Herpesviruses have been previously correlated to vascular disease and shown to cause thrombogenic and atherogenic changes to host cells. The work conducted in this thesis showed that even in the absence of cells, purified cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) could initiate thrombin production. Clotting and chromogenic assays showed that purified HSV-1 and HSV-2 provide the procoagulant phospholipid (proPL) necessary for assembly of factors Xa (FXa) and Va (FVa) into prothrombinase, which is responsible for generating thrombin. These findings are consistent with earlier CMV studies. These observations were confirmed by electron microscopy and flow cytometry using FVa and annexin V, respectively, as proPL-specific probes. CMV, HSV-1 and HSV-2 each had the ability to facilitate FXa generation from the inactive precursor factor X (FX), but only when factor VII/VIIa and Ca$\sp{2+}$ were present. Monoclonal antibodies specific for the coagulation initiator, tissue factor (TF), inhibited this FX activation and furthermore enabled identification of TF antigen on each virus type by electron microscopy and flow cytometry. Collectively, these data show that CMV, HSV-1 and HSV-2 can initiate the generation of thrombin by having essential proPL and TF activities on their surface. Unlike the normal cellular source, the viral activity is constitutive and therefore not restricted to sites of vascular injury. Thus cell-independent thrombin production may be the earliest event in vascular pathology mediated by herpesviruses.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/4194 |
| Date | January 1998 |
| Creators | Sutherland, Michael R. |
| Contributors | Pryzdial, Edward, |
| Publisher | University of Ottawa (Canada) |
| Source Sets | Université d’Ottawa |
| Detected Language | English |
| Type | Thesis |
| Format | 70 p. |
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