Coronavirus disease of 2019 (COVID-19) is the clinical manifestation of the respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Following its origin as a regional outbreak in Wuhan, China, COVID-19 rapidly spread globally and eventually was designated as pandemic by the World Health Organization. Multiple studies describing the clinical characteristics of COVID-19 patients highlighted the prevalence of abnormal coagulopathy and higher incidence of thrombosis. These studies identified co-morbid inflammatory disorders as risk factors for hospitalization in SARS-CoV-2 infections. While early evidence suggested inflammatory conditions as the leading cause of abnormal coagulopathy in COVID-19 patients, the mechanisms behind progression of inflammation mediated hemostasis dysregulation to thrombotic outcomes in susceptible individuals are not well understood. In addition, a sensitive and temporal assessments of coagulation and fibrinolysis is still lacking. Von Willebrand Factor (VWF) and ADAMTS13 interactions play an important role in the maintenance of hemostasis and prevention of unwanted thrombosis. In inflammatory conditions, VWF-ADAMTS13 imbalance characterized by elevated VWF levels and inhibited and/or reduced activity of ADAMTS13 is reported. Also, an imbalance between ADAMTS13 activity and VWF antigen is associated with organ dysfunction and death in patients with systemic inflammation. Despite the natural antithrombotic activity of ADAMTS13, its role in COVID-19 pathophysiology, specifically thrombotic outcomes has not yet been investigated. A thorough understanding of VWF-ADAMTS13 interactions during early and advanced phases of COVID-19 could help define the pathophysiology, guide thromboprophylaxis and treatment and improve clinical prognosis.