TABLE 1

Effects of endogenous anticoagulants or drugs targeting coagulation proteases: evidence from preclinical and clinical studies

Pathway	Agent	Animal study outcomes		Clinical study outcomes		Recruiting COVID-19 trials
Tissue factor	TFPI	Coagulation activation	Reduced [42, 107, 108]	Coagulation activation	Reduced [37, 109]
		Inflammation	Reduced [36, 110, 111] No effect [108, 112]	Inflammation	Reduced [37] No effect [109]
		Bacterial clearance	Increased [110]	Mortality	Reduced [40]^# No effect [37, 39, 41]^¶,+
				Risk of bleeding	Increased [37, 39]^§
Factor X	Rivaroxaban Apixaban^ƒ	Inflammation	Reduced [113]			NCT04416048 NCT04394377 NCT04351724
Factor X	Rivaroxaban Apixaban^ƒ	Alveolar leak	Reduced [113]			NCT04416048 NCT04394377 NCT04351724
Thrombin	Anti-thrombin Dabigatran^ƒ Bivalirudin^ƒ	Coagulation activation	Reduced [46]	Mortality	No effect [45, 47] Reduced mortality in subgroup not receiving concomitant heparin [47]
		Inflammation	Reduced [42, 46]	Risk of bleeding	Increased [47]^§
		Alveolar leak	Reduced [42, 46]
		Bacterial clearance	Increased [46]
	Heparin	Coagulation activation	Reduced [46] No effect [42]	Mortality	No effect [51–53, 79]	NCT04372589 NCT04401293 NCT04367831 NCT04345848 NCT04373707 NCT04366960 NCT04359277 NCT04397510
		Inflammation	No effect [42, 46]
		Alveolar leak	No effect [42, 46]
		Bacterial clearance	No effect [42, 46]
APC	rhAPC	Coagulation activation	Reduced [46, 60]	Coagulation activation	Reduced [63]
		Inflammation	Reduced [61] No effect [60]	Lung injury score	Reduced [63]
		Alveolar leak	Reduced [61]	Mortality	Reduced [22] No effect [55, 65–67]
		Fibrosis	Reduced [61]
		Bacterial clearance	No effect [61]
Fibrinogen	tPA uPA	Coagulation activation	No effect [74]	Mortality	Reduced [79]	NCT04356833 NCT04357730
		Inflammation	Reduced [78] No effect [74, 76]	Mortality	Reduced [79]
		Alveolar leak	Reduced [76, 78] No effect [74]
		Fibrinolysis	Increased [74, 78]
PAR-1	Vorapaxar RWJ-58269	Coagulation activation	Reduced [114]
		Inflammation	Reduced [94, 115]
		Alveolar leak	Reduced [94, 115]
		Bacterial clearance	No effect [94, 115]

TFPI: tissue factor pathway inhibitor; APC: activated protein C; rhAPC: recombinant human APC; tPA: tissue-type plasminogen activator; uPA: urokinase-type plasminogen activator; PAR-1: proteinase-activated receptor-1. ^#: trend towards reduced mortality in TFPI-treated group of community-acquired pneumonia patients who had not received concomitant heparin and in whom the pathogen was identified [40]; ^¶: trend towards reduced mortality in TFPI group not receiving concomitant heparin [39]; ⁺: trend towards reduced mortality in TFPI group (trial not powered for effect on mortality) [37]; ^§: difference in risk of major bleeding was not significant in those who did not receive concomitant heparin [47]; ^ƒ: no relevant studies were identified using this anticoagulant.