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By March 21, 2022, 6.1 million deaths from COVID-19 were reported, most of them in the United States, Brazil, and India. Between January 1, 2020, and December 31, 2021, the global estimated mortality due to the COVID-19 pandemic was 120.3 deaths (113.1-129.3) per 100,000 of the population for all ages. So far, many of the potentially fatal mechanisms of COVID-19 have been reported. In this manuscript, we analyzed the available data on the causes of deaths from COVID-19. This analysis suggests that the primary attributable cause of death from COVID-19 is multiple organ failure resulting from numerous pathological mechanisms, including genetic predisposition to the severe inflammatory response. Increased inflammatory response affects the lungs locally as well as systemic thrombotic microangiopathy. It seems that many comorbidities associated with an increased mortality rate among patients with COVID-19 per se predispose them to an increased risk of thrombotic changes. Furthermore, the role of inflammation in the lungs and the changes that lead to hypoxia cannot be overlooked. However, the thrombotic changes in microcirculation seem to be the most dominant.