Discussion
Only few patients under 18 years with COVID-19 have been reported with
PE5-7. The vast majority of literature data 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 age above 12 years increase the thrombotic risk in
children2. 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-dependent12. 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 women13. 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
context14. 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-1915. 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-thrombosis16.
COVID-19 as well induces per se a hypercoagulable
state17. The suggested
mechanism18,19 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-220 this endotheliitis21was 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 damage22 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 VTE23.
Coagulopathy in COVID-19 has further laboratory features, overlapping
with other coagulopathies but also differing24,25.
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.,>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 VTE2.
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-1926. 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 < 70%, like in our case, might be
needed27,28.
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.