The Prevalence and Risk Factors of Coagulopathy in Pediatric Patients Undergoing Surgery for Epilepsy
Conditions: Epilepsy in Children, Coagulation and Hemorrhagic Disorders, Epilepsy; Seizure, Antiepileptic Adverse Reaction
Sponsor: Children's Hospital of Fudan University

Study Protocol and Statistical Analysis Plan 
 
Title: The prevalence and risk factors of coagulopathy in pediatric patients 
undergoing surgery for epilepsy: a retrospective cohort study 
 
Date: 2022-11-02 
 
 

Background: 
Epilepsy is a common disease of the nervous system with severe consequences. 
Epidemiological surveys have shown that the prevalence of epilepsy in China is approximately 
0.4–0.7%, comprising 7–10 million patients with epilepsy(1), most of whom are children(2). 
Although most symptoms of epilepsy can be controlled with the use of anti-seizure 
medications (ASMs), there are still a few patients who cannot achieve satisfactory seizure 
control with such medications or cannot tolerate their side effects, thus requiring surgical 
treatment. Surgical treatment of epilepsy has been recognized as a valuable treatment option 
for carefully selected patients to achieve better seizure control and quality of life(3). 
Compared to adults, children with epilepsy with indications for surgery usually have a better 
prognosis after surgical treatment(4–8). Many children undergoing surgery for epilepsy have 
a long history of using ASMs. Moreover, ASM therapy usually consists of multiple varieties of 
drugs, thereby bringing significant attention to the side effects of ASMs, especially those that 
may be relevant in the perioperative surgical setting. 
ASMs have been associated with multiple adverse effects on platelets and the coagulation 
system(9). Valproic acid (VPA), one of the most commonly used traditional ASM, has been 
reported to cause multiple hematologic abnormalities, including thrombocytopenia, platelet 
aggregation dysfunction, fibrinogen (FBG) depletion, bone marrow suppression, decreased 
factor XIII, and acquired von Willebrand disease(10–17). However, the wide use of novel ASMs 
in recent decades has led to decreased reports of adverse events. The hematologic 
consequences of these novel ASMs or combined therapies are rarely reported. Few studies 
have suggested that levetiracetam (LEV) does not cause clinically significant or relevant 
hematological disorders(18).  
Such reported side effects may be more significant in pediatric patients with epilepsy due to 
individual differences in age, weight, and pharmacokinetic action of the body on the drugs. 
The incidence of coagulopathies has been reported to be higher in children than in adults, 
especially hypofibrinogenemia(19,20). Nevertheless, whether these coagulation dysfunctions 
increase the risk of perioperative bleeding remains controversial. Most investigators suggest 
that ASMs, including VPA, are not associated with surgery-related blood loss or transfusion 
requirements(21–23). However, a few studies have suggested that considering the extra risk 
of perioperative bleeding, VPA should be discontinued before surgery(14).  
 
Objectives: 
This retrospective analysis of 390 children with epilepsy systematically investigated the 
incidence and risk factors of preoperative coagulation dysfunction in children undergoing 
surgery for epilepsy and their impact on surgery, with the objective to provide detailed and 
valuable clinical information. 
 
Design: 
This study was a retrospective cohort study. 
 
Methods: 
Study population 
This retrospective study focused on children who underwent surgery for epilepsy between 

January 2015 and December 2021 at the Neurosurgery Department of our hospital. 
Consecutive patients under 18 years who satisfied the following criteria were enrolled: a 
discharge diagnosis of “epilepsy” according to the International Classification of Diseases 
(ICD-10) and surgical treatment during the hospitalization. The following clinical data were 
collected: sex, age, weight, epilepsy course, and anti-seizure therapy. The initial laboratory 
data after admission included platelet count (PLT), prothrombin time (PT), activated partial 
thromboplastin time (APTT), FBG, alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST). The patients’ record of intra/post-operative transfusion or no 
transfusion was obtained from the medical records. The researchers also collected data on 
non-epileptic children who underwent non-epilepsy neurological surgery and were admitted 
at the same period from the Hospital Information System (HIS) as a control cohort. A total of 
539 patients were initially included in the study. Patients were excluded if the clinical 
information or laboratory examinations were incomplete, or had concomitant diseases 
affecting coagulation or liver function. Patients were also excluded if they refuse to be enrolled 
to the study. Overall, 390 epilepsy cases and 104 non-epilepsy controls were included in the 
study (figure 1). All the surgeries were performed by the same surgeon. 
 
ASM therapy 
All ASM therapies were administered by a specialist at our hospital and recorded once the 
patient was admitted. Therapy was defined as the ASMs taken at the time of admission, and 
all ASM therapies were continued till surgery at our center. Based on the frequency of use of 
ASMs, drugs taken over 10 times in all cases were included in the statistics, including, VPA, 
LEV, oxcarbazepine (OXC), carbamazepine (CBZ), topiramate (TPM), and lamotrigine (LTG). 
Simultaneous administration of two or more types of ASMs was defined as “polytherapy.” 
 
Laboratory tests 
Following the clinical routine at our center, routine blood tests, coagulation function tests, 
and liver function tests were performed after admission. The following laboratory data were 
collected: 
PLT, 
PT, 
APTT, 
FBG, 
ALT, 
and 
AST 
levels. 
Abnormal 
coagulation 
function/coagulation dysfunction/coagulopathy was confirmed if the values obtained were 
more (or less) than the highest (or lowest) normal range values of either PT, APTT, FBG, or 
PLT (PT>14.5 s, APTT>45 s, FBG< 2 g/L, PLT<150×10^9/L). Abnormal liver function was 
defined as values higher than the highest range of ALT or AST (ALT>42 U/L, AST>59 U/L).  
 
Statistical analyses 
Categorical variables are presented as absolute (n) and relative frequencies (%). Continuous 
variables are shown as the mean (±standard deviation) or median ( interquartile range), where 
applicable. The 
2 test was used to evaluate differences among categorical variables. 
Continuous variables with normal and skewed distributions were compared using the t-test 
and Wilcoxon rank-sum test, respectively.  
Univariate logistic regression analyses were performed to identify possible determinants of 
coagulation function. Possible relevant variables were included as covariates for multivariate 
logistic regression analysis to further filter out distractions. The results of the univariate and 
multivariate logistic regression analyses are presented as OR and 95% CI. The researchers used 

R V4.1.2 to conduct statistical analyses.  
 
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