Glanzmann's thrombasthenia pathophysiology

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

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

• Integrin (ITG) αIIbβ3, formerly known as GPIIb/IIIa^[1] 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^[2]
• 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. ^[3]
• Hematopoietic stem cell generates Integrin αIIbβ3
• ITG αIIbβ3 consist of 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 insertions, deletion,nonsense, frameshifts or missense.

• 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]}