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Thromb Haemost 2012; 107(04): 760-768
DOI: 10.1160/TH11-08-0601
Wound Healing and Inflammation / Infection
Schattauer GmbH

Herpesviruses enhance fibrin clot lysis

Edwin S. Gershom
1   Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia Canadian Blood Services, Research and Development Department, Vancouver, British Columbia, Canada
,
Amanda L. Vanden Hoek
1   Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia Canadian Blood Services, Research and Development Department, Vancouver, British Columbia, Canada
,
Scott C. Meixner
1   Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia Canadian Blood Services, Research and Development Department, Vancouver, British Columbia, Canada
,
Michael R. Sutherland
1   Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia Canadian Blood Services, Research and Development Department, Vancouver, British Columbia, Canada
,
Edward L.G. Pryzdial
1   Department of Pathology and Laboratory Medicine, Centre for Blood Research, University of British Columbia Canadian Blood Services, Research and Development Department, Vancouver, British Columbia, Canada
› Author Affiliations Financial support: This study was supported by a Heart and Stroke Foundation of British Columbia and Yukon Grant in Aid (EP), AVH was the recipient of a Canadian Blood Services Graduate Fellowship.
Further Information

Publication History

Received: 31 August 2011

Accepted after major revision: 04 January 2012

Publication Date:
29 November 2017 (online)

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Summary

The incorporation of virus- and host-derived procoagulant factors initiates clotting directly on the surface of herpesviruses, which is an explanation for their correlation to vascular disease. The virus exploits the resulting thrombin to enhance infection by modulating the host cell through protease activated receptor (PAR) 1 signalling. Prior reports demonstrated that at least one herpesvirus expresses surface annexin A2 (A2), a cofactor for tissue plasminogen activator (tPA)-dependent activation of plasminogen to plasmin. Since plasmin is both a fibrinolytic protease and PAR agonist, we investigated whether herpesviruses enhance fibrinolysis and the effect of plasmin on cell infection. Herpes simplex virus types 1 (HSV1) and 2, and cytomegalovirus (CMV) purified from various cell lines each accelerated the proteolytic activation of plasminogen to plasmin by tPA. Ligand blots identified A2 as one of several plasminogen binding partners associated with the virus when compared to an A2-deficient virus. This was confirmed with inhibitory A2-antibodies. However, A2 was not required for virus-enhanced plasmin generation. HSV1, HSV2 and CMV accelerated tPA-dependent fibrin clot lysis by up to 2.8-fold. Modest plasmin generation and fibrinolysis was detected independent of exogenous tPA, which was inhibited by plasminogen activator inhibitor type-1 and ε-aminocaproic acid; however, the molecular basis remains speculative. Up to a ∼6-fold enhancement of infection was provided by plasmin-mediated cell infection. Inhibitory antibodies revealed that plasmin increased HSV1 infection through a mechanism involving PAR2. Thus, virus-enhanced fibrinolysis may help explain the paradox of the highly procoagulant in vitro herpesvirus surface eliciting only relatively weak independent vascular disease risk.

Keywords

Fibrinolysis - herpes simplex virus - cytomegalovirus - tissue plasminogen activator - plasmin
 

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