Fibrinogen-independent platelet adhesion and thrombus formation on subendothelium mediated by glycoprotein IIb-IIIa complex at high shear rate.

Weiß, H.; Hawiger, Jacek; Ruggeri, Zaverio M.; Turitto, Vincent T.; Thiagarajan, Perumal; Hoffmann, Thomas J.

doi:10.1172/jci113871

Cited by 260 publications

(109 citation statements)

References 77 publications

(34 reference statements)

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“…These non-receptor tyrosine kinases play a critical role in integrin signal transduction but are not essential for soluble agonist-induced calcium flux (21). 2 Finally, the demonstration that PLC␥2 Ϫ/Ϫ mouse platelets have a defective calcium response during platelet adhesion to fibrinogen is consistent with its previously defined role in adhesion receptor signal transduction (40). FIG.…”

Section: Discussionsupporting

confidence: 53%

“…2 Third, the cytosolic calcium response was strictly dependent on Src kinases. These non-receptor tyrosine kinases play a critical role in integrin signal transduction but are not essential for soluble agonist-induced calcium flux (21).…”

Section: Discussionmentioning

confidence: 99%

“…The two principle adhesive ligands promoting platelet aggregation are von Willebrand factor (vWf) 1 and fibrinogen, with each having distinct, complementary roles in this process (1)(2)(3)(4)(5). Fibrinogen acts as a bridging molecule between adjacent activated platelets and is the principle adhesive ligand promoting platelet aggregation under low and intermediate shear flow conditions (1,2). In addition, it also contributes to stable aggregate formation under high shear (1,5,6).…”

mentioning

confidence: 99%

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Integrin αIIbβ3-dependent Calcium Signals Regulate Platelet-Fibrinogen Interactions under Flow

Goncalves

Hughan

Schoenwaelder

et al. 2003

Journal of Biological Chemistry

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Platelet adhesion to fibrinogen is important for platelet aggregation and thrombus growth. In this study we have examined the mechanisms regulating platelet adhesion on immobilized fibrinogen under static and shear conditions. We demonstrate that integrin ␣ IIb ␤ 3 engagement of immobilized fibrinogen is sufficient to induce an oscillatory calcium response, necessary for lamellipodial formation and platelet spreading. Released ADP increases the proportion of platelets exhibiting a cytosolic calcium response but is not essential for calcium signaling or lamellipodial extension. Pretreating platelets with the Src kinase inhibitor PP2, the inositol 1,4,5-trisphosphate (IP 3 ) receptor antagonist 2-aminoethoxydiphenyl borate (APB-2), or the phospholipase C (PLC) inhibitor U73122 abolished calcium signaling and platelet spreading, suggesting a major role for Src kinase-regulated PLC isoforms in these processes. Analysis of PLC␥2 ؊/؊ mouse platelets revealed a major role for this isoform in regulating cytosolic calcium flux and platelet spreading on fibrinogen. Under flow conditions, platelets derived from PLC␥2 ؊/؊ mice formed less stable adhesive interactions with fibrinogen, particularly in the presence of ADP antagonists. Our studies define an important role for PLC␥2 in integrin ␣ IIb ␤ 3 -dependent calcium flux, necessary for stable platelet adhesion and spreading on fibrinogen. Furthermore, they establish an important cooperative signaling role for PLC␥2 and ADP in regulating platelet adhesion efficiency on fibrinogen.Platelet adhesion and aggregation at sites of vascular injury are critical for the arrest of bleeding in traumatized vessels and also for the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and stroke. The two principle adhesive ligands promoting platelet aggregation are von Willebrand factor (vWf) 1 and fibrinogen, with each having distinct, complementary roles in this process (1-5). Fibrinogen acts as a bridging molecule between adjacent activated platelets and is the principle adhesive ligand promoting platelet aggregation under low and intermediate shear flow conditions (1, 2). In addition, it also contributes to stable aggregate formation under high shear (1,5,6). It is well established that the binding of fluid-phase fibrinogen to the platelet surface is dependent on the activation of integrin ␣ IIb ␤ 3 (GPIIb-IIIa) through intracellular signaling processes linked to various G protein-coupled and tyrosine kinase-linked receptors (7).Platelets can also adhere to immobilized fibrinogen, a process that is important for primary platelet adhesion onto artificial surfaces, including vascular prostheses (8, 9), and for normal thrombus development (5, 6). In the case of thrombus formation, active integrin ␣ IIb ␤ 3 on the surface of firmly adherent platelets adsorbs soluble fibrinogen to the thrombus surface, thereby providing a reactive substrate for the recruitment of additional platelets. In contrast to soluble fibrinogen, the adhesion of platelets onto...

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Integrin αIIbβ3-dependent Calcium Signals Regulate Platelet-Fibrinogen Interactions under Flow

Goncalves

Hughan

Schoenwaelder

et al. 2003

Journal of Biological Chemistry

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“…3 The continued ability of ADP to induce aggregation of PRP from the PG-1 F(ab') 2 -treated animals suggests that the reduction of thrombus formation in these animals is not mediated by inhibition of fibrinogen binding to platelet GPIIb/IIIa. In the case of human platelets, Weiss and coworkers 5 have recently demonstrated that other adhesive ligands such as vWF, vitronectin, or fibronectin may be involved in platelet adhesion and thrombus formation on subendothelium when studied at high shear rates. Whether such ligands may contribute to hemostasis in the guinea pig by binding to guinea pig platelet GPIIb/ Ilia is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Reduction in thrombus formation by PG-1 F(ab')2, an anti-guinea pig platelet glycoprotein Ib monoclonal antibody.

Miller¹,

Thiam-Cisse²,

Drouet³

1991

Arterioscler Thromb

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We have recently demonstrated that intraperitoneal injection into guinea pigs of F(ab') 2 fragments of PG-1, a murine monoclonal antibody recognizing the guinea pig homologue of human platelet glycoprotein Ib, produces virtually complete functional block of the platelet von Willebrand factor receptor without inducing a hemorrhagic state. To assess the ability of this antibody to protect against thrombosis resulting from laser-induced injury to mesenteric small arteries, we injected guinea pigs with either PG-1 F(ab') 2 (2.3 mg/kg) or with buffer alone 24 hours before study. For each animal, four mesenteric vessels were studied consecutively for 15 minutes each. The number of thrombi, time to first thrombus, and time to embolization of first thrombi were recorded. In the control animals most individual vessels had three to four thrombi, whereas in the antibody-treated animals, vessels most frequently had only a single thrombus or even none at all. The mean number of thrombi per vessel in the antibody-treated animals (1.125) was significantly lower than the mean in the control animals (3.40), with p< 0.001. However, there was no significant difference between groups with respect to time to first thrombus after laser injury. Detachment of thrombi in the control animals occurred in an easily recordable, discrete fashion, with 75% of first thrombi embolizing in less than 5 minutes. In the antibody-treated animals, gradual dissolution rather than discrete detachment was typically observed. In 31% of the vessels studied in these animals, no embolus occurred; for the remaining vessels only 9% of thrombi were observed to embolize within 5 minutes of their formation. PG-1 F(ab') 2 treatment accordingly served to break the repetitive cycle of thrombus production, embolization, and rethrombosis in this model system. MoAbs recognizing membrane glycoproteins (GPs) of guinea pig platelets that show very close structural homology to human platelet GPIb/IX and GPIIb/IIIa have been developed. MoAb PG-1 in particular recognizes the guinea pig homologue of human GPIb in surface-labeled platelets and in metabolically labeled megakaryocytes. PG-1 F(ab') 2 , as well as intact PG-1, incubated in vitro with washed guinea pig platelets inhibits the von

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“…Mature VWF comprises a series of multimers from 500 kD to over 10 000 kD (Chopek et al, 1986), the larger multimers most effectively promoting platelet adhesion (Meyer & Girma, 1993). Two platelet receptors have been shown to bind VWF, glycoprotein (GP) Ib involved in primary adhesion, and GPIIb/IIIa which plays a major role in the subsequent steps of platelet spreading and aggregation Baumgartner et al, 1980;Sakariassen et al, 1986;Ruggeri & Zimmerman, 1987;Weiss et al, 1989;Savage et al, 1992). Platelets do not bind soluble VWF in the absence of high shear forces.…”

mentioning

confidence: 99%

Platelet activation by a novel solid‐phase agonist: effects of VWF immobilized on polystyrene beads

et al. 1997

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Summary.The interaction between platelets stirred in suspension and VWF immobilized on polystyrene beads was studied. Platelets aggregated and released ATP in response to stirring with VWF beads. Closer examination of the interaction using transmission electron microscopy revealed that the platelets did not simply aggregate with one another but initially adhered to the beads and spread. Platelets in suspension then bound to the bead-adherent platelets forming layers of platelets associated with each bead. The VWF bead-induced platelet activation was completely inhibited by addition of monoclonal antibody (mAb) to GPIb or GPIIb/IIIa. In addition, the activation response was inhibited in the presence of aspirin, indomethacin or the thromboxane receptor antagonist BM13.177, demonstrating a dependence on an intact cyclo-oxygenase pathway.Platelet function studies were carried out on 30 patients with a history of mild bleeding using conventional optical aggregation and VWF bead-induced platelet activation. 12 patients were abnormal by conventional optical aggregometry, whereas 27 patients showed depressed ATP release in response to VWF beads. The results suggest that easily-bruised patients may have a platelet function defect rather than a vascular-based abnormality and that VWF bead-induced platelet activation is a more sensitive test for detecting platelet dysfunction.

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Fibrinogen-independent platelet adhesion and thrombus formation on subendothelium mediated by glycoprotein IIb-IIIa complex at high shear rate.

Cited by 260 publications

References 77 publications

Integrin αIIbβ3-dependent Calcium Signals Regulate Platelet-Fibrinogen Interactions under Flow

Integrin αIIbβ3-dependent Calcium Signals Regulate Platelet-Fibrinogen Interactions under Flow

Reduction in thrombus formation by PG-1 F(ab')2, an anti-guinea pig platelet glycoprotein Ib monoclonal antibody.

Platelet activation by a novel solid‐phase agonist: effects of VWF immobilized on polystyrene beads

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