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.