Glanzmann's thrombasthenia pathophysiology: Difference between revisions
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The GPIIb/IIIa, or ITG αIIbβ3, is a large heterodimeric cell transmembrane receptor comprised 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. Electron microscope images of the heterodimer have shown an 8×12 nm nodular head and two 18 nm stalks. The stalks extend through the cell, and contain the cytoplasmic and transmembrane domains that serve as attachment points for intracellular signaling molecules and proteins, while the bent head contains the ligand-binding site.12 The β3 subunit consists of large, disulfide epidermal growth factor (EGF)-domains responsible for activation of ITG αIIbβ3 as a whole. The calcium binding sites involved in complex formation and platelet-platelet adherence are located on the β-propeller region of the αIIb subunit. The receptor head functionality – binding fibrinogen, VWF, vitronectin and fibronectin – is necessary for platelet aggregation. ITG αIIbβ3 controls cell-to-cell communications by regulation of cell migration, platelet aggregation and adhesion, and the formation of a thrombus. | The GPIIb/IIIa, or ITG αIIbβ3, is a large heterodimeric cell transmembrane receptor comprised 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. Electron microscope images of the heterodimer have shown an 8×12 nm nodular head and two 18 nm stalks. The stalks extend through the cell, and contain the cytoplasmic and transmembrane domains that serve as attachment points for intracellular signaling molecules and proteins, while the bent head contains the ligand-binding site.12 The β3 subunit consists of large, disulfide epidermal growth factor (EGF)-domains responsible for activation of ITG αIIbβ3 as a whole. The calcium binding sites involved in complex formation and platelet-platelet adherence are located on the β-propeller region of the αIIb subunit. The receptor head functionality – binding fibrinogen, VWF, vitronectin and fibronectin – is necessary for platelet aggregation. ITG αIIbβ3 controls cell-to-cell communications by regulation of cell migration, platelet aggregation and adhesion, and the formation of a thrombus. | ||
Roughly 100,000 copies of the GPIIb/IIIa receptor are expressed along a platelet’s surface, which differs by two-fold between individuals. The gene ITGA2B, located on chromosome 17q21. codes for the platelet GPαIIb, while the gene ITGB3 encoding for the glycoprotein subunit IIIa lies on chromosome 17q21 | Roughly 100,000 copies of the GPIIb/IIIa receptor are expressed along a platelet’s surface, which differs by two-fold between individuals. The gene ITGA2B, located on chromosome 17q21. codes for the platelet GPαIIb, while the gene ITGB3 encoding for the glycoprotein subunit IIIa lies on chromosome 17q21. Mutations have been found more commonly in the ITGA2B gene, possibly due to the voluminous number of exons when compared to the ITGB3 gene (30 compared to 15). Deletions, insertions, frameshifts, nonsense, and missense mutations have been frequently recognized. Missense mutations have been further studied, and display interruption in integrin maturation or subunit formation. Biogenesis of ITG αIIbβ3 arises from the hematopoietic stem cell. The subunit αIIb is arranged from a single peptide, and is closely linked to the megakaryocyte lineage, whereas β3 is linked to the vitronectin receptor (αvβ3) involved in transport processes, with distribution among multitudes of tissues. Both subunits are amassed from endoplasmic reticulum precursors, with further processing occurring in the Golgi apparatus. The αvβ3 receptor will be most abundant on platelets in patients with an ITGA2B mutation. Both αIIbβ3 and αvβ3 will be absent when a mutation prevents β3 synthesis, but a missense mutation in β3 can have varying effects. For example, mutations in β3 Leu262Pro and Ser162Leu have been shown to provide residual αIIbβ3 platelet complexes with the capacity to bind fibrin and retract clots, but, when stimulated, are incapable of adhering fibrinogen. In contrast, a mutation in β3 Leu196Pro is able to sustain partial clot retraction. A review by Nurden et al more closely examined the β-propeller ectodomain mutations of the αIIb subunit. Nurden et al concluded that a large series of mutations affecting the β-propeller domain interrupted calcium binding and had numerous deleterious effects on αIIbβ3 expression and function, giving rise to the different types of GT. Mutations in the αIIb subunit that allow for partial complex formation were found to be distant from the junction between αIIb and β3, inferring a variant form of GT. Different effects are noted between mutations occurring in either subunit of αIIbβ3, and between αIIbβ3 and αvβ3; however, αvβ3 is more resilient to change than αIIbβ3. Some mutations of αIIbβ3 do not lead to GT. For example, Kashiwagi et al recently described three gain of function mutations, ITGA2B p.Gly991Cys, ITGA2B p.Phe993del, and ITGB3 p.(Asp621_Glu660del), that led to a highly activated conformation of αIIbβ3 and spontaneous tyrosine phosphorylation of FAK in transfected cells. These mutations resulted in abnormalities in both platelet morphology and number, with impaired surface αIIbβ3 expression, but did not lead to GT. | ||
Homozygous or heterozygous mutations found at either gene locus determine the severity of abnormality seen in GT. Mutations can arrest subunit manufacturing, impede complex formation, and/or inhibit intracellular trafficking. When complex formation is hindered, residual subunits of αIIb or β3 degrade. Based on the expression and functionality of residual subunits, GT is classified into three types: <5% of residual αIIbβ3 signifies type I GT; 5%–20% of residual αIIbβ3 comprises type II GT; and rarely, >20% of residual αIIb β3, with dysfunctional properties, constitutes variant-type GT. Early work by George et al failed to correlate the subtype of GT with severity of bleeding. However, it has been noted by Fiore et al that phenotypic bleeding is more influenced by a mutation in the ITGB3 gene.<ref name="pmid1990;75:1383–95">{{cite journal| author=Arimura H| title=Correlation between molecular size and interferon- inducing activity of poly I:C. | journal=Acta Virol | year= 1975 | volume= 19 | issue= 6 | pages= 457-66 | pmid=1990;75:1383–95 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1990 }}</ref> | Homozygous or heterozygous mutations found at either gene locus determine the severity of abnormality seen in GT. Mutations can arrest subunit manufacturing, impede complex formation, and/or inhibit intracellular trafficking. When complex formation is hindered, residual subunits of αIIb or β3 degrade. Based on the expression and functionality of residual subunits, GT is classified into three types: <5% of residual αIIbβ3 signifies type I GT; 5%–20% of residual αIIbβ3 comprises type II GT; and rarely, >20% of residual αIIb β3, with dysfunctional properties, constitutes variant-type GT. Early work by George et al failed to correlate the subtype of GT with severity of bleeding. However, it has been noted by Fiore et al that phenotypic bleeding is more influenced by a mutation in the ITGB3 gene.<ref name="pmid1990;75:1383–95">{{cite journal| author=Arimura H| title=Correlation between molecular size and interferon- inducing activity of poly I:C. | journal=Acta Virol | year= 1975 | volume= 19 | issue= 6 | pages= 457-66 | pmid=1990;75:1383–95 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1990 }}</ref> | ||
Revision as of 14:36, 2 July 2018
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Glanzmann's thrombasthenia |
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Differentiating Glanzmann's thrombasthenia from other Diseases |
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Glanzmann's thrombasthenia pathophysiology On the Web |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
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.
The understanding of its pathophysiology led to the development of GpIIb/IIIa inhibitors, a class of powerful antiplatelet agents.[1]
The GPIIb/IIIa, or ITG αIIbβ3, is a large heterodimeric cell transmembrane receptor comprised 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. Electron microscope images of the heterodimer have shown an 8×12 nm nodular head and two 18 nm stalks. The stalks extend through the cell, and contain the cytoplasmic and transmembrane domains that serve as attachment points for intracellular signaling molecules and proteins, while the bent head contains the ligand-binding site.12 The β3 subunit consists of large, disulfide epidermal growth factor (EGF)-domains responsible for activation of ITG αIIbβ3 as a whole. The calcium binding sites involved in complex formation and platelet-platelet adherence are located on the β-propeller region of the αIIb subunit. The receptor head functionality – binding fibrinogen, VWF, vitronectin and fibronectin – is necessary for platelet aggregation. ITG αIIbβ3 controls cell-to-cell communications by regulation of cell migration, platelet aggregation and adhesion, and the formation of a thrombus.
Roughly 100,000 copies of the GPIIb/IIIa receptor are expressed along a platelet’s surface, which differs by two-fold between individuals. The gene ITGA2B, located on chromosome 17q21. codes for the platelet GPαIIb, while the gene ITGB3 encoding for the glycoprotein subunit IIIa lies on chromosome 17q21. Mutations have been found more commonly in the ITGA2B gene, possibly due to the voluminous number of exons when compared to the ITGB3 gene (30 compared to 15). Deletions, insertions, frameshifts, nonsense, and missense mutations have been frequently recognized. Missense mutations have been further studied, and display interruption in integrin maturation or subunit formation. Biogenesis of ITG αIIbβ3 arises from the hematopoietic stem cell. The subunit αIIb is arranged from a single peptide, and is closely linked to the megakaryocyte lineage, whereas β3 is linked to the vitronectin receptor (αvβ3) involved in transport processes, with distribution among multitudes of tissues. Both subunits are amassed from endoplasmic reticulum precursors, with further processing occurring in the Golgi apparatus. The αvβ3 receptor will be most abundant on platelets in patients with an ITGA2B mutation. Both αIIbβ3 and αvβ3 will be absent when a mutation prevents β3 synthesis, but a missense mutation in β3 can have varying effects. For example, mutations in β3 Leu262Pro and Ser162Leu have been shown to provide residual αIIbβ3 platelet complexes with the capacity to bind fibrin and retract clots, but, when stimulated, are incapable of adhering fibrinogen. In contrast, a mutation in β3 Leu196Pro is able to sustain partial clot retraction. A review by Nurden et al more closely examined the β-propeller ectodomain mutations of the αIIb subunit. Nurden et al concluded that a large series of mutations affecting the β-propeller domain interrupted calcium binding and had numerous deleterious effects on αIIbβ3 expression and function, giving rise to the different types of GT. Mutations in the αIIb subunit that allow for partial complex formation were found to be distant from the junction between αIIb and β3, inferring a variant form of GT. Different effects are noted between mutations occurring in either subunit of αIIbβ3, and between αIIbβ3 and αvβ3; however, αvβ3 is more resilient to change than αIIbβ3. Some mutations of αIIbβ3 do not lead to GT. For example, Kashiwagi et al recently described three gain of function mutations, ITGA2B p.Gly991Cys, ITGA2B p.Phe993del, and ITGB3 p.(Asp621_Glu660del), that led to a highly activated conformation of αIIbβ3 and spontaneous tyrosine phosphorylation of FAK in transfected cells. These mutations resulted in abnormalities in both platelet morphology and number, with impaired surface αIIbβ3 expression, but did not lead to GT.
Homozygous or heterozygous mutations found at either gene locus determine the severity of abnormality seen in GT. Mutations can arrest subunit manufacturing, impede complex formation, and/or inhibit intracellular trafficking. When complex formation is hindered, residual subunits of αIIb or β3 degrade. Based on the expression and functionality of residual subunits, GT is classified into three types: <5% of residual αIIbβ3 signifies type I GT; 5%–20% of residual αIIbβ3 comprises type II GT; and rarely, >20% of residual αIIb β3, with dysfunctional properties, constitutes variant-type GT. Early work by George et al failed to correlate the subtype of GT with severity of bleeding. However, it has been noted by Fiore et al that phenotypic bleeding is more influenced by a mutation in the ITGB3 gene.[2]
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.
- ↑ Arimura H (1975). "Correlation between molecular size and interferon- inducing activity of poly I:C". Acta Virol. 19 (6): 457–66. PMID 1990;75:1383–95 Check
|pmid=value (help).