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Spatial-temporal model of platelet deposition and blood coagulation under flow
FIGURE 1
Achievement/Results
IGERT trainee Karin Leiderman and Professor Aaron Fogelson at the University of Utah have developed the first spatial-temporal model of platelet deposition and blood coagulation under flow that includes detailed descriptions of the coagulation biochemistry, chemical activation and deposition of blood platelets, as well as the two-way interaction between the fluid dynamics and the growing platelet mass.
In the event of a vascular injury, a blood clot will form to prevent bleeding. This response involves with two intertwined processes: platelet aggregation and coagulation. Platelets in their resting state bind directly to collagen at an injury site and become activated, meaning that they release agonists, such as adenosine diphosphate (ADP), that activate and recruit other resting platelets. Activated platelets also change shape and present newly-activated receptors on their membranes which play a key role in allowing activated platelets to cohere and form aggregates. Meanwhile, material at the injury site exposed to flowing plasma initiates the coagulation cascade. Activated platelets are critical to coagulation in that they provide localized reactive surfaces on which many of the coagulation reactions occur. In fact, many coagulation enzymes must move through fluid to get from their site of activation to their region of intended function. The final product from the coagulation cascade is thrombin. This enzyme directly couples the coagulation system to platelet aggregation by acting as a strong activator of platelets and cleaving blood-borne fibrinogen into fibrin which then forms a mesh to help stabilize platelet aggregates. Together, the fibrin mesh and the platelet aggregates comprise a blood clot, which in some cases, can grow to occlusive diameters, becoming fatal by depleting vital organs of nutrients and oxygen. Gaining knowledge about how these systems interact in a flowing environment is of major medical importance.
Transport of coagulation proteins to and from the vicinity of the injury is controlled largely by the dynamics of the blood flow. It is crucial to learn how blood flow affects the growth of clots, and how the growing masses, in turn, feed back and affect the fluid motion.
The NSF-funded researchers at the University of Utah used mathematics to build a sophisticated and biologically-detailed model representing this fluid-clot interaction. The players in the model, shown on the left side of the schematic in Figure (1), are the platelets in unactivated and activated form, the coagulation proteins, either free-flowing, bound to platelets or bound to the subendothelium (i.e. to the injury site), and the fluid (flowing plasma). A large coupled system of partial differential equations is solved to track concentrations in space and time. The right side of Figure (1) shows a schematic of the coagulation reaction system, including activation, inhibition, binding/unbinding and physical transport.
A novel attribute of this model is its ability to monitor the activation of platelets by the distinct chemical activatorys thrombin and ADP. Figure (2) shows the fluid-clot interaction and patterns of chemical activation. On the left side of figure, the pseudo color plot shows the density of activated platelets that have bound to the subendothelium and to each other to form a significant platelet mass. The white arrows are velocity vectors that illustrate the effect that the growing mass has upon the blood flow. On the right side of the figure the pseudo color plots show how the rate of activation of platelets by thrombin (center) and ADP (right) is distributed in space at select time during the clot’s growth.
Although in its early stages of development, the model already provides a first look into aspects of blood clotting that are currently not available from laboratory experiments. It allows for the systematic turning-off and turning-on of enzymes when searching for the critical players involved in this large and complex system. The ability to track the distinct chemical activators of platelets may lead to information for specific drug targeting. The ability to investigate the spatial and temporal transport of coagulation proteins and platelets within the fluid is a pivotal step towards overcoming a long standing challenge in blood clotting research.
Address Goals
Although in its early stages of development, the model already provides a first look into aspects of blood clotting that are currently not available from laboratory experiments. It allows for the systematic turning-off and turning-on of enzymes when searching for the critical players involved in this large and complex system. The ability to track the distinct chemical activators of platelets may lead to information for specific drug targeting. The ability to investigate the spatial and temporal transport of coagulation proteins and platelets within the fluid is a pivotal step towards overcoming a long standing challenge in blood clotting research.
