The Influence of Hindered Transport on the Development of Platelet Thrombi Under Flow

Abstract

Vascular injury triggers two intertwined processes, platelet deposition and coagulation, and can lead to the formation of an intravascular clot (thrombus) that may grow to occlude the vessel. Formation of the thrombus involves complex biochemical, biophysical, and biomechanical interactions that are also dynamic and spatially-distributed, and occur on multiple spatial and temporal scales. We previously developed a spatial-temporal mathematical model of these interactions and looked at the interplay between physical factors (flow, transport to the clot, platelet distribution within the blood) and biochemical ones in determining the growth of the clot. Here we extend this model to include reduction of the advection and diffusion of the coagulation proteins in regions of the clot with high platelet number density. The effect of this reduction, in conjunction with limitations on fluid and platelet transport through dense regions of the clot, can be profound. We found that hindered transport leads to the formation of smaller and denser clots compared to the case with no protein hindrance. The limitation on protein transport confines the important activating complexes to small regions in the interior of the thrombus and greatly reduces the supply of substrates to these complexes. Ultimately, this decreases the rate and amount of thrombin production and leads to greatly slowed growth and smaller thrombus size. Our results suggest a possible physical mechanism for limiting thrombus growth.

A systems approach to hemostasis: 4. How hemostatic thrombi limit the loss of plasma-borne molecules from the microvasculature

“…Hemostatic thrombi halt both forms of loss by restricting movement within and across the thrombus microenvironment. [10][11][12][13][14][15] Consistent with this role, we have previously shown that thrombi formed from human blood flowing over a collagen/tissue factor (TF) surface have a Darcy permeability approaching that of intact endothelium (k 5 2 3 10 214 cm 2 ). 5 Since plasma and platelets are the source of numerous coagulation factors, [16][17][18] growth factors, [19][20][21][22] and mediators of inflammation, 23,24 transport properties at the injury site can also be viewed as regulators of wound healing and recovery.…”

Platelets and hemostasis: a new perspective on an old subject

“…Computational studies that recapitulate platelet accumulation and transport may prove helpful in this regard, especially as the simulations become even more refined. 10,17,[45][46][47][48][49][50] …”

Mechanical Platelet Activation Potential in Abdominal Aortic Aneurysms

“…In the medium to large arteries, tens of millions to billions of platelets can pass through the artery each second [39], making direct tracking of physiological platelet counts computationally infeasible in such domains. Instead, some researchers have utilized an Eulerian framework, in which concentrations of activated platelets are tracked as a continuum quantity [40][41][42][43][44]. To date, these Eulerian frameworks have been applied to the biochemical activation of platelets, and use of such methods to investigate biomechanical activation has been less explored.…”