Table 1.

Mechanisms of sepsis and COVID-19-associated coagulopathies.

Commonalities between Sepsis and COVID-19-Associated Coagulopathies	Characteristics of Sepsis-Induced Coagulopathy	Characteristics of COVID-19-Associated Coagulopathy
TLRs and CLRs found on cell membranes and endosomes interact with PAMPs and DAMPs [10,11].   The synthesis of proinflammatory cytokines is activated via MAPK and NF-κB pathways [10,11,209].   Increased PAI-1 levels can be found in both COVID-19 and sepsis. [45,46]   TF, FVIII, u-PA, PAI-1, TFPI, antithrombin and thrombomodulin are endpoints of the NF-κB pathway [12,13,14,15,16].   Histones promote platelet aggregation, bind prothrombotic molecules, and damage the antithrombotic properties of the endothelial glycocalyx [50,51].   Activated neutrophils generate prothrombotic and hyperinflammatory states via NETs formation and inflammasome activation, leading to immunothrombosis [88,89,90,91,92,93,94,95,96].   Intercellular interactions between platelets, endothelial cells, neutrophils and monocytes lead to MPs release and TF exposure [145,179].   Monocytes, as a source of soluble TF, promote the activation of coagulation via the extrinsic pathway [72,73].   Active platelets and MPs induce adhesion molecules’ expression and the dysfunction of endothelial cells [127,128,129,130].   The antithrombin pathway and protein C anticoagulant system become dysfunctional due to impaired protein C synthesis and activation via thrombomodulin and endothelial protein C receptor deficiency [52,53,54,226,227].   Tie2, NF-κB and MAPK signaling lead to ECs acquisitionof a proinflammatory and prothrombotic phenotype [207,208,209,210,211,212,213].   IL-6 contributes to vascular permeability and TNF-α worsens the glycocalyx disruption of endothelial cells [219].	HMGB1 can modulate fibrinolysis by interacting with plasminogen and t-PA, can promote coagulation via TF exposure on macrophages and inhibits the protein C pathway [25,26,27,28,29,30,31,32,33,34,35,36,37,38,39].   cfDNA activates coagulation via FXI and FXII [40,41].   High cfDNA concentrations inactivate t-PA by PAI-1 [42,43,44].   Increased TF release from monocytes occurs upon stimulation by LPS [74,75,76].   Fibrinolysis resistance is enhanced via plasminogen altering within NETs, the formation of fibrin–DNA tight complexes insensitive to plasmin and the activation of PAI-1 by cfDNA [42,114,123,124].   Sepsis is associated withADAMTS13 deficiency, which generates large circulating vWF multimers, excessively activating platelets [234,235,236,237].   Platelet activation can arise via direct and indirect bacterial–platelet interactions [153].   A septic proinflammatory status induces (via IL-6 and IL-3 stimulation) the release of thrombopoietin-independent thrombocytes with more numerous TLRs and interleukin receptors, more IL-6 and TNF-α [72,196].   Endothelial cells’ activation can be triggered by TNF-α and thrombin, bacterial LPS and other PAMPs, HMGB1 and other DAMPs, cytokines, such as IFN-γ and IL-1β and shear stress [72,207,208,209,210,211,212,213,214].   Reduced TFPI and t-PA synthesis and increased PAI-1 expression by ECs potentiate the prothrombotic status [179,209,219,224,228].   Glycocalyx injury is initiated by specific enzymes (glucuronidases, hyaluronidases, plasmin, ROS) and hypervolemia (via excessive fluid administration within sepsis management) [227,228,229,230,231].	Activated coagulation FX and thrombin may cleave S protein and promote viral entry in a potential inflammation–coagulation positive feedback loop [61].   Platelet–monocyte interactions are themain stimulus for monocyte activation with robust cytokine and chemokine secretion and TF expression [77].   Low-density granulocytes are found in greater proportions in COVID-19 patients; they are more active in generating NETs, further enhancing hypercoagulability-mediated organ damage [94,95,96].   Platelets from COVID-19 patients exhibit a particular hyperreactivity to low-dose common agonists (such as collagen, α-thrombin or ADP) [143,144,145].   IL-6 and TNF-α can directly activate platelets; IL-6 and IL-1β can prime platelets before stimulation by classical agonists [161].   Pulmonary-residing megakaryocytes are theoretically susceptible to SARS-CoV-2 infection and may transfer viral particles and cytokines when new circulating platelets are generated [144].   SARS-CoV-2 can infect endothelial cells via ACE2 and TMPRSS2, with endotheliitis as a result of direct viral entry [208].   S-protein-related damage increases adhesion molecules’ exposure, ROS synthesis and matrix metalloproteinases’ release with the disruption of the endothelial barrier [179,209,215,216,217,218,219].   COVID-19 induces a hyperactive state of the KKS pathway, promoting vascular permeability [217,220,221].   Excessive complement activation via the lectin pathway accentuates endothelial-derived immunothrombosis [217,220,221].

ACE2—angiotensin-converting enzyme 2; ADAMTS13—ADisintegrinandMetalloprotease with ThromboSpondin type 1 motif, member13; ADP—adenosinediphosphate; cfDNA—cell-free desoxyribonucleic acid; CLR—C-type lectin receptor; COVID-19—coronavirus disease 2019; DAMP—damage-associated molecular pattern; EC—endothelial cell; FVIII, FX, FXI, FXII—coagulation factor VIII, X, XI, XII; HMGB1—high mobility group box 1; IFN-γ—interferonγ; IL-1β, IL-3, IL-6—interleukin 1β, 3, 6; KKS—kallikrein-kinin system; LPS—lipopolysaccharides; MAPK—mitogen-activated protein kinase; MP—microparticle; NET—neutrophil extracellular trap; NF-κB—nuclear factor kappa B; PAI-1—plasminogen activator inhibitor-1; PAMP—pathogen-associated molecular pattern; ROS—reactive oxygen species; TF—tissue factor; TFPI—tissue factor pathway inhibitor; Tie2—tyrosine kinase with immunoglobulin-like loops and epidermal growth factor homology domains-2; TLR—Toll-like receptor; TMPRSS2—transmembrane protease serine 2; TNF-α—tumor necrosis factor α; tPA—tissue type plasminogen activator; TxA2—thromboxane A2; u-PA—urokinase-type plasminogen activator; vWF—von Willebrand factor.