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

Figures & data

Table 1 Glanzmann Thrombasthenia in All Its Forms

Disease Description	Comments
Type I Subgroup
- Absence of platelet aggregation and little or no clot retraction. Levels of αIIbβ3 <5% or absent. Platelet Fg storage pool lacking or negligible. AR inheritance.	- The most common type of GT, given by defects in ITGA2B and ITGB3 genes. With ITGA2B defects αvβ3 may still be present and functional. Patients susceptible to form isoantibodies reactive with αIIbβ3 and/or αvβ3 after blood transfusion or pregnancy.
Type II Subgroup
- Absence of platelet aggregation but clot retraction can be partial or normal. Residual αIIbβ3 historically defined as 5–15% of normal levels. Platelet Fg pool can be substantial. AR inheritance.	- Frequency variable within populations but usually less than 20% of the patients. Given by defects in ITGA2B and ITGB3. Clot retraction defects and the platelet Fg storage capacity are mutation dependent.
Variant Forms
- Absence of platelet aggregation but clot retraction and Fg storage highly variable. Residual αIIbβ3 mainly >50% or even normal but non-functional with little or no activation-dependent Fg binding as also shown by a lack of PAC-1 binding. AR inheritance.	- Rare. Can be given by defects in ITGA2B but mostly by ITGB3 variants. Extracellular mutations directly or indirectly abrogate Fg-binding sites. Intracellular mutations stop signals for αIIbβ3 activation. Clot retraction and Fg storage are mutation dependent. Can be confused with defects in FERMT3 and RASGRP2 that prevent kindlin-3 (LAD-III disease) and CalDAG-GEFI signaling.
Upregulated αIIbβ3 and Macrothrombocytopenia (MTP)
- Much reduced platelet aggregation with clot retraction and Fg storage again variable. Residual αIIbβ3 normally >30% but with spontaneous binding of PAC-1 (but rarely Fg). MTP mostly moderate with subpopulations of enlarged even giant platelets. AD inheritance.	- Rare. Patients with up-regulated αIIbβ3 interfering with megakaryocyte maturation and platelet biogenesis with enlarged platelets in variable numbers. Bleeding mostly due to defective αIIbβ3 function. Single allele mutations on ITGA2B but mostly ITGB3. Often these affect cytoplasmic domains.

Notes: The above criteria are basic for each subtype, but there is much overlap between them and clear boundaries do not exist. PAC-1 is an activation dependent IgM monoclonal antibody to αIIbβ3.

Abbreviations: AR, autosomal recessive; AD, autosomal dominant; LAD-III, leukocyte adhesion deficiency syndrome type III.

Figure 1 Structural representation of αIIbβ3 in its bent conformation showing the mutations that give rise to selected variant forms of GT or to related phenotypes. This model is based on the crystal structure of αIIbβ3; it was constructed using the PyMol Molecular Graphics System, version 1.3 Schrödinger, LLC and 3fcs and 2knc pdb files as described.¹⁶ The αIIb subunit is in green and β3 is in blue. Precision crystallography and modeling showed that αIIb has 4 major extracellular domains (β-propeller, thigh, calf-1 and calf-2) whereas β3 has more (β-I or β-A, hybrid, plexin-semaphorin-integrin (PSI), 4 epidermal growth factor (EGF) and the β-tail domain).^8,10 Loss-of-function mutations (in blue) in the β3 extracellular head prevent binding of Fg or other adhesive proteins to the opened integrin headpiece following platelet activation, while those in the β3 cytoplasmic tail prevent binding of kindlin-3 and/or talin, and block steps essential for integrin activation. Gain-of-function mutations (in red) lead to at least partial activation of αIIbβ3 and often associated with MTP accompanied by a variable loss of αIIbβ3 function. All mutations are detailed and referenced in the text.

Nurden AT, Pillois X. ITGA2B and ITGB3 gene mutations associated with Glanzmann thrombasthenia. Platelets. 2018;29(1):98–101. doi:10.1080/09537104.2017.1371291

 PubMed Web of Science ®Google Scholar

Coller BS, Shattil SJ. The GPIIb/IIIa (integrin alphaIIbbeta3) odyssey: a technology-driven saga of a receptor with twists and even a bend. Blood. 2008;112(8):3011–3025. doi:10.1182/blood-2008-06-077891

 PubMed Web of Science ®Google Scholar

Xiao T, Takagi J, Coller BS, Wang JH, Springer TA. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature. 2004;432(7013):59–67.

 PubMed Web of Science ®Google Scholar