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.13 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.