OC 51.2 - Anti-GPIbα antibodies in FNAIT are associated with recurrent miscarriages

Tuesday, June 25, 2024

09:45 – 10:00 ICT

Room: Ballroom B1

Co-Author(s)

CK

Christopher Khoury

MSc Student
University of Toronto
Mississauga, Ontario, Canada
PC

Pingguo Chen

Research scientist
St Michael's Hospital
Toronto, Ontario, Canada
GZ

Guangheng Zhu

Research staff
St. Michael's Hospital
Toronto, Ontario, Canada
YW

Yiming Wang

Assistant Professor
The Hospital for Sick Children
Toronto, Ontario, Canada
ZT

Zoya Tawhidi

PhD Candidate
University of Toronto
Toronto, Ontario, Canada
AL

Alan Lazarus

Principal Investigator
University of Toronto
Toronto, Ontario, Canada
KC

Karen Chong

Clinical Geneticist
The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital.
Toronto, Ontario, Canada
DC

David Chitayat

Clinical Geneticist
The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital.
Toronto, Ontario, Canada

Presenting Author(s)

Heyu Ni, MD, PhD

Professor
University of Toronto / Canadian Blood Services
Toronto, Ontario, Canada

Background: Recurrent miscarriages (RM), defined as three or more consecutive pregnancy losses before week 20 of gestation, affects approximately 1-2% of couples. Numerical chromosome abnormalities are identified in 50% of cases, while the etiology remains unknown in the remaining cases. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is suspected to cause RM, but clinical evidence is limited. FNAIT is classically defined by maternal antibody-mediated destruction of fetal platelets causing thrombocytopenia and bleeding in the fetus and/or newborn. We previously described a non-classical mechanism of FNAIT in a murine model where maternal anti-GPIbα antibodies led to platelet activation and thrombosis in the placenta, ultimately causing miscarriage in >83% of pregnant mice (J Clin Invest, 2011). Whether anti-GPIbα antibodies cause unexplained RM in humans has not been explored.

Aims: Examine sera from women with unexplained RM for anti-platelet antibodies and evaluate their effect on platelet function.

Methods: Monoclonal antibody immobilization of platelet antigen (MAIPA) assays and flow cytometry was used to detect platelet-specific IgG in patient sera and determine the antibody glycoprotein specificities. Flow cytometry was also used to measure markers of activation (P-selectin and PAC-1) and desialylation (RCA-I) on gel-filtered donor platelets incubated with patient serum or serum-purified IgG.

Results: MAIPA assays revealed high levels of anti-GPIbα antibodies in sera of two out of three patients experiencing unexplained RM. We found their antibodies strongly bind to donor platelets and the binding was markedly reduced to GPIbα-depleted platelets. One mother with anti-GPIbα also had anti-β3 antibodies. Additionally, serum and purified IgG from both anti-GPIbα positive mothers induced platelet activation and desialylation.

Conclusion(s): These findings provide the first evidence that anti-GPIbα antibodies in FNAIT are associated with RM in humans, which may explain the paucity of GPIbα-mediated FNAIT. Our data suggests GPIbα-mediated FNAIT should be investigated in a large cohort as a potential cause of pregnancy losses.