Involvement of the contact phase and intrinsic pathway in herpes simplex virus-initiated plasma coagulation

Background: A hemostatic response to vascular injury is initiated by the extrinsic pathway of coagulation and amplified by the intrinsic pathway. We previously reported that purified herpes simplex virus type-1 (HSV1) has constitutive extrinsic pathway tissue factor (TF) and anionic phospholipid on its surface derived from the host cell, and can consequently bypass strict cellular control of coagulation. Objective: The current work addresses the hypothesis that HSV1-induced plasma coagulation also involves intrinsic pathway, factor VIII (FVIII), and upstream contact activation pathway, factor XII (FXII). Results: HSV1-initiated clotting was accelerated when purified FVIII was added to FVIII-deficient plasma and in normal plasma attenuated by an inhibitory anti-FVIII antibody (Ab). High HSV1 concentrations predictably reduced the effect of FVIII due to the availability of excess viral TF. To further define TF-independent clotting mechanisms initiated by HSV1, the extrinsic pathway was disabled using factor VII-deficient plasma. The intrinsic pathway is triggered by activation of FXII associated with surface-bound kallikrein, which subsequently activates factor XI. Here we found that an inhibitor of activated FXII, corn trypsin inhibitor, and anti-FXII, anti-kallikrein and anti-FXI Abs inhibited HSV1-initiated clotting. HSV1-enhanced activation of purified FXII was confirmed by Western blot, but required prekallikrein. Conclusion: The current work shows that HSV1 can trigger and amplify coagulation through the contact phase and intrinsic pathway, and suggests an additional mechanism that may contribute to vascular pathology.