Abnormal cytoplasmic extensions associated with active alpha IIb beta 3 are probably the cause for macrothrombocytopenia in Glanzmann thrombasthenia-like syndrome

作者：Hauschner Hagit^*; Mor Cohen Ronit; Messineo Stefania; Mansour Wissam; Seligsohn Uri; Savoia Anna; Rosenberg Nurit

来源：Blood Coagulation & Fibrinolysis, 2015, 26(3): 302-308.

DOI：10.1097/MBC.0000000000000241

• alpha-IIb beta3
• alpha-v beta-3
• Glanzmann thrombasthenia
• integrins
• platelets
• thrombocytopenias

Mutations in the ITGA2B or ITGB3 genes that encode for the aIIbb3 platelet integrin usually cause Glanzmann thrombasthenia, a severe autosomal recessive bleeding disorder characterized by absence of platelet aggregation, but normal platelet number and size. Several rare mutations cause a Glanzmann-like syndrome which manifests macrothrombocytopenia and usually displays autosomal dominant inheritance. The exact mechanism causing Glanzmann-like syndrome is unknown. One typical example of Glanzmann-like mutations causes deletion of 40 amino acids (p.647-686) in the beta 3 beta-tail domain (beta TD_del) that was found in the heterozygous state in Italian and Japanese families. A second example is a missense mutation, C560R, located in the epidermal growth factor-like domain, found in the homozygous state in a French patient. Both mutations cause constitutive activation of alpha IIb beta 3, but differ in their surface expression. In the current study, we generated cultured cells expressing beta 3-beta TD_del or beta 3-C560R mutations along with wild-type alpha II beta, and examined the cells' ability to create tubulin-dependent protrusions compared to cells expressing wild-type alpha IIb beta 3. Unlike cells expressing wild-type alpha IIb beta 3, cells harboring each of the mutations exhibited abnormal cytoplasmic extensions on immobilized fibrinogen or Von Willebrand factor, which resembled extensions formed in megakaryocyte leading to proplatelets. Moreover, we showed that formation of abnormal extensions occurred also in wild-type alpha IIb beta 3 cells when activated by activating antibody. These results suggest that the active conformation of alpha IIb beta 3 can induce cytoskeletal rearrangements that lead to impaired proplatelet formation.

• 出版日期2015-4