The powerful enzyme thrombin is by far the most robust activator of platelets and blood clotting (coagulation) in both physiological haemostasis and pathological thrombotic response. A major problem with thrombolysis is the release of clot-bound thrombin. Fibrin clots contain a large amount of thrombin, which is released into the circulation following rtPA lysis of the fibrin clot. This pool of thrombin remains highly active and is responsible for the activation of platelets (blood clotting cells) and generation of additional fibrin, leading to rethrombosis. Therefore, a strong mechanistic rationale exists for the use of thrombin inhibitors to enhance thrombolysis in stroke.
Therapeutic inhibition of thrombin has been shown to be an effective antithrombotic agent, however, all current inhibitors of this enzyme lead to severe bleeding complications. In an NHMRC joint funded collaboration with Professor Richard Payne at The University of Sydney’s School of Chemistry, we have characterised novel anticlotting agents that have been based around naturally occurring proteins found in saliva of mosquitos.
Our studies have demonstrated that these bug-derived proteins are able to dissolve blood clots in a disease model of thrombosis with fewer bleeding complications. The outcomes of these studies have laid the foundation for the development of safe anticoagulants for the treatment of thromboembolic diseases such as stroke in the future