By Rolinda Carter, PhD Candidate in Pryzdial Lab
Effectively sealing a damaged blood vessel is the key to stopping bleeding. Physiologically, this is achieved by an initial platelet plug followed by a more stable fibrin rich blood clot. Fibrin, which is formed from fibrinogen, is the molecular mesh of the clot. It is stabilized and attached to the site of vessel injury by clotting factor XIIIa (FXIIIa) through irreversible crosslinking. When physiological adhesives are depleted, fibrinogen replacement therapy is used to stop bleeding. This strategy, however, is not fail-safe from re-bleeding due to normal fibrin clot dissolution. Thus, alternative mechanisms to increase clot adhesion are needed.
Karen Chan, a PhD candidate in the Kastrup lab at the CBR, along with other scientists, saw a promising alternative therapeutic in the use of FXIIIa-crosslinkable synthetic polymers such as Q-PEG. Q-PEG is a previously characterized 8-armed polyethylene glycol that is conjugated to a glutamine-containing peptide derived from α2-antiplasmin. In a recently published Biomacromolecules article, Karen and team demonstrated that Q-PEG can be formulated with spermidine, a polyamine substrate enabling crosslink formation by FXIIIa. This changes clot properties when added to blood, and the combination was shown to increase the adhesive strength of endogenous clots, restore the adhesion of fibrin poor clots and increase the resistance of clots to dissolution in the presence of the serine protease, tissue plasminogen activator. This is the first time that a material exogenous to the coagulation cascade has been shown to increase clot adhesion when copolymerized with endogenous components during clotting.
When asked about the expected impact of their research, Karen answered, “We believe that strategies for artificially enhancing blood clot adhesion may lead to the development of novel hemostatic agents that can mitigate bleeding under coagulopathic conditions in which fibrin may be depleted or degraded. We are currently exploring modifications to the Q-PEG material and its formulation and hope to take this towards new therapies for trauma-induced coagulopathy (TIC)”. In TIC, patients often develop fibrinogen deficiency and are more prone to enhanced fibrinolytic activity.
Read the UBC Coverage article.