COVID‐19 hypothesis: Activated protein C for therapy of virus‐induced pathologic thromboinflammation

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.

Large-Scale Multi-omic Analysis of COVID-19 Severity

“…THBD is normally tethered to the surface of endothelial cells, where it forms a complex with thrombin that efficiently activates PROC to APC ( Ikezoe, 2015 ). APC also serves to modulate inflammatory response, and administration of recombinant APC mutant has been proposed as a therapy to mitigate thrombo-inflammation, which occurs with ARDS and in severe COVID-19 patients ( Griffin and Lyden, 2020 ).…”

Large-scale Multi-omic Analysis of COVID-19 Severity

“…THBD is normally tethered to the surface of endothelial cells, where it forms a complex with thrombin that efficiently activates PROC to APC ( Ikezoe, 2015 ). APC also serves to modulate inflammatory response, and administration of recombinant APC mutant has been proposed as a therapy to mitigate thromboinflammation which occurs with ARDS and in severe COVID-19 patients ( Griffin and Lyden, 2020 ).…”

“…Anticoagulation strategies in non-COVID-19 critical illness have been extensively discussed, but no treatment has yet been identified. Evidence suggests that heparinization in COVID-19 patients may be beneficial ( Cattaneo et al, 2020 ), and mutant APC is another proposed therapeutic for the thrombo-inflammation of COVID-19 ( Griffin and Lyden, 2020 ). Our data offer several additional candidate therapeutics.…”

Stroke, Research and Science in the Time of COVID

“… 9 Knowing the central role played by the PAR (protease activated receptor) in mediating neuroinflammatory toxicity, we proposed a speculative hypothesis that therapy targeting PARs may prove useful in managing a variety of SARS-Cov-2 complications. 10 …”