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{{Glanzmann's thrombasthenia}}
{{Glanzmann's thrombasthenia}}


{{CMG}}
{{CMG}} {{AE}} {{OK}}, [[User:Niush.D|Niyousha Danesh, MD-MPH]]


==Overview==
==Overview==
[[Glanzmann's thrombasthenia]] is an [[autosomal recessive]] [[hematologic]] disorder. [[Megakaryocyte]] lineage is affected in this disease, and leads to dysfunctional [[platelet aggregation]].The [[pathogenesis]] is related to a quantitative and/or qualitative defect in [[GpIIb/IIIa]] (αIIbβ3 [[integrin]]) construction. This [[receptor]] mediates [[platelet aggregation]] and [[thrombus]] formation when the [[blood vessel]] is damaged. The [[GpIIb/IIIa]] is an adhesion [[receptor]] and is expressed in [[Platelet|platelets]]. This [[receptor]] is activated when the [[platelet]] is stimulated by [[Adenosine diphosphate|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 vessel|blood vessels]]. [[Integrin]] (ITG) αIIbβ3 has roll in [[platelet aggregation]] and [[adhesion]], connection between [[cells]], [[cell migration]] and [[thrombus]] formation


==Pathophysiology ==
==Pathophysiology ==
The [[GpIIb/IIIa]] is an adhesion receptor and is expressed in [[thrombocytes]]. This receptor is activated when the thrombocyte is stimulated by [[Adenosine diphosphate|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]].
* [[Integrin]] (ITG) αIIbβ3, formerly known as [[GPIIb/IIIa]]<ref name="pmid21917754">{{cite journal| author=Nurden AT, Fiore M, Nurden P, Pillois X| title=Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models. | journal=Blood | year= 2011 | volume= 118 | issue= 23 | pages= 5996-6005 | pmid=21917754 | doi=10.1182/blood-2011-07-365635 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21917754  }}</ref> 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<ref name="pmid26185478">{{cite journal |vauthors=Solh T, Botsford A, Solh M |title=Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options |journal=J Blood Med |volume=6 |issue= |pages=219–27 |date=2015 |pmid=26185478 |pmc=4501245 |doi=10.2147/JBM.S71319 |url=}}</ref>
* 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. <ref name="pmid5102406">{{cite journal| author=Lévy JM, Mayer G, Sacrez R, Ruff R, Francfort JJ, Rodier L| title=[Glanzmann-Naegeli thrombasthenia. Study of a strongly endogamous ethnic group]. | journal=Ann Pediatr (Paris) | year= 1971 | volume= 18 | issue= 2 | pages= 129-37 | pmid=5102406 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5102406  }}</ref>
*<nowiki/>[[Hematopoietic stem cell|Hematopoietic stem cel]]<nowiki/>l generates Integrin αIIbβ3
* ITG αIIbβ3 consist of <nowiki/>αIIb subunit and β3 subunit. [[Endoplasmic reticulum]] precursors accumulate these subunits and the [[Golgi apparatus]] process them.
* The αIIb subunit includes β-propeller area, which takes part in making a compound binding to [[calcium]] and [[platelet]] for [[platelet]] adhesion.
*  ITG αIIbβ3  is activated through the attachment with [[epidermal growth factor]] ([[EGF]]) site of the β3 subunit. β3 is connected to the [[vitronectin]] receptor (αvβ3). Transport process and [[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.
* [[ITGA2B]] [[mutations]] prevent β3 [[synthesis]] and lead to lack of αIIbβ3 and αvβ3 ([[vitronectin]]) [[receptors]] in individuals.
* 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]].
* GT manifestation and severity differ with [[homozygous]] or [[heterozygous]] mutations in gene.
* [[Mutations]] are capable of inhibiting [[intracellular]] trafficking, interfering with subunit production and complex formation. Remaining [[subunits]] of αIIb or β3 are diminished in complex formation abnormalities,
* Some [[mutation]] consequently defect [[fibrinogen]] [[receptor]] αIIbβ3 and platelet’s function. Most of these [[mutations]] occur in ITGA2B [[gene]], because the number of [[exon]] in  ITGA2B(30) is greater than ITGB3 [[gene]] (15).
* [[Mutations]] could be either [[Insertion|insertions]], [[Deletion (genetics)|deletion]],[[nonsense]], [[Frameshift mutation|frameshift]]<nowiki/>s or [[missense]].


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.
* [[Missense mutations]] have different presentations it can block formation of [[subunits]] and [[maturation]] of [[integrin]]. By Leu196Pro β3 [[mutation]] [[clot retraction]] can take place partially, but when [[mutations]] in β3 Ser162Leu and Leu262Pro occur αIIbβ3 although [[platelets]] bind to [[fibrin]] and retract clot, they are not able to adhere to [[fibrinogen]] after stimulation .
 
* [[Mutations]] in  β-propeller domain of the αIIb subunit is observed in various types of GT, these mutations affect vastly αIIbβ3 expression and function other than interfering with [[calcium]] binding . Partial complex formation can be made despite some [[mutations]] in the αIIb subunit, even some individuals do not present GT symptoms contrary to [[mutations]] in αIIbβ3.<ref name="pmid219177542">{{cite journal| author=Nurden AT, Fiore M, Nurden P, Pillois X| title=Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models. | journal=Blood | year= 2011 | volume= 118 | issue= 23 | pages= 5996-6005 | pmid=21917754 | doi=10.1182/blood-2011-07-365635 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21917754  }}</ref>
The understanding of its pathophysiology led to the development of [[GpIIb/IIIa inhibitors]], a class of powerful [[antiplatelet agent]]s.<ref name="seligsohn">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. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ArtikelNr=73569&ProduktNr=224034&Ausgabe=229381&filename=73569.pdf Free Full Text].</ref>
* [[Mutations]] could happen in [[subunit]] of αIIbβ3, or between αvβ3 and αIIbβ3. Hence αvβ3 tolerates [[mutations]] better than αIIbβ3. As an example there exist three kinds of [[mutations]] in αIIbβ3, in which αIIbβ3 complex is extremely activated and in the FAK of [[platelets]] [[tyrosine]] is [[phosphorylated]] when ITGA2B p.Phe993del, ITGB3 p.(Asp621_Glu660del) and ITGA2B p.Gly991Cysthat are [[mutated]], though The mentioned [[mutations]] affect surface αIIbβ3 expression and change [[platelet]] morphology and count, but doesn’t manifest GT. <ref name="pmid24498605">{{cite journal| author=Kashiwagi H, Kunishima S, Kiyomizu K, Amano Y, Shimada H, Morishita M et al.| title=Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype. | journal=Mol Genet Genomic Med | year= 2013 | volume= 1 | issue= 2 | pages= 77-86 | pmid=24498605 | doi=10.1002/mgg3.9 | pmc=3865572 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24498605  }}</ref> <ref name="pmid219177543">{{cite journal| author=Nurden AT, Fiore M, Nurden P, Pillois X| title=Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models. | journal=Blood | year= 2011 | volume= 118 | issue= 23 | pages= 5996-6005 | pmid=21917754 | doi=10.1182/blood-2011-07-365635 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21917754  }}</ref> <ref name="pmid2180491">{{cite journal| author=George JN, Caen JP, Nurden AT| title=Glanzmann's thrombasthenia: the spectrum of clinical disease. | journal=Blood | year= 1990 | volume= 75 | issue= 7 | pages= 1383-95 | pmid=2180491 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2180491 }}</ref> <ref name="pmid22781097">{{cite journal| author=Fiore M, Nurden AT, Nurden P, Seligsohn U| title=Clinical utility gene card for: Glanzmann thrombasthenia. | journal=Eur J Hum Genet | year= 2012 | volume= 20 | issue= 10 | pages=  | pmid=22781097 | doi=10.1038/ejhg.2012.151 | pmc=3449071 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22781097  }}</ref> <ref name="pmid26185478">{{cite journal| author=Solh T, Botsford A, Solh M| title=Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options. | journal=J Blood Med | year= 2015 | volume= 6 | issue= | pages= 219-27 | pmid=26185478 | doi=10.2147/JBM.S71319 | pmc=4501245 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26185478 }}</ref>
 
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.<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><ref name="pmidhttps://dx.doi.org/10.2147/JBM.S71319">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=https://dx.doi.org/10.2147/JBM.S71319 | doi= | pmc=5922622 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10 }}</ref>


==References==
==References==
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[[Category:Disease]]
[[Category:Disease]]
[[Category:Hematology]]
[[Category:Hematology]]
[[Category:Primary care]]

Latest revision as of 21:52, 29 July 2020

Glanzmann's thrombasthenia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Niyousha Danesh, MD-MPH

Overview

Glanzmann's thrombasthenia is an autosomal recessive hematologic disorder. Megakaryocyte lineage is affected in this disease, and leads to dysfunctional platelet aggregation.The pathogenesis is related to a quantitative and/or qualitative defect in GpIIb/IIIa (αIIbβ3 integrin) construction. This receptor mediates platelet aggregation and thrombus formation when the blood vessel is damaged. The GpIIb/IIIa is an adhesion receptor and is expressed in platelets. This receptor is activated when the platelet 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

Pathophysiology

  • Missense mutations have different presentations it can block formation of subunits and maturation of integrin. By Leu196Pro β3 mutation clot retraction can take place partially, but when mutations in β3 Ser162Leu and Leu262Pro occur αIIbβ3 although platelets bind to fibrin and retract clot, they are not able to adhere to fibrinogen after stimulation .
  • Mutations in  β-propeller domain of the αIIb subunit is observed in various types of GT, these mutations affect vastly αIIbβ3 expression and function other than interfering with calcium binding . Partial complex formation can be made despite some mutations in the αIIb subunit, even some individuals do not present GT symptoms contrary to mutations in αIIbβ3.[4]
  • Mutations could happen in subunit of αIIbβ3, or between αvβ3 and αIIbβ3. Hence αvβ3 tolerates mutations better than αIIbβ3. As an example there exist three kinds of mutations in αIIbβ3, in which αIIbβ3 complex is extremely activated and in the FAK of platelets tyrosine is phosphorylated when ITGA2B p.Phe993del, ITGB3 p.(Asp621_Glu660del) and ITGA2B p.Gly991Cysthat are mutated, though The mentioned mutations affect surface αIIbβ3 expression and change platelet morphology and count, but doesn’t manifest GT. [5] [6] [7] [8] [2]

References

  1. ↑ 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.
  2. ↑ 2.0 2.1 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.
  3. ↑ Lévy JM, Mayer G, Sacrez R, Ruff R, Francfort JJ, Rodier L (1971). "[Glanzmann-Naegeli thrombasthenia. Study of a strongly endogamous ethnic group]". Ann Pediatr (Paris). 18 (2): 129–37. PMID 5102406.
  4. ↑ 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.
  5. ↑ Kashiwagi H, Kunishima S, Kiyomizu K, Amano Y, Shimada H, Morishita M; et al. (2013). "Demonstration of novel gain-of-function mutations of αIIbβ3: association with macrothrombocytopenia and glanzmann thrombasthenia-like phenotype". Mol Genet Genomic Med. 1 (2): 77–86. doi:10.1002/mgg3.9. PMC 3865572. PMID 24498605.
  6. ↑ 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.
  7. ↑ George JN, Caen JP, Nurden AT (1990). "Glanzmann's thrombasthenia: the spectrum of clinical disease". Blood. 75 (7): 1383–95. PMID 2180491.
  8. ↑ Fiore M, Nurden AT, Nurden P, Seligsohn U (2012). "Clinical utility gene card for: Glanzmann thrombasthenia". Eur J Hum Genet. 20 (10). doi:10.1038/ejhg.2012.151. PMC 3449071. PMID 22781097.
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