To address this challenge, the we have developed microparticles that propel upstream through blood and deliver therapeutics deep into wounds. These microparticles, loaded with a powerful pro-coagulant enzyme, thrombin, successfully reduced blood loss and mortality in small and large animal models of bleeding in trauma, surgery and endoscopy. These hemostatic products are being translated in collaboration with commercial and military partners. We are currently testing the ability of these microparticles to deliver antimicrobials into wounds to prevent infection during injury.

Thrombosis is also treated with anticoagulants that target events upstream of fibrin crosslinking to prevent additional clots from forming in the patient. However, these carry the risk of unwanted bleeding. We hypothesized that a safer approach is instead to inhibit the crosslinking of fibrin, which would allow an initial plug to form and seal the wound, but also increase the susceptibility of the clot to degradation. To test this hypothesis, we are exploring whether knockdown of FXIIIa, and proteins that regulate its activity, are alternative therapies for thrombosis.

Neurodegenerative diseases have also been linked to defective clotting. For example, amyloid beta (Aβ), a key protein associated with Alzheimer’s disease, interacts with coagulation proteins and can accumulate along the inside of blood vessels during cerebral amyloid angiopathy. We recently showed that FXIIIa can crosslink Aβ to itself and to fibrinogen to make clots stiffer. We are currently exploring the physiological significance of this interaction to determine whether Aβ is a normal component of blood clots in the brain, or if FXIIIa contributes to the pathology of cerebral amyloid angiopathy. As platelets are an abundant source of Aβ precursor protein, we are also investigating the physiological role of Aβ precursor protein in platelets.

The Kastrup lab has an ongoing partnership with spin-off company CoMotion Drug Delivery Systems Inc. and also collaborates with SeraGene Therapeutics and NanoVation Therapeutics.