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LitCovid-PD-FMA-UBERON

LitCovid-PD-UBERON

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T45","span":{"begin":2145,"end":2149},"obj":"Body_part"},{"id":"T46","span":{"begin":2157,"end":2164},"obj":"Body_part"},{"id":"T47","span":{"begin":3590,"end":3594},"obj":"Body_part"},{"id":"T48","span":{"begin":4030,"end":4045},"obj":"Body_part"},{"id":"T49","span":{"begin":4039,"end":4045},"obj":"Body_part"},{"id":"T50","span":{"begin":5351,"end":5355},"obj":"Body_part"},{"id":"T51","span":{"begin":5641,"end":5647},"obj":"Body_part"},{"id":"T52","span":{"begin":6845,"end":6849},"obj":"Body_part"},{"id":"T53","span":{"begin":7419,"end":7425},"obj":"Body_part"},{"id":"T54","span":{"begin":7513,"end":7519},"obj":"Body_part"}],"attributes":[{"id":"A45","pred":"uberon_id","subj":"T45","obj":"http://purl.obolibrary.org/obo/UBERON_0000025"},{"id":"A46","pred":"uberon_id","subj":"T46","obj":"http://purl.obolibrary.org/obo/UBERON_0000945"},{"id":"A47","pred":"uberon_id","subj":"T47","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A48","pred":"uberon_id","subj":"T48","obj":"http://purl.obolibrary.org/obo/UBERON_0004449"},{"id":"A49","pred":"uberon_id","subj":"T49","obj":"http://purl.obolibrary.org/obo/UBERON_0001637"},{"id":"A50","pred":"uberon_id","subj":"T50","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A51","pred":"uberon_id","subj":"T51","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"},{"id":"A52","pred":"uberon_id","subj":"T52","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A53","pred":"uberon_id","subj":"T53","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"},{"id":"A54","pred":"uberon_id","subj":"T54","obj":"http://purl.obolibrary.org/obo/UBERON_0000479"}],"text":"The potential of targeting coagulation in COVID-19\nAs previously highlighted, severe COVID-19 is associated with overwhelming clinical complications of coagulation activation. A retrospective study of 107 patients who had received at least 1 month of anticoagulation therapy prior to SARS-COV-2 infection demonstrated that none developed clinically relevant thrombotic complications [97]. Prophylactic dose heparin is therefore recommended for all patients admitted to hospital with COVID-19 [98]. The enhanced inhibition of thrombin with higher doses of LMWH may further benefit patients by subsequently reducing the downstream signalling involved in inflammation, although the bleeding risk would need to be carefully considered. Clinical trials of low dose versus full dose LMWH are currently underway (NCT04372589, NCT04401293, NCT04367831, NCT04345848, NCT04373707, NCT04366960, NCT04359277 and NCT04397510) and will inform the future clinical management of COVID-19. However, in the context of diseases with a profound inflammatory response and potential lower levels of AT such as COVID-19 [8, 70], LMWH may not be effective. Indeed, anecdotal observations from clinicians caring for patients with COVID-19 report that patients continue to develop clinically identifiable clots, despite receiving prophylactic doses of LMWH, and that higher doses of heparin are needed according to factor Xa analysis, especially in patients with significantly elevated levels of D-dimer [98]. This suggests that it may be important to target coagulation proteinases that do not rely on the presence of circulating endogenous anticoagulants. In this context, some reports suggest that bivalirudin may improve haemofilter and extracorporeal membrane oxygenation filter survival [99, 100].\nDirect oral anticoagulants that specifically inhibit thrombin and factor Xa are now available. These agents would not be suitable for all patients, particularly if drug interactions with potential antiviral medication are expected, or in mechanically ventilated patients requiring enteral feeding. Although rivaroxaban and apixaban can be delivered via a nasogastric tube to the stomach, they should not be mixed with enteral nutrition [101]. As with LMWH there is an increased risk of bleeding with direct oral anticoagulants but in COVID-19, complications related to bleeding are anecdotally not commonly seen, but a recent study has suggested an increased risk of bleeding in non-critically ill patients receiving heparin [102]. Hence the risk of bleeding complications may be lower for patients at increased risk of death with COVID-19 compared to other causes of severe sepsis/ARDS. Furthermore, idarucizumab and andexanet alfa are now available for the reversal of dabigatran and rivaroxaban/apixaban, respectively, mitigating the fear that the effects of these agents cannot be reversed should bleeding occur.\nAPC showed beneficial effects in the PROWESS study, particularly in the subgroup of patients with CAP and a high risk of death. Heterogeneity within patient populations has hampered previous studies of APC; any future trials in COVID-19 will need patients to be carefully sub-phenotyped because the benefit in COVID-19 will likely be seen in those at high risk of death with low endogenous levels of APC. Nebulised streptokinase has shown reduced mortality in one study of ARDS patients [79] and fibrinolysis is currently being targeted in COVID-19 with trials of nebulised and systemically administered tPA; these trials are welcomed and have the potential to reduce pulmonary microthrombi and lung injury.\nTargeting PAR1 is another potential attractive approach that could counter the negative effects of both thrombin formation and activation of pro-inflammatory pathways by the coagulation system. Although PAR1 antagonists are unlikely to impact on VTE they could have beneficial effects in COVID-19 pneumonia through several potential mechanisms: 1) direct anti-platelet effect potentially reducing the incidence of coronary and cerebral artery thrombosis [103]; 2) inhibition of inflammatory signalling pathways downstream of thrombin resulting in attenuated inflammatory responses and inflammatory cell recruitment; 3) protection from the development of post-ARDS pulmonary fibrosis [104]; 4) maintaining integrity of the endothelial alveolar barrier, reducing pulmonary oedema; and 5) indirectly attenuating coagulation activation by reducing inflammation. Several PAR1 antagonists are in development but only one has been clinically approved, vorapaxar (Zontivity). Vorapaxar is a highly selective small molecule PAR1 antagonist but its long half-life (20 h) and inhibitory effects on platelets (24–48 h) [105, 106] call for cautious use in critically ill patients, particularly because a reversal agent does not exist. Trials in the secondary prevention of acute coronary syndromes have shown that there is also potential for bleeding, although in these trials patients were on dual anti-platelet medication. PAR1 antagonism could therefore represent a potential approach to halt progression of the disease in hospitalised patients at risk of critical illness. Future research and carefully designed trials in this area would be welcomed. Table 1 provides a summary of the effects of therapeutics targeting coagulation proteinases in pneumonia, lung injury and sepsis in preclinical and clinical studies.\nTABLE 1 Effects of endogenous anticoagulants or drugs targeting coagulation proteases: evidence from preclinical and clinical studies\nPathway Agent Animal study outcomes Clinical study outcomes Recruiting COVID-19 trials\nTissue factor TFPI Coagulation activation Reduced [42, 107, 108] Coagulation activation Reduced [37, 109]\nInflammation Reduced [36, 110, 111]No effect [108, 112] Inflammation Reduced [37]No effect [109]\nBacterial clearance Increased [110] Mortality Reduced [40]#No effect [37, 39, 41]¶,+\nRisk of bleeding Increased [37, 39]§\nFactor X RivaroxabanApixabanƒ Inflammation Reduced [113] NCT04416048NCT04394377NCT04351724\nAlveolar leak Reduced [113]\nThrombin Anti-thrombinDabigatranƒBivalirudinƒ Coagulation activation Reduced [46] Mortality No effect [45, 47]Reduced mortality in subgroup not receiving concomitant heparin [47]\nInflammation Reduced [42, 46] Risk of bleeding Increased [47]§\nAlveolar leak Reduced [42, 46]\nBacterial clearance Increased [46]\nHeparin Coagulation activation Reduced [46]No effect [42] Mortality No effect [51–53, 79] NCT04372589NCT04401293NCT04367831NCT04345848NCT04373707NCT04366960NCT04359277NCT04397510\nInflammation No effect [42, 46]\nAlveolar leak No effect [42, 46]\nBacterial clearance No effect [42, 46]\nAPC rhAPC Coagulation activation Reduced [46, 60] Coagulation activation Reduced [63]\nInflammation Reduced [61]No effect [60] Lung injury score Reduced [63]\nAlveolar leak Reduced [61] Mortality Reduced [22]No effect [55, 65–67]\nFibrosis Reduced [61]\nBacterial clearance No effect [61]\nFibrinogen tPAuPA Coagulation activation No effect [74] Mortality Reduced [79] NCT04356833NCT04357730\nInflammation Reduced [78]No effect [74, 76]\nAlveolar leak Reduced [76, 78]No effect [74]\nFibrinolysis Increased [74, 78]\nPAR-1 VorapaxarRWJ-58269 Coagulation activation Reduced [114]\nInflammation Reduced [94, 115]\nAlveolar leak Reduced [94, 115]\nBacterial clearance No effect [94, 115]\nTFPI: 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."}

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PubTator

LitCovid-PD-GO-BP

MyTest

{"project":"MyTest","denotations":[{"id":"33004529-32407672-29393064","span":{"begin":493,"end":495},"obj":"32407672"},{"id":"33004529-32073213-29393065","span":{"begin":1098,"end":1099},"obj":"32073213"},{"id":"33004529-32302438-29393066","span":{"begin":1101,"end":1103},"obj":"32302438"},{"id":"33004529-32407672-29393067","span":{"begin":1479,"end":1481},"obj":"32407672"},{"id":"33004529-20973685-29393068","span":{"begin":1772,"end":1775},"obj":"20973685"},{"id":"33004529-31262641-29393069","span":{"begin":3383,"end":3385},"obj":"31262641"},{"id":"33004529-22443427-29393070","span":{"begin":4058,"end":4061},"obj":"22443427"},{"id":"33004529-15855637-29393071","span":{"begin":4287,"end":4290},"obj":"15855637"},{"id":"33004529-19286091-29393072","span":{"begin":4711,"end":4714},"obj":"19286091"},{"id":"33004529-22742648-29393073","span":{"begin":4716,"end":4719},"obj":"22742648"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"The potential of targeting coagulation in COVID-19\nAs previously highlighted, severe COVID-19 is associated with overwhelming clinical complications of coagulation activation. A retrospective study of 107 patients who had received at least 1 month of anticoagulation therapy prior to SARS-COV-2 infection demonstrated that none developed clinically relevant thrombotic complications [97]. Prophylactic dose heparin is therefore recommended for all patients admitted to hospital with COVID-19 [98]. The enhanced inhibition of thrombin with higher doses of LMWH may further benefit patients by subsequently reducing the downstream signalling involved in inflammation, although the bleeding risk would need to be carefully considered. Clinical trials of low dose versus full dose LMWH are currently underway (NCT04372589, NCT04401293, NCT04367831, NCT04345848, NCT04373707, NCT04366960, NCT04359277 and NCT04397510) and will inform the future clinical management of COVID-19. However, in the context of diseases with a profound inflammatory response and potential lower levels of AT such as COVID-19 [8, 70], LMWH may not be effective. Indeed, anecdotal observations from clinicians caring for patients with COVID-19 report that patients continue to develop clinically identifiable clots, despite receiving prophylactic doses of LMWH, and that higher doses of heparin are needed according to factor Xa analysis, especially in patients with significantly elevated levels of D-dimer [98]. This suggests that it may be important to target coagulation proteinases that do not rely on the presence of circulating endogenous anticoagulants. In this context, some reports suggest that bivalirudin may improve haemofilter and extracorporeal membrane oxygenation filter survival [99, 100].\nDirect oral anticoagulants that specifically inhibit thrombin and factor Xa are now available. These agents would not be suitable for all patients, particularly if drug interactions with potential antiviral medication are expected, or in mechanically ventilated patients requiring enteral feeding. Although rivaroxaban and apixaban can be delivered via a nasogastric tube to the stomach, they should not be mixed with enteral nutrition [101]. As with LMWH there is an increased risk of bleeding with direct oral anticoagulants but in COVID-19, complications related to bleeding are anecdotally not commonly seen, but a recent study has suggested an increased risk of bleeding in non-critically ill patients receiving heparin [102]. Hence the risk of bleeding complications may be lower for patients at increased risk of death with COVID-19 compared to other causes of severe sepsis/ARDS. Furthermore, idarucizumab and andexanet alfa are now available for the reversal of dabigatran and rivaroxaban/apixaban, respectively, mitigating the fear that the effects of these agents cannot be reversed should bleeding occur.\nAPC showed beneficial effects in the PROWESS study, particularly in the subgroup of patients with CAP and a high risk of death. Heterogeneity within patient populations has hampered previous studies of APC; any future trials in COVID-19 will need patients to be carefully sub-phenotyped because the benefit in COVID-19 will likely be seen in those at high risk of death with low endogenous levels of APC. Nebulised streptokinase has shown reduced mortality in one study of ARDS patients [79] and fibrinolysis is currently being targeted in COVID-19 with trials of nebulised and systemically administered tPA; these trials are welcomed and have the potential to reduce pulmonary microthrombi and lung injury.\nTargeting PAR1 is another potential attractive approach that could counter the negative effects of both thrombin formation and activation of pro-inflammatory pathways by the coagulation system. Although PAR1 antagonists are unlikely to impact on VTE they could have beneficial effects in COVID-19 pneumonia through several potential mechanisms: 1) direct anti-platelet effect potentially reducing the incidence of coronary and cerebral artery thrombosis [103]; 2) inhibition of inflammatory signalling pathways downstream of thrombin resulting in attenuated inflammatory responses and inflammatory cell recruitment; 3) protection from the development of post-ARDS pulmonary fibrosis [104]; 4) maintaining integrity of the endothelial alveolar barrier, reducing pulmonary oedema; and 5) indirectly attenuating coagulation activation by reducing inflammation. Several PAR1 antagonists are in development but only one has been clinically approved, vorapaxar (Zontivity). Vorapaxar is a highly selective small molecule PAR1 antagonist but its long half-life (20 h) and inhibitory effects on platelets (24–48 h) [105, 106] call for cautious use in critically ill patients, particularly because a reversal agent does not exist. Trials in the secondary prevention of acute coronary syndromes have shown that there is also potential for bleeding, although in these trials patients were on dual anti-platelet medication. PAR1 antagonism could therefore represent a potential approach to halt progression of the disease in hospitalised patients at risk of critical illness. Future research and carefully designed trials in this area would be welcomed. Table 1 provides a summary of the effects of therapeutics targeting coagulation proteinases in pneumonia, lung injury and sepsis in preclinical and clinical studies.\nTABLE 1 Effects of endogenous anticoagulants or drugs targeting coagulation proteases: evidence from preclinical and clinical studies\nPathway Agent Animal study outcomes Clinical study outcomes Recruiting COVID-19 trials\nTissue factor TFPI Coagulation activation Reduced [42, 107, 108] Coagulation activation Reduced [37, 109]\nInflammation Reduced [36, 110, 111]No effect [108, 112] Inflammation Reduced [37]No effect [109]\nBacterial clearance Increased [110] Mortality Reduced [40]#No effect [37, 39, 41]¶,+\nRisk of bleeding Increased [37, 39]§\nFactor X RivaroxabanApixabanƒ Inflammation Reduced [113] NCT04416048NCT04394377NCT04351724\nAlveolar leak Reduced [113]\nThrombin Anti-thrombinDabigatranƒBivalirudinƒ Coagulation activation Reduced [46] Mortality No effect [45, 47]Reduced mortality in subgroup not receiving concomitant heparin [47]\nInflammation Reduced [42, 46] Risk of bleeding Increased [47]§\nAlveolar leak Reduced [42, 46]\nBacterial clearance Increased [46]\nHeparin Coagulation activation Reduced [46]No effect [42] Mortality No effect [51–53, 79] NCT04372589NCT04401293NCT04367831NCT04345848NCT04373707NCT04366960NCT04359277NCT04397510\nInflammation No effect [42, 46]\nAlveolar leak No effect [42, 46]\nBacterial clearance No effect [42, 46]\nAPC rhAPC Coagulation activation Reduced [46, 60] Coagulation activation Reduced [63]\nInflammation Reduced [61]No effect [60] Lung injury score Reduced [63]\nAlveolar leak Reduced [61] Mortality Reduced [22]No effect [55, 65–67]\nFibrosis Reduced [61]\nBacterial clearance No effect [61]\nFibrinogen tPAuPA Coagulation activation No effect [74] Mortality Reduced [79] NCT04356833NCT04357730\nInflammation Reduced [78]No effect [74, 76]\nAlveolar leak Reduced [76, 78]No effect [74]\nFibrinolysis Increased [74, 78]\nPAR-1 VorapaxarRWJ-58269 Coagulation activation Reduced [114]\nInflammation Reduced [94, 115]\nAlveolar leak Reduced [94, 115]\nBacterial clearance No effect [94, 115]\nTFPI: 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."}

LitCovid-PD-HP

{"project":"LitCovid-PD-HP","denotations":[{"id":"T94","span":{"begin":2653,"end":2659},"obj":"Phenotype"},{"id":"T95","span":{"begin":3900,"end":3909},"obj":"Phenotype"},{"id":"T96","span":{"begin":4039,"end":4056},"obj":"Phenotype"},{"id":"T97","span":{"begin":4267,"end":4285},"obj":"Phenotype"},{"id":"T98","span":{"begin":4364,"end":4380},"obj":"Phenotype"},{"id":"T99","span":{"begin":5340,"end":5349},"obj":"Phenotype"},{"id":"T100","span":{"begin":5367,"end":5373},"obj":"Phenotype"},{"id":"T101","span":{"begin":7710,"end":7719},"obj":"Phenotype"}],"attributes":[{"id":"A94","pred":"hp_id","subj":"T94","obj":"http://purl.obolibrary.org/obo/HP_0100806"},{"id":"A95","pred":"hp_id","subj":"T95","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A96","pred":"hp_id","subj":"T96","obj":"http://purl.obolibrary.org/obo/HP_0004420"},{"id":"A97","pred":"hp_id","subj":"T97","obj":"http://purl.obolibrary.org/obo/HP_0002206"},{"id":"A98","pred":"hp_id","subj":"T98","obj":"http://purl.obolibrary.org/obo/HP_0100598"},{"id":"A99","pred":"hp_id","subj":"T99","obj":"http://purl.obolibrary.org/obo/HP_0002090"},{"id":"A100","pred":"hp_id","subj":"T100","obj":"http://purl.obolibrary.org/obo/HP_0100806"},{"id":"A101","pred":"hp_id","subj":"T101","obj":"http://purl.obolibrary.org/obo/HP_0002090"}],"text":"The potential of targeting coagulation in COVID-19\nAs previously highlighted, severe COVID-19 is associated with overwhelming clinical complications of coagulation activation. A retrospective study of 107 patients who had received at least 1 month of anticoagulation therapy prior to SARS-COV-2 infection demonstrated that none developed clinically relevant thrombotic complications [97]. Prophylactic dose heparin is therefore recommended for all patients admitted to hospital with COVID-19 [98]. The enhanced inhibition of thrombin with higher doses of LMWH may further benefit patients by subsequently reducing the downstream signalling involved in inflammation, although the bleeding risk would need to be carefully considered. Clinical trials of low dose versus full dose LMWH are currently underway (NCT04372589, NCT04401293, NCT04367831, NCT04345848, NCT04373707, NCT04366960, NCT04359277 and NCT04397510) and will inform the future clinical management of COVID-19. However, in the context of diseases with a profound inflammatory response and potential lower levels of AT such as COVID-19 [8, 70], LMWH may not be effective. Indeed, anecdotal observations from clinicians caring for patients with COVID-19 report that patients continue to develop clinically identifiable clots, despite receiving prophylactic doses of LMWH, and that higher doses of heparin are needed according to factor Xa analysis, especially in patients with significantly elevated levels of D-dimer [98]. This suggests that it may be important to target coagulation proteinases that do not rely on the presence of circulating endogenous anticoagulants. In this context, some reports suggest that bivalirudin may improve haemofilter and extracorporeal membrane oxygenation filter survival [99, 100].\nDirect oral anticoagulants that specifically inhibit thrombin and factor Xa are now available. These agents would not be suitable for all patients, particularly if drug interactions with potential antiviral medication are expected, or in mechanically ventilated patients requiring enteral feeding. Although rivaroxaban and apixaban can be delivered via a nasogastric tube to the stomach, they should not be mixed with enteral nutrition [101]. As with LMWH there is an increased risk of bleeding with direct oral anticoagulants but in COVID-19, complications related to bleeding are anecdotally not commonly seen, but a recent study has suggested an increased risk of bleeding in non-critically ill patients receiving heparin [102]. Hence the risk of bleeding complications may be lower for patients at increased risk of death with COVID-19 compared to other causes of severe sepsis/ARDS. Furthermore, idarucizumab and andexanet alfa are now available for the reversal of dabigatran and rivaroxaban/apixaban, respectively, mitigating the fear that the effects of these agents cannot be reversed should bleeding occur.\nAPC showed beneficial effects in the PROWESS study, particularly in the subgroup of patients with CAP and a high risk of death. Heterogeneity within patient populations has hampered previous studies of APC; any future trials in COVID-19 will need patients to be carefully sub-phenotyped because the benefit in COVID-19 will likely be seen in those at high risk of death with low endogenous levels of APC. Nebulised streptokinase has shown reduced mortality in one study of ARDS patients [79] and fibrinolysis is currently being targeted in COVID-19 with trials of nebulised and systemically administered tPA; these trials are welcomed and have the potential to reduce pulmonary microthrombi and lung injury.\nTargeting PAR1 is another potential attractive approach that could counter the negative effects of both thrombin formation and activation of pro-inflammatory pathways by the coagulation system. Although PAR1 antagonists are unlikely to impact on VTE they could have beneficial effects in COVID-19 pneumonia through several potential mechanisms: 1) direct anti-platelet effect potentially reducing the incidence of coronary and cerebral artery thrombosis [103]; 2) inhibition of inflammatory signalling pathways downstream of thrombin resulting in attenuated inflammatory responses and inflammatory cell recruitment; 3) protection from the development of post-ARDS pulmonary fibrosis [104]; 4) maintaining integrity of the endothelial alveolar barrier, reducing pulmonary oedema; and 5) indirectly attenuating coagulation activation by reducing inflammation. Several PAR1 antagonists are in development but only one has been clinically approved, vorapaxar (Zontivity). Vorapaxar is a highly selective small molecule PAR1 antagonist but its long half-life (20 h) and inhibitory effects on platelets (24–48 h) [105, 106] call for cautious use in critically ill patients, particularly because a reversal agent does not exist. Trials in the secondary prevention of acute coronary syndromes have shown that there is also potential for bleeding, although in these trials patients were on dual anti-platelet medication. PAR1 antagonism could therefore represent a potential approach to halt progression of the disease in hospitalised patients at risk of critical illness. Future research and carefully designed trials in this area would be welcomed. Table 1 provides a summary of the effects of therapeutics targeting coagulation proteinases in pneumonia, lung injury and sepsis in preclinical and clinical studies.\nTABLE 1 Effects of endogenous anticoagulants or drugs targeting coagulation proteases: evidence from preclinical and clinical studies\nPathway Agent Animal study outcomes Clinical study outcomes Recruiting COVID-19 trials\nTissue factor TFPI Coagulation activation Reduced [42, 107, 108] Coagulation activation Reduced [37, 109]\nInflammation Reduced [36, 110, 111]No effect [108, 112] Inflammation Reduced [37]No effect [109]\nBacterial clearance Increased [110] Mortality Reduced [40]#No effect [37, 39, 41]¶,+\nRisk of bleeding Increased [37, 39]§\nFactor X RivaroxabanApixabanƒ Inflammation Reduced [113] NCT04416048NCT04394377NCT04351724\nAlveolar leak Reduced [113]\nThrombin Anti-thrombinDabigatranƒBivalirudinƒ Coagulation activation Reduced [46] Mortality No effect [45, 47]Reduced mortality in subgroup not receiving concomitant heparin [47]\nInflammation Reduced [42, 46] Risk of bleeding Increased [47]§\nAlveolar leak Reduced [42, 46]\nBacterial clearance Increased [46]\nHeparin Coagulation activation Reduced [46]No effect [42] Mortality No effect [51–53, 79] NCT04372589NCT04401293NCT04367831NCT04345848NCT04373707NCT04366960NCT04359277NCT04397510\nInflammation No effect [42, 46]\nAlveolar leak No effect [42, 46]\nBacterial clearance No effect [42, 46]\nAPC rhAPC Coagulation activation Reduced [46, 60] Coagulation activation Reduced [63]\nInflammation Reduced [61]No effect [60] Lung injury score Reduced [63]\nAlveolar leak Reduced [61] Mortality Reduced [22]No effect [55, 65–67]\nFibrosis Reduced [61]\nBacterial clearance No effect [61]\nFibrinogen tPAuPA Coagulation activation No effect [74] Mortality Reduced [79] NCT04356833NCT04357730\nInflammation Reduced [78]No effect [74, 76]\nAlveolar leak Reduced [76, 78]No effect [74]\nFibrinolysis Increased [74, 78]\nPAR-1 VorapaxarRWJ-58269 Coagulation activation Reduced [114]\nInflammation Reduced [94, 115]\nAlveolar leak Reduced [94, 115]\nBacterial clearance No effect [94, 115]\nTFPI: 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."}

2_test

{"project":"2_test","denotations":[{"id":"33004529-32407672-29393064","span":{"begin":493,"end":495},"obj":"32407672"},{"id":"33004529-32073213-29393065","span":{"begin":1098,"end":1099},"obj":"32073213"},{"id":"33004529-32302438-29393066","span":{"begin":1101,"end":1103},"obj":"32302438"},{"id":"33004529-32407672-29393067","span":{"begin":1479,"end":1481},"obj":"32407672"},{"id":"33004529-20973685-29393068","span":{"begin":1772,"end":1775},"obj":"20973685"},{"id":"33004529-31262641-29393069","span":{"begin":3383,"end":3385},"obj":"31262641"},{"id":"33004529-22443427-29393070","span":{"begin":4058,"end":4061},"obj":"22443427"},{"id":"33004529-15855637-29393071","span":{"begin":4287,"end":4290},"obj":"15855637"},{"id":"33004529-19286091-29393072","span":{"begin":4711,"end":4714},"obj":"19286091"},{"id":"33004529-22742648-29393073","span":{"begin":4716,"end":4719},"obj":"22742648"}],"text":"The potential of targeting coagulation in COVID-19\nAs previously highlighted, severe COVID-19 is associated with overwhelming clinical complications of coagulation activation. A retrospective study of 107 patients who had received at least 1 month of anticoagulation therapy prior to SARS-COV-2 infection demonstrated that none developed clinically relevant thrombotic complications [97]. Prophylactic dose heparin is therefore recommended for all patients admitted to hospital with COVID-19 [98]. The enhanced inhibition of thrombin with higher doses of LMWH may further benefit patients by subsequently reducing the downstream signalling involved in inflammation, although the bleeding risk would need to be carefully considered. Clinical trials of low dose versus full dose LMWH are currently underway (NCT04372589, NCT04401293, NCT04367831, NCT04345848, NCT04373707, NCT04366960, NCT04359277 and NCT04397510) and will inform the future clinical management of COVID-19. However, in the context of diseases with a profound inflammatory response and potential lower levels of AT such as COVID-19 [8, 70], LMWH may not be effective. Indeed, anecdotal observations from clinicians caring for patients with COVID-19 report that patients continue to develop clinically identifiable clots, despite receiving prophylactic doses of LMWH, and that higher doses of heparin are needed according to factor Xa analysis, especially in patients with significantly elevated levels of D-dimer [98]. This suggests that it may be important to target coagulation proteinases that do not rely on the presence of circulating endogenous anticoagulants. In this context, some reports suggest that bivalirudin may improve haemofilter and extracorporeal membrane oxygenation filter survival [99, 100].\nDirect oral anticoagulants that specifically inhibit thrombin and factor Xa are now available. These agents would not be suitable for all patients, particularly if drug interactions with potential antiviral medication are expected, or in mechanically ventilated patients requiring enteral feeding. Although rivaroxaban and apixaban can be delivered via a nasogastric tube to the stomach, they should not be mixed with enteral nutrition [101]. As with LMWH there is an increased risk of bleeding with direct oral anticoagulants but in COVID-19, complications related to bleeding are anecdotally not commonly seen, but a recent study has suggested an increased risk of bleeding in non-critically ill patients receiving heparin [102]. Hence the risk of bleeding complications may be lower for patients at increased risk of death with COVID-19 compared to other causes of severe sepsis/ARDS. Furthermore, idarucizumab and andexanet alfa are now available for the reversal of dabigatran and rivaroxaban/apixaban, respectively, mitigating the fear that the effects of these agents cannot be reversed should bleeding occur.\nAPC showed beneficial effects in the PROWESS study, particularly in the subgroup of patients with CAP and a high risk of death. Heterogeneity within patient populations has hampered previous studies of APC; any future trials in COVID-19 will need patients to be carefully sub-phenotyped because the benefit in COVID-19 will likely be seen in those at high risk of death with low endogenous levels of APC. Nebulised streptokinase has shown reduced mortality in one study of ARDS patients [79] and fibrinolysis is currently being targeted in COVID-19 with trials of nebulised and systemically administered tPA; these trials are welcomed and have the potential to reduce pulmonary microthrombi and lung injury.\nTargeting PAR1 is another potential attractive approach that could counter the negative effects of both thrombin formation and activation of pro-inflammatory pathways by the coagulation system. Although PAR1 antagonists are unlikely to impact on VTE they could have beneficial effects in COVID-19 pneumonia through several potential mechanisms: 1) direct anti-platelet effect potentially reducing the incidence of coronary and cerebral artery thrombosis [103]; 2) inhibition of inflammatory signalling pathways downstream of thrombin resulting in attenuated inflammatory responses and inflammatory cell recruitment; 3) protection from the development of post-ARDS pulmonary fibrosis [104]; 4) maintaining integrity of the endothelial alveolar barrier, reducing pulmonary oedema; and 5) indirectly attenuating coagulation activation by reducing inflammation. Several PAR1 antagonists are in development but only one has been clinically approved, vorapaxar (Zontivity). Vorapaxar is a highly selective small molecule PAR1 antagonist but its long half-life (20 h) and inhibitory effects on platelets (24–48 h) [105, 106] call for cautious use in critically ill patients, particularly because a reversal agent does not exist. Trials in the secondary prevention of acute coronary syndromes have shown that there is also potential for bleeding, although in these trials patients were on dual anti-platelet medication. PAR1 antagonism could therefore represent a potential approach to halt progression of the disease in hospitalised patients at risk of critical illness. Future research and carefully designed trials in this area would be welcomed. Table 1 provides a summary of the effects of therapeutics targeting coagulation proteinases in pneumonia, lung injury and sepsis in preclinical and clinical studies.\nTABLE 1 Effects of endogenous anticoagulants or drugs targeting coagulation proteases: evidence from preclinical and clinical studies\nPathway Agent Animal study outcomes Clinical study outcomes Recruiting COVID-19 trials\nTissue factor TFPI Coagulation activation Reduced [42, 107, 108] Coagulation activation Reduced [37, 109]\nInflammation Reduced [36, 110, 111]No effect [108, 112] Inflammation Reduced [37]No effect [109]\nBacterial clearance Increased [110] Mortality Reduced [40]#No effect [37, 39, 41]¶,+\nRisk of bleeding Increased [37, 39]§\nFactor X RivaroxabanApixabanƒ Inflammation Reduced [113] NCT04416048NCT04394377NCT04351724\nAlveolar leak Reduced [113]\nThrombin Anti-thrombinDabigatranƒBivalirudinƒ Coagulation activation Reduced [46] Mortality No effect [45, 47]Reduced mortality in subgroup not receiving concomitant heparin [47]\nInflammation Reduced [42, 46] Risk of bleeding Increased [47]§\nAlveolar leak Reduced [42, 46]\nBacterial clearance Increased [46]\nHeparin Coagulation activation Reduced [46]No effect [42] Mortality No effect [51–53, 79] NCT04372589NCT04401293NCT04367831NCT04345848NCT04373707NCT04366960NCT04359277NCT04397510\nInflammation No effect [42, 46]\nAlveolar leak No effect [42, 46]\nBacterial clearance No effect [42, 46]\nAPC rhAPC Coagulation activation Reduced [46, 60] Coagulation activation Reduced [63]\nInflammation Reduced [61]No effect [60] Lung injury score Reduced [63]\nAlveolar leak Reduced [61] Mortality Reduced [22]No effect [55, 65–67]\nFibrosis Reduced [61]\nBacterial clearance No effect [61]\nFibrinogen tPAuPA Coagulation activation No effect [74] Mortality Reduced [79] NCT04356833NCT04357730\nInflammation Reduced [78]No effect [74, 76]\nAlveolar leak Reduced [76, 78]No effect [74]\nFibrinolysis Increased [74, 78]\nPAR-1 VorapaxarRWJ-58269 Coagulation activation Reduced [114]\nInflammation Reduced [94, 115]\nAlveolar leak Reduced [94, 115]\nBacterial clearance No effect [94, 115]\nTFPI: 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."}

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