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\begin{document}

\title{Deep vein thrombosis and pulmonary embolism in pediatric COVID-19}



\author[1]{Loukia Ioannidou}%
\author[1]{Athina Dettoraki }%
\author[2]{Maria Noni}%
\author[1]{Dimitra  Koukou}%
\author[1]{Aiketarini Michalopoulou}%
\author[1]{Zoey Kapsimalli}%
\author[3]{Evanthia Botsa}%
\author[4]{Athanasios Michos}%
\author[2]{Vana Spoulou}%
\author[1]{Helen Pergantou}%
\author[3]{Christina Kanaka-Gantenbein}%
\affil[1]{Agia Sofia Children's Hospital}%
\affil[2]{National and Kapodistrian University of Athens}%
\affil[3]{National and Kapodistrian University of Athens - Faculty of Medicine}%
\affil[4]{University of Athens}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Thrombotic complications of SARS-CoV-2 have been increasingly recognized
as an important component of COVID-19 in adults; however, they have been
less evident in children. We report a case of a teenager with positive
SARS-CoV-2 RT--PCR and underlying prothrombotic risk factors, including
aromatase inhibitor therapy, who developed deep vein thrombosis
resulting in pulmonary embolism. Laboratory tests revealed deranged
coagulation parameters (high D-dimers and Factor VIII and low
antithrombin). The patient required intensive care and was managed with
anticoagulants, dexamethasone and antithrombin concentrate. Clinical
condition and hemostatic profile gradually improved. A review of the
available literature for similar cases is presented.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), has various extra-pulmonary
manifestations, including venous thromboembolism
(VTE)\textsuperscript{1}. Pediatric recommendations for
hospital-associated VTE in COVID-19 have been
provided\textsuperscript{2,3}, though data regarding VTE risk in
non-hospitalized children are limited. We describe the case of an
adolescent with a positive SARS-CoV-2 reverse transcription polymerase
chain reaction (RT --PCR) and underlying prothrombotic risk factors who
developed deep vein thrombosis (DVT), resulting in pulmonary embolism
(PE).

\textbf{Case Description}

A 15-year-old male was referred to our emergency department with a
four-day history of gradually progressive pain and swelling of the right
lower limb, in the absence of any recent history of injury. A magnetic
resonance imaging (MRI) of the hip, undertaken previously in outpatient
setting following orthopedic referral, demonstrated a thrombus in the
external iliac vein(Figs. 1A and 1B). The patient also reported
gastrointestinal symptoms two weeks earlier, i.e., diarrhea and
vomiting, along with low-grade fever of 37.3oC, lasting for two days.
With regards to his medical history, he was under anastrozole, an
aromatase inhibitor (AI), over the last two years, as prescribed by his
physician for short stature.

The adolescent was overweight with body mass index (BMI) of 25.2
kg/m\textsuperscript{2}. On admission, he had body temperature of 38.9oC
and exhibited pain in the right hip with limited mobility of the joint
and edema of the right knee. Triplex ultrasound of the right lower
extremity depicted an extended DVT, from the external iliac vein down to
the great saphenous and popliteal vein. Further laboratory
investigations were undertaken, including SARS-CoV-2 RT-PCR on
nasopharyngeal sample. Initial management consisted of combined
antibiotic therapy with intravenous (IV) ceftriaxone and teicoplanin and
anticoagulation treatment with subcutaneous low molecular weight heparin
(LMWH) i.e., tinzaparin in a therapeutic dose of 175 IU/ kg body weight
once daily.

Within the first hour, he developed hypotension with low diastolic blood
pressure (25 mmHg), not responding to IV fluids, tachycardia (125
beats/min) and reduced urine output. Saturation of oxygen dropped to
94\%, few hours later. Computed tomography pulmonary angiogram (CTPA)
demonstrated embolus in the left pulmonary artery. (Figs. 1C and 1D),
whereas the SARS-CoV-2 RT-PCR revealed high viral
load.\textsuperscript{4}

The patient was urgently transferred to the COVID-19 pediatric intensive
care unit where IV dexamethasone 0.15 mg/kg (max 6 mg/day) was added to
his treatment plan. Oxygen supply was maintained to 2-3 L/min without
further need of intubation or mechanical ventilation. Subcutaneous
tinzaparin was continued and a single dose of IV antithrombin
concentrate was administered due to low levels, resulting in immediate
response to 125\%. Systematic thrombolysis was not required. High
temperature subsided 24 hours later, oxygen was weaned off and
antibiotic treatment was discontinued following negative blood cultures.

The patient stepped down to the COVID-19 pediatric ward after 72 hours
where he gradually improved. A total of ten days of IV dexamethasone was
completed and subcutaneous tinzaparin was substituted by oral warfarin,
after completion of three weeks. Anastrozole was discontinued. He was
discharged34 days after admission under warfarin 5 mg once daily.
Hemostatic parameters and SARS-CoV-2 RT-PCR were regularly evaluated
during hospital stay and post discharge, as summarized in Table 1.
Genetic testing for hereditary thrombophilia has been scheduled after
the acute phase of thrombosis.

\textbf{Discussion}

Only few patients under 18 years with COVID-19 have been reported with
PE\textsuperscript{5-7}. The vast majority of literature data refers to
critically ill adults\textsuperscript{8-10}, where local pulmonary
thrombotic microangiopathy appears to be the underlying
pathophysiological mechanism\textsuperscript{11}. In contrast, our
patient had mild COVID-19 prior to manifestation of VTE, without
hyperinflammatory state, and PE was secondary to embolization from the
lower limb.

Puberty and age above 12 years increase the thrombotic risk in
children\textsuperscript{2}. Nevertheless, the adolescent had additional
prothrombotic risk factors. Aromatase inhibitor (AI) therapies prevent
the conversion of androgens to estrogens and are mainly used in estrogen
receptor-positive breast cancer. In children with short stature, they
are supposed to allow for greater height potential by delaying the
epiphysial maturation, given the fact that the ultimate fusion of the
growth plates in both males and females is
estrogen-dependent\textsuperscript{12}.~Thromboembolism is an adverse
effect of AI in female breast cancer patients and women receiving
anastrozole are found to have greater risk for VTE compared to
untreated, healthy women\textsuperscript{13}. Such adverse effects have
been poorly investigated in children. Therefore, the inhibition of the
estrogens production through the inhibition of the aromatase may lead to
increased testosterone concentration. In turn, the increased
testosterone levels in pubertal boys could lead to erythrocytosis and
thrombotic events, but further investigation is needed in this
context\textsuperscript{14}. Moreover, in our patient, the reported
pre-existing symptoms from gastrointestinal system could induce
hypercoagulability in view of dehydration and increased blood viscosity,
as described in adults with COVID-19\textsuperscript{15}. The patient
also reported excessive screen time due to his tele-education over the
last weeks and the resulting immobilization, i.e. being sedentary for
many hours, could constitute an additional risk factor through
circulatory stasis, as described under the term of
e-thrombosis\textsuperscript{16}.

COVID-19 as well induces per se a hypercoagulable
state\textsuperscript{17}. The suggested
mechanism\textsuperscript{18,19} is that the disease leads to an
immunothrombosis response through the interplay between inflammatory and
coagulation pathways, resulting in cytokine storm, neutrophil and
complement activation which propagate a pro-agulant state. Furthermore,
the virus itself provokes a direct endothelial injury activating the
coagulation cascade. The vascular endothelium is a key target-organ of
SARS-Cov-2\textsuperscript{20} this endotheliitis\textsuperscript{21}was
evident in our case, as high levels of Factor VIII (FVIII) were
persistent. FVIII is a blood-clotting protein associated with
inflammation but also direct endothelial damage\textsuperscript{22} and
it has been suggested as a predictive coagulation biomarker in COVID-19,
as reported in a cohort study of adult patients, where high levels at
admission were linked to early-onset VTE\textsuperscript{23}.

Coagulopathy in COVID-19 has further laboratory features, overlapping
with other coagulopathies but also differing\textsuperscript{24,25}.
Similarly, our patient presented high fibrinogen, which normalized soon
after the initiation of anticoagulation, and significantly increased
levels of D-dimers, which gradually decreased but remained above normal
limits even after six weeks. Such elevated D-dimers e.g.,\textgreater{}5
times the upper limit of normal values, are suggested as a marker for
introducing thromboprophylaxis in children hospitalized with COVID-19,
independently of clinical risk factors for VTE\textsuperscript{2}.
Moreover, prothrombin time (PT) was mildly prolonged, with subsequently
low Factor VII, whereas activated partial thromboplastin time (aPTT) and
platelets count were, unlike in disseminated intravascular coagulation,
normal.

The patient, additionally, demonstrated persistent low levels of
antithrombin even after supplementation. Interestingly, his mother -who
had also a positive SARS-CoV2 RT-PCR but remained asymptomatic- was
found with low antithrombin (59\%). During her reevaluation one month
later (with negative RT-PCR), levels were almost restored (78\%). These
findings support the correlation between the virus and acquired
antithrombin deficiency, as seen in studies showing low antithrombin in
a high proportion of patients with COVID-19\textsuperscript{26}. This
should be taken into consideration when introducing anticoagulation to
patients with COVID-19; antithrombin deficiency induces heparin
resistance and higher heparin doses or antithrombin concentrateto
correct values \textless{} 70\%, like in our case, might be
needed\textsuperscript{27,28}.

In conclusion, our case underlines the fact that pediatric patients with
SARS-CoV-2 infection, even the non -- hospitalized, could develop
serious VTE in the co-existence of underlying prothrombotic risk factors
and COVID-19 associated coagulopathy. Clinical suspicion should be high
in specific age groups like adolescents, who may receive therapies like
AI or are more sedentary during the pandemic. Therefore, there is a need
for further recommendations regarding VTE risk assessment, hemostatic
monitoring and application of anticoagulation in children and
adolescents with COVID-19.

\textbf{Acknowledgments}

The authors would like to acknowledge the Pediatric Intensive Care Unit
of ''P \& A Kyriakou'' Children's Hospital for the acute management of
our patient, all the physicians involved in our patient's care, Dr Irene
Pantou, radiologist in Radiology Department of Eginition Hospital, for
the assistance in the radiological findings

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\textbf{FIGURE 1}

Imaging confirmation of VTE. Coronal (A) and axial (B) fat-suppressed
T2-weighted images of MRI scan of right hip joint, demonstrating a
hyperintense clot in the right external iliac vein, and coronal (C) and
axial (D) views of lung CTPA scan revealing a large pulmonary embolus of
approximately 3 cm longitudinal diameter in left pulmonary artery's
branch which supplies the left lower lobe.\selectlanguage{english}
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\textbf{Hosted file}

\verb`TABLE 1 Changes in laboratory parameters.docx`  available at \url{https://authorea.com/users/437900/articles/539238-deep-vein-thrombosis-and-pulmonary-embolism-in-pediatric-covid-19}

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