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Background The cell membrane‐derived initiators of coagulation, tissue factor (TF) and anionic phospholipid (aPL), are constitutive on the herpes simplex virus type 1 (HSV1) surface, bypassing physiological regulation. TF and aPL accelerate proteolytic activation of factor (F) X to FXa by FVIIa to induce clot formation and cell signaling. Thus, infection in vivo is enhanced by virus surface TF. HSV1‐encoded glycoprotein C (gC) is implicated in this tenase activity by providing viral FX binding sites and increasing FVIIa function in solution. Objective To examine the biochemical influences of gC on FVIIa‐dependent FX activation. Methods Immunogold electron microscopy (IEM), kinetic chromogenic assays and microscale thermophoresis were used to dissect tenase biochemistry. Recombinant TF and gC were solubilized (s) by substituting the transmembrane domain with poly‐histidine, which could be orientated on synthetic unilamellar vesicles containing Ni‐chelating lipid (Ni‐aPL). These constructs were compared to purified HSV1 TF±/gC ± variants. Results IEM confirmed that gC, TF, and aPL are simultaneously expressed on a single HSV1 particle where the contribution of gC to tenase activity required the availability of viral TF. Unlike viral tenase activity, the cofactor effects of sTF and sgC on FVIIa was additive when bound to Ni‐aPL. FVIIa was found to bind to sgC and this was enhanced by FX. Orientation of sgC on a lipid membrane was critical for FVIIa‐dependent FX activation. Conclusions The assembly of gC with FVIIa/FX parallels that of TF and may involve other constituents on the HSV1 envelope with implications in virus infection and pathology.

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.