Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: A novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis

Abstract

Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy. In this paper, we present an immunothrombosis model of COVID-19. We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients.

COVID-19 and Sex-/Gender-Specific Differences: Understanding the Discrimination

“…63,66 SARS-CoV-2 decreases ACE2 levels, leading to accumulation of angiotensin II, aldosterone, and ACE, shifting the hemostatic balance toward a hypercoagulable and hypofibrinolytic state, further characterized by decreased tissue plasminogen activator (tPA) to plasminogen activator inhibitor-1 (PAI-1) ratio. 3 Angiotensin II directly increases PAI-1 expression from endothelial cells and from adipocytes. 3 Aldosterone increases ACE expression, which increases bradykinin breakdown, inhibiting bradykinin-mediated increase in tPA.…”

“…3 Angiotensin II directly increases PAI-1 expression from endothelial cells and from adipocytes. 3 Aldosterone increases ACE expression, which increases bradykinin breakdown, inhibiting bradykinin-mediated increase in tPA. 3 Thus, high baseline ACE2 levels could be protective, as they may mitigate the procoagulant effects of angiotensin II, aldosterone, and ACE, and in doing so attenuate the risk of severe COVID-19.…”

“…3 Aldosterone increases ACE expression, which increases bradykinin breakdown, inhibiting bradykinin-mediated increase in tPA. 3 Thus, high baseline ACE2 levels could be protective, as they may mitigate the procoagulant effects of angiotensin II, aldosterone, and ACE, and in doing so attenuate the risk of severe COVID-19. This is supported by previous studies which demonstrated that recombinant ACE2 can rapidly decrease angiotensin II and IL-6 levels, 67 and can reduce the viral load of SARS-CoV-2.…”

Intracerebral hemorrhage in COVID-19 patients with pulmonary failure – a propensity score matched registry study

“…(25-27) A local reaction such as a virus associated endothelitis or a systemic in ammation might also trigger these prothrombotic events. (2,28) Limitations:…”

“…Several studies point out a state of hypercoagulability occurring in coronavirus disease 2019 (COVID- 19) probably due to in ammatory changes comparable to disseminated intravascular coagulopathy. (1,2) Additionally, clinical and pathohistological reports about micro-and macrothrombosis as typical complications in critically ill COVID-19 patients emphasize the need for adjusted thromboprophylaxis treatment. (3)(4)(5) Until today, there is no concrete evidence to manage thromboprophylaxis beyond standard indications.…”