Enhanced thrombin generation and platelet binding on herpes simplex virus-infected endothelium.

Abstract

Atherosclerotic lesions have been reported to contain herpes simplex virus 1 (HSV-1) genomic material. This, and other previous evidence, suggests that latent viral infection may be an atherogenic trigger. Moreover, active HSV-1 lesions manifest marked fibrin deposition in microvessels. In this report we show that very early infection of human endothelial cells with HSV-1 appears to alter surface conformation as detected by merocyanine 540 staining. Concomitantly, the efficiency of prothrombinase complex assembly increases, resulting in a 2-to 3-fold accelerated rate of thrombin generation on the cell surface. Increased thrombin generation is probably doubly procoagulant, since we also demonstrate that thrombin-induced platelet accumulation on HSV-infected endothellum (50.7 ± 9.3%) is increased compared to uninfected endothelium (9.5 ± 2.1%; P < 0.002). Associated with HSV infection, prostacyclin secretion in response to thrombin is diminished by a factor of 20, probably explaining the enhanced platelet attachment. We conclude that HSV infection shifts endothelial cell properties from anticoagulant to procoagulant, both by promoting prothrombinase complex formation and function and by increasing platelet binding, well before cell disruption takes place. Virus-induced changes in the endothellal plasma membrane and diminished prostacyclin secretion are suggested as the pathways for this pathophysiologic mechanism, which may be germane to atherosclerotic thrombosis as well as HSV-mediated tissue necrosis.An intact vascular endothelium is actively antithrombotic. Rather than forming a passive vascular lining, endothelium has a variety of natural anticoagulant properties that are able to exert a dampening effect upon the coagulation cascade (1, 2): heparin-like species, thrombomodulin, plasminogen activator, and prostacyclin are endothelial constituents thought to contribute to vascular thromboresistance. Consequently, a breach of this barrier by mechanical disruption of the endothelial lining with frank endothelial loss and exposure of the subendothelium can lead to massive coagulation activation and platelet adherence. More subtle injury to endothehum that might alter its thromboresistant properties has only recently emerged as a topic of inquiry (3). Theoretically, several different mechanisms may be involved in diminished endothelial thromboresistance: (i) decreased production or exhibition of the above-mentioned antithrombotic factors; (ii) increased production or secretion ofthrombogenic factors such as tissue factor, platelet-activating factor, von Willebrand factor, and plasminogen-activator inhibitor; and (iii) changes in the endothelial cell surface, leading to altered exposure of proteins or procoagulant phospholipids.With regard to mechanism iii, endothelial cell surface alterations can result from viral infection, which readily occurs with several viruses in vitro. Diverse viruses replicate readily in cultured endothelium, including herpesviruses, adenoviruses, and enteroviruses, among others (4,...

The Role of Viruses in Cardiac Allograft Vasculopathy

“…Studies have demonstrated that infected endothelial cells have increased synthesis of tissue factor, cell surface thrombin expression, platelet adherence, and expression of adhesion molecules, cytokines and growth factors and decrease prostacyclin release (36)(37)(38)(39). Studies have reported that patients with multiple past infections (high pathogen burden) demonstrate endothelial dysfunction, and that the 'pathogen burden' is an independent predictor of endothelial dysfunction (40).…”

Herpesvirus Infection Accelerates Atherosclerosis in the Apolipoprotein E–Deficient Mouse

“…Both HCMV and HSV can infect ECs, initiating cellular responses similar to those in atherogenesis. 37,38 Furthermore, HCMV behaves differently in aortic ECs (a vessel susceptible to atheroma) than in brain microvascular ECs (in which atheroma is not found). 39 In aortic ECs, HCMV is nonlytic and is released persistently, whereas in small vessel ECs, it causes rapid lysis.…”

Herpesviruses in Atherosclerosis and Thrombosis

“…Changes in EC membrane phospholipid topography after herpesviral infection alter the efficiency of assembly of the prothrombinase complex and lead to enhanced thrombin generation. 96 HSV-infected ECs, in the presence of purified prothrombin, factor Va, and factor Xa, generated twofold to threefold more thrombin relative to uninfected ECs. 96 Furthermore, enhanced thrombin production resulted in increased platelet binding to the HSV-infected endothelium.…”

“…96 HSV-infected ECs, in the presence of purified prothrombin, factor Va, and factor Xa, generated twofold to threefold more thrombin relative to uninfected ECs. 96 Furthermore, enhanced thrombin production resulted in increased platelet binding to the HSV-infected endothelium. Thrombin-induced PGI 2 production by the infected endothelium was substantially reduced.…”