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Targeting coagulation activation in severeCOVID-19 pneumonia:lessons frombacterial pneumonia and sepsisRicardo J.Jos1,2,Andrew Williams1,Ari Manuel3,Jeremy S.Brown1,4andRachel C.Chambers1Affiliations:1Centre for Inflammation and Tissue Repair,University College London,London,UK.2RespiratoryMedicine,Royal Brompton Hospital,London,UK.3University Hospital Aintree,Liverpool,UK.4Dept of ThoracicMedicine,University College London Hospital,London,UK.Correspondence:Ricardo J.Jos,Centre for Inflammation and Tissue Repair,UCL Respiratory,UniversityCollege London,5 University Street,WC1E 6JF,UK.E-mail:r.joseucl.ac.ukERSpublicationsA large armamentarium of potentially beneficial anticoagulant agents exists,and well-designedrandomised clinical trials are now needed to investigate the wide range of anticoagulant and anti-fibrinolytic therapies to determine the optimal strategy https:/bit.ly/2CI459qCite this article as:Jos RJ,Williams A,Manuel A,et al.Targeting coagulation activation in severeCOVID-19 pneumonia:lessons from bacterial pneumonia and sepsis.Eur Respir Rev 2020;29:200240https:/doi.org/10.1183/16000617.0240-2020.ABSTRACTNovel coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome-coronavirus-2(SARS-CoV-2),has rapidly spread throughout the world,resulting in a pandemic with highmortality.There are no effective treatments for the management of severe COVID-19 and currenttherapeutic trials are focused on antiviral therapy and attenuation of hyper-inflammation with anti-cytokine therapy.Severe COVID-19 pneumonia shares some pathological similarities with severe bacterialpneumonia and sepsis.In particular,it disrupts the haemostatic balance,which results in a procoagulantstate locally in the lungs and systemically.This culminates in the formation of microthrombi,disseminatedintravascular coagulation and multi-organ failure.The deleterious effects of exaggerated inflammatoryresponses and activation of coagulation have been investigated in bacterial pneumonia and sepsis and thereis recognition that although these pathways are important for the host immune response to pathogens,they can lead to bystander tissue injury and are negatively associated with survival.In the past twodecades,evidence from preclinical studies has led to the emergence of potential anticoagulant therapeuticstrategies for the treatment of patients with pneumonia,sepsis and acute respiratory distress syndrome,and some of these anticoagulant approaches have been trialled in humans.Here,we review the evidencefrom preclinical studies and clinical trials of anticoagulant treatment strategies in bacterial pneumonia andsepsis,and discuss the importance of these findings in the context of COVID-19.IntroductionNovel coronavirus disease 2019(COVID-19)first emerged in Wuhan,China,and has rapidly spreadacross the globe.COVID-19 is caused by severe acute respiratory syndrome-coronavirus-2(SARS-CoV-2)and,as of August 7,2020,there have been 19 million reported cases and 700 thousand deaths 1.Theonly treatment thus far to demonstrate a reduction in mortality of severe COVID-19 is dexamethasone 2.The antiviral remdesivir has been shown to reduce hospital length of stay 3.Therefore,identifyingsuccessful therapeutic strategies still remains a major ongoing challenge.Copyright ERS 2020.This article is open access and distributed under the terms of the Creative Commons AttributionNon-Commercial Licence 4.0.Provenance:Submitted article,peer reviewed.Received:26 July 2020|Accepted after revision:20 Aug 2020https:/doi.org/10.1183/16000617.0240-2020Eur Respir Rev 2020;29:200240REVIEWINFECTIOUS DISEASEThe pathogenesis of severe COVID-19 pneumonia has similarities with that of severe bacterial pneumonia,with both causing severe hypoxia that often requires ventilatory support.Both are characterised byextensive inflammatory cell recruitment to the lungs,a potent acute phase reaction and raised levels ofpro-inflammatory cytokines(figure 1)4,5.Severe COVID-19 pneumonia and severe bacterialpneumonia are both associated with widespread activation of the coagulation system,evidenced byelevated activated partial thromboplastin time(APPT)and prothrombin time(PT)and markedly elevatedD-dimer levels,with raised levels of the latter being associated with poor prognosis 69.Evidence ofdisseminated intravascular coagulation is seen frequently in patients at increased risk of death fromCOVID-19 8.In severe COVID-19,the clinical relevance of activation of the coagulation system isevidenced by a high incidence of pulmonary and peripheral venous thromboembolic(VTE)disease,strokeand acute coronary syndromes,even in patients receiving prophylactic heparin 8,10,11.Thedevelopment of microthrombi in lung capillaries 12 may partially explain the profound hypoxia seen insome patients with COVID-19,and similar microthrombi may contribute to renal and cardiacinvolvement.Recent studies suggest that the rapid accumulation of neutrophil extracellular traps in themicrovessels of patients with severe COVID-19 results in occlusion of these vessels and promotesmicrothrombosis 13.Although endothelial dysfunction occurs in bacterial pneumonia and sepsis,it is pronounced inCOVID-19,with SARS-CoV-2 having a direct effect on the endothelium.Post mortem studies have shownevidence of intracellular virus and microangiopathy 12.SARS-CoV-2 uses the angiotensin-convertingenzyme(ACE)-2 receptor to enter the host cells and activates the reninangiotensin system,which caninduce a prothrombotic state 14.Furthermore,the host inflammatory response to the virus promotesactivation of coagulation and reduced fibrinolysis.Older age,low lymphocyte count,prolonged PT andAPPT,and admission to the intensive care unit have been identified as risk factors for thrombosis 15.COVID-19 pneumonia is characterised by increases in multiple cytokines,including tumor necrosis factor(TNF)and interleukin-6(IL-6)16,which are potent activators of the tissue factor(TF)-dependentcoagulation cascade 1719.Activation of the coagulation system is known to be pro-inflammatory andcould drive further increases in inflammation;in tissues with a delicate architecture such as the distal lung,this can be highly detrimental,impairing gas exchange 20 and culminating in acute respiratory distresssyndrome(ARDS)21,22.The extensive activation of coagulation in patients with severe COVID-19could stimulate further inflammation via the mechanisms described below,resulting in a positive feedbackloop that maintains high levels of inflammation for a prolonged period.Hence,effective anticoagulationstrategies may prevent complications associated with aberrant clotting,attenuate coagulation-inducedexaggerated inflammatory responses and potentially reduce the severity and extent of pulmonaryinfiltrates.AsymptomaticMildVirusesPRRSIRSOrgan failureBacteriaDysregulated inflammationBacterial sepsisModerateSevereDeathViral sepsisResolutionFIGURE 1 Similarity in progression of severe viral and bacterial pneumonia.During viral and bacterialinfection,the pathogens are recognised by host pathogen recognition receptors(PRR)on the surface ofepithelial cells,mononuclear phagocytes and other cell types,resulting in initiation of various inflammatorycascades triggering systemic inflammatory response syndrome(SIRS).At this stage patients will have viral/bacterial sepsis with life-threatening organ dysfunction.Most individuals will clear the pathogen(withantimicrobial/antiviral therapy)and the body resolves the inflammation.Others,however,will not be able toclear the pathogen,or despite clearance of the pathogen will continue to exhibit dysregulated inflammatoryresponses that are unabated,resulting in tissue injury and organ failure.Of these patients,some receivingsupportive care will recover and some will die.https:/doi.org/10.1183/16000617.0240-20202INFECTIOUS DISEASE|R.J.JOS ET AL.Although less clinically evident than in COVID-19,severe bacterial pneumonia and sepsis are alsoassociated with activation of coagulation locally in the lungs and systemically,and are associated withbystander tissue injury and correlate negatively with survival 9,23,24.As a consequence,therapies thatmodulate inflammatory responses caused by activation of coagulation have been extensively investigated inbacterial pneumonia and sepsis.Several anticoagulant therapeutic strategies for treating pneumonia,sepsisand ARDS have been identified and some of these anticoagulants have been trialled in humans.The highfrequency of coagulation abnormalities and prolonged inflammation that occurs in severe COVID-19suggests these therapies are attractive potential therapies.Here,we review the evidence from preclinical studies and clinical trials of anticoagulant treatmentstrategies in bacterial pneumonia and sepsis and discuss how these data could be relevant for managingCOVID-19 pneumonia.The data will be discussed in relation to 1)activation of the TFthrombingeneration pathway,2)endogenous anticoagulants and 3)coagulationinflammation crosstalk(figure 2).The TF-dependent pathwayThe TF pathway is the main initiator of procoagulant activity secondary to tissue injury and inflammation,and it plays an important role in pneumonia and ARDS 25,26.TF is a transmembrane glycoproteinexpressed by mononuclear cells,endothelial cells,fibroblasts,vascular smooth muscle cells and alveolarepithelial cells but it can also be detected in extracellular fluids and in cell-derived microparticles shedfrom activated cells 2729.Under normal physiological conditions,TF will only come into contact withblood or circulating coagulation zymogens after vascular injury and disruption of the endothelial barrier30,31.TF binds to and activates coagulation factors VII to VIIa,forming the TF-VIIa complex.Thisinitiates the TF-dependent pathway of coagulation by activating coagulation factor X to Xa and thenbinding factor Xa to form the TF-VIIa-Xa ternary complex.The TF-VIIa-Xa ternary complex convertsprothrombin(factor II)to thrombin(factor IIa),a process that is sustained and increased in efficiency bypositive feedback through activation of coagulation factors V and VIII,which are non-enzymatic cofactorsthat activate factor X 32,33.Thrombin converts fibrinogen to fibrin,the main constituent of clots,and isalso the main physiological activator of proteinase-activated receptor-1(PAR1),the major high-affinitythrombin receptor that promotes multiple downstream cellular responses involved in tissue repair.However,when dysregulated,these cellular responses promote inflammation and lead to disruption of theepithelial and endothelial barriers and the development of fibrosis in multiple organs,including the lung,kidney and liver 34,thereby contributing to disease pathogenesis during severe infections.TF pathway inhibitorsTF and factor VIIa levels are elevated in the bronchoalveolar lavage fluid of patients with severepneumonia,and the central role of TF for initiating coagulation makes it an attractive target fortherapeutic intervention against the potential negative consequences of coagulation activation.Tissuefactor pathway inhibitor(TFPI)is a central endogenous regulator of TF pathway activity and thrombingeneration.This glycoprotein is mainly expressed by endothelial cells and platelets and acts by directlyinhibiting factor Xa.The Xa-TFPI complex subsequently also inhibits the TF-VIIa complex.In preclinicalnon-human primate models of endotoxaemia,blockade of TF-VIIa,using a competitive inhibitor of TF(site-inactivated factor VIIa),inhibits the TF pathway and reduces lung inflammation and deposition offibrin 35,36.A phase II clinical trial of recombinant human TFPI(rhTFPI;Tifacogin)in patients withsevere sepsis decreased concentrations of IL-6,an important pro-inflammatory cytokine that is increasedin COVID-19 pneumonia and a major target in ongoing clinical trials 37,38.However,in the OptimisedPhase III Tifacogin(rTFPI)in Multicenter International Sepsis Trial(OPTIMIST phase III)for patientswith severe sepsis with a high international normalised ratio(1.2),rhTFPI did not improve 28-daymortality,despite reducing evidence of inflammation 39.Administration of rhTFPI and heparinconcomitantly was associated with increased bleeding,although a post hoc analysis did suggest rhTFPIimproved survival in patients with severe community-acquired pneumonia(CAP)for whom themicrobiological aetiology was known and heparin had not been given 40.However,the subsequentRecombinant Tissue Factor Pathway Inhibitor in Severe Community-Acquired Pneumonia(CAPTIVATE)trial 41 did not demonstrate improved survival for patients with severe CAP treated with rhTFPI.Although TFPI was largely disappointing in the setting of sepsis,the advantages of targeting the TFpathway in preventing the development of capillary microthrombi,as well as inflammation,mightoutweigh potential risks.Endogenous anticoagulants and treatment of severe pneumonia and ARDSActivation of the coagulation system is countered by endogenous anticoagulants,which act either alone orin concert to limit coagulation.A number of endogenous anticoagulants,including anti-thrombin(AT)and activated protein C(APC),have been trialled in severe pneumonia and ARDS,on the basis that theyhttps:/doi.org/10.1183/16000617.0240-20203INFECTIOUS DISEASE|R.J.JOS ET AL.were shown to be protective against lung injury in experimental animal models by reducing fibringeneration and attenuating neutrophil recruitment 4246.Anti-thrombinAT inactivates thrombin and factor Xa and has been shown to reduce systemic(after intravenousadministration)and bronchoalveolar(after both intravenous and nebulised administration)thrombin andfibrin levels and reduce lung injury in preclinical models 42,46.However,the clinical data currently donot support using AT as a treatment to improve lung injury.The KyperSept trial of high-dose ATAlveolar barrier disruptivePro-inflammatoryAlveolar barrier protectiveAnti-inflammatoryActivatedprotein CTFPIAnti-thrombinPlasmintPAuPAProcoagulant pathwaysAnticoagulant pathwaysPathogensPattern recognition receptorsIL-1,IL-6,IL-8,TNF,MCP-1PAI-1Protein CThrombomodulinPlasminogenProthrombinThrombinHeparinrAPCDabigatranrAPCPAR1antagonistRivaroxabanApixabanPAR1PAR1aProtein S+EPCR+APCFactor XFactor XaFactor VaFactor XIIIaClotFDPFibrinFibrinogenTF+Factor VIIa+FIGURE 2 Activation of the coagulation cascade and endogenous anticoagulants.Pathogens in the lungs are recognised by pattern recognitionreceptors that initiate a pro-inflammatory response and expression of tissue factor(TF)allowing factor VIIa to come in to contact with TF.TF-VIIaactivates factor X that binds to TF-VIIa to form a ternary complex that converts prothrombin to thromobin(factor IIa).Factor Va binds to theternary complex to form the prothrombinase complex and to platelets and factor Xa to form the major prothrombinase complex that generatesthe large amounts of thrombin necessary for fibrin clot formation.Thrombin also increases expression of thrombomodulin on endothelial