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Abstract: Coronavirus disease 2019 (COVID-19) is a multi-system disease that can lead to various severe complications. )%29&ck%5B%5D=abstract&ck%5B%5D=keyword'>acute limb ischemia (ALI) has been increasingly recognized as a COVID-19-associated complication that often predicts a poor prognosis. However, the pathophysiology and molecular mechanisms underlying COVID-19-associated ALI remain poorly understood. hypercoagulability and thrombosis are considered important mechanisms, but we also emphasize the roles of vasospasm, hypoxia, and acidosis in the pathogenesis of the disease. The angiotensin-converting enzyme 2 (ACE2) pathway, inflammation, and platelet activation may be important molecular mechanisms underlying these pathological changes induced by COVID-19. Furthermore, we discuss the hypotheses of risk factors for COVID-19-associated ALI from genetic, age, and gender perspectives based on our analysis of molecular mechanisms. Additionally, we summarize therapeutic approaches such as use of the interleukin-6 (IL-6) blocker tocilizumab, calcium channel blockers, and angiotensin-converting enzyme inhibitors, providing insights for the future treatment of coronavirus-associated limb ischemic diseases.

COVID-19和急性肢体缺血：病理生理学和分子机制的最新假说

[1]Abou-IsmailMY,DiamondA,KapoorS,et al.,2020.The hypercoagulable state in COVID-19: incidence, pathophysiology, and management.Thromb Res,194:101-115.

[2]AgrawalA,2013.Mechanisms and implications of age-associated impaired innate interferon secretion by dendritic cells: a mini-review.Gerontology,59(5):421-426.

[3]Ahmetaj-ShalaB,PeacockTP,BaillonL,et al.,2020.Resistance of endothelial cells to SARS-CoV-2 infection in vitro.bioRxiv, preprint.

[4]AikawaT,OginoJ,Oyama-ManabeN,et al.,2022.Vasospastic angina: a cause of post-acute COVID-19 syndrome.Intern Med,61(17):2693-2695.

[5]Al YacoubR,PatelJ,SolankyN,et al.,2022.Acute limb ischaemia due to vasospasm: a rare presentation.BMJ Case Rep,15(1):e246495.

[6]AlgahtaniH,SubahiA,ShirahB,2016.Neurological complications of middle east respiratory syndrome coronavirus: a report of two cases and review of the literature.Case Rep Neurol Med,2016:3502683.

[7]AliYM,FerrariM,LynchNJ,et al.,2021.Lectin pathway mediates complement activation by SARS-CoV-2 proteins.Front Immunol,12:714511.

[8]AlitterQT,JarrarA,AlsoudF,et al.,2023.Unilateral limb ischemia in a COVID-19 patient: a case report.Cureus,15(1):e34464.

[9]AlonsoMN,Mata-ForteT,García-LeónN,et al.,2020.Incidence, characteristics, laboratory findings and outcomes in acro-ischemia in COVID-19 patients.Vasc Health Risk Manag,16:467-478.

[10]AndersonCL,ChackoGW,OsborneJM,et al.,1995.The Fc receptor for immunoglobulin G (FcγRII) on human platelets.Semin Thromb Hemost,21(1):1-9.

[11]AlthausK,MariniI,ZlamalJ,et al.,2021.Antibody-induced procoagulant platelets in severe COVID-19 infection.Blood,137(8):1061-1071.

[12]AngeliF,ReboldiG,VerdecchiaP,2021a.Ageing, ACE2 deficiency and bad outcome in COVID-19.Clin Chem Lab Med,59(10):1607-1609.

[13]AngeliF,SpanevelloA,ReboldiG,et al.,2021b.SARS-CoV-2 vaccines: lights and shadows.Eur J Intern Med,88:1-8.

[14]AntoniakS,MackmanN,2014.Multiple roles of the coagulation protease cascade during virus infection.Blood,123(17):2605-2613.

[15]ArmanM,KrauelK,TilleyDO,et al.,2014.Amplification of bacteria-induced platelet activation is triggered by FcγRIIA, integrin αIIbβ3, and platelet factor 4.Blood,123(20):3166-3174.

[16]ArningC,SchrattenholzerA,LachenmayerL,1998.Cervical carotid artery vasospasms causing cerebral ischemia: detection by immediate vascular ultrasonographic investigation.Stroke,29(5):1063-1066.

[17]AssingerA,KralJB,YaiwKC,et al.,2014.Human cytomegalovirus-platelet interaction triggers Toll-like receptor 2-dependent proinflammatory and proangiogenic responses.Arterioscler Thromb Vasc Biol,34(4):801-809.

[18]BakerAT,BoydRJ,SarkarD,et al.,2021.ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome.Sci Adv,7(49):eabl8213.

[19]Bautista-VargasM,Bonilla-AbadíaF,CañasCA,2020.Potential role for tissue factor in the pathogenesis of hypercoagulability associated with in COVID-19.J Thromb Thrombolysis,50(3):479-483.

[20]BellostaR,LuzzaniL,NataliniG,et al.,2020.Acute limb ischemia in patients with COVID-19 pneumonia.J Vasc Surg,72(6):1864-1872.

[21]BellostaR,PiffarettiG,BonardelliS,2021.Regional survey in lombardy, northern italy, on vascular surgery intervention outcomes during the COVID-19 pandemic.Eur J Vasc Endovasc Surg,61(4):688-697.

[22]Blanco-RiveroJ,CachofeiroV,LaheraV,et al.,2005.Participation of prostacyclin in endothelial dysfunction induced by aldosterone in normotensive and hypertensive rats.Hypertension,46(1):107-112.

[23]BoryM,MatteiM,EgreA,et al.,1979.Acute ischemic syndrome and apparently spontaneous spasms of the lower leg arteries.Coeur Med Interne,18(4):607-611.

[24]BouckEG,DenormeF,HolleLA,et al.,2021.COVID-19 and sepsis are associated with different abnormalities in plasma procoagulant and fibrinolytic activity.Arterioscler Thromb Vasc Biol,41(1):401-414.

[25]BrillA,FuchsTA,SavchenkoAS,et al.,2012.Neutrophil extracellular traps promote deep vein thrombosis in mice.J Thromb Haemost,10(1):136-144.

[26]BuieJNJ,OatesJC,2014.Role of interferon alpha in endothelial dysfunction: insights into endothelial nitric oxide synthase-related mechanisms.Am J Med Sci,348(2):168-175.

[27]Cappel,MA,Cappel,JA,Wetter,DA,2021.Pernio (chilblains), SARS-CoV-2, and COVID toes unified through cutaneous and systemic mechanisms.Mayo Clin Proc,96(4):989-1005.

[28]Centers for Disease Control and Prevention,2023.Underlying Medical Conditions Associated with Higher Risk for Severe COVID-19: Information for Healthcare Professionals.https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fscience%2Fscience-briefs%2Funderlying-evidence-table.html [Accessed on Apr. 5, 2023].

[29]ChangY,WeiW,2015.Angiotensin II in inflammation, immunity and rheumatoid arthritis.Clin Exp Immunol,179(2):137-145.

[30]ChenT,WuD,ChenHL,et al.,2020.Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.BMJ,368:m1091.

[31]ChenZW,TsaiCH,PanCT,et al.,2019.Endothelial dysfunction in primary aldosteronism.Int J Mol Sci,20(20):5214.

[32]ChouCH,HungCS,LiaoCW,et al.,2018.IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis.Cardiovasc Res,114(5):690-702.

[33]ConwayEM,MackmanN,WarrenRQ,et al.,2022.Understanding COVID-19-associated coagulopathy.Nat Rev Immunol,22(10):639-649.

[34]DangEV,BarbiJ,YangHY,et al.,2011.Control of T_H17/T_reg balance by hypoxia-inducible factor 1.Cell,146(5):772-784.

[35]de MassonA,BouazizJD,SulimovicL,et al.,2020.Chilblains is a common cutaneous finding during the COVID-19 pandemic: a retrospective nationwide study from france.J Am Acad Dermatol,83(2):667-670.

[36]DemirŞ,AkinŞ,TercanF,et al.,2010.Ergotamine-induced lower extremity arterial vasospasm presenting as acute limb ischemia.Diagn Interv Radiol,16(2):165-167.

[37]DengY,LiuW,LiuK,et al.,2020.Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: a retrospective study.Chin Med J (Engl),133(11):1261-1267.

[38]DeshotelsMR,XiaHJ,SriramulaS,et al.,2014.Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism.Hypertension,64(6):1368-1375.

[39]DöringY,SoehnleinO,WeberC,2017.Neutrophil extracellular traps in atherosclerosis and atherothrombosis.Circ Res,120(4):736-743.

[40]DotanA,ShoenfeldY,2021.Perspectives on vaccine induced thrombotic thrombocytopenia.J Autoimmun,121:102663.

[41]EscherR,BreakeyN,LämmleB,2020.Severe COVID-19 infection associated with endothelial activation.Thromb Res,190:62.

[42]FanBE,2020.Hematologic parameters in patients with COVID‐19 infection: a reply.Am J Hematol,95(8):E215.

[43]FiebelerA,SchmidtF,MüllerDN,et al.,2001.Mineralocorticoid receptor affects AP-1 and nuclear factor-κB activation in angiotensin II-induced cardiac injury.Hypertension,37(2):787-793.

[44]FoleyJH,ConwayEM,2016.Cross talk pathways between coagulation and inflammation.Circ Res,118(9):1392-1408.

[45]ForresterSJ,BoozGW,SigmundCD,et al.,2018.Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology.Physiol Rev,98(3):1627-1738.

[46]Galván CasasC,CatalàA,Carretero HernándezG,et al.,2020.Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases.Br J Dermatol,183(1):71-77.

[47]GheblawiM,WangKM,ViveirosA,et al.,2020.Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2.Circ Res,126(10):1456-1474.

[48]Giamarellos-BourboulisEJ,NeteaMG,RovinaN,et al.,2020.Complex immune dysregulation in COVID-19 patients with severe respiratory failure.Cell Host Microbe,27(6):992-1000.e3.

[49]GiannisD,ZiogasIA,GianniP,2020.Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past.J Clin Virol,127:104362.

[50]GoeijenbierM,van WissenM,van de WegC,et al.,2012.Review: viral infections and mechanisms of thrombosis and bleeding.J Med Virol,84(10):1680-1696.

[51]GoldmanIA,YeK,ScheinfeldMH,2020.Lower-extremity arterial thrombosis associated with COVID-19 is characterized by greater thrombus burden and increased rate of amputation and death.Radiology,297(2):E263-E269.

[52]Gomez-ArbelaezD,Ibarra-SanchezG,Garcia-GutierrezA,et al.,2020.COVID-19-related aortic thrombosis: a report of four cases.Ann Vasc Surg,67:10-13.

[53]GouldTJ,VuTT,SwystunLL,et al.,2014.Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms.Arterioscler Thromb Vasc Biol,34(9):1977-1984.

[54]HermanEW,KezisJS,SilversDN,1981.A distinctive variant of pernio: clinical and histopathologic study of nine cases.Arch Dermatol,117(1):26-28.

[55]HermidorffMM,de AssisLVM,IsoldiMC,2017.Genomic and rapid effects of aldosterone: what we know and do not know thus far.Heart Fail Rev,22(1):65-89.

[56]HolterJC,PischkeSE,de BoerE,et al.,2020.Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients.Proc Natl Acad Sci USA,117(40):25018-25025.

[57]HubicheT,Le DuffF,ChiaveriniC,et al.,2021.Negative SARS-CoV-2 PCR in patients with chilblain-like lesions.Lancet Infect Dis,21(3):315-316.

[58]IbaT,LevyJH,2022.The roles of platelets in COVID-19-associated coagulopathy and vaccine-induced immune thrombotic thrombocytopenia.Trends Cardiovasc Med,32(1):1-9.

[59]IbaT,LevyJH,LeviM,et al.,2020.Coagulopathy in COVID-19.J Thromb Haemost,18(9):2103-2109.

[60]InoueK,MakitaN,MatsuoK,et al.,2009.OE-045 Clinical significance of aldosterone levels and C-reactive protein in patients with coronary vasospasm (OE08, atherosclerosis (clinical/diagnosis) (IHD), oral presentation (English), the 73rd Annual Scientific Meeting of the Japanese Circulation Society).Circ J,73:185.

[61]JabalameliN,RajabiF,FiroozA,et al.,2022.The overlap between genetic susceptibility to COVID-19 and skin diseases.Immunol Invest,51(4):1087-1094.

[62]JahaniM,DokaneheifardS,MansouriK,2020.Hypoxia: a key feature of COVID-19 launching activation of HIF-1 and cytokine storm.J Inflamm,17(1):33.

[63]JainA,ReddyA,MurugesanR,et al.,2022.Outcomes of patients with acute limb ischemia in patients with COVID-19: a systemic review and meta-analysis.Cureus,14(7):e27370.

[64]KambasK,ChrysanthopoulouA,VassilopoulosD,et al.,2014.Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease.Ann Rheum Dis,73(10):1854-1863.

[65]KaneyamaJ,KawaradaO,SakamotoS,et al.,2014.Vasospastic limb ischemia presenting acute and chronic limb ischemia.Ann Vasc Dis,7(2):169-172.

[66]KangSJ,KishimotoT,2021.Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms.Exp Mol Med,53(7):1116-1123.

[67]KangSJ,TanakaT,InoueH,et al.,2020.IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome.Proc Natl Acad Sci USA,117(36):22351-22356.

[68]KartikasariU,DjajalaksanaS,MartiniH,2021.Acute limb ischemia in a patient with Covid-19 pneumonia: a case report.J Thromb Thrombolysis,52(3):974-979.

[69]KeserZ,Suarez-CedenoG,SahaRK,et al.,2018.An atypical presentation of varicella zoster (VZV) vasculopathy.J Vasc Interv Neurol,10(1):23-24.

[70]KhattabK,KempaAT,AtasR,et al.,2021.Peripheral ischemic limb necrosis (Acro-ischemia) associated with severe COVID-19 patients (COVID-19 limbs): a report of three cases.Lung India,38(S1):S58-S60.

[71]KimOY,ChaeJS,PaikJK,et al.,2012.Effects of aging and menopause on serum interleukin-6 levels and peripheral blood mononuclear cell cytokine production in healthy nonobese women.AGE,34(2):415-425.

[72]KlingerMH,WilhelmD,BubelS,et al.,1995.Immunocytochemical localization of the chemokines RANTES and MIP-1α within human platelets and their release during storage.Int Arch Allergy Immunol,107(4):541-546.

[73]KlokFA,KruipMJHA,van der MeerNJM,et al.,2020.Incidence of thrombotic complications in critically ill ICU patients with COVID-19.Thromb Res,191:145-147.

[74]KolivrasA,DehavayF,DelplaceD,et al.,2020.Coronavirus (COVID-19) infection-induced chilblains: a case report with histopathologic findings.JAAD Case Rep,6(6):489-492.

[75]KuchynkovaS,ChocholaM,VarejkaP,et al.,2017.A rare cause of acute limb ischemia of both upper and lower limbs caused by prolonged vasospasm.Cor Vasa,59(5):e503-e506.

[76]KyriazopoulouE,LeventogiannisK,Norrby-TeglundA,et al.,2017.Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis.BMC Med,15:172.

[77]LariE,LariA,AlqinaiS,et al.,2020.Severe ischemic complications in Covid-19—a case series.Int J Surg Case Rep,75:131-135.

[78]LeeN,HuiD,WuAL,et al.,2003.A major outbreak of severe acute respiratory syndrome in Hong Kong.N Engl J Med,348(20):1986-1994.

[79]LiX,WangLW,YanSN,et al.,2020.Clinical characteristics of 25 death cases with COVID-19: a retrospective review of medical records in a single medical center, Wuhan, China.Int J Infect Dis,94:128-132.

[80]LiaoMF,LiuY,YuanJ,et al.,2020.Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19.Nat Med,26(6):842-844.

[81]LimbJ,BinningA,2009.Thrombosis associated with varicella zoster in an adult.Int J Infect Dis,13(6):e498-e500.

[82]LiuJY,LiuY,XiangP,et al.,2020.Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage.J Transl Med,18:206.

[83]LiuYM,WangHQ,ShaoZH,2021.SARS-CoV-2 vaccines induced immune thrombotic thrombocytopenia.Chin J Hematol,42(7):607-610(in Chinese).

[84]MackmanN,GroverSP,AntoniakS,2021.Tissue factor expression, extracellular vesicles, and thrombosis after infection with the respiratory viruses influenza a virus and coronavirus.J Thromb Haemost,19(11):2652-2658.

[85]MaggioM,BasariaS,BleA,et al.,2006.Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men.J Clin Endocrinol Metab,91(1):345-347.

[86]ManneBK,DenormeF,MiddletonEA,et al.,2020.Platelet gene expression and function in patients with COVID-19.Blood,136(11):1317-1329.

[87]MarceauF,BawolakMT,FortinJP,et al.,2018.Bifunctional ligands of the bradykinin B₂ and B₁ receptors: an exercise in peptide hormone plasticity.Peptides,105:37-50.

[88]MaseriA,L'AbbateA,BaroldiG,et al.,1978.Coronary vasospasm as a possible cause of myocardial infarction—a conclusion derived from the study of preinfarction angina.N Engl J Med,299(23):1271-1277.

[89]MassbergS,GrahlL,von BruehlML,et al.,2010.Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.Nat Med,16(8):887-896.

[90]MastAE,WolbergAS,GailaniD,et al.,2021.SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung.eLife,10:e64330.

[91]MazzottaF,TroccoliT,2020.Acute acro-ischemia in the child at the time of COVID-19.Eur J Pediat Dermatol,30(2):71-74.

[92]MiddletonEA,HeXY,DenormeF,et al.,2020.Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.Blood,136(10):1169-1179.

[93]MohamediN,MiraultT,DurivageA,et al.,2021.Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty.J Med Vasc,46(1):13-21.

[94]MöhlendickB,SchönfelderK,BreuckmannK,et al.,2021.ACE2 polymorphism and susceptibility for SARS-CoV-2 infection and severity of COVID-19.Pharmacogenet Genomics,31(8):165-171.

[95]MonovD,LilyanovN,BogovskyS,et al.,2022.Cerebral vasospasm after subarachnoid hemorrhage from intracranial aneurysm rupture in SARS-CoV-2 positive patients. A retrospective review from two bulgarian hospitals.Biotechnol Biotechnol Equip,36(1):413-417.

[96]NagataD,TakahashiM,SawaiK,et al.,2006.Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity.Hypertension,48(1):165-171.

[97]NeumannFJ,OttI,MarxN,et al.,1997.Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity.Arterioscler Thromb Vasc Biol,17(12):3399-3405.

[98]NgKHL,WuAKL,ChengVCC,et al.,2005.Pulmonary artery thrombosis in a patient with severe acute respiratory syndrome.Postgrad Med J,81(956):e3.

[99]NichollsJM,PoonLLM,LeeKC,et al.,2003.Lung pathology of fatal severe acute respiratory syndrome.Lancet,361(9371):1773-1778.

[100]NowroozpoorA,BankMA,JafariD,2021.Limb ischemia due to extensive arterial thrombosis in the absence of venous occlusion as an unusual complication of critical illness from COVID-19.Case Rep Acute Med,4(1):23-31.

[101]OmarIM,WeaverJS,SametJD,et al.,2022.Musculoskeletal manifestations of COVID-19: currently described clinical symptoms and multimodality imaging findings.RadioGraphics,42(5):1415-1432.

[102]OrrapinS,ReanpangT,OrrapinS,et al.,2015.Case series of HIV infection-associated arteriopathy: diagnosis, management, and outcome over a 5-year period at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University.Int J Low Extrem Wounds,14(3):251-261.

[103]OzbeyR,AlganMF,2022.Acro‐ischemic lesions in COVID‐19 patients: a case series.J Cosmet Dermatol,21(5):‍1822-1829.

[104]PapamichalisP,PapadogoulasA,KatsiafylloudisP,et al.,2020.Combination of thrombolytic and immunosuppressive therapy for coronavirus disease 2019: a case report.Int J Infect Dis,97:90-93.

[105]ParkSH,KimTJ,KoSB,et al.,2022.Transcranial doppler monitoring in subarachnoid hemorrhage.J Neurosonol Neuroimag,14(1):1-9.

[106]PeerschkeEI,YinW,GhebrehiwetB,2010.Complement activation on platelets: implications for vascular inflammation and thrombosis.Mol Immunol,47(13):2170-2175.

[107]PeriniP,NabulsiB,MassoniCB,et al.,2020.Acute limb ischaemia in two young, non-atherosclerotic patients with COVID-19.Lancet,395(10236):1546.

[108]PredenciucA,CasianD,CuliucV,2023.Outcomes of surgical revascularization for acute limb ischemia in COVID-19 patients comparing to noninfected cohort: a single-center observational prospective study.Ann Vasc Surg,91:81-89.

[109]PutkoRM,BedrinMD,ClarkDM,et al.,2021.SARS-CoV-2 and limb ischemia: a systematic review.J Clin Orthop Trauma,12(1):194-199.

[110]RamosSG,da Cruz Rattis BA,OttavianiG,et al.,2021.ACE2 down-regulation may act as a transient molecular disease causing RAAS dysregulation and tissue damage in the microcirculatory environment among COVID-19 patients.Am J Pathol,191(7):1154-1164.

[111]RiederM,WirthL,PollmeierL,et al.,2021.Serum ACE2, angiotensin II, and aldosterone levels are unchanged in patients with COVID-19.Am J Hypertens,34(3):278-281.

[112]RosasIO,BräuN,WatersM,et al.,2021.Tocilizumab in hospitalized patients with severe Covid-19 pneumonia.N Engl J Med,384(16):1503-1516.

[113]SalamaC,HanJ,YauL,et al.,2021.Tocilizumab in patients hospitalized with Covid-19 pneumonia.N Engl J Med,384(1):20-30.

[114]SchultzK,WolfJM,2020.Digital ischemia in COVID-19 patients: case report.J Hand Surg,45(6):518-522.

[115]The Severe Covid-19 GWAS Group,2020.Genomewide association study of severe Covid-19 with respiratory failure.N Engl J Med,383(16):1522-1534.

[116]ShahiV,WetterDA,CappelJA,et al.,2015.Vasospasm is a consistent finding in pernio (chilblains) and a possible clue to pathogenesis.Dermatology,231(3):274-279.

[117]SodhiCP,Wohlford-LenaneC,YamaguchiY,et al.,2018.Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg⁹ bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration.Am J Physiol Lung Cell Mol Physiol,314(1):L17-L31.

[118]SouyrisM,CenacC,AzarP,et al.,2018.TLR7 escapes X chromosome inactivation in immune cells.Sci Immunol,3(19):eaap8855.

[119]StelzerM,HenesJ,SaurS,2021.The role of antiphospholipid antibodies in COVID-19.Curr Rheumatol Rep,23(9):72.

[120]TanakaK,KoikeY,ShimuraT,et al.,2014.In vivo characterization of neutrophil extracellular traps in various organs of a murine sepsis model.PLoS ONE,9(11):e111888.

[121]TangN,LiDJ,WangX,et al.,2020.Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost,18(4):844-847.

[122]TeixeiraJG,PittaGBB,da SilvaCRA,et al.,2022.Diagnosis and management of patients with acute limb ischemia after Covid-19 infection: a case series.J Vasc Bras,21:e20220044.

[123]TiedeA,SachsUJ,CzwalinnaA,et al.,2021.Prothrombotic immune thrombocytopenia after COVID-19 vaccination.Blood,138(4):350-353.

[124]TobaiqyM,ElkoutH,MacLureK,2021.Analysis of thrombotic adverse reactions of COVID-19 astrazeneca vaccine reported to eudravigilance database.Vaccines,9(4):393.

[125]TukiainenT,VillaniAC,YenA,et al.,2017.Landscape of X chromosome inactivation across human tissues.Nature,550(7675):244-248.

[126]van de VeerdonkF,NeteaMG,van DeurenM,et al.,2020.Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach. Preprints.org, preprint.

[127]VickersC,HalesP,KaushikV,et al.,2002.Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.J Biol Chem,277(17):‍14838-14843.

[128]VillardO,MorquinD,MolinariN,et al.,2020.The plasmatic aldosterone and C-reactive protein levels, and the severity of Covid-19: the Dyhor-19 study.J Clin Med,9(7):2315.

[129]WallsAC,ParkYJ,TortoriciMA,et al.,2020.Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.Cell,181(2):281-292.e6.

[130]WangDW,HuB,HuC,et al.,2020.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA,323(11):1061-1069.

[131]WangRY,LeeJH,KimJ,et al.,2023.SARS-CoV-2 restructures host chromatin architecture.Nat Microbiol,8(4):679-694.

[132]WinckiewiczM,StanišićMG,SzajkowskiR,et al.,2007.Acute lower limb ischemia in a young woman with arterial hypoplasia: a case report.Angiology,58(4):494-497.

[133]WuZY,HuR,ZhangCZ,et al.,2020.Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients.Crit Care,24:290.

[134]XavierFE,Aras-LópezR,Arroyo-VillaI,et al.,2008.Aldosterone induces endothelial dysfunction in resistance arteries from normotensive and hypertensive rats by increasing thromboxane A₂ and prostacyclin.Br J Pharmacol,154(6):1225-1235.

[135]XieBW,SemaanDB,BinkoMA,et al.,2023.COVID-associated acute limb ischemia during the delta surge and the effect of vaccines.J Vasc Surg,77(4):1165-1173.e1.

[136]XieXD,ChenJZ,WangXX,et al.,2006.Age- and gender-related difference of ACE2 expression in rat lung.Life Sci,78(19):2166-2171.

[137]XingDQ,NozellS,ChenYF,et al.,2009.Estrogen and mechanisms of vascular protection.Arterioscler Thromb Vasc Biol,29(3):289-295.

[138]YeamanMR,2014.Platelets: at the nexus of antimicrobial defence.Nat Rev Microbiol,12(6):426-437.

[139]YoonHE,KimEN,KimMY,et al.,2016.Age-associated changes in the vascular renin-angiotensin system in mice.Oxid Med Cell Longev,2016:6731093.

[140]YuJ,YuanX,ChenH,et al.,2020.Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor d inhibition.Blood,136(18):2080-2089.

[141]ZhangHB,PenningerJM,LiYM,et al.,2020.Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target.Intensive Care Med,46(4):586-590.

[142]ZhangS,LiuYY,WangX F,et al.,2020.SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19.J Hematol Oncol,13:120.

[143]ZhangX,YuJ,PanLY,et al.,2020.ACEI/ARB use and risk of infection or severity or mortality of COVID-19: a systematic review and meta-analysis.Pharmacol Res,158:104927.

[144]ZhangY,CaoW,XiaoM,et al.,2020.Clinical and coagulation characteristics in 7 patients with critical COVID-2019 pneumonia and acro-ischemia.Chin J Hematol,41(4):302-307(in Chinese).

[145]ZhaoY,ZhaoZX,WangYJ,et al.,2020.Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2.Am J Respir Crit Care Med,202(5):756-759.

[146]ZhouF,YuT,DuRH,et al.,2020.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet,395(10229):1054-1062.

[147]ZhuHB,WeiL,NiuP,2020.The novel coronavirus outbreak in Wuhan, China.Glob Health Res Policy,5:6.

[148]ZhuLL,LiuL,ZhangY,et al.,2018.High level of neutrophil extracellular traps correlates with poor prognosis of severe influenza A infection.J Infect Dis,217(3):428-437.

[149]ZimmermannN,WolfC,SchwenkeR,et al.,2019.Assessment of clinical response to Janus kinase inhibition in patients with familial chilblain lupus andTREX1 mutation.JAMA Dermatol,155(3):342-346.

[150]ZuoY,YalavarthiS,ShiH,et al.,2020.Neutrophil extracellular traps in COVID-19.JCI Insight,5(11):e138999.