Platelet glycoprotein Ibα forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF
Tadayuki Yago, … , Rodger P. McEver, Cheng Zhu
Tadayuki Yago, … , Rodger P. McEver, Cheng Zhu
Published August 21, 2008
Citation Information: J Clin Invest. 2008;118(9):3195-3207. https://doi.org/10.1172/JCI35754.
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Platelet glycoprotein Ibα forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF

Abstract

Arterial blood flow enhances glycoprotein Ibα (GPIbα) binding to vWF, which initiates platelet adhesion to injured vessels. Mutations in the vWF A1 domain that cause type 2B von Willebrand disease (vWD) reduce the flow requirement for adhesion. Here we show that increasing force on GPIbα/vWF bonds first prolonged (“catch”) and then shortened (“slip”) bond lifetimes. Two type 2B vWD A1 domain mutants, R1306Q and R1450E, converted catch bonds to slip bonds by prolonging bond lifetimes at low forces. Steered molecular dynamics simulations of GPIbα dissociating from the A1 domain suggested mechanisms for catch bonds and their conversion by the A1 domain mutations. Catch bonds caused platelets and GPIbα-coated microspheres to roll more slowly on WT vWF and WT A1 domains as flow increased from suboptimal levels, explaining flow-enhanced rolling. Longer bond lifetimes at low forces eliminated the flow requirement for rolling on R1306Q and R1450E mutant A1 domains. Flowing platelets agglutinated with microspheres bearing R1306Q or R1450E mutant A1 domains, but not WT A1 domains. Therefore, catch bonds may prevent vWF multimers from agglutinating platelets. A disintegrin and metalloproteinase with a thrombospondin type 1 motif–13 (ADAMTS-13) reduced platelet agglutination with microspheres bearing a tridomain A1A2A3 vWF fragment with the R1450E mutation in a shear-dependent manner. We conclude that in type 2B vWD, prolonged lifetimes of vWF bonds with GPIbα on circulating platelets may allow ADAMTS-13 to deplete large vWF multimers, causing bleeding.

Authors

Tadayuki Yago, Jizhong Lou, Tao Wu, Jun Yang, Jonathan J. Miner, Leslie Coburn, José A. López, Miguel A. Cruz, Jing-Fei Dong, Larry V. McIntire, Rodger P. McEver, Cheng Zhu

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Figure 6

Flowing platelets agglutinate with microspheres bearing R1306Q A1 or R1450E A1 (and R1450E A1A2A3), but not with microspheres bearing WT A1 (and A1A2A3), allowing ADAMTS-13 to cleave R1450E A1A2A3.

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Flowing platelets agglutinate with microspheres bearing R1306Q A1 or R14...
Mixtures of platelets and Yellow-Green–labeled microspheres coated with WT A1 (A and D), R1306Q A1 (B), or R1450E A1 (C, E, and F) or with WT A1A2A3 or R1450E A1A2A3 domain triplet and then incubated with or without ADAMTS-13 (G) were perfused through a flow chamber coated with HSA in medium without or with 20 μg/ml anti-GPIbα mAb. After exiting the flow chamber, suspensions were fixed, stained with PE-conjugated anti-CD61 mAb, and analyzed by flow cytometry (A–C and G) or by fluorescence microscopy (D–F). (A–C) Flow cytometry of samples gated for single green particles. The red fluorescence histograms measured without (red curve) or with (blue curve) anti-GPIbα mAb are compared. The percentage of particles in the anti-GPIbα mAb curve with significant increase in fluorescence intensity relative to the curve without this mAb is indicated for 1 experiment; the mean ± SD of 3 or 4 experiments is shown in Results. (D–F) Representative fluorescence micrographs of mixtures of platelets and microspheres bearing WT A1 (D), R1450E A1 (E), or R1450E A1 plus anti-GPIbα mAb (F). Scale bar: 10 μm. (G) Percentage (mean ± SD of 3 experiments) of single green particles with red fluorescence, as measured by flow cytometry after the samples prepared as indicated were subjected to different shears. Inset shows the WT groups subjected to shear rate of 2,000 s–1 on a smaller scale. *P < 0.01, Student’s t test.