Aggregate formation is more strongly inhibited at high shear rates by dRGDW, a synthetic RGD-containing peptide.

Saelman, E. U. M.; Hese, Katrin; Nieuwenhuis, H. K.; Uzan, A.; Cavero, Icilio; Marguerie, G; Sixma, Jan J.; Groot, Philip G. de

doi:10.1161/01.atv.13.8.1164

Cited by 19 publications

(10 citation statements)

References 30 publications

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“…Interestingly, to date no study has showed the equal importance of these receptors in the signaling. Some studies showed that GPVI is the main receptor mediating both adhesion and the signaling response (Nieswandt et al, 2001;Masberg et al, 2003), while others reported the importance of ␣ 2 ␤ 1 in adhesion and aggregation of platelets (Saelman et al, 1994). Therefore our results may bring a new perspective to the recruitment of the platelet receptors in the signaling pathway under no-flow conditions.…”

Section: Discussionsupporting

confidence: 52%

Real-time monitoring of adhesion and aggregation of platelets using thickness shear mode (TSM) sensor

Ergezen

Appel

Shah

et al. 2007

Biosensors and Bioelectronics

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Section: Discussionsupporting

confidence: 52%

Real-time monitoring of adhesion and aggregation of platelets using thickness shear mode (TSM) sensor

Ergezen

Appel

Shah

et al. 2007

Biosensors and Bioelectronics

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“…Consistent with these findings, it was previously shown that inhibition of GPVI via the monoclonal antibody 9O12 reduced the platelet aggregate formation under flow conditions but still permits the initial platelet adhesion via integrin α 2 ß 1 with the adherence of numerous single platelets [15]. The inhibition of platelet activation via anti‐α IIb ß 3 antibodies or RGD‐containing peptides also resulted in increased platelet adhesion to collagen, as platelets that are not incorporated in the aggregates are now available to adhere [16]. Remarkably, the PFA100 closure time for collagen/ADP was shortened for the patient; 62 and 64 s with a reference value of CT/ADP = 71–118 s. The closure time for collagen/epinephrine was normal; 113 s with a reference value of CT/EPI = 94–193 s. Her mother had normal PFA100 closure times.…”

Section: Resultsmentioning

confidence: 99%

A compound heterozygous mutation in glycoprotein VI in a patient with a bleeding disorder

Hermans

Wittevrongel

Thys

et al. 2009

Journal of Thrombosis and Haemostasis

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Summary. Background: The physiological relevance of the collagen glycoprotein VI (GPVI) receptor was known prior to its recognition as a platelet membrane receptor as several patients lacking GPVI as a consequence of autoantibody inhibition presented with a mild bleeding diathesis. Remarkably, patients with a proven GPVI gene mutation have not yet been identified. Results: In the present study, we describe a patient with a lifelong history of bleeding problems, structurally normal platelets but a functional platelet defect. Platelet aggregations are normal except for an absent response to Horm collagen, convulxin and the collagen-related peptide (CRP). ATP dense granule secretion is normal with ADP but absent with Horm collagen. Thrombus formation on a collagen surface in flowing blood is reduced but more single platelets are attached. Remarkably, the platelet function analyzer-100 shows a shortened collagen/ADP closure time. Flow cytometry demonstrates an absent expression of GPVI whereas immunoblot analysis shows strongly reduced levels of GPVI. The patient is compound heterozygous for an out-of-frame 16-bp deletion and a missense mutation S175N in a highly conserved residue of the 2nd Ig-like GPVI domain. The parents without clinical bleeding problems are heterozygous carriers. The mother carries the S175N mutation and presents with a mild functional platelet defect. In vitro studies show a reduced membrane expression and convulxin binding with the mutated S175N compared with the wild-type (WT) GPVI receptor. Conclusions: This study presents the first patient with a proven genetic GPVI defect.Keywords: bleeding disorder, collagen signaling, GPVI, platelets. IntroductionGlycoprotein VI (GPVI) is a 63-kDa transmembrane protein consisting of two immunoglobulin (Ig)-like domains in the extracellular region connected to a highly glycosylated linker, a transmembrane domain and a cytoplasmic tail [1][2][3]. GPVI is a member of the Ig-like receptors within the leukocyte Ig-like receptor complex (LRC) on human chromosome 19q13.4 [4]. It is the major signaling receptor for collagen on platelets but is also activated by laminin, the collagen-related peptide (CRP) and snake toxins, such as convulxin and alborrhagin [5][6][7][8]. The surface expression of GPVI requires the concomitant expression of the c-subunit of the FcR receptor (FcRc) and their association is functionally relevant as collagen binding to GPVI results in platelet signaling via the immunoreceptor tyrosinebased activation motif (ITAM) located within the FcRc subunits.More than 20 years after the initial report of a patient with a GPVI defect [9], a total of 11 patients have been described in a recent review [10]. These patients have been described with either an acquired deficiency as a result of the anti-GPVI autoantibodies or a congenital deficiency with normal to strongly reduced or even absent GPVI levels and a defective GPVI-related signaling. However, the possible cases described to date with a congenital GPVI defect have yet to be defined at the mo...

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“…Monomeric collagen type III was solubilized in 50 mmol/L acetic acid and sprayed with a density of 30 g/cm 2 on glass coverslips with a retouching airbrush (Badger model 100, Badger Brush Co). 12,13 After the spraying procedure, the collagen surface was blocked for 1 hour with 1% human albumin in PBS (10 mmol/L phosphate buffer, pH 7.4, and 0.15 mol/L NaCl) to prevent nonspecific protein binding during the subsequent perfusion and then incubated with 20 g/mL vWF in PBS for 2 hours.…”

Section: Coating Of the Coverslipsmentioning

confidence: 99%

Platelet Thrombus Formation on Collagen at High Shear Rates Is Mediated by von Willebrand Factor–Glycoprotein Ib Interaction and Inhibited by von Willebrand Factor–Glycoprotein IIb/IIIa Interaction

Vink

Schiphorst

et al. 2000

ATVB

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Abstract-We studied the role of von Willebrand Factor (vWF) in platelet thrombus formation in flowing blood by using a perfusion system and mutant forms of vWF lacking either interaction with glycoprotein Ib (GpIb) or with glycoprotein IIb/IIIa (␣IIb-␤3). These mutants were added to the blood of patients with severe von Willebrand's disease (vWD) or to normal blood reconstituted with a human albumin solution instead of plasma. This blood was then perfused over collagen type III spray-coated on a glass surface and preincubated for 2 hours with 20 g/mL plasma vWF. In this way, the adhesion step was mediated by the preincubated plasma vWF bound to collagen type III, whereas thrombus formation was mediated by mutant vWF added to the perfusate. Thrombus formation was absent at all 3 shear rates studied (300, 800, and 2600 s Ϫ1 ) when ⌬A1-vWF, lacking interaction with GpIb, was added to the perfusate, indicating the importance of GpIb-vWF interaction for thrombus formation. The interaction of vWF and GpIb is currently thought to be possible under physiological conditions in which the conformation of vWF has been changed by adsorption to a surface. Our results regarding the role of GpIb-vWF interaction in thrombus formation suggest that a second mechanism may operate by which a change may occur in GpIb on the surface of adhered platelets either by activation of the molecule or as a consequence of shear stress. Increased thrombus formation was observed when the Arg-Gly-Gly-ServWF, which does not interact with ␣IIb-␤3, was added to vWD blood and perfused at 2600 s Ϫ1 . This increase was not observed in vWD blood at lower shear rates or after addition of Arg-Gly-Gly-Ser-vWF to reconstituted normal blood. Thrombus formation at a high shear rate was largest when either vWF or fibrinogen was present as a single ligand for ␣IIb-␤3 at a high shear rate. When both were present, thrombus formation was decreased. We postulate that thrombus formation is less efficient because of incomplete bridge formation when vWF and fibrinogen are both present as ligands for ␣IIb-␤3. Key Words: von Willebrand factor Ⅲ thrombus formation Ⅲ GpIb Ⅲ collagen P latelet adhesion to collagen in flow is followed by thrombus formation, which is, in many respects, similar to the aggregate formation in plasma that occurs when platelets are activated and stirred in a cuvette. This aggregation is dependent on the integrin glycoprotein IIb/IIIa (␣IIb-␤3). Fibrinogen (and perhaps also fibronectin) serves as a bridge between adjacent platelets. 1 A role for von Willebrand factor (vWF) has not been shown for aggregation in a cuvette; in this respect, aggregation differs from thrombus formation in flow, which is dependent on vWF at high shear. 2,3 Exposure of platelets to high shear stress in a cone/plate viscometer causes platelet aggregation 4,5 as consequence of interaction between vWF and glycoprotein Ib (GpIb). This interaction leads to platelet activation and subsequent exposure of ␣IIb-␤3 6 -8 ; this is then followed by binding to ␣IIb-␤3 of ligands, whic...

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Aggregate formation is more strongly inhibited at high shear rates by dRGDW, a synthetic RGD-containing peptide.

Cited by 19 publications

References 30 publications

Real-time monitoring of adhesion and aggregation of platelets using thickness shear mode (TSM) sensor

Real-time monitoring of adhesion and aggregation of platelets using thickness shear mode (TSM) sensor

A compound heterozygous mutation in glycoprotein VI in a patient with a bleeding disorder

Platelet Thrombus Formation on Collagen at High Shear Rates Is Mediated by von Willebrand Factor–Glycoprotein Ib Interaction and Inhibited by von Willebrand Factor–Glycoprotein IIb/IIIa Interaction

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