Glanzmann Thrombasthenia: Perspectives from Clinical Practice on Accurate Diagnosis and Optimal Treatment Strategies

Abstract

Glanzmann thrombasthenia (GT) is a rare autosomal recessive disorder of fibrinogen-mediated platelet aggregation due to a quantitative or qualitative deficit of the α_IIbβ₃ integrin at the platelet surface membrane resulting from mutation(s) in ITGA2B and/or ITGB3. Patients tend to present in early childhood with easy bruising and mucocutaneous bleeding. The diagnostic process requires consideration of more common disorders of haemostasis and coagulation prior to confirming the disorder with platelet light transmission aggregation, flow cytometry of CD41 and CD61 expression, and/or exon sequencing of ITGA2B and ITGB3. Antifibrinolytic therapy, recombinant activated factor VII, and platelet transfusions are the mainstay of therapy, although the latter may trigger formation of anti-platelet antibodies in GT patients and inadvertent platelet-refractory disease. The management of these patients therefore remains complex, particularly in the context of trauma, labour and delivery, and perioperative care. Bone marrow transplantation remains the sole curative option, although the venue of gene therapy is being increasingly explored as a future alternative for definitive treatment of GT.

Keywords: ITGA2B; ITGB3; bleeding disorders; inherited platelet defects; platelet aggregation; αIIbβ3.

Figure 1

Schematic of α_IIbβ₃ integrin composed of α_IIb and β₃ subunits. The mature α_IIb subunit contains extracellular heavy and light chains linked together via disulfide bridge. Both subunits contain extracellular, transmembrane, and cytoplasmic domains; the latter domains are linked via salt bridge.

Figure 2

Schematic of α_IIbβ₃ integrin undergoing inside-out and outside-in signaling. (A) Bent confirmation of α_IIbβ₃ integrin with intact salt bridge linking cytosolic domains of the subunits (low affinity for binding fibrinogen). (B) Binding of intracellular protein talin disrupts salt bridge and triggers separation of the cytosolic region of β₃ from that of α_IIb, resulting in a conformational change of the α_IIbβ₃ integrin into the upright position. In this position, fibrinogen is able to bind extracellular domains (high affinity for binding fibrinogen; inside-out signaling). (C) Fibrinogen, in turn, binds additional α_IIbβ₃ integrins to facilitate platelet aggregation, resulting in activation and recruitment of additional intracellular and cytosolic proteins, such as c-Src tyrosine kinase (c-Src), integrin-linked kinase (ILK), spleen tyrosine kinase (Syk), protein kinase C (PKC), and protein tyrosine phosphatase (PTP1B) and others, to facilitate processes including cytoskeletal reorganization for platelet spreading, clot stabilization, and clot retraction (outside-in signaling).

Figure 3

Diagnostic algorithm for GT. *Consider proceeding to platelet light transmission aggregometry if suspicion for platelet defect remains high. **Consider genetic testing to identify specific mutation of ITGA2B and ITGB3 and/or flow cytometry to differentiate GT type. ^†Consider clot retraction assay (if available) and platelet light transmission aggregometry or genetic testing of ITGA2B and ITGB3 to make the diagnosis of GT Type III. ^††Consider genetic testing to identify specific mutation of ITGA2B or ITGB3.