Therapeutic use of α2-antiplasmin as an antifibrinolytic and hemostatic agent in surgery and regenerative medicine
The biomaterial fibrin is widely used as a clinical tissue sealant in surgery. In these applications, premature fibrin degradation leads to recurrent bleeding, tissue dehiscence and limited regenerative efficacy. Therefore, fibrinolysis inhibitors have been added to clinical fibrin formulations, for example the bovine-derived serine protease inhibitor aprotinin.
Aprotinin is currentlyusedin the clinic as a broad-spectrum serine protease inhibitor to stabilize fibrin biomaterials and to reduce bleeding loss during surgery. Nevertheless, the bovine origin of aprotinin raised immune-related safety concerns, particularly upon drug re-exposure.
In this study, we explore the therapeutic use of α2-antiplasmin(α2PI) as a potential substitute to aprotinin for local and systemic applications. Since α2PI is naturally present in human blood and can be efficiently extracted from it, blood is a donation source for its medicinal use. α2PI is the main inhibitor of plasmin in humans, with plasmin being one of the most important fibrinolytic protease. Interestingly, α2PI naturally crosslinks into fibrin during clotting due to the presence of a transglutaminase substrate sequence (α2PI1–8) at its N-terminus, which could sustain its antifibrinolytic effects by preventing its rapid release from fibrin. This, along with the human origin of α2PI, might constitute strong advantages over aprotinin.
Recombinant α2PI can successfully prolong the durability of fibrin biomaterials as compared to aprotinin in a model of subcutaneous implantation in mice mimicking application as a tissue sealant. We used α2PI to enhance the delivery of engineered vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF)-BB in fibrin in promoting diabetic wound healing, which lead to improved wound closure, granulation tissue formation and angiogenesis. Lastly, we demonstrated that α2PI can be as effective as aprotinin as an intravenous hemostatic agent to prevent blood loss, using a tail-vein bleeding model in mice.
It would be important to evaluate side-by-side the efficacy and safety of the α2PI as compared to the use of TXA and aprotinin in specific applications. In general, the clinical development of α2PI as a human-derived fibrinolytic inhibitor, might be valuable in multiple applications of regenerative medicine.
https://www.nature.com/articles/s41536-022-00230-x
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