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 caused by 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 that 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, although 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 epidermal growth factor (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 diseases, including allogeneic stem cell transfer and the potential for gene therapy.

Figure 1

A large series of missense mutations are identified within the αIIb N-terminal β-propeller. Panel (A) is a linear representation. In light blue are domains and mutations at the interface with the β3 headpiece; in blue marine are those affecting the 7 blades; and in deep blue are those away from the interface. Mutations in green lie within the FG-GAP-G motif while that in red-brown is within a Ca²⁺-binding domain. Asterisks represent the same mutation found in different patients. Panels (B) and (D) are computer-drawn diagrams of the Ca²⁺-binding motif and the FG-GAP-G motif respectively. In (C) is a computer drawn ribbon diagram of the β-propeller domain with mutations represented as red graphical sticks. Panel (E) is a Table showing the mutation count as a function of their localization. Models were obtained using the PyMol Molecular Graphics System Version 1.3; Schrödinger LLC (www.pymol.org) and the 3vdo pdb file.^, The mutations are listed on the GT database (http://sinaicentral.mssm.edu/intranet/research/glanzmann).

Figure 2

Panel (A) is a linear representation of the four consecutive IEGF domains (in grades of green) of the β3 subunit with each mutation localized. Asterisks represent the same mutation found in different patients. Panel (B) is a computer drawn ribbon diagram of the IEGF region of β3. Mutations are represented as red graphical sticks. Models were obtained using the PyMol Molecular Graphics System, version 1.3, Schrödinger, LLC (www.pymol.org) and the 3ije pdb file.