Introduction
Recurrent spontaneous abortion (RSA) is defined as two or more consecutive clinical pregnancy failures that affect 1-5% of women of reproductive age 1. RSA has a significant negative impact on women’s physical and psychological health and is a serious reproductive problem whose incidence has been on the rise in recent years 2. Currently, RSA is known to have various causes, including genetic, thrombotic, infectious factors, immune and endocrine dysfunction, and anatomical abnormalities of the reproductive tract 3, 4. Thrombin-activated fibrinolysis inhibitor (TAFI) is the main inhibitor of fibrinolysis, and it plays an important role in RSA due to its role in the coagulation and fibrinolytic system as well as in inflammation 5.
TAFI is a procarboxypeptidase that is synthesized primarily by the liver and is present in the circulation as an inactive zymogen6. TAFI can be activated by thrombin, thrombin-thrombin regulatory protein, and plasma proteins. The activated form of TAFI cleaves its C-terminal lysine or arginine residue from the peptide substrate, resulting in partial degradation of fibrin from the C-terminal lysine residue 7, 8. This mechanism enables TAFI to exert antifibrinolytic effects 9. In vivo studies have shown that fibrin degradation products may induce apoptosis in trophoblast cells, leading to embryonic cell death and fetal loss in mice 10. However, the association of TAFI with RSA is less studied and controversial. A case-control study in Italy provided evidence that high activity TAFI levels are associated with a reduced risk of early recurrent fetal loss 11, while another Dutch case-control study showed that TAFI was not associated with RSA12.
Additionally, TAFI may play a broad role in the regulation of inflammation. Its activated form inactivates several inflammatory mediators by removing the C-terminal arginine, including bradykinin, bovine toxin C3a and C5a 9, 13. And inflammation is closely associated with thyroid autoimmunity (TAI), which is defined as the presence of anti-thyroid antibodies (ATA), including thyroid peroxidase antibodies (Anti-TPO) and thyroglobulin antibodies (Anti-TG) 14. It is generally accepted that Anti-TPO positive women are at higher risk of incidental miscarriage, preterm birth, and postpartum thyroid disease15, 16. Some studies have shown that patients with RSA have higher levels of Anti-TPO 17. Furthermore, it has been shown that TAI is associated with resistance to fibrinolysis ex vivo and C3 plasma levels 18. Therefore, there may be an association between ATA and TAFI in terms of inflammation.
To our knowledge, limited previous research has been conducted to investigate the relationship between plasma levels of TAFI and RSA in varying conditions of ATA. Therefore, the objective of this study is to investigate this association among 1,068 pregnant Chinese women (402 cases and 666 controls) and to explore independent risk factors for RSA in the presence of different conditions of ATA. Furthermore, this research aims to analyze the influence of TAFI and ATA on RSA in terms of inflammation, to provide suitable recommendations for the diagnosis of RSA.