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Kastrup Lab Uses Simulations to Uncover a Potential New Player in Thrombosis

By July 24, 2017No Comments

The formation of blood clots is mediated by an intricate and dynamic interplay between platelets, blood clotting proteins, and small molecules. While rapid clot formation is essential for stopping blood loss at wound sites, uncontrolled blood clotting can evolve into thrombosis, causing organ failure and even death if left untreated. In order to better understand the underlying complex biochemistry of coagulation, it is important to investigate the individual contributions of the various activators of clot formation.  Integrating both theoretical and experimental studies, researchers from Dr. Christian Kastrup’s lab have shed light on the mechanisms behind one such activator: short‑chain polyphosphate (PolyP).

Stored in platelet dense granules, short-chain PolyP is released into the bloodstream upon activation during the onset of thrombosis. While it is known that PolyP that does not originate from platelets can accelerate blood coagulation, the specific role of platelet-originating PolyP in thrombosis merits further study.

Earlier studies have demonstrated that higher local concentrations of coagulation activators increase the rate of clot formation. One way to increase the local concentration of such activators is to localize them to sites by immobilization onto surfaces.  Such effects have been observed with long-chain PolyP, which was found to be a better activator of coagulation when aggregated onto particles.

In a paper published in Scientific Reports, Kastrup lab members Ju Hun Yeon, former postdoctoral fellow, and PhD candidate Nima Mazinani, investigated whether short-chain PolyP exhibits accelerated clot formation when its local concentration is increased. To examine the influence of localization, they used numerical simulations with key parameters of blood clotting under flow including diffusion, convection, and enzyme reaction rates. The simulations suggested a localized burst of thrombin as a key contributor to enhanced coagulation on locally concentrated PolyP.

These predictions were substantiated through the use of a microfluidic model of thrombosis. Various lengths of synthetic PolyP, ranging from long‑chain PolyP to platelet‑derived short-chain PolyP, were either immobilized onto the walls of the microfluidic channels, assembled into nanoparticles, or dispersed in solution at several concentrations. Using flow conditions that mimic those seen in large veins and valves, the effects of surface‑immobilization on clot formation were studied. All findings reveal that immobilized PolyP of all lengths were more potent activators of coagulation, compared to when they were assembled into nanoparticles or dispersed in solution.

Together, these observations shed light on a potential biophysical role for short-chain PolyP released from platelets during thrombosis. The PolyP stored in platelet dense granules could contribute to accelerating thrombosis at flow conditions that mimic those in large veins. Future directions will aim at determining if these observations can be replicated in vivo, leading to the discovery of a new role for the PolyP in platelet dense granules.