Characterization of Patients with Glanzmann Thrombasthenia and Identification of 17 Novel Mutations

Background: Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder. Platelets from patients with GT show quantitative and/or qualitative defects of the platelet membrane glycoprotein (GP) IIb/IIIa complex, also called integrin αIIbβ3. On activated platelets the αIIbβ3 binds von fibrinogen and Willebrand factor which leads to platelet spreading and formation of platelet-platelet protein bridges.

Patients: In this study, 18 patients with GT were investigated with molecular genetic analyses. The patients presented with bleeding symptoms such as epistaxis, mucocutaneous bleeding, haematomas, petechiae, gastrointestinal bleeding, and menorrhagia.

Methods and Results: As cause of GT in the patients homozygous or compound heterozygous mutations in ITGA2B or ITGB3 were identified through sequencing of genomic DNA. All exons including exon/intron boundaries of both genes were analyzed. In summary, 16 of 18 patients revealed 27 different mutations (ITGA2B: n = 17, ITGB3: n = 10). Of these mutations, 17 have not been published yet.

Conclusion: In 16 patients mutations in ITGA2B or ITGB3 were identified as cause of GT. A total of 27 mutations including 17 novel missense, nonsense, frameshift and splice site mutations were detected. None of these mutations were present more than once in unrelated patients. In addition, 2 patients were without molecular genetic findings in ITGA2B or ITGB3 that could explain the suspected diagnosis of GT. We hypothesize that these patients may harbour defects in a regulatory element affecting the transcription of these genes or there may exist other proteins important for the activation of the αIIbβ3 complex that could be affected.