Interpretation
A possible explanation for our findings is that TAFI is involved in regulating the immune response and complement-mediated vascular inflammation. High TAFI levels suppress the inflammatory response in vivo and reduce the incidence of miscarriage. TAFI regulates the levels of inflammatory mediators such as C3a, C5a, bradykinin, and bone bridging proteins and suppresses inflammation in vivo by inactivating inflammatory mediators19, 20. For instance, it has been shown that there is a significant negative correlation between serum TAFI and C3a levels21. Some investigators have identified a role for TAFI in inflammation, and their results suggest that TAFI plays an important role during pneumococcal meningitis, which is likely to be mediated through inhibition of the complement system, and influences the occurrence of inflammation 22. The presence of ATA in the body leads to an inflammatory and immune response, and a recent meta-analysis suggests that they may increase the risk of pregnancy failure, although the exact mechanism is not yet known23. ATA can cause thyroid cell damage through activation of the complement system and cytotoxicity24, which are associated with the outcome of pregnancy failure. It is reasonable to speculate that TAFI may exert a protective effect on RSA by inhibiting the inflammation caused by ATA. In the study population of two positive groups, there were more inflammatory mediators, and when TAFI was at a low level (<24ug/mL), the anti-inflammatory ability was weaker, which presented as a risk factor.
It is worth noting that when the plasma TAFI level is lower than the normal range of TAFI, the risk of RSA in the Anti-TPO negative population is also increased, but the OR value of 1.429 is significantly smaller than that of the two positive groups. We speculate that this is related to coagulation and fibrinolysis system disorders. A possible explanation for this result is that a low fibrinolytic state may be beneficial for pregnancy. The fibrinolytic system plays an important role in helping with placental implantation, fetal growth, and development during pregnancy 25. An animal experiment had shown that degradation products of fibrinogen can cause apoptosis of mouse trophoblast cells, leading to fetal loss 10. Reducing the activation of TAFI can enhance the degradation of fibrinogen, thereby increasing fibrinogen degradation products. Therefore, low levels of TAFI can increase the risk of RSA.
This outcome is supported by several studies on TAFI levels and the risk of RSA. Several European case-control studies provide evidence that high levels of TAFI may be associated with a decreased risk of RSA11, 26, 27. These findings have important implications for the prevention and management of RSA. However, there are studies in the Netherlands and Turkey that show no association between the level of TAFI and RSA 12, 28. In contrast, a retrospective case-control study conducted in Spain showed that patients with RSA had statistically significantly higher TAFI antigen levels compared to other groups 29. The observed differences in the risk of RSA associated with TAFI levels may be attributed to several reasons. Firstly, varying definitions of RSA exist across studies. Some studies define RSA as three or more consecutive pregnancy losses11, 28, 29, whereas other studies define RSA as two or more consecutive pregnancy losses. When different definitions are used to diagnose or study RSA, it can result in different populations being included in the study, thereby reducing the reliability of the comparative results. Secondly, different studies have used different methods to measure TAFI levels. Some studies used a colorimetric assay11, 12, and the enzyme-linked immunosorbent assay (ELISA) method is used in most studies. It is worth mentioning that the different sensitivity of ELISA for various isoforms of TAFI can lead to large differences in TAFI levels among studies 30, 31. Lastly, TAFI levels may vary by geographic region. Despite the differing conclusions of these studies, our dose-response correlation further supports the notion that increased plasma TAFI levels reduce the risk of RSA in our study population.
In addition, The magnitude of the associations between TAFI and RSA was different in subgroups by age, coagulation indicators, and thyroid function indicators. Age and thyroid function were reported as potential influencing factors of TAFI levels. Specifically, a study indicated a positive correlation between TAFI levels and age 32. Furthermore, TSH levels were identified as predictors of TAFI levels, and fibrinolytic activity was reduced in patients with impaired thyroid function 33, 34.