Research ArticleBioengineering

A synthetic fibrin cross-linking polymer for modulating clot properties and inducing hemostasis

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Science Translational Medicine  04 Mar 2015:
Vol. 7, Issue 277, pp. 277ra29
DOI: 10.1126/scitranslmed.3010383

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Bioinspired polymers fortify blood clots

Major blood loss is a leading cause of death after trauma, and currently available intravenously delivered clotting agents are expensive, require special storage, have limited shelf life, and carry risk of immunogenicity. In this issue, Chan et al. describe an off-the-shelf, synthetic, bioinspired polymer called PolySTAT that stops the bleeding after trauma and restores hemostasis. In healthy animals, the polymer flows throughout the body, harmless and passive. Upon encountering a blood clot at a site of vascular injury, PolySTAT cross-links the fledgling fibrin matrix much like the transglutaminase factor XIII, strengthening the clot and fortifying it against degrading enzymes that are overactive in trauma. In a rat model of femoral artery injury and fluid resuscitation, PolySTAT or control therapies were injected immediately after the onset of bleeding. All animals treated with PolySTAT survived, whereas only 4 of the remaining 20 animals in various control groups survived. Additionally, none of the PolySTAT-treated animals experienced rebleeding, suggesting that the clots formed were strong, despite increased blood pressure from the infusions. This polymer-based solution to clotting could be a welcomed addition in critical care medicine, because its specificity minimizes risk of distant thrombosis (for example, in the heart or lungs) and has scalable manufacturing properties as well as favorable biodistribution and pharmacokinetics. Further preclinical studies will be needed in larger animal models to evaluate not only clotting function but also the extent of organ injury in surviving animals.

Abstract

Clotting factor replacement is the standard management of acute bleeding in congenital and acquired bleeding disorders. We present a synthetic approach to hemostasis using an engineered hemostatic polymer (PolySTAT) that circulates innocuously in the blood, identifies sites of vascular injury, and promotes clot formation to stop bleeding. PolySTAT induces hemostasis by cross-linking the fibrin matrix within clots, mimicking the function of the transglutaminase factor XIII. Furthermore, synthetic PolySTAT binds specifically to fibrin monomers and is uniformly integrated into fibrin fibers during fibrin polymerization, resulting in a fortified, hybrid polymer network with enhanced resistance to enzymatic degradation. In vivo hemostatic activity was confirmed in a rat model of trauma and fluid resuscitation in which intravenous administration of PolySTAT improved survival by reducing blood loss and resuscitation fluid requirements. PolySTAT-induced fibrin cross-linking is a novel approach to hemostasis using synthetic polymers for noninvasive modulation of clot architecture with potentially wide-ranging therapeutic applications.

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