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Published on: May 24, 2024
COVID-19 hypothesis: Activated protein C for therapy of virus-induced pathologic thromboinflammation
John H Griffin1,2, Patrick Lyden3
1Department of Molecular Medicine The Scripps Research Institute La Jolla California USA.
Insights
Activated protein C (APC) may help seriously ill COVID-19 patients by reducing inflammation and blood clotting. A modified APC, 3K3A-APC, with reduced anticoagulant effects, shows promise for clinical trials.
Area of Science:
- Biomedical Research
- Pharmacology
- Critical Care Medicine
Background:
- Critically ill COVID-19 patients often show high levels of inflammatory markers and D-dimer, indicating a risk of mortality.
- Comorbidities linked to vascular dysfunction are common in severe COVID-19 cases.
- Preclinical studies suggest activated protein C (APC) can mitigate excessive inflammation, thrombin generation, and organ damage.
Purpose of the Study:
- To evaluate the potential of activated protein C (APC) and its mutant, 3K3A-APC, for treating severe COVID-19.
- To explore the cell-signaling properties of 3K3A-APC for therapeutic benefit in COVID-19.
Main Methods:
- Review of preclinical data on APC's anti-inflammatory, anti-thrombotic, and organ-protective effects.
- Consideration of Phase 1 and 2 trial data on the safety of 3K3A-APC.
- Speculative analysis based on APC's known mechanisms of action.
Main Results:
- APC demonstrates preclinical efficacy in downregulating inflammation and thrombin generation.
- APC has shown protective effects against ischemia-reperfusion injury and reduced mortality in pneumonia models.
- The 3K3A-APC mutant, with diminished anticoagulant activity but retained cell-signaling actions, has proven safe in human trials.
Conclusions:
- 3K3A-APC's cell-signaling activities offer anti-inflammatory and anti-apoptotic benefits.
- The safety profile and preclinical efficacy suggest 3K3A-APC warrants clinical investigation for severe COVID-19.
- Further clinical trials are proposed for 3K3A-APC in selected critically ill COVID-19 patients.
Abstract:
Seriously ill patients with coronavirus disease 2019 (COVID-19) at risk for death exhibit elevated cytokine and chemokine levels and D-dimer, and they often have comorbidities related to vascular dysfunctions. In preclinical studies, activated protein C (APC) provides negative feedback downregulation of excessive inflammation and thrombin generation, attenuates damage caused by ischemia-reperfusion in many organs including lungs, and reduces death caused by bacterial pneumonia. APC exerts both anticoagulant activities and direct cell-signaling activities. Preclinical studies show that its direct cell-signaling actions mediate anti-inflammatory and anti-apoptotic actions, mortality reduction for pneumonia, and beneficial actions for ischemia-reperfusion injury. The APC mutant 3K3A-APC, which was engineered to have diminished anticoagulant activity while retaining cell-signaling actions, was safe in phase 1 and phase 2 human trials. Because of its broad spectrum of homeostatic effects in preclinical studies, we speculate that 3K3A-APC merits consideration for clinical trial studies in appropriately chosen, seriously ill patients with COVID-19.
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