatidylinositol-anchored protein. Platelet glycoproteins function by interacting with extracellular matrix protein and coagulation factors to achieve hemostasis. Glycoprotein IV, a class B scavenger receptor, can elicit a FNAIT-like clinical picture. Deficiency in this glycoprotein is more common in those with African or Asian descent (Figure 23.2).11
von Willebrand receptor; GPIIb/IIIa, an αIIb/β3 integrin and fibrinogen receptor; heparin platelet (HP) Ia/IIa, a collagen receptor; and cluster of differentiation (CD) 109, a glycosylphosphatidylinositol-anchored protein. Platelet glycoproteins function by interacting with extracellular matrix protein and coagulation factors to achieve hemostasis. Glycoprotein IV, a class B scavenger receptor, can elicit a FNAIT-like clinical picture. Deficiency in this glycoprotein is more common in those with African or Asian descent (Figure 23.2).11
 Figure 23.1 Pathophysiology of fetal neonatal alloimmune thrombocytopenia. (Reprinted from Paidas MJ, Thung S, Beardsley DS. Unmasking the many faces of maternal and fetal thrombocytopenia. Contemp Ob Gyn. 2006;51(9):42-52.) |
Many HPAs are biallelic and codominant. The most commonly implicated platelet antibody in FNAIT is due to anti-HPA-1a alloimmunization in mothers who are HPA-1b homozygous, which is responsible for approximately 80% of cases of FNAIT in non-Hispanic white women.3 The HPA-1a and HPA-1b alleles are variants of the β3 integrin molecule on glycoprotein IIIa which are a result of a substitution of a proline for leucine base at amino acid 33.12 The next most common antibodies implicated in FNAIT in non-Hispanic whites are against HPA-5a and HPA-15. In contrast, in Asian women, HPA-4a, HPA-6a, and HPA-21b incompatibility is more frequently causative.11,13
Additionally, an increased immunologic susceptibility to alloimmunization has been associated with certain human leukocyte antigens (HLAs). HLA-DRB3*0101 is an example of one of these HLAs studied due to its association with alloimmunization in women who are HPA-1a-negative. Women who carry one or two copies of HLA-DBR3*0101 and are delivering a HLA-1a-positive child have a 12.7% risk of alloimmunization versus a 0.5% risk in those negative for the allele.12 An increased risk of alloimmunization is also seen in women with Dw52a, DQB1*0201, and DR6 alleles.14
Table 23.1 Human Platelet Antigen (HPA) System | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Diagnosis
FNAIT should be suspected in all the cases of fetal ICH identified sonographically or when neonatal thrombocytopenia is identified. Scenarios that warrant a parental evaluation for FNAIT include a history of an affected child, direct relation to an affected child, previous child with unexplained thrombocytopenia, and a woman incidentally found to lack the HPA-1a antigen (Algorithm 23.1). The diagnosis is typically made following maternal and paternal HPA genotyping identifying platelet antigen incompatibility and maternal antibodies to the foreign paternal antigen. Murphy et al used platelet immunofluorescence tests and monoclonal antibody immobilization of platelet antigen assays for platelet typing and detection of HPA antibodies (Table 23.2).15 In the setting of paternal platelet antigen heterozygosity, fetal platelet antigen typing may be evaluated by polymerase chain reaction. Fetal DNA may be obtained via chorionic villus sampling or amniocentesis. However, chorionic villus sampling is typically avoided due to theoretical risk of increased sensitization with the procedure. Fetal HPA-1a genotyping via cell-free DNA testing in the early second trimester produces reliable results but is not widely available as a routine clinical test.16
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
