PB1243 - ITGB3/ITGA2B-related platelet disorders: phenotypic and genetic aspects of a series of 20 families evaluated in a single centre

Tuesday, July 12, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Catarina Monteiro, MsC

MSc, Clinical Biochemistry
Unidade de Trombose e Hemostase, Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal; Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, CHUPorto; Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Biomédicas (UMIB/ICBAS/UP) e Laboratório para a Investigação Integrativa e translacional em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
Porto, Porto, Portugal

Co-Author(s)

AG

Ana Gonçalves

MSc, Molecular and Cell Biology
Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal; Unidade de Investigação Biomédica (UMIB/ICBAS/UP) e Laboratório para a Investigação Integrativa e translacional em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
Porto, Porto, Portugal
MP

Mónica Pereira

MSc, Biochemistry
Unidade de Trombose e Hemostase, Serviço de Hematologia Clínica, Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal; Unidade de Investigação Biomédica (UMIB/ICBAS/UP) e Laboratório para a Investigação Integrativa e translacional em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
Porto, Porto, Portugal
MG

Marta Gonçalves

PhD, Pharmaceutical Sciences
Unidade de Diagnóstico Hematológico Margarida Lima, Serviço de Hematologia Clínica, Centro Hospitalar Universitário do Porto (CHUPorto), Porto; Unidade de Investigação Biomédica (UMIB/ICBAS/UP) e Laboratório para a Investigação Integrativa e translacional em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
Porto, Porto, Portugal
CL

Catarina Lau

MD, Consultant in Hematology
Unidade de Diagnóstico Hematológico Margarida Lima, Serviço de Hematologia Clínica, Centro Hospitalar Universitário do Porto (CHUPorto), Porto; Unidade de Investigação Biomédica (UMIB/ICBAS/UP) e Laboratório para a Investigação Integrativa e translacional em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
Porto, Porto, Portugal
EC

Eugénia Cruz

PhD, MD, Consultant in Hematology
Unidade de Trombose e Hemostase, Serviço de Hematologia Clínica, Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal
Porto, Porto, Portugal
RS

Rosário Santos

Clinical Laboratory Geneticist (ErCLG), Head of Molecular Genetics Unit, CHUPorto
Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal; Unidade de Investigação Biomédica (UMIB/ICBAS) e Laboratório para a Investigação Integrativa e translacional em Saúde Populacional (ITR), Universidade do Porto, Porto, Portugal
Porto, Porto, Portugal
SM

Sara Morais

Senior Physician, MD
Thrombosis and Hemostasis Unit, Clinical Haematology Service, Centro Hospitalar Universitário do Porto, Porto, Portugal
Porto, Porto, Portugal

Background: Pathogenic variants in ITGB3 and ITGA2B, the genes coding for integrin αIIbβ3 have been linked to Glanzmann thrombasthenia (GT) and, most recently, to an inherited macrothrombocytopenia entity, designated as ITGB3/ITGA2B-related thrombocytopenia (ITGB3/ITGA2B-RT).

Aims: To describe 20 families with variants in either ITGA2B and ITGB3 genes linked to phenotypes of both Glanzmann Thrombasthenia and ITGA2B/ITGB3-related thrombocytopenia.

Methods: Clinical data (bleeding scores and family history), platelet (PLT) count and morphology, and functional studies (lumi-aggregometry, glycoprotein expression by flow cytometry and integrin activation evaluation), were assessed. Genetic analysis of ITGB3 and ITGA2B was performed by NGS gene panel and/or direct Sanger sequencing.

Results: Patients with ITGB3/ITGA2B-RT had absent to moderate bleeding, autosomal dominant macrothrombocytopenia associated with impaired platelet aggregation/ATP release and low αIIbβ3 expression and activation. In contrast, patients with GT had an autosomal recessive disorder, with severe bleeding and PLT dysfunction (defective PLT aggregations and diminished/absent platelet αIIbβ3 expression and activation). Besides the previously reported 10 families with ITGB3/ITGA2B-RT (Morais et al. 2020), we describe 3 new families with heterozygous variants in ITGB3/ITGA2B, in a total of 13 families and additional 2 novel variants. Furthermore, 7 families with GT, including 3 novel homozygous variants, were identified and presumed as causative. The novel variants were established as clinically relevant based on allele frequency, bioinformatics predictions, disease correlation and familiar co-segregations analysis.

Conclusion(s): Our study details the phenotypic, functional, and genetic defects observed in ITGA2B/ITGB3-RT and GT and expands the number of the associated αIIbβ3 variants. The high number of families with ITGA2B/ITGB3-RT found in our Centre is probably due to a systematic screening for αIIbβ3 deficiency in patients with familial macrothrombocytopenia. The relatively high number of families with variants in ITGB3 or ITGA2B suggests that the frequency of these entities may be higher than previously thought. Future studies are necessary to proceed with variants’ evaluation of pathogenicity.