Table 2.

Protein C Variants and Pathway Modulators

Drug	Mechanism of Action	Phase of Development	Reported BleedingRisk	Rationale for COVID-19
Recombinant thrombomodulin	Binds to thrombin and enhances proteinC activation	Approved in Japan since 2008	No increased bleeding in 3 randomized controlled trials, which included over 1600 patients	Its anticoagulant actions are thrombin dependent so patients with the most thrombin generation will have the most proteinC activation
		Has been studied in both phase II and phase III trials in septic patients with disseminated intravascular coagulation		COVID-19 patients have increased factorVIII activity and increased proinflammatory signaling from endothelial cells, which it can counteract
3K3A-APC	Induces biased protease-activated receptor 1 anti-inflammatory signaling in endothelial cells	Phase II randomized controlled trial completed in ischemic stroke patients	Less hemorrhagic stroke conversion in treated patients than in placebo control group	Biased anti-inflammatory signaling can be induced in endothelial cells
	Minimal anticoagulant activity			If anticoagulant actions are desired in patients with hypercoagulability 3K3A-APC can be combined with low molecular weight heparin or unfractionated heparin

Abbreviation: COVID-19, coronavirus disease 2019.