Glanzmann Thrombasthenia: State of the Art and Future Directions

Abstract

Glanzmann thrombasthenia (GT) is the principal inherited disease of platelets and the most commonly encountered disorder of an integrin. GT is characterized by spontaneous mucocutaneous bleeding and an exaggerated response to trauma due to platelets that fail to aggregate when stimulated by physiologic agonists. GT is caused by quantitative or qualitative deficiencies of αIIbβ3, an integrin coded by the ITGA2B and ITGB3 genes and which by binding fibrinogen and other adhesive proteins joins platelets together in the aggregate. Widespread genotyping has revealed mutations spread across both genes, yet the reason for the extensive variation in both the severity and intensity of bleeding between affected individuals remains poorly understood. Furthermore, while genetic defects of ITGB3 affect other tissues with β3 present as αvβ3 (the vitronectin receptor), the bleeding phenotype continues to dominate. Here, we look in detail at mutations that affect (i) the β-propeller region of the αIIb head domain and (ii) the membrane proximal disulfide-rich EGF domains of β3 and which often result in spontaneous integrin activation. We also examine deep vein thrombosis as an unexpected complication of GT and look at curative procedures for the disease including allogeneic stem cell transfer and the potential for gene therapy.

Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: results from a collaborative study

“…The molecular characterization of patients revealed 16 mutations (half of them not reported previously) along both genes encoding for the α IIb β 3 receptor: 11 mutations were located in the ITGA2B gene within 8 patients (3 of them were compound heterozygous) and 5 in the ITGB3 in 4 more patients. According to a regularly updated database ( http://sinaicentral.mssm.edu/intranet/research/glanzmann ), and to what has been previously stated [ 15 ], we observed more mutations affecting ITGA2B possibly because, although a smaller gene than ITGB3 , it has 30 exons (and double number of splice sites) compared to 15 in ITGB3 . In patient GT-12, who has unequivocally been diagnosed by functional studies as GT, no mutations were detected.…”

“…Presented information includes data from the “Functional and Molecular Characterization of Patients with Inherited Platelet Disorders” a collaborative project that was undertaken under the scientific sponsorship of the Spanish Society of Thrombosis and Hemostasis. The main part of this manuscript focuses on describing our findings from patients diagnosed with two severe autosomal recessive IPDs affecting the platelet adhesion and aggregation, BSS and GT respectively [ 14 , 15 ].…”

Platelet Activation after Presyncope by Lower Body Negative Pressure in Humans

“…During activation, platelets undergo a shape change following activation of GPIIb/IIIa, which creates the foundation for platelet aggregation and formation of a platelet plug [9] . The importance of GPIIb/IIIa activation is demonstrated in patients suffering from Glanzmann's thrombasthenia whose platelets fail to aggregate due to a lack of functional GPIIb/IIIa, causing excessive hemorrhage after trauma or surgery [12] . PAC-1 binds to activated GPIIb/IIIa and, in the present study, the increased PAC-1 binding after LBNP demonstrates that platelets were activated and that their aggregation ability was enhanced.…”

Functional Comparison of Induced Pluripotent Stem Cell- and Blood-Derived GPIIbIIIa Deficient Platelets

“…Despite a general bleeding disorder in GT patients, bleeding severity differs considerably between affected individuals, even within the same family or ethnic group [ 39 ]. Understanding the molecular basis leading to this high phenotypic variability is subject of intensive research [ 40 ]. However, the scattered geographic distribution of patients with rare platelet diseases such as Glanzmann thrombasthenia impedes frequent clinical contact and scientific workflow even in specialized centers.…”