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

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.

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).

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.

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.