Dominant inheritance of a novel integrin  3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families

Gresele, Paolo; Falcinelli, Emanuela; Giannini, Silvia; D’Adamo, Pio; D’Eustacchio, Angela; Corazzi, Teresa; Mezzasoma, Anna Maria; Bari, Filomena Di; Guglielmini, Giuseppe; Cecchetti, Luca; Noris, Patrizia; Balduini, Carlo L.; Savoia, Anna

doi:10.3324/haematol.2008.002246

Cited by 66 publications

(64 citation statements)

References 28 publications

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“…The content of polymerized actin (F-actin) of CHO cells expressing each of the heterozygous, β 3 -activating mutants described so far 11,[17][18][19] together with normal α IIb was higher than that of CHO cells expressing normal α IIb β 3 , and it did not increase after stimulation with DTT ( Figure 4A). Similarly, F-actin content was significantly higher in resting patients' platelets as compared with con- Cytoskeletal protein content was higher in resting patients' platelets than in resting control platelets.…”

Section: Constitutive α Iib β 3 Activation Leads To Impaired Cytoskelmentioning

confidence: 94%

“…Spreading of patients' platelets was initially faster ( Figure 2B), but after 30 min became defective 11 . Moreover, patients' platelets spread spontaneously on von Willebrand factor, unlike control platelets that required α IIb β 3 activation to undergo full spreading 18,24 ( Figure 2C).…”

Section: Constitutively Activated α Iib β 3 Triggers Outside-in Signamentioning

confidence: 99%

“…11 All subjects gave written informed consent in accordance with the Declaration of Helsinki. The study was approved by the ethical committee of the University of Perugia.…”

Section: Methodsmentioning

confidence: 99%

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Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

et al. 2015

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Several patients have been reported to have variant dominant forms of Glanzmann thrombasthenia, associated with macrothrombocytopenia and caused by gain-of-function mutations of ITGB3 or ITGA2B leading to reduced surface expression and constitutive activation of integrin α IIb β 3 . The mechanisms leading to a bleeding phenotype of these patients have never been addressed. The aim of this study was to unravel the mechanism by which ITGB3 mutations causing activation of α IIb β 3 lead to platelet dysfunction and macrothrombocytopenia. Using platelets from two patients carrying the β 3 del647-686 mutation and Chinese hamster ovary cells expressing different α IIb β 3 -activating mutations, we showed that reduced surface expression of α IIb β 3 is due to receptor internalization. Moreover, we demonstrated that permanent triggering of α IIb β 3 -mediated outside-in signaling causes an impairment of cytoskeletal reorganization arresting actin turnover at the stage of polymerization. The induction of actin polymerization by jasplakinolide, a natural toxin that promotes actin nucleation and prevents depolymerization of stress fibers, in control platelets produced an impairment of platelet function similar to that of patients with variant forms of dominant Glanzmann thrombasthenia. del647-686β 3 -transduced murine megakaryocytes generated proplatelets with a reduced number of large tips and asymmetric barbell-proplatelets, suggesting that impaired cytoskeletal rearrangement is the cause of macrothrombocytopenia. These data show that impaired cytoskeletal remodeling caused by a constitutively activated α IIb β 3 is the main effector of platelet dysfunction and macrothrombocytopenia, and thus of bleeding, in variant forms of dominant Glanzmann thrombasthenia. Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

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Section: Constitutive α Iib β 3 Activation Leads To Impaired Cytoskelmentioning

confidence: 94%

Section: Constitutively Activated α Iib β 3 Triggers Outside-in Signamentioning

confidence: 99%

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Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

et al. 2015

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“…As normal numbers of MKs are generally found in the bone marrow of these patients, it is likely that the macrothrombocytopaenia is related to an error in the terminal stages of PLT production. Moreover, the novel identification of an autosomal dominant macrothrombocytopaenia associated with PLT dysfunction in Glanzmann's Thrombasthaenia 19 raises interesting questions about the role of GPIIIa and its beta terminal domain in proPLT formation and PLT release. Myosin IIA, the non-muscle myosin heavy chain product of the MYH9 gene, has also been implicated in restraining proPLT formation in developing MKs 20 .…”

Section: Discussionmentioning

confidence: 99%

Microtubule and cortical forces determine platelet size during vascular platelet production

et al. 2012

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megakaryocytes release large preplatelet intermediates into the sinusoidal blood vessels. Preplatelets convert into barbell-shaped proplatelets in vitro to undergo repeated abscissions that yield circulating platelets. These observations predict the presence of circular-preplatelets and barbell-proplatelets in blood, and two fundamental questions in platelet biology are what are the forces that determine barbell-proplatelet formation, and how is the final platelet size established. Here we provide insights into the terminal mechanisms of platelet production. We quantify circular-preplatelets and barbell-proplatelets in human blood in high-resolution fluorescence images, using a laser scanning cytometry assay. We demonstrate that force constraints resulting from cortical microtubule band diameter and thickness determine barbellproplatelet formation. Finally, we provide a mathematical model for the preplatelet to barbell conversion. We conclude that platelet size is limited by microtubule bundling, elastic bending, and actin-myosin-spectrin cortex forces.

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“…9 The expression of platelet membrane glycoproteins was investigated by whole blood flow cytometry using FITC-conjugated monoclonal antibodies anti GPIIb (P2), GPIIIa (SZ21), GPIbα (SZ2), GPIX (SZ1), GPIV (FA6-152), CD9 (ALB6) and CD31 (5.6E) and a PE conjugated platelet-specific monoclonal antibody, as described. 11,12 Samples were analyzed in an EPICS XL-MCL flow cytometer (Coulter Corporation, Miami, Florida, USA).…”

Section: Laboratory Studiesmentioning

confidence: 99%

Diagnosis of platelet-type von Willebrand disease by flow cytometry

Giannini¹,

Cecchetti²,

Mezzasoma³

et al. 2009

Haematologica

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Dominant inheritance of a novel integrin 3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families

Cited by 66 publications

References 28 publications

Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

Microtubule and cortical forces determine platelet size during vascular platelet production

Diagnosis of platelet-type von Willebrand disease by flow cytometry

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