key: cord-265899-skpkuzyu
authors: Pryzdial, Edward L. G.; Sutherland, Michael R.; Lin, Bryan H.; Horwitz, Marc
title: Antiviral anticoagulation
date: 2020-07-06
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12406
sha: 
doc_id: 265899
cord_uid: skpkuzyu

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a novel envelope virus that causes coronavirus disease 2019 (COVID‐19). Hallmarks of COVID‐19 are a puzzling form of thrombophilia that has elevated D‐dimer but only modest effects on other parameters of coagulopathy. This is combined with severe inflammation, often leading to acute respiratory distress and possible lethality. Coagulopathy and inflammation are interconnected by the transmembrane receptor, tissue factor (TF), which initiates blood clotting as a cofactor for factor VIIa (FVIIa)‐mediated factor Xa (FXa) generation. TF also functions from within the nascent TF/FVIIa/FXa complex to trigger profound changes via protease‐activated receptors (PARs) in many cell types, including SARS‐CoV‐2–trophic cells. Therefore, aberrant expression of TF may be the underlying basis of COVID‐19 symptoms. Evidence suggests a correlation between infection with many virus types and development of clotting‐related symptoms, ranging from heart disease to bleeding, depending on the virus. Since numerous cell types express TF and can act as sites for virus replication, a model envelope virus, herpes simplex virus type 1 (HSV1), has been used to investigate the uptake of TF into the envelope. Indeed, HSV1 and other viruses harbor surface TF antigen, which retains clotting and PAR signaling function. Strikingly, envelope TF is essential for HSV1 infection in mice, and the FXa‐directed oral anticoagulant apixaban had remarkable antiviral efficacy. SARS‐CoV‐2 replicates in TF‐bearing epithelial and endothelial cells and may stimulate and integrate host cell TF, like HSV1 and other known coagulopathic viruses. Combined with this possibility, the features of COVID‐19 suggest that it is a TFopathy, and the TF/FVIIa/FXa complex is a feasible therapeutic target.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1,2 is a novel envelope 3 virus that causes life-threatening thrombotic coagulopathy 4-10 and inflammation, 1, 11, 12 The overall mortality rate of confirmed infections is > 1.5%, although this is likely an overestimate since it is known that there is a dangerously significant number of unaccounted asymptomatic carriers 14 and mass screening is not yet practical. Medical scientists from all pillars of investigation have united from around the globe toward developing therapeutics that will mitigate the morbidity and mortality of COVID-19 and stop the virus replication cycle. Here, we draw attention to the fact that SARS-CoV-2 is an extreme example within a broad spectrum of coagulopathic envelope viruses. The pathology manifested is specific to the virus but may be explained by a unifying constituent, tissue factor (TF), the physiological initiator of coagulation and potent cell-modulating cofactor. Thus, therapeutics F I G U R E 1 Tissue factor (TF) in viral D-dimer production. TF activity localized on the stimulated cell or on the envelope virus surface combines with the protease factor VII (FVIIa) to accelerate factor Xa (FXa) generation in the presence of anionic phospholipid (green polar head groups) and calcium. Release of FXa from the nascent TF/FVIIa/FXa complex facilitates thrombin production (factor IIa [FIIa] ). Thrombin is the pivotal effector of fibrin clot formation by proteolytic excision of fibrinopeptides (green) from fibrinogen triggering noncovalent (red lines) polymerization of soluble fibrin. Thrombin also activates the transglutaminase factor XIII (FXIII), which crosslinkstabilizes the interfibrin associations (green bars). Both the TF/FVIIa/FXa complex and thrombin are potent protease-activated receptor 2 (PAR2) agonists, which may induce the release of tissue-type plasminogen activator (t-PA) from cells to enhance plasminogen (Pg) to plasmin (Pn) activation, resulting in D-dimer and fibrin degradation product formation. Thus, inhibition of FXa with small molecule inhibitors (eg apixaban) may attenuate both signaling and procoagulant branches of TF function toward D-dimer formation targeting TF are prime candidates to consider for SARS-CoV-2 intervention.

SARS-CoV-2 infection is associated with coagulopathy. 15 The compelling clinical laboratory evidence is that COVID-19 results in elevated D-dimer, 11, [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] which is a dogmatic metric of hypercoagulation. D-dimer is a fragment of factor XIIIa (FXIIIa)-crosslinked fibrin and is produced when tissue-type plasminogen activator (t-PA) converts plasminogen to the activated fibrinolytic protease plasmin in response to thrombin-driven clot accumulation ( Figure 1 ). Therefore, D-dimer may also suggest hyperfibrinolysis. Supporting this possibility in COVID-19, elevated plasminogen has been reported as a risk factor. 25 Thrombin is also known to stimulate the secretion of t-PA, priming the local milieu for a fibrinolytic response. [30] [31] [32] When stratified according to severity of disease or need for mechanical ventilation, D-dimer is found to be a predictor of COVID-19 disease progression. 28 Additional evidence of coagulopathy is provided by a meta-analysis of 9 studies reporting data on platelet counts from 1779 patients with COVID-19, of which 399 were severe. 34 The weighted mean difference in this report revealed an ~ 15% drop in platelet number, which is reduced another ~ 10% for nonsurvivors. While numerous factors may contribute to a reduced platelet count in virus infection, 35 thrombocytopenia is usually attributed to enhanced thrombin production with consequent platelet activation and subsequent senescence.

Fibrinogen, clinically evaluated in the diagnosis of coagulopathy, is reported to increase in patients during severe disease compared to mild COVID-19 27, [36] [37] [38] and may be the result of an acute-phase response. Interestingly, an exception to this trend was observed at late hospitalization when 2 severely diseased patients became hypofibrinogenemic. 27 This late-stage observation is consistent with the parameters of conventional disseminated intravascular coagulation (DIC). 39 Together, these observations make a compelling argument for SARS-CoV-2-induced coagulopathy. Although elevated D-dimer alludes to DIC, COVID-19 does not satisfy the other prominent characteristics of overt thrombin generation consistent within the ISTH definition 39 ; COVID-19 does not have prolonged PT of > 3 seconds, platelet count dropping to < 100 × 10 9 /L or fibrinogen dropping to < 1 gm/L. It follows that COVID-19 coagulopathy does not lead to a hemorrhagic condition but rather to a prothrombotic state.

To substantiate this, there is overwhelming evidence for prevalent pulmonary embolism, thrombotic microangiopathy, and arterial thrombosis. [4] [5] [6] [7] [8] [9] [10] Whether the virus causes these events or patient predisposition to hypercoagulation favors infection, or both, is unknown.

Severe pneumonia and the associated respiratory distress, originally attributed as the leading cause of death in COVID-19, 1,11 is now known to involve pulmonary embolism. [4] [5] [6] [7] [8] [9] [10] The severity of the hallmark pulmonary inflammation correlates to lymphocyte subgroups 40 and glassy alveolar opacities have been documented in computed tomography images. 6 When uncontrolled, the prolonged inflammatory imbalance ultimately leads to multiple organ failure. This progression may be influenced by the broad tissue distribution of the virus's primary host cell docking site, the angiotensin-converting enzyme 2 (ACE2) receptor, 41, 42 found in the lungs, kidneys, brain, gastrointestinal tract, and cardiovascular system. 43, 44 The severity of COVID-19 presentation and disease progression range widely for unknown reasons, and thus treatment options vary.

However, prophylactic anticoagulation is the accepted standard.

General predictors of poor outcome were identified quite early in the SARS-CoV-2 pandemic as advanced age and male sex, 45, 46 while comorbidities include, diabetes, 16, 28 hypertension, cardiovascular disease, 12 and obesity. 47 These underlying pathologies are all characterized by chronic inflammation, presenting clinically as elevated levels of acute-phase reactants, most notably C-reactive protein. 11, 16, 20, 21, 29 Secretion of high levels of circulating proinflammatory cytokines, interleukin (IL)-6, IL-1, interferon-γ, and tumor necrosis factor have also been documented and attributed to an immune-surveillance response. 11 

It is not surprising that evidence is accumulating to show the etiology of COVID-19 pneumonia is both coagulopathic (ie, elevated D-dimer) and inflammatory (ie, elevated IL-6), since the 2 pathways are intimately connected. The molecular bridge between hemostasis and the innate inflammatory response is the coagulation trigger, TF. 50 TF has been unequivocally identified as a mechanistic pathophysiological mediator in numerous mouse models of disease and clinical correlations have been made; examples include cancer, 51, 52 sickle cell disease, 53, 54 obesity and diabetes, 55-57 rheumatoid arthritis, 58, 59 and cardiovascular disease. 60, 61 Thus, TF is a probable effector of the progression and severity of thrombosis and inflammation seen in COVID-19.

TF is a transmembrane receptor essential for mammalian life. [62] [63] [64] It is pivotal in the blood clotting mechanism and best understood as the extrinsic tenase cofactor, 65 functioning to accelerate factor VIIa (FVIIa)-dependent proteolytic activation of factor X (FX) to FXa in the presence of an anionic phospholipid (aPL)-containing membrane and calcium ( Figure 1 ). However, TF also participates to accelerate FVIIa activity toward the initial activation of factor IX (FIX)

to FIXa and FVIII to FVIIIa, and autoactivation of FVII. [66] [67] [68] [69] [70] The coagulopathic consequence of enhanced clotting factor activation is that downstream thrombin acts as its own feedback amplifier for subsequent clot formation. Thus, enhanced TF activity may be extrapolated using clinical laboratory values of D-dimer elevation as a surrogate marker.

Of equal or greater importance to the clotting function of TF is its critical role as a cell-signaling cofactor from within the TF/VIIa cofactor/protease and nascent TF/FVIIa/FXa cofactor/protease/product complexes. 71 These facilitate cell signaling via protease activated receptors (PARs) (Figure 1 ). PAR extracellular domains are cleaved by the TF-enhanced protease, and the new N-terminus acts as a tethered ligand that sends a transmembrane signal transduced by G-protein-and β-arrestin-coupled intracellular pathways. 72 These stimulate fundamental biochemical pathways such as kinase cycles, gene transcription, and protein synthesis. 73, 74 The biological result may be profound, ranging from effects on storage granule release (eg, cytokines) to cell trafficking, which likely impacts COVID-19-dependent pulmonary inflammation.

The stimulatory effects of the TF-protease complexes are predominantly conferred through PAR1 and PAR2, although indirect effects on PAR3 and PAR4 also occur through mobilization of effector proteases. TF is prevalent throughout the body and is constitutively expressed by fibroblasts, pericytes, smooth muscle cells, epithelial cells, astrocytes, and cardiomyocytes, and inducibility expressed on endothelial and monocyte lineage cells. 64 Similarly, PARs have an extremely broad cellular and tissue distribution that includes key contributors in COVID-19 progression: vascular endothelium, platelets, leukocytes, smooth muscle cells, and airway epithelium. 75 Thus, the TF-PAR pathway is positioned at crucial interfaces where a multitude of relevant physiological and pathological processes occur. 71, 76, 77 TF/FVIIa exclusively cleaves and activates PAR2 with relatively low affinity; however, the cofactor signaling effects of TF are greatly enhanced after thiol oxidation and in the presence of nascent FXa. 71 Within the ternary TF/FVIIa/FXa complex, FXa becomes the proteolytic subunit. TF-mediated signaling is enhanced by additional cell-specific receptors. On the endothelial cell vascular lining and alveolar epithelial lining, 78 a major site of SARS-CoV-2 infection, the endothelial protein C receptor-TF/ FVIIa/FXa complex cleaves and activates PAR2 and PAR1. 79, 80 Consequently, the effective concentration of FVIIa is reduced by more than 10-fold. 79, 80 Thrombin is also an efficient activator of PAR1 and does not require an accessory cofactor because PAR1 has a high-affinity binding site. 81 The combined effects of cell surface-localized hemostatic proteases in the vicinity of PARs creates a potent trigger for inflammation and other pathophysiological consequences. To stimulate discussion in a novel area of clinical intervention strategies to alleviate COVID-19, here anticoagulation of the TF-PAR axis is proposed as having an additional antiviral therapeutic value.

Different viruses manifest diverse illnesses because of the unique proteins encoded by their genome and the cell and organ tropism dictated by those proteins. As an example, the SARS-CoV-2 envelope surface "spike" protein facilitates fundamental docking with the cell surface receptor ACE2. However, contrary to the dogma that each virus encodes unique proteins and must therefore give rise to unique pathology, numerous virus types have in common the modulation of the blood clotting system with correlations to hemostatic pathology.

The symptoms range widely depending on the virus type and are driven by complicated virus-host mechanisms, involving hemostatic proteins (clotting, anticoagulant, and fibrinolytic), 82 108, 109 and the cold sore virus (herpes simplex virus type 2 [HSV1]). [110] [111] [112] [113] We propose that a mutual molecular basis explains this diverse and extensive list.

Each of the viruses above and many more have an envelope as a common structural feature, which is a surrounding phospholipid bilayer acquired from infected host cellular membranes.

Within the envelope are membrane-associated proteins. Some of these envelope proteins are encoded by the virus genome, like the SARS-CoV-2 spike protein. 114, 115 However, many other proteins are associated with the envelope but are encoded by the host and derived from the cell where the virus replicates and acquires the envelope. While much is known about the roles of virus-encoded envelope proteins and their roles in the infection mechanism, the functions of host-encoded proteins on the virus surface have been given relatively little consideration in the prevailing paradigm. 116 Many cells known to bear TF are permissive to infection by clinically important enveloped viruses, including SARS-CoV-2, 117 HSV1, 118 Ebola, 119 influenza, 120 HIV, 121 dengue, 122 Zika virus, 123 HCV, 124 and others. It is reasonable to speculate that the surface of these and other viruses display TF, which may account for hemostatic and inflammatory symptoms associated with their infection. Therefore, the TF-initiated mechanisms may serve as a broad-specificity target to alleviate viral pathology, such as in COVID-19.

To investigate TF as a general surface constituent of envelope viruses, we have studied HSV1 as a model virus. Over two-thirds of the world's population is infected by HSV1, which is the leading cause of infectious blindness, 125 sporadic encephalitis, 126 and genital herpes 127, 128 and is associated with intestinal dysregulation. 129 Although known as the cold sore virus and typically not life threatening, there are numerous correlations between HSV1 and other members of the herpesvirus family to cardiovascular disease, 130, 131 suggesting links to TF: (i) HSV1 seropositivity is associated with a 2-fold increase in myocardial infarction incidence and death due to coronary heart disease 113 ; (ii) fibrin deposits in the microvasculature are linked to HSV1 infection 132, 133 ; (iii) DIC in neonates may occur during severe HSV1 infection 134 ; (iv) HSV2 is linked to ischemic and hemorrhagic stroke due to DIC 107, 135 ; (v) a history of CMV infection is linked to subclinical and clinical arterial thickening [136] [137] [138] ; (vi) CMV is strongly correlated to accelerated atherosclerosis in immunosuppressed organ transplant recipients [139] [140] [141] [142] ; and (vii) CMV infection is a strong risk factor for restenosis after angioplasty. 143, 144 When paired with other known cardiovascular risk factors, viral correlation to vascular disease is strong. [110] [111] [112] [113] A clear cause-and-effect relationship has been established in several animal models, which confirm that herpesviruses accelerate thrombosis and atherosclerosis. [145] [146] [147] Indeed, HSV1 and CMV are known to induce TF activity on vascular endothelial cells, 148, 149 which support infection and from which the replicative viruses derive their envelope. 74 Electron microscopy can definitively identify the presence of a macromolecular structure associated with the surface of a virus.

Using HSV1 propagated in TF-expressing cultured cells and purified by sucrose gradient differential ultracentrifugation, 74 multiple-sized electron-dense gold beads were used to simultaneously distinguish 3 constituents on a single HSV1. 150 Confirming the identity of the particle as HSV1, the largest gold bead shown in Figure 2 denotes HSV1 encoded glycoprotein C (gC). gC is a multifunctional contributor to virus infection known to participate in virus attachment to the cell through association with heparan sulfate proteoglycan and in the evasion of host defense by complement. 153, 154 When expressed on the surface of infected cells, gC has been shown to be involved in FX activation and binding, 148, 155, 156 which is another reason it was selected as a marker to confirm virus identity. We have reported that purified gC and gC on the virus surface mimics the cofactor function of TF toward FVIIaenhanced FXa generation. 150, 151 Like TF, it binds directly to both FVIIa and FX forming a cofactor-protease-substrate complex. 150 A further similarity to TF is that FX stabilizes gC-FVIIa cofactor-protease assembly, which for TF would rigorously localize the hemostatic response to sites of aPL accessibility. This similarly applies to the virus surface and would initiate symptomatic consequences with severity dependent on accessory constituents on the envelope and the cells that are affected.

The mimicry of TF by gC implies an advantage to the virus when hemostatic proteases are activated at the site of virus-cell docking.

Pretreatment of endothelial cell monolayers with nanomolar concentrations of proteases known to trigger PARs, including FVIIa, FXa, thrombin, and plasmin, enhanced viral plaque formation by up to an order of magnitude when in combination, 73, 74 as did in situ FX zymogen activation. 74 To discriminate between viral and cellular effects of TF in the infection cycle, a novel panel of HSV1 was created using a TF-inducible human A7 melanoma cell line 157 and combining this with engineered HSV1 deficient in gC production. 74 Thus, HSV1/TF-/gC-, HSV1/TF+/gC-, HSV1/TF-/gC + and HSV1/TF+/ F I G U R E 3 Viral tissue factor (TF) and hemostatic proteases enhance infection via protease-activated receptors (PARs) in vitro. 73 

The effects of envelope TF on infection have been investigated in mice using HSV1/TF±. 158 a much lower antiviral dose will also be efficacious but this remains untested. Consistent with in vitro PAR studies, 74 these in vivo data

show that directly anticoagulating the nascent TF/FVIIa/FXa complex or the proteases subsequently generated in the TF pathway, FXa and thrombin, is antiviral.

While the specific involvement of TF in coagulopathy induced by SARS-CoV-2 or other viruses has not yet been widely studied, enhanced TF activity has been associated with the primary complication of COVID-19, acute respiratory distress syndrome (ARDS). 165 ARDS typifies severe influenza virus infection, and this correlates to patient microvesicle-associated TF. 166 TF is known to play a role in Ebola virus-induced coagulopathy, 89, 167 where NAPc2 reduced symptoms and increased survival of infected rhesus macaques. Of note, NAPc2 treatment also reduced virus load. 104 Combined with HSV1 results (Figures 4 and 5) , TF is emerging as a key effector of viral pathophysiology and replication cycle.

Like severe COVID-19, D-dimer is elevated in Ebola virus infection. 103 In surviving Ebola-infected animals, treatment with NAPc2 However, simultaneously mitigating thromboinflammation and the underlying basis, persistent virus replication, will reduce the duration of morbidity and mitigate tissue damage.

To address the high prothrombotic rates that are being reported for COVID-19, 4-10 thrombolysis with recombinant t-PA has been used to treat patients with respiratory distress syndrome. 175 In this case report, 3 patients initially showed symptomatic improvement, with 1 surviving. However, the downstream enzyme produced by t-PA, plasmin, has been predicted to proteolytically prepare the SARS-CoV-2 spike-protein for entry into ACE2-containing cells. 25 virus. These latter effects may involve PAR2 signaling that is distal from the initial role played by envelope TF. Thus, the timing that anticoagulant therapy is delivered may impact its concomitant anticoagulant, antiviral, and anti-inflammatory properties.

Envelope TF may be a virulence effector and the long-sought common denominator linking numerous prevalent envelope viruses. The monumental question is how to singularly exploit TF as an antiviral target and to diminish inflammation when its roles in physiology are vast? FXa-specific DOACs have been reported as having both 

The authors declare nothing to report.

EP wrote the manuscript; MS analyzed data, prepared figures, and edited the manuscript; BL prepared figures, and edited the manuscript. MH edited the manuscript.

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Zika and chikungunya virus and risk for venous thromboembolism

Interleukin 6 is a stronger predictor of clinical events than high-sensitivity C-reactive protein or D-dimer during HIV infection

Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease

Thrombin-mediated activation of PAR-1 contributes to microvascular stasis in mouse models of sickle cell disease

Pleiotropic effects of factor Xa and thrombin: what to expect from novel anticoagulants

Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo

Protective role for protease-activated receptor-2 against influenza virus pathogenesis via an IFN-gammadependent pathway

PAR-1 contributes to the innate immune response during viral infection

PAR1 contributes to influenza A virus pathogenicity in mice