Abstract
Summary Background Factor XII (FXII) deficiency and autoantibodies that bind to FXII (anti-FXII) have been described in patients with adverse pregnancy outcomes, including recurrent pregnancy loss. It has been reported that FXII functions not only as a coagulation protein but also as a growth factor. Objectives We studied the association between anti-FXII and the epidermal growth factor (EGF) system in patients with recurrent pregnancy loss. Patients/Methods We used synthetic peptides that span the second EGF-like domain in the heavy chain of FXII (EGF2) in inhibition and direct binding studies to determine if anti-FXII antibodies recognize EGF2. Furthermore, we examined whether anti-FXII antibodies, which recognize EGF2, also recognize recombinant EGF and heparin-binding EGF-like growth factor (HB-EGF). Results Among 100 patients with recurrent pregnancy loss, the plasma of 23 patients (23.0%) recognized the synthetic peptide ASQ41, which covers EGF2. Among the 23 anti-ASQ41-positive patients, plasma samples from 13 patients (56.5%) recognized the 22-residue segment C-terminal half of ASQ41. Among the 23 anti-ASQ41-positive patients, the plasma of 17 patients (73.9%) recognized recombinant human EGF. Affinity-purified anti-FXII antibodies, which recognize ASQ41, also recognized recombinant EGF family proteins such as EGF and HB-EGF. Conclusions The autoantibodies in patients with recurrent pregnancy loss recognized the EGF2 domain in FXII and other proteins of the EGF family. Since proteins in the EGF family play an important role in normal pregnancy, autoantibody-associated disruption of the EGF system may cause pregnancy loss.
Highlights
Several studies have observed associations between recurrent pregnancy loss and factor XII (FXII) deficiency.[1,2,3] Schved et al[1] reported cases where three young women with FXII deficiencies had a clinical history of spontaneous abortion
We examined whether anti-FXII antibodies, which recognize EGF2, recognize recombinant epidermal growth factor (EGF) and heparinbinding EGF-like growth factor (HB-EGF)
Each patient was evaluated for uterine anomalies according to three-dimensional vaginal ultrasound, endocrine monitoring, FXII activity, anti-FXII, antinuclear antibodies, anti-EGF2, and the presence of antiphospholipid antibodies such as lupus anticoagulant (LA), anticardiolipin antibodies, and antiphosphatidylethanolamine antibodies
Summary
Several studies have observed associations between recurrent pregnancy loss and factor XII (FXII) deficiency.[1,2,3] Schved et al[1] reported cases where three young women with FXII deficiencies had a clinical history of spontaneous abortion. Braulke et al[2] reported eight patients with moderately reduced levels of FXII among 43 patients with recurrent pregnancy loss. Gris et al[3] evaluated the prevalence of hemostatic abnormalities in 500 consecutive women with unexplained recurrent pregnancy loss. They found that 9.4% of patients exhibited an isolated FXII deficiency. It has been reported that FXII functions as a coagulation protein and as a growth factor
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