Function of glycoprotein Ib alpha in platelet activation induced by alpha-thrombin.

Marco, Luigi De; Mazzucato, M.; Masotti, Adriana; Fenton, John W.; Ruggeri, Zaverio M.

doi:10.1016/s0021-9258(18)54350-7

Cited by 125 publications

(28 citation statements)

References 59 publications

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“…18,19,41,42 Thrombin binding to platelet surfaces takes place through GPIba. 43,44 On binding to GPIba, thrombin is then brought into close Figure 6 aggIgG-induced thrombin hypersensitivity is provoked by FcgRIIa signaling A: Platelets isolated from healthy volunteers were treated with buffer (closed symbols) or an inhibitor of Src kinase activity (open symbols) (PP2). Platelets were then incubated with buffer (black) or aggIgG (gray), and then stimulated with indicated doses of thrombin.…”

Section: Discussionmentioning

confidence: 99%

FcγRIIa Ligation Induces Platelet Hypersensitivity to Thrombotic Stimuli

Berlacher

Vieth

Heflin

et al. 2013

The American Journal of Pathology

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Platelets are known for their important role in hemostasis, however their significance in other functions, including inflammation and infection, are becoming more apparent. Patients with systemic lupus erythematosus (SLE) are known to have circulating IgG complexes in their blood and are highly susceptible to thrombotic events. Because platelets express a single receptor for IgG, we tested the hypothesis that ligation of this receptor (FcγRIIa) induces platelet hypersensitivity to thrombotic stimuli. Platelets from SLE patients were considerably more sensitive to thrombin compared to healthy volunteers, and this correlated with elevated levels of surface IgG on SLE platelets. To test whether FcγRIIa ligation stimulated thrombin hypersensitivity, platelets from healthy volunteers were incubated with buffer or heat-aggregated IgG, then stimulated with increasing concentrations of thrombin. Interestingly, heat-aggregated IgG-stimulated platelets, but not buffer-treated platelets, were hypersensitive to thrombin, and hypersensitivity was blocked by an anti-FcγRIIa monoclonal antibody (mAb). Thrombin hypersensitivity was not due to changes in thrombin receptor expression (GPIbα or PAR1) but is dependent on activation of shared signaling molecules. These observations suggest that ligation of platelet FcγRIIa by IgG complexes induces a hypersensitive state whereby small changes in thrombotic stimuli may result in platelet activation and subsequent vascular complications such as transient ischemic attacks or stroke.

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Section: Discussionmentioning

confidence: 99%

FcγRIIa Ligation Induces Platelet Hypersensitivity to Thrombotic Stimuli

Berlacher

Vieth

Heflin

et al. 2013

The American Journal of Pathology

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“…Platelet activation plays a crucial role in hemostasis and in the pathogenesis of thrombosis. Thrombin is one of the most potent agonists for platelet activation, mediating cellular effects via glycoprotein Ib␣ and protease-activating receptors (PARs) 4 coupled to G proteins (1)(2)(3)(4). Two PARs, PAR1 and PAR4, are present in human platelets (5)(6)(7)(8).…”

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confidence: 99%

Protease-activating Receptor-4 Induces Full Platelet Spreading on a Fibrinogen Matrix

Mazharian

Roger

Berrou

et al. 2007

Journal of Biological Chemistry

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Although the involvement of protease-activating receptor PAR1 and PAR4 is well established in platelet aggregation, their role in platelet adhesion and spreading has yet to be characterized. We investigated platelet adhesion and spreading on a fibrinogen matrix after PAR1 and PAR4 stimulation in correlation with the activation of two MAPKs, ERK2 and p38. Of the two PAR-activating peptides (PAR-APs), PAR1-AP and PAR4-AP, which both induce adhesion, only PAR4-AP induced full platelet spreading. Although both PAR1-AP and PAR4-AP induced ADP secretion, which is required for platelet spreading, only PAR4-AP induced sustained Ca(2+) mobilization. In these conditions of PAR4 induction, ERK2 and p38 activation were involved in platelet spreading but not in platelet adhesion. p38 phosphorylation was dependent on ADP signaling through P2Y12, its receptor. ERK2 phosphorylation was triggered through integrin alphaIIbbeta3 outside-in signaling and was dependent on the Rho pathway. ERK2 and p38 activation induced phosphorylation of the myosin light chain and actin polymerization, respectively, necessary for cytoskeleton reorganization. These findings provide the first evidence that thrombin requires PAR4 for the full spreading response. ERK2 and p38 and sustained Ca(2+) mobilization, involved in PAR4-induced platelet spreading, contribute to the stabilization of platelet thrombi at sites of high thrombin production.

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“…Whether GPIX interacts primarily with GPIbβ, or with GPIbα, remains controversial (Lopez et al, 1994;Wu et al, 1996).Initial insight into the functional significance of the GPIb-IX-V complex came from studies of the Bernard-Soulier syndrome, where the membrane complex is congenitally absent or structurally defective (Jenkins et al, 1976;Roth, 1996). Affected individuals demonstrate a bleeding disorder characterized by thrombocytopenia, enlarged platelets with markedly decreased adhesion to rabbit aortic subendothelium (Weiss et al, 1974;Caen et al, 1976), and decreased responsiveness to thrombin (DeMarco et al, 1991). The amino-terminal extracytoplasmic region of GPIbα displays closely associated binding sites for both von Willebrand factor and thrombin Manuscript…”

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confidence: 99%

Von Willebrand Factor Receptor GPIbα is Expressed by Human Factor XIIIa-Positive Dermal Dendrocytes and is Upregulated by Mast Cell Degranulation

Monteiro

Shapiro

Takafuta

et al. 1999

Journal of Investigative Dermatology

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GPIb alpha, a glycoprotein component of the GPIb-IX-V complex, serves as a platelet membrane receptor that mediates adhesion to von Willebrand factor normally present in the vascular subendothelium. Recent data have demonstrated that GPIb alpha is not restricted to platelets, but is also expressed by endothelium in vitro. In this study, we describe the expression and distribution of GPIb alpha in normal adult and neonatal human skin. GPIb alpha is present, as detected by immunohistochemistry, on endothelial cells and on highly dendritic cells localized within the perivascular space, dermal-epidermal junction, and reticular dermis. By dual-labeling immunofluorescence and confocal microscopy, GPIb alpha-positive cells within the dermal interstitium are demonstrated to represent factor XIIIa-positive dermal dendrocytes. In organ cultures of neonatal human foreskin, mast cell degranulation induced by either substance P or compound 48/80 resulted in transiently increased GPIb alpha expression by dermal dendrocytes. Because the GPIb-IX-V complex plays a part in regulating hemostasis and may be important for cellular interactions with extracellular matrix molecules, these data provide additional insight into the potential function of FXIIIa-positive dermal dendrocytes in skin remodeling and repair.

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Function of glycoprotein Ib alpha in platelet activation induced by alpha-thrombin.

Cited by 125 publications

References 59 publications

FcγRIIa Ligation Induces Platelet Hypersensitivity to Thrombotic Stimuli

FcγRIIa Ligation Induces Platelet Hypersensitivity to Thrombotic Stimuli

Protease-activating Receptor-4 Induces Full Platelet Spreading on a Fibrinogen Matrix

Von Willebrand Factor Receptor GPIbα is Expressed by Human Factor XIIIa-Positive Dermal Dendrocytes and is Upregulated by Mast Cell Degranulation

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