# ITGA2B/ITGB3‐Related Macrothrombocytopenia Associated With Gain‐of‐Function Mutations in ITGA2B or ITGB3 Genes

## TL;DR

This paper reviews how certain mutations in ITGA2B or ITGB3 genes cause a rare platelet disorder with large platelets and low counts, differing from typical Glanzmann thrombasthenia.

## Contribution

The paper provides a comprehensive review of gain-of-function mutations in ITGA2B/ITGB3 linked to macrothrombocytopenia and challenges current mechanistic understanding.

## Key findings

- Gain-of-function mutations in ITGA2B or ITGB3 are linked to macrothrombocytopenia and distinct platelet dysfunction.
- Non-activating ITGB3 mutations also cause macrothrombocytopenia, complicating the understanding of disease mechanisms.
- The disorder is inherited in an autosomal dominant manner and affects platelet size and morphology.

## Abstract

Glanzmann thrombasthenia (GT) is an inherited hemorrhagic disorder characterised by impaired platelet functions, manifested clinically as spontaneous bleeding. It is usually inherited in an autosomal recessive manner. Platelet dysfunction in patients with GT is caused by quantitative and/or qualitative deficiencies in αIIbβ3, which result from mutations in the genes encoding αIIbβ3. These genetic alterations lead to platelet dysfunction characterised by impaired fibrinogen binding capacity upon agonist stimulation, defective aggregation and spreading. While classical GT typically exhibits normal platelet counts and morphology, very rare mutations in ITGA2B (encoding αIIb) and/or ITGB3 (encoding β3) cause macrothrombocytopenia or increased platelet anisotropy (heterogeneity of platelet size and morphology). This type of mutation mainly localises in the membrane‐proximal region of αIIbβ3 and is inherited in an autosomal dominant manner. This particular type of disorder is called ITGA2B/ITGB3‐related macrothrombocytopenia and has been considered a subset of congenital macrothrombocytopenia. Current research suggests that gain‐of‐function mutations in ITGA2B or ITGB3 underlie the pathogenesis of most ITGA2B/ITGB3‐related macrothrombocytopenia and mechanistically distinguish it from classical GT. However, recent reports have documented non‐activating ITGB3 mutations that also cause macrothrombocytopenia, presenting a profound challenge to the mechanistic understanding of ITGA2B/ITGB3‐related macrothrombocytopenia. This review summarises the reported cases of gain‐of‐function mutations in ITGA2B and ITGB3 associated with ITGA2B/ITGB3‐related macrothrombocytopenia hitherto and discusses the potential molecular pathways contributing to the unique phenotypes in ITGA2B/ITGB3‐related macrothrombocytopenia.