Discussion
Only few patients under 18 years with COVID-19 have been reported with
PE.5-7 The majority of literature refers to critically
ill adults8-10, where local pulmonary thrombotic
microangiopathy appears to be the underlying pathophysiological
mechanism11. 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 BMI >85th percentile increase
the thrombotic risk in children2,12, nevertheless, the
adolescent had additional prothrombotic risk factors. 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 that the ultimate fusion of
the growth plates is
estrogen-dependent.13Â Thromboembolism is an adverse
effect of AI in female patients with breast cancer and women receiving
anastrozole are found to have greater risk for VTE compared to
untreated, healthy women14. Such adverse effects have
been poorly investigated in children. In pubertal boys, the inhibition
of testosterone aromatization to estradiol may lead to increased
testosterone concentration which, in turn, could result in
erythrocytosis and thrombotic events.15 Though,
further investigation is needed in this context. Furthermore, in our
patient, the preexisting symptoms from gastrointestinal system could
induce hypercoagulability in view of dehydration and increased blood
viscosity, as described in adults with COVID-19. 16Finally, the patient reported excessive screen time due to
tele-education over the last weeks and the resulting immobility, i.e.,
being sedentary for long hours, could constitute an additional risk
factor through circulatory stasis, as described under the term of
e-thrombosis.17
COVID-19 as well induces per se a hypercoagulable
state.18 The suggested
mechanism19,20 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 procoagulant state.
Concurrently, the virus itself provokes a direct endothelial injury
activating the coagulation cascade.21 This
endotheliitis22 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 endothelial
damage23 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.24
Coagulopathy in COVID-19 has further laboratory features, overlapping
with other coagulopathies but also differing.25,26Similarly, 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.,
>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.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-19.27 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 concentrate to
correct values < 70%, like in our case, might be
needed.28,29
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 with COVID-19.