Placental Complement Activation in Fetal and Neonatal Alloimmune Thrombocytopenia: An Observational Study

Abstract

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease that causes thrombocytopenia and a risk of bleeding in the (unborn) child that result from maternal alloantibodies directed against fetal, paternally inherited, human platelet antigens (HPA). It is hypothesized that these alloantibodies can also bind to the placenta, causing placental damage. This study aims to explore signs of antibody-mediated placental damage in FNAIT. We performed a retrospective study that included pregnant women, their newborns, and placentas. It comprised 23 FNAIT cases, of which nine were newly diagnosed (14 samples) and 14 were antenatally treated with intravenous immune globulins (IVIg) (21 samples), and 20 controls, of which 10 had anti-HLA-class I antibodies. Clinical information was collected from medical records. Placental samples were stained for complement activation markers (C1q, C4d, SC5b-9, and mannose-binding lectin) using immunohistochemistry. Histopathology was examined according to the Amsterdam criteria. A higher degree of C4d deposition was present in the newly diagnosed FNAIT cases (10/14 samples), as compared to the IVIg-treated FNAIT cases (2/21 samples, p = 0.002) and anti-HLA-negative controls (3/20 samples, p = 0.006). A histopathological examination showed delayed maturation in four (44%) placentas in the newly diagnosed FNAIT cases, five (36%) in the IVIg-treated FNAIT cases, and one in the controls (NS). C4d deposition at the syncytiotrophoblast was present in combination with low-grade villitis of unknown etiology in three newly diagnosed FNAIT cases that were born SGA. We conclude that a higher degree of classical pathway-induced complement activation is present in placentas from pregnancies with untreated FNAIT. This may affect placental function and fetal growth.

Fetal and neonatal alloimmune thrombocytopenia: No evidence of systemic inflammation as a modulator of disease severity. Could placental inflammation be key?

“…They concluded that a higher degree of classical pathway-induced complement activation is present in placentas from pregnancies with untreated FNAIT, which may affect placental function and fetal growth. 34 Further research shall aim to combine indicators of placental inflammation and dysfunction in FNAIT in order to increase our understanding of how the fetal-placental unit modifies disease severity in this disorder.…”

“…Only recently, de Vos et al, investigating placental complement activation in FNAIT, described a higher degree of C4d deposition in newly diagnosed FNAIT cases, as compared to the IVIg‐treated FNAIT cases or negative controls. They concluded that a higher degree of classical pathway‐induced complement activation is present in placentas from pregnancies with untreated FNAIT, which may affect placental function and fetal growth 34 . Further research shall aim to combine indicators of placental inflammation and dysfunction in FNAIT in order to increase our understanding of how the fetal‐placental unit modifies disease severity in this disorder.…”

Does anti‐HPA‐1a affect birthweight in fetal and neonatal alloimmune thrombocytopenia?

“…8 A third study identified C4d deposition on syncytiotrophoblasts in 10 of 14 samples from untreated FNAIT cases, including all small for gestational age (SGA) newborns, compared with two of 21 controls, demonstrating likely activation of the classical pathway of complement by IgG binding to the placenta. 9 The fourth study found chronic histiocytic intervillositis in 41% of FNAIT pregnancies compared with none in the 21 controls. 22,7,34 Extensive chronic inflammation (e.g., high-grade chronic villitis) is known to result in fetal growth restriction and SGA newborns.…”

“…Four studies [7][8][9]22 have identified increased frequency of placental chronic inflammation in HPA-1a-incompatible FNAIT-affected pregnancies, indicating a likely effect of anti-HPA-1a on the placenta and providing a potential mechanism for low neonatal birthweights in FNAIT. HPA-1a is present on GPIIIa (β 3 ), which, in addition to platelets, is found on syncytiotrophoblasts and vascular endothelial cells, where it is expressed in association with α V instead of α ΙΙ (Figure 4).…”

“…4,5 Another study reported similar findings in thrombocytopenic neonates whose mothers had HLA antibodies. 6 Based on studies demonstrating inflammation in placentas from FNAIT pregnancies, [7][8][9] the gender-nonspecific explanation for decreased birthweight is speculated to be placental inflammation (e.g., chronic villitis), presumably due to anti-HPA-1a binding to GPIIIa (β 3 ) expressed on the surface of syncytiotrophoblasts. 10,11 This study tests the clinical hypothesis that FNAIT secondary to anti-HPA-1a results in smaller newborns, and the corollary hypothesis that antenatal management of FNAIT in HPA-1a-incompatible pregnancies increases birthweight by reducing the effects of anti-HPA-1a.…”