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Antiphospholipid (aPL) antibodies are recognised risk factors for adverse obstetric outcomes. Recently, carriers of the M2 haplotype in the Annexin A5 gene have been shown to have a higher susceptibility to develop aPL antibodies. In a general obstetric population, we prospectively evaluated the possible relationship between: (1) aPL antibodies and M2 haplotype; and (2) aPL antibodies and/or M2 haplotype and obstetric outcomes. From a cohort of 3,097 consecutive pregnant women, 1,286 samples were analysed for the presence of both anti-cardiolipin and anti-human β2-glycoprotein I antibodies; samples with available DNA ( n  = 606) were also investigated for the M2 haplotype. Overall, 41/1,286 (3.2%) women showed the presence of aPL antibodies. Among them, 2 (4.8%) experienced a pregnancy loss and 38 (92.7%) gave birth to live-born babies ( p -value = non-significant vs. those without aPL antibodies). M2 haplotype was identified in 140 (23.1%) out of 606 women with DNA available: 3/140 (2.1%) M2 carriers and 17/466 (3.6%) non-carriers tested positive for aPL antibodies, respectively ( p -value = non-significant). In total, 15/150 (10%) M2 and/or aPL antibody carriers, and 38/445 (8.5%) non-aPL antibody and/or M2 carriers suffered from obstetric complications, respectively ( p -value = non-significant). No relationship between aPL antibodies and M2 haplotype was found. Furthermore, neither aPL antibodies nor the M2 haplotype is associated with obstetric complications., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Knowledge about risk factors for venous thromboembolism (VTE) is still limited. A recently found haplotype within the natural anticoagulant protein annexin A5 (ANXA5) exerts an important modulating effect on gene expression., Study Design: Eighty-three nonanticoagulated patients with a documented pregnancy-related VTE and 195 controls were investigated. The presence of the ANXA5 haplotypes was determined., Results: Twenty-seven patients (32.5%) carried the M2 haplotype. Among them, 17 (63.0%) had a history of VTE in puerperium and 10 (37.0%) during pregnancy. The prevalence of the M2 haplotype was different as compared with that recorded among controls (odds ratio, 2.7; 95% confidence interval, 1.5-4.9, P < .001). A logistic regression analysis, correcting for potential confounders (age at which the thrombotic event occurred, factor V Leiden, and factor IIA20210 variants) showed a significant increase (odds ratio, 3.4; 95% confidence interval, 1.7-6.7) of the occurrence of VTE in carriers of the M2 haplotype as compared with noncarriers., Conclusion: The M2 haplotype within the ANXA5 gene may represent a new thrombophilic risk factor for pregnancy-related VTE., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Inherited or acquired thrombophilias have been largely explored as a cause of pregnancy complications. However, pathogenesis of obstetric complications, as fetal loss and pregnancy-related hypertensive disorders is still partly unexplained. Recently, a common haplotype (M2) within the annexin A5 (ANXA5) gene has been described as a risk factor in recurrent fetal losses (RFL). It has been demonstrated to reduce the promoter activity of the ANXA5 promoter in luciferase reporter assays. Aim of this study was to investigate the prevalence of M2 haplotype in three different settings of women with previous obstetric complications: RFL, intra-uterine fetal death (IUFD) and pregnancy-related hypertension (gestational hypertension [GH] and pre-eclampsia [PE]). One hundred three patients with previous RFL, 54 with IUFD, 158 with hypertensive disease (67 GH, 91 PE) were investigated. As controls, 195 women from the same ethnic background with uneventful pregnancies were enrolled. Logistic regression, correcting for age, gravidity and parity showed that the ANXA5 haplotype is significantly and independently associated with the occurrence of RFL (3.1; 95%CI: 1.1-9.5; p = 0.047) and pregnancy-related hypertensive disorders (2.1; 95%CI: 1.2-3.5; p = 0.008). The M2 haplotype might be a new and relevant risk factor for obstetric complications.

In a group of placentas from patients with preeclampsia or fetal growth restriction, reduced annexin V gene expression in those carrying the M2 haplotype was observed. This is the first "ex vivo" demonstration that annexin V gene expression in placentas is dependent on the M2 haplotype.