Pete Lollar, MD
2010-01-01
Dr. Lollar indicated no
relevant conflicts of interest.
Nesbitt WS, Westein E,
Tovar-Lopez FJ, et al. A
shear gradient-dependent platelet aggregation mechanism drives thrombus
formation. Nat Med. 2009;15:665-73.
In 1687,
Isaac Newton postulated that during fluid flow parallel to a solid surface,
fluid velocity increases proportionately with distance from the surface. The
idea is that a layer of fluid at the surface sticks to the surface, a layer of
fluid on top of that feels the opposing forces of being stuck to the layer below
it and being pulled along by the layer moving above it, and so on. This spatial
dependence of fluid velocity is called the shear rate, and the force that
produces it is called shear stress. How could a platelet 2 microns in diameter
traveling in the center of an arteriole 30 microns in diameter ever find its
way to a site of vascular injury at the vessel wall? It has been known for
nearly 40 years that shear stress plays an important role in the interaction of
platelets with surfaces.1-4 For a platelet to stick to the vessel wall
(adhesion) or to the surface of another platelet (aggregation), it must be
transported to the site by a combination of flow and radial diffusion (i.e.,
diffusion perpendicular to the flow). In whole blood, the latter increases as
shear rate increases.5 After reaching the surface, platelets bind
via inter-molecular interactions; e.g., platelet GPIb binds to von Willebrand
factor. If binding is rapid relative to transport, then the rate of adhesion and
aggregation is dominated by factors that influence transport. The extent of
platelet aggregation under flow conditions undergoes a shear-dependent optimum
that is transport-limited at low shear rates and reaction-limited at higher
shear rates.4
Standing on the shoulders
of giants so to speak, Nesbitt et al. in the laboratory of Shaun Jackson used a
combination of in vivo intravital imaging of the murine mesenteric
arteriolar circulation, in vitro microfluidic flow studies, and
computational fluid dynamics to obtain additional insights into the nature of
platelet aggregation and thrombus formation. In contrast to the earlier studies
cited above, they progressively stenosed arterioles at the site of a crush
injury or fabricated microchannels with similar stenotic geometry and measured
the kinetics and size of thrombus formation. As in previous studies, they found
that platelet aggregation in a growing thrombus is primarily driven by shear.
Additionally, they made the novel observation that thrombus formation is a
function of local changes in shear, termed shear microgradients, that are
produced by vessel geometry. In contrast, they found that platelet activation produced
by soluble agonists plays a secondary role by stabilizing aggregates.
 |
| Click to enlarge image |
The shear microgradients
that they produced consist of acceleration, peak, and deceleration zones. At
peak shear, platelets adhere to exposed thrombogenic surfaces in a
GPIb-dependent manner. The shear on these platelets results in the extrusion of
thin filamentous membrane tethers, which facilitates the recruitment of
platelets into the downstream deceleration zone. There, the reduced shear
favors the formation of αIIbβ3-dependent aggregation that results in tether
restructuring and the stabilization of the aggregates. In this process, ongoing
platelet recruitment drives the propagation of the thrombus in the downstream
deceleration zone, which may, in turn, amplify the shear microgradient and promote
further platelet aggregation. The shear-dependent formation of membrane tethers
brings together the physics (transport and diffusion under flow) and chemistry
(membrane stickiness) of platelet function.
This study provides new
insights into the potentially prothrombotic effects of blood flow at sites of stenosis.
Continued investigation of the dependence of platelet kinematics, membrane
restructuring, and aggregation on blood flow and vessel geometry may lead to
the development of safer and more effective antithrombotic therapies.
- Begent N and Born GVR.
Growth rate in vivo of platelet thrombi, produced by iontophoresis of ADP, as a function of mean
blood flow velocity. Nature. 1970;227:926-30.
- Baumgartner HR. The
role of blood flow in platelet adhesion, fibrin deposition, and formation of mural thrombi. Microvasc
Res. 1973;5:167-79.
- Turitto VT, Baumgartner
HR. Platelet deposition on subendothelium exposed to flowing blood: mathematical analysis of
physical parameters. Trans Am Soc Artif Intern Organs. 1975;21: 593-601.
- Turitto VT, Muggli R,
Baumgartner HR. Physical factors influencing platelet deposition on
subendothelium: importance of blood shear
rate. Ann N Y Acad Sci. 1977;282:284-92.
- Leonard EF, Grabowski
EF, Turitto VT. The role of convection and diffusion on platelet adhesion and aggregation. Ann
N Y Acad Sci. 1972;201:329-42.
back to top
