The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies

Abstract

Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal/neonatal platelets. It is the most common cause of severe thrombocytopenia in neonates, but the frequency of FNIT-related miscarriage is unknown, and the mechanism(s) underlying fetal mortality have not been explored. Furthermore, although platelet αIIbβ3 integrin and GPIbα are the major antibody targets in immune thrombocytopenia, the reported incidence of anti-GPIbα-mediated FNIT is rare. Here, we developed mouse models of FNIT mediated by antibodies specific for GPIbα and β3 integrin and compared their pathogenesis. We found, unexpectedly, that miscarriage occurred in the majority of pregnancies in our model of anti-GPIbα-mediated FNIT, which was far more frequent than in anti-β3-mediated FNIT. Dams with anti-GPIbα antibodies exhibited extensive fibrin deposition and apoptosis/necrosis in their placentas, which severely impaired placental function. Furthermore, anti-GPIbα (but not anti-β3) antiserum activated platelets and enhanced fibrin formation in vitro and thrombus formation in vivo. Importantly, treatment with either intravenous IgG or a monoclonal antibody specific for the neonatal Fc receptor efficiently prevented anti-GPIbα-mediated FNIT. Thus, the maternal immune response to fetal GPIbα causes what we believe to be a previously unidentified, nonclassical FNIT (i.e., spontaneous miscarriage but not neonatal bleeding) in mice. These results suggest that a similar pathology may have masked the severity and frequency of human anti-GPIbα-mediated FNIT, but also point to possible therapeutic interventions.

Plasma fibronectin supports hemostasis and regulates thrombosis

“…Preparation of plasma, platelets, and pFn. Mouse plasma and platelets were prepared as previously described (18,22,25,(50)(51)(52). For pFn-fibrin clot formation in vitro, blood was drawn from inferior vena cava with a 25-gauge needle and immediately mixed with 3.2%…”

Severe platelet desialylation in a patient with glycoprotein Ib/IX antibody-mediated immune thrombocytopenia and fatal pulmonary hemorrhage

“…12, 13 We further found in a murine model of anti-GPIb/IX-mediated ITP that anti-GPIb/IX antibodies trigger platelet activation and degranulation, which likely was accompanied by neuraminidase translocation to the cell membrane, causing platelet desialylation.…”

Are maternal antiplatelet antibodies a prothrombotic condition leading to miscarriage?

“…When immunized Itgb3 -/-and Gp1ba -/-female mice were bred to wild-type males, it was extremely difficult to obtain thrombocytopenic Gp1ba +/-pups. Strikingly, miscarriage occurred in 25 of 30 (83.3%) pregnancies resulting from breeding immunized Gp1ba -/-female mice with wildtype males versus 10 of 26 (37%) pregnancies involving immunized Itgb3 -/-female mice (12). Further, the miscarriages were observed late in pregnancy (E16.5-E18.5).…”

“…Rare cares of FNAIT associated with GPIba are antibodies to a C→T polymorphism at nucleotide position 434, which results in a substitution of threonine (HPA-2a) to methionine (HPA-2b) at amino acid position 145 (10,11). In this issue of the JCI, Li et al examine why few cases of FNAIT mediated by antibodies specific for GPIba are seen (12).…”

“…Li et al generated mice with high levels of antibodies specific for platelet antigens relevant to FNAIT and immune thrombocytopenia (12). Specifically, they immunized mice lacking integrin b3 (Itgb3 -/-mice) and mice lacking GPIba (Gp1ba -/-mice) on a BALB/c background with wild-type mouse platelets.…”