High shear–dependent loss of membrane integrity and defective platelet adhesion following disruption of the GPIbα-filamin interaction

SL Cranmer, KJ Ashworth, Y Yao… - Blood, The Journal …, 2011 - ashpublications.org
SL Cranmer, KJ Ashworth, Y Yao, MC Berndt, ZM Ruggeri, RK Andrews, SP Jackson
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
Platelets have evolved a highly specialized membrane skeleton that provides stability to the
plasma membrane and facilitates adhesion under high shear stress. The cytoskeletal
anchorage of glycoprotein (GP) Ibα plays an important role in regulating the membrane
skeleton. However, its role in regulating membrane stability remains unknown. To
investigate this role, we have developed a new mouse model that expresses wild-type
human GPIbα (hGPIbαWT), or a mutant form of human GPIbα that has a selective defect in …
Abstract
Platelets have evolved a highly specialized membrane skeleton that provides stability to the plasma membrane and facilitates adhesion under high shear stress. The cytoskeletal anchorage of glycoprotein (GP) Ibα plays an important role in regulating the membrane skeleton. However, its role in regulating membrane stability remains unknown. To investigate this role, we have developed a new mouse model that expresses wild-type human GPIbα (hGPIbαWT), or a mutant form of human GPIbα that has a selective defect in its ability to bind filamin A and anchor to the membrane skeleton (hGPIbαFW–Phe568Ala and Trp570Ala substitutions). Our study demonstrates that the link between platelet GPIb and the cytoskeleton does not alter the intrinsic ligand binding function of GPIbα or the ability of the receptor to stimulate integrin αIIbβ3-dependent spreading. However, exposure of hGPIbαFW platelets to pathologic shear rate levels (5000 to 40 000 s−1) leads to the development of unstable membrane tethers, defective platelet adhesion, and loss of membrane integrity, leading to complete disintegration of the platelet cell body. These outcomes suggest that the GPIbα–filamin A interaction not only regulates the architecture of the membrane skeleton, but also maintains the mechanical stability of the plasma membrane under conditions of high shear.
ashpublications.org