Exploiting the kinetic interplay between GPIbα–VWF binding interfaces to regulate hemostasis and thrombosis

Chen, Jianchung; Zhou, Hairu; Diacovo, Alexander; Zheng, X. Long; Emsley, Jonas; Diacovo, Thomas G.

doi:10.1182/blood-2014-04-569392

Cited by 14 publications

(14 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Administration of anesthesia, insertion of vascular catheters, fluorescent labeling of platelets, and surgical preparation of the cremaster muscle of male mice and the generation of von Willebrand factor (VWF) HA1 -mutant animals have been described previously 22 , 23 . A pulsed nitrogen dye laser was used to induce arteriole injury in the cremaster muscle of anesthetized 8- to 12-week-old animals.…”

Section: Methodsmentioning

confidence: 99%

P2Y12 Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease

Kaza

Egalka

Zhou

et al. 2017

JACC: Basic to Translational Science

Self Cite

View full text Add to dashboard Cite

SUMMERY Shunt thrombosis remains a major cause of morbidity and mortality, especially during the initial palliation for single-ventricle physiology. The authors present evidence that the P2Y12 inhibitor cangrelor may fill a therapeutic void in thromboprophylaxis. They base this theory on results showing that platelets from neonatal patients with cyanotic congenital heart disease have a robust response to adenosine diphosphate and are amenable to P2Y12 inhibition with cangrelor. Unique to this study was their ability to establish drug efficacy in an avatar mouse model that permits the in vivo evaluation of human platelet–mediated thrombus formation illustrating that this P2Y12 inhibitor yields the intended biological response.

show abstract

Section: Methodsmentioning

confidence: 99%

P2Y12 Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease

Kaza

Egalka

Zhou

et al. 2017

JACC: Basic to Translational Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…Using thermal fluctuation of beads coated with A1 and antibody bound to GPIbα, a zero-force off-rate of 0.2 s −1 was found (30). Transient tethers of A1-coated beads in shear flow over surfaces coated with platelets were extrapolated to zero force using the Bell model and yielded k off 0 of 3 s −1 and σ of 0.03 nm (31). These offrates differ by two to three orders of magnitude from our k 1 off measurement of 0.0047 s −1 and the bulk phase measurement of 0.0036 s −1 (29).…”

Section: Discussionmentioning

confidence: 99%

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

Kim

Hudson

Springer

2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mutations in the ultralong vascular protein von Willebrand factor (VWF) cause the common human bleeding disorder, von Willebrand disease (VWD). The A1 domain in VWF binds to glycoprotein Ibα (GPIbα) on platelets, in a reaction triggered, in part, by alterations in flow during bleeding. Gain-of-function mutations in A1 and GPIbα in VWD suggest conformational regulation. We report that force application switches A1 and/or GPIbα to a second state with faster on-rate, providing a mechanism for activating VWF binding to platelets. Switching occurs near 10 pN, a force that also induces a state of the receptor−ligand complex with slower off-rate. Force greatly increases the effects of VWD mutations, explaining pathophysiology. Conversion of single molecule k on (s −1 ) to bulk phase k on (s −1 M −1 ) and the k on and k off values extrapolated to zero force for the low-force pathways show remarkably good agreement with bulk-phase measurements.U nderstanding how force affects receptor and ligand binding and unbinding is a long-standing effort in mechanobiology (1-5). Bond dissociation rates typically increase under mechanical stress; however, bond stability can be enhanced through specialized mechanisms induced by force, including catch bonds and switching to a slip bond with a slower off-rate (flex bonds) (6, 7). Bond formation against an applied force has recently been measured (8). Force-regulated switching to a faster on-rate has not yet been reported for any receptor−ligand bond but would have important biological implications for adhesion in environments with high forces such as the circulation.At sites of vascular injury, hydrodynamic force in the bloodstream acting on von Willebrand factor (VWF) is pivotal in regulating the binding of the VWF A1 domain to GPIbα on platelets and commencing the crosslinking of platelets by VWF to form a platelet plug (9-11). VWF circulates in the form of long, disulfidebonded concatemers, with tens to hundreds of monomers, which mostly adopt a compact, irregularly coiled conformation during normal hemodynamics (12). At sites of hemorrhage, flow changes from shear to elongational. On transition from low to high shear and from shear to elongational flow, irregularly coiled molecules extend to a thread-like shape, and elongational (tensile) force is exerted throughout their lengths (13-16). Molecular elongation exposes the multiple A1 binding sites in VWF concatamers for multivalent binding to GPIbα (9,11,14,(16)(17)(18).In vivo, tensile force transmitted through VWF is applied to the N and C termini of individual domains, and could theoretically change A1 domain conformation before binding to GPIbα. Although this scenario has not yet been observed, single-molecule studies demonstrate two distinct force-dependent dissociation pathways (flex-bond behavior) of the wild-type (WT) A1-GPIbα complex, and thus suggest that two conformational states can be present after formation of the receptor−ligand complex (6).Mutations in VWF cause von Willebrand disease (VWD), the most common human heri...

show abstract

“…For instance, Chen et al discovered a ‘hot spot’ residue R1326 on murine VWF-A1 69. Mutating this residue to histidine weakens both the association and endurance of VWF–GPIb binding, thereby diminishing thrombus formation in arterioles in a laser-injury thrombosis model 70. The autoinhibitory effect of the N-terminal sequence Q1238-E1260 of VWF-A1 on its own binding to platelet GPIb inspires another potential antithrombotic approach: the soluble polypeptide Lp of the same sequence was shown to inhibit platelet binding to VWF under shear 57.…”

Section: Introductionmentioning

confidence: 99%

Biomechanical thrombosis: the dark side of force and dawn of mechano-medicine

Chen

2019

Stroke Vasc Neurol

View full text Add to dashboard Cite

Arterial thrombosis is in part contributed by excessive platelet aggregation, which can lead to blood clotting and subsequent heart attack and stroke. Platelets are sensitive to the haemodynamic environment. Rapid haemodynamcis and disturbed blood flow, which occur in vessels with growing thrombi and atherosclerotic plaques or is caused by medical device implantation and intervention, promotes platelet aggregation and thrombus formation. In such situations, conventional antiplatelet drugs often have suboptimal efficacy and a serious side effect of excessive bleeding. Investigating the mechanisms of platelet biomechanical activation provides insights distinct from the classic views of agonist-stimulated platelet thrombus formation. In this work, we review the recent discoveries underlying haemodynamic force-reinforced platelet binding and mechanosensing primarily mediated by three platelet receptors: glycoprotein Ib (GPIb), glycoprotein IIb/IIIa (GPIIb/IIIa) and glycoprotein VI (GPVI), and their implications for development of antithrombotic ‘mechano-medicine’ .

show abstract

Exploiting the kinetic interplay between GPIbα–VWF binding interfaces to regulate hemostasis and thrombosis

Abstract: Key Points GPIbα–VWF-A1 bond kinetics regulates platelet–VWF interactions and can be altered to correct defects in hemostasis or prevent thrombosis. Targeting a distinct GPIbα−VWF-A1 binding interface may offer a unique therapeutic approach to reducing platelet-driven thrombosis.

Cited by 14 publications

References 47 publications

P2Y12 Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease

P2Y12 Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases

Biomechanical thrombosis: the dark side of force and dawn of mechano-medicine

Contact Info

Product

Resources

About