Abstract
The COVID-19 pandemic has overwhelmed our health care capacity in an unprecedented way due to the sheer number of critically infected patients admitted to hospitals during the last two years. Endothelial injury is seen as one of the central hallmarks of COVID-19 infection that is the starting point in the generation of microthrombi and sepsis eventually leading to acute respiratory distress syndrome (ARDs) and multi-organ failure. The dramatic fall in lung function during ARDs is attributed to the microthrombi-induced coagulopathy primed by a hyperactive immune system. Due to the lack of effective antiviral agents, the line of treatment is limited to the management of two key risk factors i.e., immune activation and coagulopathy. In the present review, we describe the mechanistic role, therapeutic targets, and opportunities to control immune activation and coagulopathy during the pathogenesis of COVID-19-induced ARDs.
Keywords: COVID 19, acute respiratory distress syndrome, NETosis, complement, immunothrombosis, coagulopathy, complement activation.
Graphical Abstract
[http://dx.doi.org/10.2174/0929867327666200702151018] [PMID: 32614740]
[http://dx.doi.org/10.2174/1871526520999200905115050] [PMID: 32888278]
[http://dx.doi.org/10.1056/NEJMoa2002032] [PMID: 32109013]
[http://dx.doi.org/10.1016/j.idc.2019.07.001] [PMID: 31668196]
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
[http://dx.doi.org/10.1111/jth.14888] [PMID: 32369666]
[http://dx.doi.org/10.1515/cclm-2020-0502] [PMID: 32406381]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048488] [PMID: 32755393]
[http://dx.doi.org/10.1056/NEJMsb2005114] [PMID: 32202722]
[http://dx.doi.org/10.1182/blood.2020007214] [PMID: 32573711]
[http://dx.doi.org/10.1016/j.clim.2020.108393] [PMID: 32222466]
[http://dx.doi.org/10.1177/1076029620943293] [PMID: 32735131]
[http://dx.doi.org/10.1186/s12931-020-01462-5] [PMID: 32723327]
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[http://dx.doi.org/10.1126/science.abb2762] [PMID: 32132184]
[http://dx.doi.org/10.1038/s41577-020-0311-8] [PMID: 32346093]
[http://dx.doi.org/10.1055/s-0040-1713678] [PMID: 32607467]
[http://dx.doi.org/10.3390/v13020312] [PMID: 33671334]
[http://dx.doi.org/10.1007/s11684-020-0754-0] [PMID: 32170560]
[http://dx.doi.org/10.1001/jama.2020.1585] [PMID: 32031570]
[http://dx.doi.org/10.1097/CM9.0000000000000744] [PMID: 32044814]
[http://dx.doi.org/10.1016/j.drudis.2021.04.006] [PMID: 33865979]
[http://dx.doi.org/10.1038/nrcardio.2014.59] [PMID: 24776703]
[http://dx.doi.org/10.1186/s13054-020-03015-0] [PMID: 32503680]
[http://dx.doi.org/10.1056/NEJMoa2015432] [PMID: 32437596]
[http://dx.doi.org/10.1136/thx.2006.063305] [PMID: 17356058]
[http://dx.doi.org/10.1097/01.CCM.0000057846.21303.AB] [PMID: 12682443]
[http://dx.doi.org/10.2302/kjm.54.142] [PMID: 16237276]
[http://dx.doi.org/10.1164/ajrccm.161.2.9712038] [PMID: 10673185]
[http://dx.doi.org/10.1007/s11239-020-02172-x] [PMID: 32519164]
[http://dx.doi.org/10.1007/s00134-020-06062-x] [PMID: 32367170]
[http://dx.doi.org/10.1007/s11239-020-02245-x] [PMID: 32789730]
[http://dx.doi.org/10.1007/s11739-020-02443-8] [PMID: 32748128]
[http://dx.doi.org/10.1016/S2213-2600(20)30244-7] [PMID: 32473125]
[http://dx.doi.org/10.1111/bjh.16749] [PMID: 32330308]
[http://dx.doi.org/10.1016/j.autrev.2020.102537] [PMID: 32251717]
[http://dx.doi.org/10.1080/17474086.2018.1500173] [PMID: 29999440]
[http://dx.doi.org/10.1007/s11739-020-02601-y] [PMID: 33368021]
[http://dx.doi.org/10.1080/09537104.2020.1768523] [PMID: 32456506]
[http://dx.doi.org/10.1111/jth.14975] [PMID: 32558075]
[http://dx.doi.org/10.1016/j.jinf.2020.03.041] [PMID: 32283155]
[http://dx.doi.org/10.1177/0268355520955083] [PMID: 33249999]
[http://dx.doi.org/10.1111/jth.14817] [PMID: 32220112]
[http://dx.doi.org/10.3390/jcm9113547] [PMID: 33153216]
[http://dx.doi.org/10.1111/nan.12677] [PMID: 33249605]
[http://dx.doi.org/10.1016/j.jdcr.2020.10.009] [PMID: 33072831]
[http://dx.doi.org/10.1016/j.thromres.2019.07.013] [PMID: 31376606]
[http://dx.doi.org/10.1146/annurev.biochem.67.1.395] [PMID: 9759493]
[http://dx.doi.org/10.1056/NEJMc2011400] [PMID: 32402155]
[http://dx.doi.org/10.1007/s00414-020-02317-w] [PMID: 32500199]
[http://dx.doi.org/10.1111/jth.14981] [PMID: 32608159]
[http://dx.doi.org/10.1016/j.thromres.2020.06.027] [PMID: 32569879]
[http://dx.doi.org/10.1038/s41423-018-0024-0] [PMID: 29572545]
[http://dx.doi.org/10.1161/ATVBAHA.113.303016] [PMID: 24790143]
[http://dx.doi.org/10.1038/nm0810-851] [PMID: 20689544]
[http://dx.doi.org/10.1016/j.cca.2020.04.027] [PMID: 32348783]
[http://dx.doi.org/10.1111/jth.14872] [PMID: 32329246]
[http://dx.doi.org/10.1007/s11239-020-02224-2] [PMID: 32676883]
[http://dx.doi.org/10.1111/jth.14828] [PMID: 32267998]
[http://dx.doi.org/10.1016/j.ahj.2020.04.025] [PMID: 32497913]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051828] [PMID: 33480806]
[http://dx.doi.org/10.1038/s41379-020-0603-3] [PMID: 32572155]
[http://dx.doi.org/10.1111/bjh.16907] [PMID: 32484901]
[http://dx.doi.org/10.1007/s12185-020-03029-y] [PMID: 33161508]
[http://dx.doi.org/10.1136/thoraxjnl-2020-216243] [PMID: 33408195]
[http://dx.doi.org/10.1016/j.clim.2020.108487] [PMID: 32479986]
[http://dx.doi.org/10.1016/j.thromres.2020.06.010] [PMID: 32531548]
[http://dx.doi.org/10.1007/s00259-019-04450-0] [PMID: 31410539]
[http://dx.doi.org/10.15252/emmm.202012642] [PMID: 32559343]
[http://dx.doi.org/10.1182/blood.2020007008] [PMID: 32597954]
[http://dx.doi.org/10.1083/jcb.200606027] [PMID: 17210947]
[http://dx.doi.org/10.1172/jci.insight.98178] [PMID: 29415887]
[http://dx.doi.org/10.1038/nri.2017.105] [PMID: 28990587]
[http://dx.doi.org/10.1161/ATVBAHA.119.312463] [PMID: 31315434]
[http://dx.doi.org/10.1084/jem.20200652] [PMID: 32302401]
[http://dx.doi.org/10.1160/TH17-09-0630] [PMID: 29304522]
[http://dx.doi.org/10.23812/CONTI-E] [PMID: 32171193]
[http://dx.doi.org/10.1177/1753466620926800] [PMID: 32436460]
[http://dx.doi.org/10.1016/S0140-6736(20)30628-0] [PMID: 32192578]
[http://dx.doi.org/10.1016/j.ijantimicag.2020.105954] [PMID: 32234467]
[http://dx.doi.org/10.1002/jmv.25801] [PMID: 32253759]
[http://dx.doi.org/10.1073/pnas.2005615117] [PMID: 32350134]
[http://dx.doi.org/10.7150/ijbs.4989] [PMID: 23136552]
[http://dx.doi.org/10.1186/s40364-018-0116-0] [PMID: 29387417]
[http://dx.doi.org/10.1155/2019/7947596] [PMID: 31049028]
[http://dx.doi.org/10.1161/CIRCRESAHA.120.317055] [PMID: 32252591]
[http://dx.doi.org/10.1007/s40259-018-0324-z] [PMID: 30560413]
[http://dx.doi.org/10.3389/fimmu.2020.602395] [PMID: 33488599]
[http://dx.doi.org/10.3390/v9040064] [PMID: 28358311]
[http://dx.doi.org/10.1016/j.clim.2020.108450] [PMID: 32360516]
[http://dx.doi.org/10.26355/EURREV_202004_20875] [PMID: 32329881]
[http://dx.doi.org/10.1016/j.clim.2018.09.004] [PMID: 30217791]
[http://dx.doi.org/10.1016/j.clim.2020.108598] [PMID: 32961333]
[http://dx.doi.org/10.1038/s41577-020-0320-7] [PMID: 32327719]
[http://dx.doi.org/10.3389/fimmu.2020.01661] [PMID: 32733489]
[http://dx.doi.org/10.1101/2020.03.29.20041962]
[http://dx.doi.org/10.1073/pnas.2010540117] [PMID: 32943538]
[http://dx.doi.org/10.1182/blood.2020008925] [PMID: 33119763]
[http://dx.doi.org/10.3949/ccjm.87a.ccc065] [PMID: 33115882]
[http://dx.doi.org/10.4049/jimmunol.2000644] [PMID: 32699160]
[http://dx.doi.org/10.1038/s41591-020-0901-9] [PMID: 32398875]
[http://dx.doi.org/10.1161/CIRCRESAHA.116.306853] [PMID: 27126649]
[http://dx.doi.org/10.1038/nri1269] [PMID: 15040586]
[http://dx.doi.org/10.3390/v6082991] [PMID: 25105276]
[http://dx.doi.org/10.1128/mBio.01753-18] [PMID: 30301856]
[http://dx.doi.org/10.1084/jem.20201012] [PMID: 32926097]
[http://dx.doi.org/10.1182/blood-2020-142344]
[http://dx.doi.org/10.1182/blood.2019002973] [PMID: 33410894]
[http://dx.doi.org/10.1038/s41598-020-61253-2] [PMID: 32152402]
[http://dx.doi.org/10.4049/immunohorizons.1900026] [PMID: 31399487]
[http://dx.doi.org/10.1038/s41467-019-09801-x] [PMID: 31015489]
[http://dx.doi.org/10.1111/j.1476-5381.2012.01847.x] [PMID: 22233238]
[http://dx.doi.org/10.1016/j.apsb.2020.04.008] [PMID: 32318327]
[http://dx.doi.org/10.1172/JCI83873] [PMID: 27599294]
[http://dx.doi.org/10.1038/s41598-018-32576-y] [PMID: 30242250]
[http://dx.doi.org/10.1172/jci.insight.138999] [PMID: 32329756]
[http://dx.doi.org/10.1080/00325481.2020.1855921] [PMID: 33245005]
[http://dx.doi.org/10.1172/JCI124804] [PMID: 30990798]
[http://dx.doi.org/10.1126/sciimmunol.abd0110] [PMID: 32503877]
[http://dx.doi.org/10.1186/s12931-017-0689-4] [PMID: 29233147]
[http://dx.doi.org/10.1016/S2665-9913(21)00005-9] [PMID: 33521656]
[http://dx.doi.org/10.1056/NEJMoa2021436] [PMID: 32678530]
[http://dx.doi.org/10.1136/annrheumdis-2020-217871] [PMID: 32471903]
[http://dx.doi.org/10.1038/nature09102] [PMID: 20559388]
[http://dx.doi.org/10.7150/ijbs.47652] [PMID: 32760206]
[http://dx.doi.org/10.1016/S0009-9236(99)70054-8] [PMID: 10430110]
[http://dx.doi.org/10.1016/S2213-2600(20)30415-X] [PMID: 32979987]
[http://dx.doi.org/10.1080/02713683.2019.1657464] [PMID: 31429304]
[http://dx.doi.org/10.1007/s15010-020-01561-x] [PMID: 33331988]
[http://dx.doi.org/10.1016/j.phrs.2020.104965] [PMID: 32474087]
[http://dx.doi.org/10.1111/joim.13205] [PMID: 33258156]
[http://dx.doi.org/10.1111/joim.13228] [PMID: 33423337]
[http://dx.doi.org/10.1016/j.phrs.2020.104950] [PMID: 32450344]
[http://dx.doi.org/10.1182/bloodadvances.2020002496] [PMID: 32841342]
[http://dx.doi.org/10.1016/j.thromres.2020.09.026] [PMID: 32977137]
[http://dx.doi.org/10.1177/1076029621992128] [PMID: 33539188]
[http://dx.doi.org/10.1093/eurheartj/ehz405] [PMID: 31504429]
[http://dx.doi.org/10.1055/s-0040-1710019] [PMID: 32316065]
[http://dx.doi.org/10.1055/s-0040-1712097] [PMID: 32349132]
[http://dx.doi.org/10.1016/j.thromres.2020.04.013] [PMID: 32291094]
[http://dx.doi.org/10.1007/s11239-020-02145-0] [PMID: 32445064]
[http://dx.doi.org/10.1160/th15-03-0214] [PMID: 26632486]
[http://dx.doi.org/10.1182/blood.2020006000] [PMID: 32339221]
[http://dx.doi.org/10.1097/TA.0000000000002387] [PMID: 31454337]
[http://dx.doi.org/10.1038/s41467-020-20231-y] [PMID: 33328478]
[http://dx.doi.org/10.1371/journal.pone.0233644] [PMID: 32469940]
[http://dx.doi.org/10.1016/j.ebiom.2020.102925] [PMID: 32745993]
[http://dx.doi.org/10.3389/fimmu.2020.575047]
[http://dx.doi.org/10.1016/j.phrs.2016.08.008] [PMID: 28161237]
[http://dx.doi.org/10.1182/blood-2013-07-514984] [PMID: 24264231]
[http://dx.doi.org/10.1172/JCI110017] [PMID: 6778897]
[http://dx.doi.org/10.1016/j.lfs.2021.119376] [PMID: 33781826]
[http://dx.doi.org/10.1038/nrneph.2017.6] [PMID: 28163306]
[http://dx.doi.org/10.1111/cts.12880] [PMID: 32881340]
[http://dx.doi.org/10.1160/TH17-05-0347] [PMID: 29202212]
[http://dx.doi.org/10.1038/s41577-021-00536-9] [PMID: 33824483]
[http://dx.doi.org/10.1016/j.riam.2020.07.001] [PMID: 33041191]