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Demonstration of novel gain-of-function mutations of ?IIb?3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype.

ABSTRACT: Integrin ?IIb?3 is indispensable for normal hemostasis, but its role for thrombopoiesis is still controversial. Recently, ?IIb and ?3 mutations have been identified in patients with congenital macrothrombocytopenia. We analyzed three unrelated Japanese families with congenital macrothrombocytopenia. Expression and activation state of ?IIb?3 in platelets was examined by flow cytometry and immunoblotting. Sequence of whole coding region and exon-intron boundaries of ITGA2B and ITGB3 genes was performed. The effects of mutations on ?IIb?3 activation state and phosphorylation of FAK were analyzed in transfected cells. We newly identified three mutations: two mutations in highly conserved Gly-Phe-Phe-Lys-Arg sequence in juxtamembrane region of ?IIb, p.Gly991Cys and p.Phe993del, and one donor site mutation of intron 13 of ITGB3 leading to 40 amino acids deletion, p.(Asp621_Glu660del), in the membrane proximal ?-tail domain of ?3. One patient, who showed Glanzmann thrombasthenia-like marked reduction in surface ?IIb?3 expression (3-11% of normal control), was a compound heterozygote with ITGA2B p.Gly991Cys and a novel nonsense mutation, ITGA2B p.Arg422*. All three mutations, ITGA2B p.Gly991Cys, ITGA2B p.Phe993del, and ITGB3 p.(Asp621_Glu660del), led to highly activated conformation of ?IIb?3 and spontaneous tyrosine phosphorylation of FAK in transfected cells. These results suggest that gain-of-function mutations around membrane region of ?IIb?3 lead to abnormal platelet number and morphology with impaired surface ?IIb?3 expression.

SUBMITTER: Kashiwagi H

PROVIDER: S-EPMC3865572 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype.

Kashiwagi Hirokazu H Kunishima Shinji S Kiyomizu Kazunobu K Amano Yoshiro Y Shimada Hiroyuki H Morishita Masashi M Kanakura Yuzuru Y Tomiyama Yoshiaki Y

Molecular genetics & genomic medicine 20130422 2

Integrin αIIbβ3 is indispensable for normal hemostasis, but its role for thrombopoiesis is still controversial. Recently, αIIb and β3 mutations have been identified in patients with congenital macrothrombocytopenia. We analyzed three unrelated Japanese families with congenital macrothrombocytopenia. Expression and activation state of αIIbβ3 in platelets was examined by flow cytometry and immunoblotting. Sequence of whole coding region and exon-intron boundaries of ITGA2B and ITGB3 genes was perf ...[more]

PMID: 24498605

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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

Demonstration of novel gain-of-function mutations of ?IIb?3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype.

Publications

Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype.

Similar Datasets

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