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.