Keywords
FNAIT - CHI - anti-HPA antibody
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs in the setting of maternal
anti-human platelet antigen (anti-HPA) antibodies against paternally derived fetal
platelet antigens.[1] The most common antibody is anti-HPA-1a, although others have been implicated. These
antibodies develop following exposure to HPA antigens absent in the mother. Maternal
immunoglobulin G (IgG) antibodies form against fetal platelet antigens and are transported
across the placenta, causing destruction of fetal platelets and leading to thrombocytopenia
and bleeding in the neonate.[2] FNAIT has been reported in as high as 1/1,000 live births and likely remains underdiagnosed,
as antenatal screening for FNAIT is not routinely performed.[3]
Other causes of neonatal thrombocytopenia include prematurity, maternal pregnancy-induced
hypertensive disorders, and antenatal infection. Rarer etiologies include immune mediated
destruction, such as maternal autoimmune disease (lupus) or drug induced/dependent
antibodies; chromosomal abnormalities and other genetic disorders; increased clearance
of platelets as seen in fetal hypersplenism, Kaposiform hemangioendothelioma, and
type 2B von Willebrand disease; bone marrow or specific lineage failure; and marrow
replacing neoplasms, such as congenital leukemias or bone marrow involvement by neuroblastoma.[4]
Recent studies have also demonstrated an association between chronic placental inflammation
and FNAIT, specifically low-grade chronic histiocytic intervillositis (CHI).[3] Furthermore, it is reported that more than 40% of mothers with anti-HPA-1a antibodies
have placentas with CHI, which may contribute to the fetal growth restriction and
reduced birth weight associated with FNAIT. CHI is theorized to represent an allogeneic
humoral (antibody-associated) rejection following the transfer of IgG antibodies from
mother to fetus. Both CHI and FNAIT often recur in subsequent pregnancies, although
severity is unpredictable.
We present a neonate with profound thrombocytopenia after delivery with co-occurring
CHI, whose platelet counts recovered rapidly with platelet transfusions, but without
IVIG therapy, born to a primigravida mother with late-onset preeclampsia.
Case Report
A male neonate was born at 40 weeks' gestational age to a mother who had no known
history of pregnancies, miscarriages, or transfusions. The pregnancy was complicated
by O and Rh− blood type, obesity (BMI = 53), and late-onset preeclampsia with severe
features, diagnosed by severe range blood pressures (SRBPs) and elevated urine protein-to-creatinine
ratio (0.4), during induction of labor, requiring magnesium administration. For SRBPs,
she received hydralazine 10 mg twice and labetalol 20 mg thrice, and ultimately underwent
cesarean section for arrest of descent. Birth weight was 3,505 g, appropriate for
age,[5] and APGAR scores were 9 and 9, respectively, but, shortly after delivery, physical
exam showed inappropriate bruising on the heels of both feet, scattered petechiae
on the hard palate, a hematoma on the left thigh where his Vitamin K shot was administered,
and a 1 cm × 1 cm bruise on the upper left abdomen. He was transferred to our medical
center for signs of thrombocytopenia.
Labs from cord blood at the referring hospital revealed a platelet count of 10,000
and a subsequent serum platelet count of 9,000. On admission to our unit, his serum
platelet count was 7,000 with an immature platelet fraction of 32%. His blood type
was A and Rh − . He was transfused with platelets from a random donor at 10 mL/kg,
but his platelet count rose insufficiently from 7K to 29K, and he was given a second
platelet transfusion the following day, this time from an HPA-1a negative donor, at
15 mL/kg. His platelet count rose to 94K by day 3 of life, with resolution of clinical
symptoms of thrombocytopenia. Abdominal ultrasound and head ultrasound were unremarkable.
At this time, the differential diagnosis for the thrombocytopenia was preeclampsia
versus neonatal alloimmune thrombocytopenia (NAIT); however, preeclampsia was initially
favored. Placental pathology was also performed. The placenta was 655 g (>90th percentile
for 40 weeks of gestational age). Histology showed fetal normoblastemia without erythroblastosis
and prominent villous stromal hemorrhages ([Fig. 1]). In addition, patchy aggregates of intervillous histiocytes were noted throughout
the intervillous space ([Fig. 2]), confirmed with CD68 immunostain, suspicious for low-grade CHI ([Fig. 3]).
Fig. 1 Chorionic villi with intravillous stromal hemorrhages and increased circulating nucleated
red blood cells (H&E, 10 × ).
Fig. 2 Aggregates of intervillous histiocytes (H&E, 40 × ).
Fig. 3 Intervillous histiocytes highlighted by CD68 immunostain (40×).
Subsequent send-out laboratory results confirmed paternal HPA-1a positive platelets,
maternal HPA-1a negative platelets, and a maternal HPA-1a antibody, supporting the
diagnosis of NAIT. Due to the rise in his platelet count and resolution of clinical
symptoms, the mother and baby were discharged home on day 3 to be followed by hematology
and his pediatrician. Following discharge, the patient had no new symptoms or signs
of thrombocytopenia, and his platelet counts were 218K and 290K at 13 days and at
3 weeks of life, respectively.
Discussion
HPA-associated alloimmunization in first pregnancies is not uncommon.[6]
[7] One study showed 63% of severe FNAIT cases occurred in first-time pregnancies, with
worsening outcomes when clinical features of FNAIT appeared at an earlier gestational
age.[6] The mechanism of alloimmunization is not well understood; however, HPA-1a antigens
are also expressed on placental trophoblast cells, a possible source of alloimmunization.[8]
The CHI in this placenta is mild and similar to prior reports of CHI in the placenta
of FNAIT cases.[3] Interestingly, CHI has also been loosely associated with maternal hypertensive disorders,[9] and preeclampsia has been reported complicating FNAIT, raising the question about
preeclampsia as a symptom of FNAIT in this case, rather than an independent disease.[10]
The extravillous trophoblast (EVT) plays a critical role in maternal vascular remodeling
and regulation of placental blood flow. EVT dysfunction is thought to be the primary
cause of preeclampsia. Inappropriate EVT function leads to reduced blood flow and
placental hypoxia, leading to a hypoxia-induced inflammatory response and the clinical
features of preeclampsia. HPA-1a antigens are also expressed on EVT cells. It is interesting
to consider that the development of maternal HPA-1a antibodies during this pregnancy
may have led to an alloimmune response against EVT cells, leading to dysregulated
placental blood flow and the development of late-onset preeclampsia.[11]
Conclusion
This case is unique as it highlights a relationship between maternal alloimmunity
and placental dysfunction and provides further support for a potential causal relationship
between failed maternal immune tolerance and the development of preeclampsia.
