Upregulation of the Renin-Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients.

The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to "clinical" manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.

Transient appearance of EDTA dependent pseudothrombocytopenia in a patient with 2019 novel coronavirus pneumonia.

EDTA dependent pseudothrombocytopenia (EDTA-PCTP) is a phenomenon that characterized by a spurious decrease of platelets in vitro due to the aggregation of platelets in EDTA anticoagulant blood samples. We report the first case of a transient appearance of EDTA-PCTP in a patient with 2019 novel coronavirus pneumonia (COVID-19). A 59-year-old woman was admitted to the isolated ward for severe type of 2019 novel coronavirus pneumonia. At the time of admission, her platelet count was in a normal range. Two days later, her platelet count decreased gradually without any signs or symptoms of bleeding. Since the peripheral blood smear showed a platelet aggregation, a blood sample anticoagulanted with citrate was tested and the number of platelet was normal. The phenomenon disappeared after 17 days when the patient was cured. This case emphasized the importance of peripheral blood smear and clinical manifestation, especially in the differential diagnosis of thrombocytopenia.