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.