Annexin A5 (AnxA5) binds to phospholipid bilayers, forming two-dimensional crystals that block the phospholipids from availability for coagulation enzyme reactions. Antiphospholipid (aPL) antibodies cause gaps in the ordered crystallization of AnxA5 which expose phospholipids and thereby accelerate blood coagulation reactions. The aPL antibody-mediated disruption of AnxA5 crystallization has been confirmed on artificial phospholipid bilayers and on cell membranes including endothelial cells, placental trophoblasts and platelets. Recently, we reported that hydroxychloroquine, a synthetic antimalarial drug, can reverse this antibody-mediated process through two mechanisms: (1) by inhibiting the formation of aPL IgG-beta2glycoprotein I complexes; and (2) by promoting the formation of a second layer of AnxA5 crystal 'patches' over areas where the immune complexes had disrupted AnxA5 crystallization. In another translational application, we have developed a mechanistic assay that reports resistance to AnxA5 anticoagulant activity in plasmas of patients with aPL antibodies. AnxA5 resistance may identify a subset of aPL syndrome patients for whom this is a mechanism for pregnancy losses and thrombosis. The elucidation of aPL-mediated mechanisms for thrombosis and pregnancy complications may open new paths towards addressing this disorder with targeted treatments and mechanistic assays.

The annexin A5-mediated pathogenic mechanism in the antiphospholipid syndrome: role in pregnancy losses and thrombosis

The phospholipid binding protein, annexin A5 (AnxA5), has potent anticoagulant properties that result from its forming 2-dimensional crystals over phospholipids, blocking the availability of the phospholipids for critical coagulation enzyme reactions. This article reviews the evidence that antiphospholipid antibodies can disrupt this anticoagulant shield and unmask thrombogenic anionic phospholipids, which may thereby contribute to thrombosis in patients with the antiphospholipid syndrome (APS). This mechanism for thrombosis in APS can be monitored with coagulation assays for resistance to anticoagulant activity of AnxA5.

Resistance to annexin A5 anticoagulant activity: a thrombogenic mechanism for the antiphospholipid syndrome.

Emerging data seem to be available also on the role of active thromboprophylaxis with heparin and pregnancy outcome. In the last decades we found many data concerning the association between a hypercoagulable state and its causes and adverse pregnancy outcome, in particular recurrent pregnancy loss (RPL). First studies which focused on the association between thrombophilia and RPL underlined the role of reduced clotting inhibitors and RPL, and subsequent studies underlined a pathogenetic role of gene variant associated to hypercoagulable state in the occurrence of RPL. On the other hand, acquired thrombophilic abnormalities as antiphipsholipid syndrome are a well known cause of RPL and should be considered for a screening. These data are relevant because recent studies suggested a role of an extensive thromprophilaxis in women with RPL that should be addressed only in case of known thrombophilia and high risk of venous thromboembolism.

/pdf/recurrent-pregnancy-loss-and-thrombophilia-1k1khqj3nb.pdf

Recurrent Pregnancy Loss and Thrombophilia

In the present manuscript, we review the recent research investigating the pathogenic association between most studied autoantibodies and recurrent pregnancy loss. Pregnancy loss represents a common obstetric complication occurring in about 15%-25% of all clinically recognized pregnancies. The recurrence of pregnancy loss identifies a distinct clinical entity, that is recurrent pregnancy loss (RPL), affecting about 2%-4% of couples. Several factors, including age, chromosomal abnormalities, uterine anomalies, thrombophilic disorders, endocrinopathies, hormonal and metabolic disorders, infections, sperm quality, and lifestyle issues, are involved in RPL. The role of autoantibodies in RPL is only partially determined. In some cases (antiphospholipid antibodies [aPL]), their involvement is well established. In other cases (anti-thyroid autoantibodies, antinuclear, anti-transglutaminase, and anti-endomysial antibodies), it is still debated, despite multiple, although not fully conclusive, evidences strongly suggest a possible involvement in RPL. Further extensive research is needed to definitively confirm or exclude their actual role.

The pathogenic role of autoantibodies in recurrent pregnancy loss.

Increasing evidence supports a role for altered T helper 1 (Th1)-Th2 cytokine balance in idiopathic recurrent spontaneous abortion (RSA). The aim of this study was to investigate the association of the interleukin 10 (IL-10) promoter polymorphisms -592C/A, -819C/T and -1082A/G with RSA. Women (n = 350) with at least three consecutive spontaneous abortions (RSA cases) and 200 control women with at least two successful pregnancies were included. The frequency of the -819T allele [P = 0.05, odds ratio (OR) = 1.51], but not other single-nucleotide polymorphisms (SNPs), was higher among RSA patients. Complete linkage disequilibrium (LD) was seen between -592C and -819C and -1082G alleles, as well as between -592A and -819T and between -819C and -1082G alleles only among patients. Although the genotype frequencies (except for -819C/C) of the three polymorphisms were comparable between patients and controls, higher frequency of -592A/-819T/-1082A haplotype (OR = 4.01, 95% CI = 1.83-7.95) was seen in cases versus controls. Regression analysis indicated that, after adjusting for potential variables, -592C/A (OR = 3.32, 95% CI = 1.76-6.27) and -819C/T (OR = 5.06, 95% CI = 2.59-9.91) were associated with exclusively early but not exclusively late RSA, where negative association for both was noted. This supports the notion of involvement of IL-10-592C/A and -819C/T polymorphisms as inherited risk factors of idiopathic RSA.

Association of -592C/A, -819C/T and -1082A/G interleukin-10 promoter polymorphisms with idiopathic recurrent spontaneous abortion.

Whereas antiphospholipid antibodies (aPL) are associated with thrombotic events and recurrent spontaneous abortion (RSA), the contribution of anti-beta2 glycoprotein 1 (beta2GP1) and anti-annexin V antibodies as risk factors for RSA remain poorly understood. We investigated anti-beta2-GPI and anti-annexin V IgM and IgG antibodies as potential risk factors for RSA in 200 women with more than three consecutive idiopathic RSA, and 200 age-matched, healthy, parous women. Pearson's chi squared test analysis showed that while anti-beta2-GPI IgG (P = 0.416) and IgM (P = 0.72) were comparable between patients and controls, elevated anti-annexin V IgG (P = 0.006), but not IgM (P = 0.084), was more pronounced in patients. Higher frequencies of elevated IgG-only (P = 0.005), but not IgM-only (P = 1.000; OR = 6.66), anti-annexin V antibodies were noted among patients. Multinomial regression analysis showed that body-mass index (overweight and obesity; P = 0.008), education status (P < 0.001) and anti-beta2-GPI IgM (P = 0.033), but not IgG (P = 0.723), were associated with early abortion, while anti-beta2-GPI IgG (P = 0.030) and anti-annexin V IgG (P = 0.004) were associated with late RSA. For combined early-late RSA, the only variable selected was education status (P < 0.001), and neither anti-annexin V nor anti-beta2-GPI IgM and IgG was associated with early-late RSA. Accordingly, anti-annexin V and anti-beta2-GPI should be regarded as independent risk markers of RSA.

/pdf/a-case-control-study-on-the-association-of-idiopathic-36llruo4l1.pdf

A case-control study on the association of idiopathic recurrent pregnancy loss with autoantibodies against β2-glycoprotein I and annexin V

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A case-control study on the association of idiopathic recurrent pregnancy loss with autoantibodies against β2-glycoprotein I and annexin V