Journal
CIRCULATION
Volume 128, Issue 3, Pages 254-266Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.113.003191
Keywords
anticoagulants; blood coagulation; ticks
Funding
- Onze Lieve Vrouwe Gasthuis research fund
- National Institutes of Health [41440, 49200, 32947, T32 HL07439]
- Netherlands Organization for Health Research and Development (ZonMw) [91611065]
- [R01-HL88010]
- [P01-HL74124]
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Background Generation of active procoagulant cofactor factor Va (FVa) and its subsequent association with the enzyme activated factor X (FXa) to form the prothrombinase complex is a pivotal initial event in blood coagulation and has been the subject of investigative effort, speculation, and controversy. The current paradigm assumes that FV activation is initiated by limited proteolysis by traces of (meizo) thrombin. Methods and Results Recombinant tick salivary protein TIX-5 was produced and anticoagulant properties were studied with the use of plasma, whole blood, and purified systems. Here, we report that TIX-5 specifically inhibits FXa-mediated FV activation involving the B domain of FV and show that FXa activation of FV is pivotal for plasma and blood clotting. Accordingly, tick feeding is impaired on TIX-5 immune rabbits, displaying the in vivo importance of TIX-5. Conclusions Our data elucidate a unique molecular mechanism by which ticks inhibit the host's coagulation system. From our data, we propose a revised blood coagulation scheme in which direct FXa-mediated FV activation occurs in the initiation phase during which thrombin-mediated FV activation is restrained by fibrinogen and inhibitors.
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