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Role of high shear rate in thrombosis

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1 Role of high shear rate in thrombosis
Lauren D.C. Casa, MSME, David H. Deaton, MD, David N. Ku, MD, PhD  Journal of Vascular Surgery  Volume 61, Issue 4, Pages (April 2015) DOI: /j.jvs Copyright © 2015 Society for Vascular Surgery Terms and Conditions

2 Fig 1 Shear rate. A, Flow in a straight tube (Poiseuille flow) is characterized by a parabolic velocity profile with 0 velocity at the wall. The arrows indicate the velocity vector as a function of y across the vessel. B, Near the wall, the velocity is > 0. The near-wall velocity divided by the distance from the wall defines shear rate. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

3 Fig 2 Large-scale thrombus formation is initiated by a period of slow growth (lag time), followed by rapid platelet accumulation (RPA) growth. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

4 Fig 3 Computer simulations of platelet margination demonstrate the trajectory of platelets moving from the center of the vessel to the wall. Reprinted from Reasor et al21 with kind permission from Springer Science and Business Media. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

5 Fig 4 Platelet binding at different shear rates. Fibrinogen binds platelets at low shear, whereas von Willebrand factor (vWF) has higher binding at high shear. The range bars show the standard error of six experiments. Reprinted from Cell, Vol 84, Savage et al,27 Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor, pp , ©1996, with permission from Elsevier. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

6 Fig 5 von Willebrand factor (vWF) changes shape at high shear. vWF undergoes a reversible conformational change from globular/collapsed to elongated/stretched at a critical shear rate. Top, Molecular simulation of elongation under shear flow. Bottom, Fluorescence images of experimental vWF elongation under shear flow. Reprinted from Schneider et al,29 copyright © by the National Academy of Sciences. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

7 Fig 6 von Willebrand factor (vWF) nets. A, vWF extends from a globular form to an elongated form under high shear rate and can theoretically form intertwining nets to form many bonds to platelets, capturing them from the high shear flow. Reprinted from Wellings and Ku,14 with kind permission from Springer Science and Business Media. B, Experimental demonstration of the vWF nets at very high shear rates. The vWF strands are shown in white. Reprinted from Colace and Diamond34 with permission from Wolters Kluwer Health. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

8 Fig 7 Thrombus growth at high shear. A, Flow patterns in a stenosis with a smooth surface and with a rough thrombus surface. Note that the thrombus creates areas of both high and low shear rates at the surface. Reprinted from Journal of Biomechanics, Vol 43, Bark and Ku,5 Wall shear over high degree stenoses pertinent to atherothrombosis, pp , ©2010, with permission from Elsevier. B, Experimental thresholds for activation of circulating platelets compared with expected values in artificial heart valves. Platelet activation is expected to the upper right of the solid curves depicting the product of exposure time and shear stress. Arterial thrombosis can occur below and left of this curve at shear rates with much shorter exposure times that do not activate the circulating platelets. However, after attachment, mural platelets would then be exposed to sufficient time for activation of αIIbβ3 and release of von Willebrand factor (vWF). Reprinted from Hellums37 with kind permission from Springer Science and Business Media. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

9 Fig 8 Shear rates stimulate the lag time for initial slow deposition and then govern the rate of rapid platelet accumulation. A, Lag time decreases as shear rises >2000 s−1. B, Thrombus growth rate accelerates for shear rates >2000 s−1 by 300%. Reprinted from Bark et al40 with permission of John Wiley & Sons, Inc. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

10 Fig 9 Carstair staining of a high shear clot shows platelets (blue-gray) at the (left) region of occlusion and (right) fibrin (red) downstream of the occlusion. Reprinted from Para et al3 with kind permission from Springer Science and Business Media. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

11 Fig 10 The elements of high shear thrombosis are different from the classic Virchow triad in that it depends on high shear and von Willebrand factor (vWF) instead of stasis and coagulation factors. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

12 Fig 11 Summary of high shear thrombosis. A, Stenotic regions induce high wall shear rates, (B) von Willebrand factor (vWF) is transported to the wall by enhanced diffusivity, and (C) vWF is adsorbed to nonendothelialized surfaces. D, High shear conditions create elongation of the vWF molecules and the formation of nets, platelet margination transports platelets to the vessel wall, and enhanced diffusivity increase vWF-wall collisions. E, Nonactivated platelets bind to the tethered vWF that elongates under shear to expose many binding sites. F, Activation of the adherent platelets releases high concentrations of vWF locally and activates αIIbβ3. G and H, Newly released vWF attaches to the thrombus surface and forms nets causing rapid accumulation of every passing platelet. I, Large thrombus formation can occlude the blood vessel or embolize to an end-organ artery. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

13 Fig 11 Summary of high shear thrombosis. A, Stenotic regions induce high wall shear rates, (B) von Willebrand factor (vWF) is transported to the wall by enhanced diffusivity, and (C) vWF is adsorbed to nonendothelialized surfaces. D, High shear conditions create elongation of the vWF molecules and the formation of nets, platelet margination transports platelets to the vessel wall, and enhanced diffusivity increase vWF-wall collisions. E, Nonactivated platelets bind to the tethered vWF that elongates under shear to expose many binding sites. F, Activation of the adherent platelets releases high concentrations of vWF locally and activates αIIbβ3. G and H, Newly released vWF attaches to the thrombus surface and forms nets causing rapid accumulation of every passing platelet. I, Large thrombus formation can occlude the blood vessel or embolize to an end-organ artery. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2015 Society for Vascular Surgery Terms and Conditions


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