Profiling the Genetic and Molecular Characteristics of Glanzmann Thrombasthenia: Can It Guide Current and Future Therapies?

Abstract

Glanzmann thrombasthenia (GT) is the most widely studied inherited disease of platelet function. Platelets fail to aggregate due to a defect in platelet-to-platelet attachment. The hemostatic plug fails to form and a moderate to severe bleeding diathesis results. Classically of autosomal recessive inheritance, GT is caused by defects within the ITGA2B and ITGB3 genes that encode the αIIbβ3 integrin expressed at high density on the platelet surface and also in intracellular pools. Activated αIIbβ3 acts as a receptor for fibrinogen and other adhesive proteins that hold platelets together in a thrombus. Over 50 years of careful clinical and biological investigation have provided important advances that have improved not only the quality of life of the patients but which have also contributed to an understanding of how αIIbβ3 functions. Despite major improvements in our knowledge of GT and its genetic causes, extensive biological and clinical variability with respect to the severity and intensity of bleeding remains poorly understood. I now scan the repertoire of ITGA2B and ITGB3 gene defects and highlight the wide genetic and biological heterogeneity within the type II and variant subgroups especially with regard to bleeding, clot retraction, the internal platelet Fg storage pool and the nature of the mutations causing the disease. I underline the continued importance of gene profiling and biological studies and emphasize the multifactorial etiology of the clinical expression of the disease. This is done in a manner to provide guidelines for future studies and future treatments of a disease that has not only aided research on rare diseases but also contributed to advances in antithrombotic therapy.

Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions

“…71,73 In addition to the above heterogeneity, not all activating mutations in αIIbβ3 give macrothrombocytopenia. 4,9 Such variations have yet to be explained. It is interesting to note that in the knock-in mouse model of Akuta et al 70 while MKs and platelets from mice homozygous for αIIbW995 spontaneously expressed active αIIbβ3 (JON/A MoAb and Fg binding), this was much less evident for platelets of heterozygous mice.…”

“…Briefly, GT is the most common inherited platelet disorder (IPD) with lifelong spontaneous (easy bruising, purpura, epistaxis, gingival bleeds) and trauma-related mucocutaneous bleeding, with women having added complications of menorrhagia, pregnancy, and postpartum blood loss. 2 3 4 5 6 7 Gastrointestinal (GI) bleeding is a difficult to manage complication. Thrombus formation fails because platelets lack functional αIIbβ3 integrin (formerly termed GPIIb-IIIa) that on activation mediates platelet aggregation to natural agonists by expressing determinants for fibrinogen (Fg) and other adhesive proteins that when bound crosslink platelets.…”

“…9 Classic GT has autosomal recessive (AR) inheritance and is caused by homozygous or compound heterozygous mutations in the ITGA2B or ITGB3 genes. 2,4,[10][11][12] Mutations include missense, nonsense, and in-or out-of-frame insertions or deletions often affecting splice sites; duplications, large deletions, and complex rearrangements, although rare, have all been reported. Their effect is to block the synthesis of αIIb or β3, prevent complex formation, or interfere with αIIbβ3 trafficking in megakaryocytes (MKs).…”

“…Severe αIIbβ3 loss is termed type I, 5 to 20% residual αIIbβ3 as type II, and a greater than 20% expression of αIIbβ3 unable to bind Fg on activation as type III GT. 4,5,9 Missense mutations allowing at least partial αIIbβ3 expression, while abrogating function, have helped identify active sites on this integrin whose structure (along with that of αvβ3) has been defined by high-resolution crystallography, electron microscopy, and computer analyses. 8,10,[13][14][15] Keywords ► Glanzmann thrombasthenia ► αIIbβ3 integrin ► biology ► mutations ► prophylaxis ► gene therapy…”

State-of-the-Art Targeted High-Throughput Sequencing for Detecting Inherited Platelet Disorders

“…Some IPDs have specific pathognomonic features such as Glanzmann's thrombasthenia (GT), Bernard-Soulier syndrome (BSS), or Congenital Amegakaryocytic Thrombocytopenia (CAMT) of which the relevant gene (or genes) has been well studied. [6][7][8][9] Other examples for IPDs that have been deciphered in the last two decades include Gray platelet syndrome 10 or thrombocytopenia-absent radius syndrome. 11,12 So far approximately 60 to 80 genes are considered to be involved in IPDs.…”