Glanzmann's thrombasthenia pathophysiology
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Glanzmann's thrombasthenia |
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Differentiating Glanzmann's thrombasthenia from other Diseases |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
The GpIIb/IIIa is an adhesion receptor and is expressed in thrombocytes. This receptor is activated when the thrombocyte is stimulated by ADP, epinephrine, collagen and thrombin. The GpIIb/IIIa integrin is essential to the blood coagulation since it has the ability to bind fibrinogen, the von Willebrand factor, fibronectin and vitronectin. This enables the platelet to be activated by contact with the collagen-von Willebrand-complex that is exposed when the endothelial blood vessel lining is damaged and then aggregate with other thrombocytes via fibrinogen.
Patients suffering from Glanzmann's thrombasthenia thus have platelets less able to adhere to each other and to the underlying tissue of damaged blood vessels.
Integrin (ITG) αIIbβ3 has roll in platelet aggregation and adhesion, connection between cells, cell migration and thrombus formation.
The understanding of its pathophysiology led to the development of GpIIb/IIIa inhibitors, a class of powerful antiplatelet agents.[1]
Pathophysiology
Integrin (ITG) αIIbβ3, formerly known as GPIIb/IIIa[2] is a large heterodimeric cell transmembrane receptor consists of a larger αIIb and a smaller β3 subunit. These subunits are non-covalently linked, allowing for duplex signaling between the cell membrane and extracellular matrix, while instituting intracellular signaling pathways.
ITG αIIbβ3 has a 8×12 nm nodular head and two 18 nm stalks in electron microscope. These stalks have both transmembrane and cytoplasmic sides,which intracellular signaling proteins and molecules can attach to them, on the other hand the domain that binds to ligand is located in the head.
Hematopoietic stem cell generates ITG αIIbβ3. Integrin αIIbβ3 needs calcium for it’s function, the αIIb subunit is made of a single peptide, is cinnected to the megakaryocyte lineage includes β-propeller area, which takes part in making a compound binding to calcium and platelet to platelet adhesion. ITG αIIbβ3 is activated through the attachment with epidermal growth factor (EGF) site of the β3 subunit. The platelet aggregation is through binding the receptor in head with vitronectin, VWF, fibronectin and fibrinogen.
GPIIIa on platelet is coded by ITGB3, a gene on chromosome 17q21. Whereas GPαIIb is coded by the gene ITGA2B, again on chromosome 17q21.
The amount of GPIIb/IIIa receptor on platelet’s surface varies by two-fold between patients, therefore platelet consists of about 100,000 GPIIb/IIIa receptor copies. Platelet aggregates normally with only 50% gene-producing protein, hence mutation in these genes consequently defects fibrinogen receptor αIIbβ3 and platelet’s function. Mutations can be, insertions, deletions,nonsense, missense or frameshifts and in ITGA2B gene occur these mutations more, because ITGA2B has more exon (30 exon ) than ITGB3 gene (15 exon ). [3]
References
- ↑ Seligsohn U. Glanzmann thrombasthenia: a model disease which paved the way to powerful therapeutic agents. Pathophysiol Haemost Thromb. 2002 Sep-Dec;32(5-6):216-7. PMID 13679645. Free Full Text.
- ↑ Nurden AT, Fiore M, Nurden P, Pillois X (2011). "Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models". Blood. 118 (23): 5996–6005. doi:10.1182/blood-2011-07-365635. PMID 21917754.
- ↑ Solh T, Botsford A, Solh M (2015). "Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options". J Blood Med. 6: 219–27. doi:10.2147/JBM.S71319. PMC 4501245. PMID 26185478.