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

L Bury, E Falcinelli, D Chiasserini, TA Springer… - …, 2016 - ncbi.nlm.nih.gov
L Bury, E Falcinelli, D Chiasserini, TA Springer, JE Italiano Jr, P Gresele
haematologica, 2016ncbi.nlm.nih.gov
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 …
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 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.
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