Dataset Information

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

ABSTRACT: 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 ?IIb?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 ?IIb?3 lead to platelet dysfunction and macrothrombocytopenia. Using platelets from two patients carrying the ?3 del647-686 mutation and Chinese hamster ovary cells expressing different ?IIb?3-activating mutations, we showed that reduced surface expression of ?IIb?3 is due to receptor internalization. Moreover, we demonstrated that permanent triggering of ?IIb?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. del647-686?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 ?IIb?3 is the main effector of platelet dysfunction and macrothrombocytopenia, and thus of bleeding, in variant forms of dominant Glanzmann thrombasthenia.

SUBMITTER: Bury L

PROVIDER: S-EPMC4697891 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Bury Loredana L Falcinelli Emanuela E Chiasserini Davide D Springer Timothy A TA Italiano Joseph E JE Gresele Paolo P

Haematologica 20151009 1

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 αIIbβ3. 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 αIIbβ3 lead to platelet dysfun ...[more]

PMID: 26452979

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Project description:Standard treatment for Glanzmann thrombasthenia is platelet transfusion. Recombinant activated factor VII has been shown to be successful in patients with Glanzmann thrombasthenia with platelet antibodies or who are refractory to platelet transfusions. The Glanzmann Thrombasthenia Registry prospectively collected worldwide information on the effectiveness and safety of platelet transfusion, recombinant activated factor VII and/or antifibrinolytics for the treatment of bleeds in patients with Glanzmann thrombasthenia. Data relating to 829 non-surgical bleeding episodes were entered into the Glanzmann Thrombasthenia Registry (severe/moderate: 216/613; spontaneous/post-traumatic: 630/199). Recombinant activated factor VII alone was used in 124/829 bleeds, recombinant activated factor VII+antifibrinolytics in 107/829, platelets±antifibrinolytics in 312/829, antifibrinolytics alone in 219/829, and recombinant activated factor VII+platelets±antifibrinolytics in 67/829. The proportion of successful treatments to stop bleeding was 91.0% in cases treated with recombinant activated factor VII only, 82.7% for recombinant activated factor VII+antifibrinolytics, 72.7% for treatment with recombinant activated factor VII+platelets±antifibrinolytics, 78.8% for platelets±antifibrinolytics and 84.7% for antifibrinolytics alone. Treatment failure was documented in 18 bleeding events (2% of the total treatments), the majority of which were in patients receiving treatment with antifibrinolytics; bleeding re-started in 6% of bleeds after initial effective treatment. Thirty-five adverse events were reported, none of which was a thromboembolic event. Among treatments that included recombinant activated factor VII, only one patient reported three possibly drug-related non-serious adverse events (nausea, dyspnea and headache). To conclude, non-surgical bleeds were common and often severe in Glanzmann thrombasthenia; both platelets and recombinant activated factor VII appeared to be effective, and with good safety profiles, for the treatment of non-surgical bleeds. This trial was registered at clinicaltrials.gov identifier: NCT01476423.

Dataset Information

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

Publications

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

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