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\begin{document}

\title{Predictive value of coagulation profiles for both initial and repeated
immunoglobulin resistance in Kawasaki disease: a prospective cohort
study}



\author[1]{Shuran Shao}%
\author[1]{Lixia Yang}%
\author[1]{Xiaoliang Liu}%
\author[1]{Lei Liu}%
\author[1]{Mei Wu}%
\author[2]{Yuxin Deng}%
\author[1]{Hongyu Duan}%
\author[1]{Yifei Li}%
\author[1]{Yimin Hua}%
\author[1]{Kaiyu Zhou}%
\author[1]{Chuan Wang}%
\affil[1]{Sichuan University West China Second University Hospital}%
\affil[2]{Wenzhou Medical College}%


\vspace{-1em}



  
  \date{May 14, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Intravenous immunoglobulin (IVIG) resistance prediction
remains substantial in Kawasaki disease (KD), with limited data on the
predictive value of coagulation profile for IVIG resistance,
particularly for repeated IVIG resistance. Therefore, the aim of our
study was to testify the predictive validity of coagulation profile for
both initial and repeated IVIG resistance in KD. Methods: A total of 385
KD patients were prospectively recruited between April in 2015 and May
in 2019. Coagulation and other profiles were evaluated between
IVIG-responsive and IVIG-resistant groups. Multivariate logistic
regression analysis was applied to determine the association between
coagulation profiles and IVIG resistance. ROC curves analysis was
further performed to assess validity of coagulation profiles in
predicting both initial and repeated IVIG resistance. Results: PT, APTT
and D-dimer were significantly increased in initial IVIG-resistant group
with ATIII significantly reduced. Meanwhile, ATIII was declined markedly
in repeated IVIG-resistant patients. PT, APTT, D-dimer and ATIII cutoff
values of 13.95 s, 41.15 s, 1.48 mg/l, and 89.5\% yielded sensitivities
of 73\%, 32\%, 71\%, 81\%; specificities of 55\%, 88\%, 62\%, 51\% for
predicting initial IVIG resistance, respectively. The cutoff value of
ATIII for predicting repeated IVIG resistance was 68.5\%, with
sensitivity of 71\% and specificity of 55\%. Multivariate logistic
regression analysis showed that PT, APTT, D-dimer and ATIII were
independent risk factors for initial IVIG resistant patients with KD.
Conclusions: Coagulation profiles were significantly dysregulated in KD
patients. Some of them particularly ATIII may serve as complementary
laboratory markers for prediction of both initial and repeated IVIG
resistance.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Kawasaki disease (KD) is an acute vasculitis that is the leading cause
of acquired heart disease in children, with approximately 15-20\% of
patients with KD suffering intravenous immunoglobulin (IVIG)
resistance\textsuperscript{1}. For children who do not respond to
initial IVIG treatment, repeated IVIG infusion is recommended by many
experts\textsuperscript{2}. However, approximately 10\% of patients are
resistant to both initial and repeated IVIG therapy\textsuperscript{3},
and thus have a higher risk of coronary artery lesions (CALs).
Therefore, early identification of both initial and repeated IVIG
resistance is of great importance to reduce CALs, and most importantly,
lower medical costs.

It has long been known that inflammation triggered by acute infection
can lead to activation of the coagulation system by upregulating the
expression of cytokines\textsuperscript{4}. In an investigation of
critically ill patients, Ogura et al. found that abnormal coagulation
was associated with increased systemic inflammatory response syndrome
scores\textsuperscript{5}. In addition, the relationship between the
activation of the immune system and coagulation system is evident in
systemic autoimmune or immune-mediated diseases\textsuperscript{6}.
Therefore, the balance between coagulation and the fibrinolytic system
may be disturbed during the acute stages of KD, particularly in patients
with IVIG resistance, since KD vasculitis is accompanied by an increase
in inflammatory cells and cytokines, and IVIG resistance may reflect a
more severe inflammatory immune condition. Unfortunately, few reports
analyze the correlation between coagulopathy and IVIG resistance in KD.

Therefore, a large prospective cohort study was conducted to assess the
predictive validity of the serum coagulation profile, including
prothrombin time (PT), activated partial thromboplastin time (APTT),
thrombin time (TT), international normalized ratio (INR), and
fibrinogen, D-dimer, fibrin degradation products (FDP), and antithrombin
III (ATIII) levels for identifying patients with KD at risk for both
initial and repeated IVIG resistance.

Materials and Methods

Subjects

Patients with KD were prospectively recruited between April 2015 and May
2019 at our hospital. A diagnosis of KD relied on the standards
recommended by the American Heart Association's Scientific Statement for
the diagnosis, treatment, and long-term management of
KD\textsuperscript{7} and was confirmed by two experienced pediatricians
(at least one was a KD specialist). Informed written consent was
obtained from the parents after the nature of the study had been fully
explained to them. The University Ethics Committee on Human Subjects at
Sichuan University approved the study.

Exclusion criteria included known patients with congenital or chronic
hematologic disease affecting the coagulation cascade; patients with
end-stage renal disease requiring dialysis, acute or chronic liver
failure, and autoimmune disease; patients who had undergone surgery
recently; patients with infectious or inflammatory diseases, and
patients who received oral anticoagulant or heparin therapy. A total of
520 patients diagnosed with KD were initially screened for participation
in this study. Of these, patients who had received initial IVIG
treatment at other medical facilities (n=87), received IVIG treatment
within 10 days of fever onset (n=12), or cases where IVIG treatment was
initiated before blood sampling (n=17) were excluded. Another 19
patients were excluded because of incomplete laboratory data or lack of
follow-up results (Figure 1). Finally, data from 385 patients were
analyzed.

All patients received 2 g/kg of IVIG for 24 hours and 30--50 mg/kg/day
of aspirin until they were afebrile. Initial IVIG resistance was defined
as recurrent or persistent fever or other clinical signs of KD for at
least 36 hours but not longer than 7 days after initial IVIG treatment.
For patients with initial IVIG resistance, the second IVIG dose (2 g/kg
given as a single intravenous infusion) was administered according to
expert consensus on the diagnosis and treatment of KD in China.
Furthermore, pulse intravenous methylprednisolone (10-30 mg/kg/day for
three consecutive days) followed by oral prednisone (2 mg/kg/day)
tapered over seven days were additionally administered if the patient
had recurrent or persistent fever even after the second IVIG
administration. No patients received any additional treatment such as
infliximab, plasma exchange, or cytotoxic agents. Coronary artery
lesions (CALs) were defined on the normalization of dimensions for BSA
as Z scores, according to the AHA scientific statement of
KD\textsuperscript{7}.

Patients were subsequently categorized into two groups depending on
whether they responded to the initial IVIG treatment (initial
IVIG-responsive group, n=326; initial IVIG-resistant group, n=59). The
initial IVIG-resistant group was further divided into two subgroups
based on the effectiveness of repeated IVIG treatment {[}repeated
IVIG-responsive group (n=36) and repeated IVIG-resistant group
(n=23){]}.

Laboratory measurements

Coagulation analyses of the patient's plasma, including PT, APTT, TT,
fibrinogen, D-dimer, FDP, international normalized ratio, and ATIII
activity, were performed before initial IVIG within 10 days from fever
onset. Standard coagulation measurements were performed with a
CoagXL-automated coagulometer (Diagon Ltd., Budapest, Hungary) using
reagents from Diagon.

Statistics

Data analyses were performed using SPSS version 21.0 (SPSS Inc. Chicago,
IL, USA). Quantitative data are presented as the medians with the 25th
and 75th percentiles in square brackets, while qualitative data are
expressed as the number or percentage as appropriate. A chi-squared test
and unpaired Student's t-test or Mann--Whitney U test were used to
compare the demographic characteristics, clinical manifestations, and
laboratory data. Significant indicators from univariate analysis were
then subjected to multivariate logistic regression analysis to identify
independent predictors of IVIG resistance. Receiver operating
characteristic (ROC) curve analysis was used to evaluate the value of
coagulative biomarkers for predicting the development of initial and
repeated IVIG resistance. A P-value \textless{}0.05 was considered
statistically significant.

Results

Subjects

CALs were observed in 47 patients (12.2\%), while transient pericardial
effusion, valve regurgitation, cardiac enlargement, and ventricular
systolic dysfunction were noted in 11, 40, 38, and 2 children,
respectively. No significant difference was found in serum coagulation
profiles between the CALs and non-CALs groups. (Supplemental material
1).

Serum coagulation levels for predicting initial IVIG resistance

As shown in Table 1, there were no significant differences in age, sex,
the day of illness before IVIG treatment, sampling day of illness, and
typical clinical manifestations between the initial IVIG-responsive and
IVIG-resistant groups. As for other cardiac complications, the
percentage of patients with cardiac enlargement and pericardial effusion
was found to be significantly higher in the initial IVIG-resistant group
(p=0.003 and p=0.016, respectively). Initial IVIG-resistant patients had
much higher incidence of CALs, with substantial higher level of serum
C-reactive protein (CRP), neutrophil-lymphocyte ratio (NLR), serum total
bilirubin (TB), serum alanine aminotransferase (ALT), creatinine, urea
nitrogen, but with lower hemoglobin, platelet count, albumin, sodium,
potassium before the initial IVIG treatment (all P \textless{} 0.005).
No significant differences were found in the white blood cell count,
erythrocyte sedimentation rate, and aspartate aminotransferase between
the two groups.

The effect of KD on the coagulation system was evaluated by assessing
the coagulation profiles of initial IVIG-responsive and IVIG-resistant
subjects. The PT (14.3 {[}13.6-15.5{]} s vs. 13.8 {[}13-14.4{]} s,
p=0.005) and APTT (35.3 {[}31.9-44.7{]} s vs. 34.2 {[}30.7-38.1{]} s,
p=0.006) were significantly longer in the initial IVIG-resistant group,
with significantly higher D-dimer levels (2.1 {[}1.20-2.82{]} mg/l vs.
1.2 {[}0.8-2.07{]} mg/l, p=0.020) as well as ATIII activity (81\%
{[}65-88\%{]} vs. 89\% {[}81-100\%{]}, p\textless{}0.001) (Table 1).

Multivariate logistic regression and ROC curve analysis for predicting
initial IVIG resistance

To not affect the prediction efficiency, the correlation between
univariate factors and coagulation profiles were tested by Pearson
analysis. The strong variables were removed from the model (Supplemental
material 2). Multivariate logistic regression analysis showed that
longer PT, APTT, higher D-dimer and lower ATIII activity were
independent risk factors for initial IVIG resistance in patients with KD
(Table 2).

The validity of the serum coagulation profile in predicting initial IVIG
resistance in patients with KD was assessed using ROC curve analysis.
The areas under the curve (AUC) of the various variables for predicting
IVIG resistance were 0.662, 0.599, 0.684, and 0.706 for PT, APTT,
D-dimer, and ATIII, respectively. The PT, APTT, D-dimer and ATIII cutoff
values of 13.95 s, 41.15 s, 1.48 mg/l, and 89.5\% yielded sensitivities
of 73\%, 32\%, 71\%, 81\%; specificities of 55\%, 88\%, 62\%, 51\% for
predicting initial IVIG resistance, respectively (Table 3 and Figure
2A).

Serum coagulation levels for predicting repeated IVIG resistance

A comparison of clinical data between the repeated IVIG-responsive
(n=33) and repeated IVIG-resistant (n=26) groups is shown in Table 4.
The repeated IVIG-resistant subjects had lower ATIII activity than those
of repeated IVIG-responsive subjects (65\% {[}60-81\%{]} vs. 84\%
{[}76.23-89.75\%{]}, p=0.001). There was no significant difference in
any other examined parameters between the two groups.

ROC curve analysis for predicting repeated IVIG resistance

ROC curves were used to calculate the AUC and predictive values of each
coagulation parameter (Table 3 and Figure 2B). The AUC of ATIII for
predicting repeated-KD patients was 0.753. In repeated-KD patients, the
cutoff value of ATIII was 68.5\%, which yielded a sensitivity of 71\%,
specificity of 55\% for predicting repeated-IVIG resistance.

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
outcomes\textsuperscript{8}. 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
controls\textsuperscript{9}. 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 patients\textsuperscript{10}.
First, infection is one of the most recognized causes in patients with
KD\textsuperscript{11}. 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-responders\textsuperscript{12}. Procalcitonin has been widely proven
to be a significant biomarker for severe bacterial infection and
sepsis\textsuperscript{13}. In addition, cytokine storms, which have
been demonstrated in systemic infections, play a central role in the
different effects on the coagulation and fibrinolysis
pathways\textsuperscript{14}. 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
patients\textsuperscript{15}. PT and APTT are traditionally modeled as
extrinsic and intrinsic pathways that join to form a common
pathway\textsuperscript{16}. 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 loop\textsuperscript{17}. Several
studies have revealed that blocking tissue factor activity completely
decreases inflammation-induced coagulation activation in models of
experimental endotoxemia or bacteremia\textsuperscript{14, 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 generation\textsuperscript{19}. In our
study, significantly lower ATIII activity in the initial and repeated
IVIG-resistant patients was observed. This finding is consistent with
previous reports\textsuperscript{20} and corresponds with the fact that
inflammation leads to the activation of coagulation, and coagulation
markedly affects inflammatory activity\textsuperscript{21}. In the study
by Xie et al., ATIII reduction was found to be closely related to the
prognosis of patients with sepsis\textsuperscript{22}. One possible
explanation is that decreased ATIII activity increases fibrin formation
and insufficient fibrinolysis, which could cause microvascular
thrombus\textsuperscript{23}. 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 fibrinolysis\textsuperscript{24}.\textsuperscript{25}.
Previous studies have found that D-dimer is associated with severe
sepsis or septic shock\textsuperscript{8}. 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-dimer\textsuperscript{8}.
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 infections\textsuperscript{26}. 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 migration\textsuperscript{27, 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
inflammation\textsuperscript{29}. 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.

Conclusions

In summary, the inflammatory process mediated by KD is associated with
the cause of impaired coagulation, which supports the notion that
patients with KD who also have hypercoagulation during the acute phase
could be at higher risk of developing IVIG resistance.

\textbf{Acknowledgements:} Not Applicable

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\textbf{Tables}

\textbf{Table1.} Comparison of clinical data between the groups of
initial IVIG-resistant and IVIG-responsive in KD

\textbf{Table2.} A multivariate logistic regression model for initial
IVIG resistance in patients with KD

\textbf{Table3.} The validity of coagulation profile cut-off values in
predicting initial and repeated IVIG resistance.

\textbf{Table4.} Comparison of clinical data between the groups of
repeated IVIG-resistant and IVIG-responsive in KD

\textbf{Figure Legends}

\textbf{Figure 1.} The flowchart of our prospective study

A total of 520 patients diagnosed with KD were initially screened for
participation in this study. Of these, patients who had received initial
IVIG treatment at other medical facilities (n=87), received IVIG
treatment within 10 days of fever onset (n=12), or cases where IVIG
treatment was initiated before blood sampling (n=17) were excluded.
Another 19 patients were excluded because of incomplete laboratory data
or lack of follow-up results. Finally, data from 385 patients were
analyzed. Of the 385 patients, 326 (84.7\%) responded to initial IVIG
treatment, whereas 59 (15.3\%) did not respond. Of the 59 patients with
initial IVIG resistance, 23 did not respond to repeated IVIG treatment
and received pulse intravenous methylprednisolone infusion. Then data
analysis and multivariate logistic regression analysis were performed in
these groups.

\textbf{Figure 2.} The receiver-operating characteristic (ROC) curve for
coagulation profiles in predicting initial and repeated IVIG resistance.
(A) ROC curve for coagulation profiles (PT, APTT, D-dimer, ATIII) in
predicting initial IVIG resistance. (B) ROC curve for ATIII in
predicting repeated IVIG resistance.

\textbf{Supplemental material 1} . Comparison of coagulation profiles
between the groups of CALs and non-CALs group in KD

\textbf{Supplemental material 2} . Clinical correlation between
univariate factors and coagulation profile in the KD subjects\selectlanguage{english}
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