Dataset Information

Platelet transport rates and binding kinetics at high shear over a thrombus.

ABSTRACT: Thrombus formation over a ruptured atherosclerotic plaque cap can occlude an artery with fatal consequences. We describe a computational model of platelet transport and binding to interpret rate-limiting steps seen in experimental thrombus formation over a collagen-coated stenosis. The model is used to compute shear rates in stenoses with growing boundaries. In the model, moving erythrocytes influence platelet transport based on shear-dependent enhanced diffusivity and a nonuniform platelet distribution. Adhesion is modeled as platelet-platelet binding kinetics. The results indicate that observed thrombus growth rates are limited by platelet transport to the wall for shear rates up to 6000 s(-1). Above 7000 s(-1), the thrombus growth rate is likely limited by binding kinetics (10(-4) m/s). Thrombus growth computed from these rate-limiting steps match the thrombus location and occlusion times for experimental conditions if a lag time for platelet activation is included. Using fitted parameters, the model is then used to predict thrombus size and shape at a higher Reynolds number flow consistent with coronary artery disease.

SUBMITTER: Bark DL

PROVIDER: S-EPMC3714887 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Platelet transport rates and binding kinetics at high shear over a thrombus.

Bark David L DL Ku David N DN

Biophysical journal 20130701 2

Thrombus formation over a ruptured atherosclerotic plaque cap can occlude an artery with fatal consequences. We describe a computational model of platelet transport and binding to interpret rate-limiting steps seen in experimental thrombus formation over a collagen-coated stenosis. The model is used to compute shear rates in stenoses with growing boundaries. In the model, moving erythrocytes influence platelet transport based on shear-dependent enhanced diffusivity and a nonuniform platelet dist ...[more]

PMID: 23870271

Similar Datasets

Project description:The formation of wall-adherent platelet aggregates is a critical process in arterial thrombosis. A growing aggregate experiences frictional drag forces exerted on it by fluid moving over or through the aggregate. The magnitude of these forces is strongly influenced by the permeability of the developing aggregate; the permeability depends on the aggregate's porosity. Aggregation is mediated by formation of ensembles of molecular bonds; each bond involves a plasma protein bridging the gap between specific receptors on the surfaces of two different platelets. The ability of the bonds existing at any time to sustain the drag forces on the aggregate determines whether it remains intact or sheds individual platelets or larger fragments (emboli). We investigate platelet aggregation in coronary-sized arteries using both computational simulations and in vitro experiments. The computational model tracks the formation and breaking of bonds between platelets and treats the thrombus as an evolving porous, viscoelastic material, which moves differently from the background fluid. This relative motion generates drag forces which the fluid and thrombus exert on one another. These forces are computed from a permeability-porosity relation parameterized from experimental measurements. Basing this relation on measurements from occlusive thrombi formed in our flow chamber experiments, along with other physiological parameter values, the model produced stable dense thrombi on a similar timescale to the experiments. When we parameterized the permeability-porosity relation using lower permeabilities reported by others, bond formation was insufficient to balance drag forces on an early thrombus and keep it intact. Under high shear flow, soluble agonist released by platelets was limited to the thrombus and a boundary layer downstream, thus restricting thrombus growth into the vessel lumen. Adding to the model binding and activation of unactivated platelets through von Willebrand-factor-mediated processes allowed greater growth and made agonist-induced activation more effective.

Project description:In combination with microspotting, whole-blood microfluidics can provide high-throughput information on multiple platelet functions in thrombus formation. Based on assessment of the inter- and intra-subject variability in parameters of microspot-based thrombus formation, we aimed to determine the platelet factors contributing to this variation. Blood samples from 94 genotyped healthy subjects were analyzed for conventional platelet phenotyping: i.e. hematologic parameters, platelet glycoprotein (GP) expression levels and activation markers (24 parameters). Furthermore, platelets were activated by ADP, CRP-XL or TRAP. Parallel samples were investigated for whole-blood thrombus formation (6 microspots, providing 48 parameters of adhesion, aggregation and activation). Microspots triggered platelet activation through GP Ib-V-IX, GPVI, CLEC-2 and integrins. For most thrombus parameters, inter-subject variation was 2-4 times higher than the intra-subject variation. Principal component analyses indicated coherence between the majority of parameters for the GPVI-dependent microspots, partly linked to hematologic parameters, and glycoprotein expression levels. Prediction models identified parameters per microspot that were linked to variation in agonist-induced αIIbβ3 activation and secretion. Common sequence variation of GP6 and FCER1G, associated with GPVI-induced αIIbβ3 activation and secretion, affected parameters of GPVI-and CLEC-2-dependent thrombus formation. Subsequent analysis of blood samples from patients with Glanzmann thrombasthenia or storage pool disease revealed thrombus signatures of aggregation-dependent parameters that were subject-dependent, but not linked to GPVI activity. Taken together, this high-throughput elucidation of thrombus formation revealed patterns of inter-subject differences in platelet function, which were partly related to GPVI-induced activation and common genetic variance linked to GPVI, but also included a distinct platelet aggregation component.

Dataset Information

Platelet transport rates and binding kinetics at high shear over a thrombus.

Publications

Platelet transport rates and binding kinetics at high shear over a thrombus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets