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\title{Inherited thrombophilia and risk of thrombosis in children with cancer:
a single-center experience}



\author[1]{Ana Dordevic}%
\author[1]{Gianni Sava}%
\author[2]{Blazenka Grahovac}%
\author[2]{Lidija Bilic Zulle}%
\author[3]{Jelena  Roganovic}%
\affil[1]{University of Trieste}%
\affil[2]{University of Rijeka Faculty of Medicine}%
\affil[3]{Clinical Hospital Center Rijeka}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Thrombosis is an increasingly recognized complication of
childhood malignancy and its treatment. The etiology of pediatric
cancer-related thrombosis is multifactorial and not well understood at
present. The aim of this study was to evaluate the prevalence of common
prothrombotic genetic conditions in children with cancer, the frequency
of thrombosis, and the role of inherited thrombophilia in the
development of thrombosis in a pediatric oncology population. Methods:
Forty-seven children (36 treated for hematological malignancies and 11
for solid tumors) with the median age of 8.8. years (range 0.4 -- 19.3
years) were included in the study. Genetic polymorphisms of Factor V
Leiden, prothrombin G20210A mutation, and methylenetetrahydrofolate
reductase (MTHFR) C677T were determined by real-time polymerase chain
reaction-based DNA analysis. Results: Four (8.5\%) patients were
heterozygous for Factor V Leiden, 3 (6.4\%) were heterozygous for
prothrombin G20210A mutation, and 3 (6.4\%) were homozygous for MTHFR
C677T mutation. All patients had inserted central venous lines. Four
(8.5\%) children had documented thrombosis, 3 of which were located in
the upper venous system. Two of four patients with thrombosis had Factor
V Leiden heterozygosity. Conclusions: Thrombosis is an important
complication of childhood cancer. Our results suggest that congenital
prothrombotic abnormalities could be implicated in increasing the risk
of thrombosis and support a recommendation that children with cancer be
evaluated for inherited thrombophilia.%
\end{abstract}%



\sloppy


TITLE PAGE

Manuscript title: Inherited thrombophilia and risk of thrombosis in
children with cancer: a single-center experience

Authors: Ana Dordevic\textsuperscript{1}, Gianni
Sava\textsuperscript{2}, Blazenka Grahovac\textsuperscript{3}, Lidija
Bilic Zulle\textsuperscript{4,5}, Jelena Roganovic\textsuperscript{6,7}

Affiliations

\textsuperscript{1} Department of Chemical and Pharmaceutical Sciences,
University of Trieste, Trieste, Italy

\textsuperscript{2} Department of Life Sciences, University of Trieste,
Trieste, Italy

\textsuperscript{3} Department of Pathology, Faculty of Medicine,
University of Rijeka, Rijeka, Croatia

\textsuperscript{4} Department of Medical Informatics, Faculty of
Medicine, University of Rijeka, Rijeka, Croatia

\textsuperscript{5} Clinical Institute for Laboratory Diagnostics,
Clinical Hospital Center Rijeka, Rijeka, Croatia

\textsuperscript{6} Department of Pediatrics, Faculty of Medicine,
University of Rijeka, Rijeka, Croatia

\textsuperscript{7} Division of Hematology and Oncology, Department of
Pediatrics, Clinical Hospital Center Rijeka, Rijeka, Croatia

Correspondence: Jelena Roganovic, Department of Pediatrics, Clinical
Hospital Centre Rijeka, Istarska 43, HR-51000 Rijeka, Croatia

Phone: + 38551659214, Fax: + 38551659123

Email: roganovic.kbcri@gmail.com; jelena.roganovic@uniri.hr

Word Count

Abstract: 217

Main text: 2876

The number of Tables: 1

A short running title: Thrombophilia and pediatric cancer

Keywords: Inherited thrombophilia -- cancer -- thrombosis -- children

Abbreviations\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
ALL & acute lymphoblastic leukemia\tabularnewline
\midrule
\endhead
APCR & activated protein C resistance\tabularnewline
CVL & central venous line\tabularnewline
MTHFR & methylenetetrahydrofolate reductase\tabularnewline
RT-PCR & real-time polymerase chain reaction\tabularnewline
\bottomrule
\end{longtable}

ABSTRACT

Background: Thrombosis is an increasingly recognized complication of
childhood malignancy and its treatment. The etiology of pediatric
cancer-related thrombosis is multifactorial and not well understood at
present. The aim of this study was to evaluate the prevalence of common
prothrombotic genetic conditions in children with cancer, the frequency
of thrombosis, and the role of inherited thrombophilia in the
development of thrombosis in a pediatric oncology population.

Methods: Forty-seven children (36 treated for hematological malignancies
and 11 for solid tumors) with the median age of 8.8. years (range 0.4 --
19.3 years) were included in the study. Genetic polymorphisms of Factor
V Leiden, prothrombin G20210A mutation, and methylenetetrahydrofolate
reductase (MTHFR) C677T were determined by real-time polymerase chain
reaction-based DNA analysis.

Results: Four (8.5\%) patients were heterozygous for Factor V Leiden, 3
(6.4\%) were heterozygous for prothrombin G20210A mutation, and 3
(6.4\%) were homozygous for MTHFR C677T mutation. All patients had
inserted central venous lines. Four (8.5\%) children had documented
thrombosis, 3 of which were located in the upper venous system. Two of
four patients with thrombosis had Factor V Leiden heterozygosity.

Conclusions: Thrombosis is an important complication of childhood
cancer. Our results suggest that congenital prothrombotic abnormalities
could be implicated in increasing the risk of thrombosis and support a
recommendation that children with cancer be evaluated for inherited
thrombophilia.

INTRODUCTION

Thrombosis is a well-recognized complication of malignancy. It is
estimated that up to 20\% of all cancer patients develop thrombotic
event during the course of the disease, with the annual incidence rate
of 0.5\% compared to 0.1\% in the general
population.\textsuperscript{1,2} There is substantially less knowledge
about thrombosis in pediatric cancer populations, with reported rates
varying from 2 to 16\%, depending on the type of
malignancy.\textsuperscript{3} Children with cancer and thrombosis have
increased risk of mortality, higher rates of recurrent thrombosis and
thrombosis-related morbidity, and decreased quality of
life.\textsuperscript{4,5}

The pathogenesis of pediatric cancer-related thrombosis is
multifactorial and may reflect genetic prothrombotic factors,
tumor-related and treatment-related factors.\textsuperscript{6} The role
of hereditary thrombophilia in the development of thrombosis in children
with cancer is poorly investigated and still unclear.

This study was undertaken to determine the prevalence of Factor V
Leiden, prothrombin G20210A mutation and methylenetetrahydrofolate
reductase (MTHFR) C677T mutation in children with hematological
malignancies and malignant solid tumors, the frequency of
cancer-associated thrombosis, and the role of inherited thrombophilic
abnormalities in thrombotic events.

PATIENTS AND METHODS

Patients: Forty-seven children with primary cancer (36 with
hematological malignancies and 11 with malignant solid tumors) referred
to the Division of Hematology and Oncology, Department of Pediatrics,
Clinical Hospital Centre Rijeka, Croatia, were included in the study.
The following data were collected from medical records: gender, age at
diagnosis, the type of cancer, previous and family history of
thrombosis, insertion/type of a central venous line, and the
presence/developmental time/site of thrombotic event. An informed
written consent was obtained from the parents of all patients. The
ethical approval from an institutional ethics board was obtained.

Methods: The samples were taken from peripheral blood in EDTA-containing
tubes. The genomic DNA was prepared from whole blood with the NucleoSpin
Blood kit (Macherey-Nagel GmbH \& Co. KG, D\selectlanguage{ngerman}üren, Germany). Genetic
polymorphisms of Factor V G1691A (Factor V Leiden), Factor
II-Prothrombin G20210A and MTHFR C677T were screened with real-time
polymerase chain reaction (RT-PCR) on the Light Cycler® 1.5 Instrument,
Roche Diagnostics, Germany. Tests were performed by binding specific DNA
probes marked with fluorescent colors during PCR and melting curve
analysis of marked PCR products, according to the manufacturer's
instructions. Plasma homocysteine levels were not assessed routinely.

Statistical analysis: Descriptive statistics was used to summarize data.
The results were compared with the relative frequencies of heterozygous
and homozygous variants of each polymorphism in general population.
Fisher's exact test was used to compare the prevalence of Factor II and
Factor V Leiden polymorphism between boys and girls with cancer, and
between children with hematological malignancies and solid tumors. The
Chi-squared test was used to describe MTHFR genotype distribution in
boys and girls with cancer, and between patients with hematological
malignancies and solid tumors. P value of \textless{} 0.05 was
considered statistically significant.

RESULTS

Thirteen (27.7\%) girls and 34 (72.3\%) boys were included in the study.
The median age of patients was 8.8 years (range 0.4 -- 19.3 years).
Thirty-six patients had hematological malignancies (acute lymphoblastic
leukemia {[}ALL{]} = 26, acute myeloid leukemia = 2, non-Hodgkin
lymphoma = 7, Hodgkin lymphoma = 1) and 11 patients had solid tumors
(malignant brain tumor = 3, soft tissue sarcoma = 3, osteosarcoma = 2,
Ewing sarcoma = 1, neuroblastoma = 1, nasopharyngeal carcinoma = 1). All
patients had inserted central venous lines: 33 patients had Broviac
catheter and 14 had Port-a-cath.

Three (6.4\%) patients (all boys) had heterozygous Factor II G20210A
mutation, while no homozygosity was detected. Heterozygous Factor V
Leiden was identified in 4 (8.5\%) children (2 boys and 2 girls) with
cancer, and no homozygous Factor V Leiden was found. MTHFR C677T
heterozygosity was present in 21 (44.7\%) patients, and homozygosity in
3 (6.4\%). Six (46.2\%) girls and 15 (44.1\%) boys were heterozygous for
MTHFR C677T, while 1 (7.7\%) girl and 2 (5.9\%) boys were homozygous.
There was no statistical significance in the prevalence of FII G20210A
mutation (Fisher's exact test, P=0.550), Factor V G1691A mutation
(Fisher's exact test, P=0.304), and MTHFR C677T mutation (Chi-squared
test, P=0.928) between male and female patients.

Two (5.6\%) patients with hematological malignancies and one (9.1\%)
with solid tumor had heterozygosity for Factor II G20210A mutation,
while no homozygosity was found. Factor V Leiden was identified in 3
(8.3\%) children with hematological malignancies, and in 1 (9.1\%) with
solid tumor, and all patients had heterozygous form. Heterozygous MTHFR
C667T mutation was identified in 14 (44.4\%) children with hematological
malignancies and in 5 (45.5\%) children with solid tumors, while 2
(5.6\%) patients with hematological malignancies and 1 (9.1\%) with
solid tumor had MTHFR C667T homozygosity. No statistical significance
was found in the prevalence of Factor II G20210A mutation (Fisher's
exact test, P=0.560), Factor V Leiden (Fisher's exact test, P=01.000)
and MTHFR C667T mutation (Chi-squared test, P=0.936) between patients
with hematological malignancies and solid tumors.

Combined thrombophilic defect were detected in 5 patients. Four children
had heterozygous Factor V Leiden and MTHFR C667T heterozygosity. One
patient had a combination of heterozygosity for Factor II G20210A and
for MTHFR C667T heterozygosity. A previous or family history of
thrombosis were negative in all patients.

Four (8.5\%) children (all boys) had documented thrombotic event during
the course of the disease: right axillar and brachial vein thrombosis in
a patient with non-Hodgkin lymphoma, right brachial vein thrombosis in a
patient with neuroblastoma, right subclavian, axillary and brachial vein
thrombosis in a patient with nasopharyngeal carcinoma, and right atrial
thrombosis in a patient with osteosarcoma. No patient had a recurrent
thrombosis. Two patients had heterozygous Factor V Leiden (both combined
with heterozygous but no homozygous MTHFR C677T mutation), one patient
had heterozygous MTHFR C677T mutation, and one patient had no
thrombophilia gene mutation detected.

The characteristics of pediatric oncology patients with thrombosis are
shown in Table 1.

DISCUSSION

The frequency of a specific genetic polymorphism varies from population
to population, reflecting ancient adaptation to specific environments.
The most common inherited forms of thrombophilia in the United States
and European general population are heterozygosity for Factor V Leiden
and heterozigosity for prothrombin G20210A mutation, with the reported
prevalence approximately 3 to 8\%, and 1 to 6\%
respectively.\textsuperscript{7,8}Homozygosity for MTHFR is common
worldwide with estimated prevalence 10 to 25\% among Caucasians, and
combinations of other thrombophilic risk factors with MTHFR homozygosity
are not unusual.\textsuperscript{9} Two case-control studies
investigated the frequency of inherited thrombophilia in Croatian
population. Alfirevic et al. reported the frequency of heterozygous
Factor V Leiden in 2.9\% healthy individuals, heterozygous Factor II
G20210A in 6\%, heterozygous MTHFR C677T in 57\%, and homozygous MTHFR
T677T in 7\% healthy controls. They found more frequent Factor V Leiden
heterozygosity in patients with the thromboembolic disease (16\%)
compared to controls.\textsuperscript{10}Coen and coworkers found the
prevalence of 4\% for both Factor V Leiden and PT20210A in healthy
subjects. The prevalence of Factor V Leiden and prothrombin G20210A was
higher in patients with venous thromboembolism, 21\% and 8\%
respectively.\textsuperscript{11} No homozygous Factor V Leiden or
Factor II mutation was found in both Croatian
studies.\textsuperscript{10,11}

We found the prevalence of 8.5\% for heterozygous Factor V Leiden, 6.4\%
for heterozygous Factor II G20210A mutation, 44.7\% for heterozygous
MTHFR C677T, and 6.4\% for homozygous MTHFR C677T in our cohort. Several
studies on the prevalence of inherited thrombophilic factors in children
with malignancies obtained similar results. Akin and al. reported data
for 135 Turkish patients with leukemia aged 1 to 15 years; 11 (8\%)
children were heterozygous for Factor V G1691A mutation, and 7 (5.1\%)
were heterozygous for prothrombin G20210A
mutation.\textsuperscript{12}Nowak-Göttle and coworkers conducted a
large German prospective study of the thrombotic risk in 301 children
with newly diagnosed ALL aged 6 months to 17 years, and found a single
thrombophilic factor in 55 (18.2\%). After exclusion of 12 patients, in
the remaining 289 consecutively admitted children, 20 (6.9 \%) showed
MTHFR T677T genotype, 11 (3.8\%) were carriers of Factor V G1691A
mutation (10 heterozygous and 1 homozygous), 5 (1.7\%) had heterozygous
prothrombin G20210A variant, 4 (1.4\%) showed protein C deficiency, 4
(1.4\%) had protein S deficiency, 2 (0.7\%) had antithrombin deficiency,
and 9 (3.1\%) patients had familiarly elevated lipoprotein
concentrations. In addition, combined thrombophilia was found in further
10 (3.5\%) patients. The prevalence of all tested thrombophilic factors
was within the prevalence reported for healthy white
population.\textsuperscript{13} Elhasid et al. found thrombophilic
polymorphisms in 43\% (13/27) children with ALL of Arab and Israeli
origin older than 12 months of age. Prothrombin G20210A mutation was
documented in 3 (11\%), heterozygosity for Factor V Leiden in 5
(18.5\%), and homozygosity for MTHFR C677T mutation in 5 (18.5\%)
children. One girl of Arab origin had triple thrombophilia. The higher
prevalence was explained by higher frequency of heterozygosity for
Factor V Leiden and Factor II mutation in the Israeli population of
northern Israel.\textsuperscript{14}

Studies on adult cancer patients showed conflicting results. Pihusch et
al. found an increased prevalence of prothrombin G20210A mutation in
patients with gastrointestinal carcinoma compared to normal population
(5.7\% versus 0.8\%), while there was no difference in the prevalence of
Factor V Leiden and MTHFR homozygosity, 6.9\% and 9.7\%
respectively.\textsuperscript{15} On the contrary, Turkish study
reported significantly greater prevalence (30.2\%) of Factor V Leiden in
43 cancer patients with thromboembolism compared to 3.7\% those without,
but no significant difference in the prevalence of prothrombin G20210A
among the groups.\textsuperscript{16} Battistelli and coworkers found no
difference in the prevalence of Factor V Leiden and prothrombin G20210A
gene mutation between 121 patients with gastric carcinoma and 130
healthy subjects from central Italy, matched for sex, age, and ethnicity
(3.3\% versus 4.6\%, and 8.3\% versus 6.1\%
respectively).\textsuperscript{17} A large German population-based
case-control study reported a 6-fold increased risk for colorectal
cancer for homozygous carriers of Factor V Leiden compared with
non-carriers. A reduced risk was demonstrated for heterozygous Factor V
Leiden carriers and for heterozygous prothrombin G20210A carriers. No
association was found between MTHFR polymorphisms with colon or rectal
cancer.\textsuperscript{18}Paspatis et al. reported a high frequency of
activated protein C resistance (APCR) but no significant differences in
the prevalence of Factor V Leiden or prothrombin G20210A mutation in
Greek patients with colorectal cancer compared to colonoscopically
selected controls.\textsuperscript{19} Martinelli et al. studied the
role of Factor V Leiden and prothrombin G20210A mutation for the
development of thrombosis in 430 patients with hepatocellular carcinoma
who underwent liver transplantation. They found 4-times higher risk of
thrombosis in patients with inherited thrombophilia than in those
without, and 6-times higher risk when the analysis was restricted to
venous thrombosis. The presence of inherited thrombophilia in donors did
not increase the risk of thrombosis of recipients.\textsuperscript{20}
Although dissimilarities in these studies could be partly explained by
different ethnic background of subjects, they point the need of larger
prospective multicentric investigations.

In our cohort, thrombosis was documented in 4 of 47 (8.5\%) children
with cancer, which is much higher than in the general pediatric
population. The reported incidence of thrombosis ranges from 0.14 to
0.21 per 10,000 children per year, and 0.2 to 0.6\% among hospitalized
pediatric patients.\textsuperscript{21} The majority of affected
children have at least one underlying condition or trigger for
thrombosis, the most common being central venous catheter, inherited
thrombophilia, malignancy, congenital heart disease, chronic
neuromuscular disease, surgery, major trauma, immobility,
estrogen-containing contraceptives, obesity, and severe
infection.\textsuperscript{21-24}

The risk of thrombosis is considerably lower in children compared to
adults. Several factors are considered to contribute to the small
incidence of pediatric thrombosis: lower frequency of diseases causing
vascular endothelium damage, less frequent exposure to acquired
prothrombotic risk factors, and significant physiological differences in
the coagulation system (lower plasma levels of vitamin K-dependent
factors, higher levels of thrombin inhibitor and \selectlanguage{greek}α\selectlanguage{english}2-macroglobulin, and
reduced capacity to generate thrombin).\textsuperscript{21,25}

The association between thrombosis and pediatric cancer is well
established, and overall 25\% of children with thrombosis have
underlying diagnosis of cancer.\textsuperscript{26} The reported
prevalence of thrombosis in children with cancer ranges from 2 to 16\%,
while the occurrence of asymptomatic events is approximately
40\%.\textsuperscript{27-33} The risk is highest in children with ALL,
followed by sarcoma and lymphoma, and the lowest risk is in children
with brain tumors.\textsuperscript{4,34,35} In the present study, the
occurrence of thrombosis of 8.5\% is in agreement with published data,
but thrombosis was more frequent in children with solid tumors (3/11)
compared to hematological malignancies (1/36).

The etiology of thrombosis in children with cancer is multifactorial,
and includes patient-related predisposition (congenital thrombophilia),
disease-related factors and treatment-related factors. Cancer may be
considered a hypercoagulable state. Tumor cells express tissue factor,
procoagulant proteins, metalloproteases, and molecules that can induce
direct and indirect activation of coagulation. Several additional
mechanisms, such as inflammatory, immune, and angiogenic responses, are
involved.\textsuperscript{36,37} Major risk factors for thrombosis in
children with hematological malignancies include presence of central
venous catheter, older age, prothrombotic genetic defects, non-O blood
group, obesity, and medications (asparaginase, concomitant use of
steroids, anthracyclines).\textsuperscript{4,38-40} Proposed thrombotic
risk factors in children with solid tumors include presence of central
venous line, age \textgreater{} 10 years, certain types and sites of
tumor, metastatic disease, thrombophilia, obesity, and type of treatment
(surgery, radiation, anthracyclines and
platinum).\textsuperscript{4,31,41} Central venous catheters are the
most important risk factor.\textsuperscript{42} Reported rates of
symptomatic catheter-related thrombosis range from 2.6 to 36.7\%, and
rates of asymptomatic catheter-related thrombosis range from 5.9 to
43\%.\textsuperscript{3,43} The pathogenesis of catheter-related
thrombosis is not well characterized, and it may involve endothelial
damage and local activation of blood coagulation.\textsuperscript{44}The
most common site is upper venous system, and lower extremities for
non-catheter-related thrombosis.\textsuperscript{42,45} Central nervous
system thrombosis is more common in children with ALL, with
approximately half of patients having sinus venous
thrombosis.\textsuperscript{33,42} The incidence of cerebral sinus
venous thrombosis in pediatric ALL patients varies from 1.4 to
10.5\%.\textsuperscript{46-49} Right atrial thrombosis is reported in
2\% of patients with symptomatic thrombosis.\textsuperscript{50}

In our cohort study, 3 of 4 children with thrombosis were adolescents
aged \textgreater{} 15 years. All patients had implanted central venous
access devices, and all thrombotic events occurred during chemotherapy.
Three patients had an upper extremity thrombosis, and one had right
atrial thrombosis. All patients were male. Two patients had documented
thrombophilic gene mutations, both heterozygous Factor Leiden (combined
with MTHFR C677T heterozygosity).

The contribution of inherited thrombophilia to the occurrence of
thrombosis in cancer patients has been documented. The two most common
genetic causes of thrombophilia identified to date are Factor V Leiden
and prothrombin gene mutation.\textsuperscript{51,52} Although MTHFR
C677T heterozygosity is very frequent polymorphism, it is proven that
this gene alteration increases the risk of thrombosis only when results
in hyperhomocysteinemia.\textsuperscript{53} A meta-analysis of 17
prospective studies comprising 1752 pediatric patients with ALL reported
the overall thrombotic risk of 5.2\%. Prothrombotic genetic defects were
studied in 557 children. Thirty-one thrombotic events were observed in
113 children affected by at least one genetic alteration, pointing an
approximately 8-fold increased thrombotic risk (relative risk
{[}RR{]}:8.5; 95\% CI: 4.4-17.4) in all patients with inherited
thrombophilia.\textsuperscript{40} Similar results were reported by
Nowak-G\selectlanguage{ngerman}öttle and coworkers, who documented venous thrombosis in 46.5\%
(27/58) children with ALL carrying a prothrombotic defect compared to
2.2\% (5/131) children with no identified prothrombotic defect (P
\textless{} 0.0001; chi-square 137.0). Homozygous MTHFR mutation with
hyperhomocysteinemia was diagnosed in 12.5\% (4/32) children with
thrombosis, and in further 9.4\% (3/32) patients combined with Factor V
Leiden or increased lipoprotein A concentrations. In addition, an
increased risk of thrombotic complications was clearly demonstrated in
leukemia patients with combined prothrombotic risk factors compared to
patients with single alterations.\textsuperscript{13} The study of
Knöfler et al. included 77 children with malignancies; in 11 (14\%) of
them catheter-related thrombosis was detected. Prothrombotic genetic
defects were found in 23\% (17/77) of all patients, and in 7 of 11
(64\%) patients with thrombosis. Three children had combined defects
(heterozygous Factor V G1691A mutation combined with heterozygous
prothrombin G20210A variant, protein S deficiency or
hyperlipoproteinemia), and 4 had a single defect (heterozygous Factor V
G1691A mutation, heterozygous prothrombin G20210A mutation,
hyperlipoproteinemia, and protein C deficiency type
I).\textsuperscript{54} Ünal and coworkers evaluated inherited and
acquired prothrombotic risk factors in 37 children with malignancies and
thrombosis. Congenital defects were detected in 15 (40\%) patients: 8
had heterozygous Factor V G1691A mutation, 1 had heterozygous
prothrombin G20210A mutation, 4 had lipoprotein(a) elevation, 1 had
decreased protein S level, and 1 had decreased protein C level. The risk
of thrombosis increased when accompanied by additional prothrombotic
risk factors.\textsuperscript{55} A large population-based study in
Israel on 1191 children with ALL reported venous thromboembolism in 89
(7.5\%) children. Thrombophilia screening was performed in 584 children,
and findings were positive in 84 (14.4\%). Patients with thrombophilia
had significantly more thrombotic events compared to children without
thrombophilia (p \textless{} 0.001).\textsuperscript{56} Other studies
failed to show any impact of thrombophilic gene mutations on thrombosis
risk in patients with cancer.\textsuperscript{42,57-60} Thus, the impact
of inherited thrombophilic markers on the development of thrombosis in
pediatric oncology patients has not been completely clarified.

Our study confirms the higher occurrence of thrombosis in children with
cancer. Although it has considerable limitations in terms of
retrospective design, small number of patients, heterogenous diagnoses,
and a limited panel of tested genetic prothrombotic traits, the results
suggest that inherited thrombophilia could be implicated in increasing
the risk of thrombosis in children with cancer. Larger multicenter
prospective studies, development of guidelines for thrombophilia
screening, identification of high-risk groups, individualized
reevaluation of additional prothrombotic risk factors, and appropriate
measures might help in the prevention and early intervention of
thrombotic events.

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest.

ORCID\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Ana Dordevic

https://orcid.org/0000-0003-3896-6698\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

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Gianni Sava

https://orcid.org/0000-0002-5138-6041\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

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\end{figure}

Blazenka Grahovac

https://orcid.org/0000-0001-7783-208 1\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

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\end{figure}

Lidija Bilic Zulle

https://orcid.org/0000-0002-4497-6457\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

Jelena Roganovic https://orcid.org/0000-0002-7960-6069

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