Discussion
To the best of our knowledge, this is the first study to clarify the
association between coagulation and IVIG resistance in patients with KD
based on a relatively large clinical dataset. In this prospective study,
we support the hypothesis that there are marked differences in
coagulation profiles, including longer PT and APTT, higher D-dimer
levels, and lower ATIII activity, that may predict initial IVIG
resistance. In addition, using multivariate logistic regression
analysis, we found that longer PT, APTT, higher D-dimer and lower ATIII
activity before initial IVIG were significant independent risk factors
for initial IVIG resistance. Furthermore, significantly lower ATIII
activity was found in patients with repeated IVIG resistance. Our
results suggest that patients with impaired coagulation who are
resistant to IVIG (initial and/or repeated) may need more aggressive
treatment to reduce the likelihood of developing CALs.
Previous evidence has shown that coagulative profiles play an important
role in sepsis and are associated with severe
outcomes8. However,
whether coagulative biomarkers can predict the development of IVIG
resistance in KD remains unclear as few studies have been published to
date. Recently, Chen et al. compared the changes in coagulation between
acute KD patients and healthy
controls9. The authors
showed higher D-dimer levels and prolonged APTT and PT in KD, suggesting
hypercoagulation as a common complication of KD. However, the results
were limited by the small sample size (n=20) and retrospective nature of
the study. Unlike previous studies, we found the predictive validity of
coagulation biomarkers in IVIG resistance based on a relatively larger
sample size. Severe infection and inflammation might be the possible
pathomechanisms for impaired coagulation in IVIG-resistant
patients10. First,
infection is one of the most recognized causes in patients with
KD11. In our
preliminary study, we found that serum procalcitonin was significantly
elevated in both the initial and repeated IVIG-resistant groups compared
to that in
non-responders12.
Procalcitonin has been widely proven to be a significant biomarker for
severe bacterial infection and
sepsis13. In addition,
cytokine storms, which have been demonstrated in systemic infections,
play a central role in the different effects on the coagulation and
fibrinolysis
pathways14. Therefore,
longer PT and APTT, higher D-dimer levels, and lower ATIII activity in
IVIG-resistant patients with KD in our study may suggest a more
noticeable impact of coagulation and reflect more severe inflammation in
this population.
The present study indicated that initial IVIG-resistant patients have
longer PT and APTT. The results of our study were consistent with those
of Benediktsson et al., who found prolonged APTT and PT in sepsis
patients15. PT and APTT
are traditionally modeled as extrinsic and intrinsic pathways that join
to form a common
pathway16. In the study
by Aird et al., inflammation-induced activation of the coagulation
system was found to be initiated by the extrinsic pathway and amplified
by the intrinsic pathway via crosstalk and a feedback
loop17. Several studies
have revealed that blocking tissue factor activity completely decreases
inflammation-induced coagulation activation in models of experimental
endotoxemia or
bacteremia14,
18. Therefore, elevated PT and APTT may
be associated with initial IVIG resistance in KD. However, APTT should
be cautiously used in clinical settings as a single biomarker for
predicting initial IVIG resistance because of the relatively low
sensitivity (32.0%).
AT, also called AT III, is the main inhibitor of thrombin and factor Xa,
which plays a role in thrombin
generation19. In our
study, significantly lower ATIII activity in the initial and repeated
IVIG-resistant patients was observed. This finding is consistent with
previous reports20 and
corresponds with the fact that inflammation leads to the activation of
coagulation, and coagulation markedly affects inflammatory
activity21. In the
study by Xie et al., ATIII reduction was found to be closely related to
the prognosis of patients with
sepsis22. One possible
explanation is that decreased ATIII activity increases fibrin formation
and insufficient fibrinolysis, which could cause microvascular
thrombus23. Therefore,
based on the results of the present study, ATIII activity may be a risk
factor for predicting IVIG resistance in patients with KD.
D-dimer is the smallest FDP (molecular weight: 180 kDa) in the process
of fibrinolysis, it is relatively stable and considered the final
product of
fibrinolysis24.25. Previous studies
have found that D-dimer is associated with severe sepsis or septic
shock8. In our study,
patients with initial IVIG resistance had higher D-dimer levels. This
result was in line with a study by Panigada et al., who found that
sepsis patients were characterized by higher levels of
D-dimer8. Similar
results were also reported by Wang et al., who demonstrated that
elevated D-dimer was a risk factor for severe outcomes in patients with
bacterial infections26.
The above findings may be explained by the imbalance between the
coagulation system and inflammatory pathways in infected patients as
fibrinolytic activators and inhibitors modulate the inflammatory
response by their effects on inflammatory cell recruitment and
migration27,
28. In a study by Shorr et al., higher
proinflammatory cytokine levels were found in those with higher D-dimer
levels, indicating a potential relationship between the coagulation
system and
inflammation29.
Therefore, in the acute stage of KD, increased D-dimer levels may be
used as a predictor for initial IVIG treatment failure.
The strengths of this study were its prospective design and relatively
large sample size. However, the present study has several limitations.
First, this study was performed at a single institution. Our hospital is
the largest pediatric medical center in Southwest China, which may lead
to a selection bias due to a higher number of severely ill patients
being admitted to this facility. Second, the present study was a
prospective cohort study with strict inclusion and exclusion criteria.
The findings of this study are, therefore, applicable only to Chinese
patients with KD receiving standardized IVIG treatment (2 g/kg) within
10 days of fever onset.
Despite these limitations, this prospective study is the first to report
pronounced changes in PT, APTT, D-dimer levels, and ATIII activity in
the acute stage of KD, which may serve as complementary laboratory
biomarkers for predicting IVIG resistance. In addition, the predictive
validity of ATIII activity as a single biomarker for IVIG resistance may
be superior to other coagulation biomarkers with a relatively high
sensitivity.