Blood flow velocity effects and role of activation delay time on growth and form of platelet thrombi

Abstract

Mural thrombi are composed dominantly of platelets and develop under a blood flow. Portions can break off and are carried in the blood flow as emboli. Thrombus growth rates are affected by the velocity of the blood flow, but they do not simply increase with it, they exhibit a maximum, with subsequent decrease. Whereas this variation indicates an interaction of biochemical and physical processes, studies have concentrated widely on understanding only the biochemical processes. Here we show results of simulation of thrombus formation in 3D flows by accounting for the movements of individual platelets. Each platelet follows prescribed rules for interactions while the local flow around the thrombus continuously adjusts to the growing structure of the thrombus, also when embolization occurs. With an activation delay time assigned to each platelet we demonstrate the dependence of thrombus growth rate on blood velocity as found experimentally by Begent and Born [Begent N, Born GV (1970) Nature 227:926 -930]. With activated platelets having mutual tensile action sustainable up to a prescribed distance we achieve thrombus growth faster than with shorter maximum distances that make a thrombus less porous; when the prescribed maximum distance is large enough the thrombus shape is not like a ''hill'' but like a ''carpet.'' We find that thrombus growth rate is enhanced by modest pulsatility but less so when pulsations are amplified in part because of more embolization.direct numerical simulations ͉ platelet aggregation ͉ in vivo comparison ͉ stochastic modeling A cute thrombogenesis in a flowing bloodstream can occur on damaged tissues in normal circulation (1). It has also been observed in blood flow over vascular prostheses (2) and in artificial internal organs, such as prosthetic heart valves (3). The thrombi are composed predominantly of platelets, and they can develop even in the presence of systemic anticoagulants such as heparin (4).Blood flow velocity effects were investigated systematically in vivo by Begent and Born (1), who obtained quantitative data on thrombus growth rates for a range of blood flow rates. Their study remains the clearest time-resolved in vivo study of the effect of blood flow rates on thrombus formation. Richardson (5) subsequently proposed that Begent and Born's observations were consistent with a shear-flow aggregation process (6, 7) in which an activation delay time of the platelets is allowed for, a delay time between each platelet's close encounter with the thrombus and its development of ability to adhere to the thrombus, and which was estimated then to be the order of 0.1-0.2 s. A predicted consequence of this finding was that the height-to-length ratio for thrombi would be lower in blood flows, where a significant fraction of the activated platelets escaped the primary thrombus before their activation delay time had elapsed; this was demonstrated later by Born and Richardson (8). More recent experiments by Petrishchev and Mikhailova (9) in vivo and van Gestel et al. (10) in vitro produc...

Multiscale prediction of patient-specific platelet function under flow

“…38 Our results indicate that cAMP elevation is more effective than COX-1 or P2Y 1 inhibition under these conditions. The multiscale and patient-specific modeling presented here extends earlier modeling efforts of platelet function and/or coagulation 20,21,[39][40][41][42] by including a highly robust description of intracellular platelet signaling through GPVI, P2Y 1 , TP, and IP. To our knowledge, our NN/multiscale model is the first such approach to make donor-specific predictions of platelet function under flow in the presence of both released ADP and thromboxane and pharmacologic modulators of clinical relevance.…”

Computational Approaches to Studying Thrombus Development

“…In studies by Wang et al 31 33 introduced a 3-dimensional thrombus formation model. Each platelet is treated as a spherical object, and the suspension of red blood cells is treated as a continuum.…”

Methods of Blood Flow Modelling

“…In this sense they are often considered in terms of multiscale modelling. In the last decade several different hybrid models of blood coagulation in flows were developed [49,50,109,128,146].…”

“…Concentrations of blood factors and of platelets can be described by reaction-diffusion-convection equations [5,10,19,60,135]. Individual cell model with cell interaction in the process of clot growth are studied in [50,109,128,146]. Hybrid models combine continuous and discrete methods in order to describe different aspects of the studied phenomenon.…”