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A Novel Hemizygous Variant in GATA1 Associated with Bleeding Diathesis and Platelet Dysfunction in Two Unrelated Patients

J.M. Bastida1,2,3,4, D. Boeckelmann5,6, V. Palma-Barqueros7,8, M. Wolter5,6, M.L Lozano7,8, H. Glonnegger5,6, R. Benito2,3, F.H Schilling9, N. Morgan10, K. Freson11, J. Rivera7,8,4, B. Zieger5,6

1Complejo Asistencial Universitario de Salamanca (CAUSA), Salamanca, Spain, 2Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain, 3Universidad de Salamanca (USAL), Salamanca, Spain, 4Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC), SETH, Spain, 5Division of Pediatric Hematology and Oncology Medical Center, Freiburg, Germany, 6University of Freiburg, Faculty of Medicine, Freiburg, Germany, 7Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Murcia, Spain, 8Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, Murcia, Spain, 9Children's Hospital, Kantonsspital Luzern, Lucerne, Switzerland, 10Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom, 11Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium

Abstract Number: PB0896

Meeting: ISTH 2021 Congress

Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Platelet Function Disorders, Hereditary

Background: The GATA1 transcription factor is essential for normal erythropoiesis and megakaryocytic development. Germline GATA1 pathogenic variants (PV) are typically associated with X-linked thrombocytopenia, dyserythropoietic anemia and/or platelet dysfunction. Phenotype/genotype correlation is important to better understand the diversity of rare GATA1 PV.

Aims: To characterize bleeding and platelet phenotype in two patients with a novel GATA1 variant identified by high throughput sequencing (HTS).

Methods: Two male index patients,  (G1, 14 y; S2, 46 y), who presented with lifelong bleeding tendency have been investigated. Bleeding score (BS) was recorded with ISTH-BAT. Platelet phenotyping included full blood count (FBC), aggregometry (LTA), flow cytometry (FC), and electron microscopy (EM). Molecular analysis was performed by HTS panel.

Results: Patient characteristics are shown in table 1.

Patient German 1 (G1) Spanish 2 (S2)
Bleeding symptoms Epistaxis, ecchymosis, prolonged bleeding after dental surgery, impaired wound healing Epistaxis, ecchymosis, prolonged bleeding after dental surgery (required profylaxis with tranexamic acid and DDVAP) impaired wound healing
FBC:
RBC (T/L)
Hb (g/dL)
MCV (fL)
Platelet (G/L)
MPV (fL)
3.73 (N: 3,7-5,5)
11.5 (N: 11-15)
97 (N: 70-90)
256 (N: 100-436)
7.9 (N: 7-12)
4.1 (N: 3.5-5.8)
12.8 (N: 13-18)
99.3 (79-100)
123, 215, 134 (N: 150-400)
10.9 (N: 6.8-11.8)
LTA:
Collagen (2,0µg/mL)
Collagen (10µg/mL)
CRP (5.0µg/mL)
Ristocetin (1.2mg/mL)
ADP (4µM) / (5µM)
ADP (20 µM) / (10 µM)
Epinephrine (8µM) / (5µM)
Epinephrine (40µmol/L)
Arachidonic (0.3mg/mL)
Arachidonic (1.5 mM)
TRAP (25 uM)
41 (N >70)
–
–
61 (N >85)
12 (N >70)
37 (N >70)
6 (N >70)
8 (N >70)
46 (N >70)
–
–
2 (N>85)
33 (N>85)
15 (n>85)
93 (N>85)
54 (N>85)
67 (N>85)
35 (N>85)
–
2 (N>85)
73 (N>85)
61 (N>85)
FC
GP expression (GPIb/IX, GPIIb/IIIa and GPVI)
CD62
CD63
 
Normal
 Severely decreased
Moderate decreased
Normal
Severely decreased
Moderate decreased
EM Not conducted Mild defect in α-granules

BS, for both patients, was 10. FBC showed mild anemia and anisocytosis and poikilocytosis in both patients, and normal platelet count in G1 but variable in S2 ranging from 123-215 G/L in multiple analysis. In both patients, LTA showed severe impaired response to Col, ADP, Epi, TRAP and CRP but normal expression of platelet glycoproteins. FC revealed severely decreased agonist-induced alpha and moderate dense granules secretion. EM (S2) also showed moderated alpha-granule defect. HTS panel identified a novel missense variant (c.865C>T; p.His289Tyr) in GATA1 classified as a likely PV that is absent in gnomAD population database. This variant is located in the C-terminal Zn-finger domain and disrupts a highly conserved amino acid residue. G1 mother´s, a heterozygous carrier, presented with menorrhagia (BS=2). Five females in the S2 pedigree were also heterozygous carriers of the variant but only two of these present with a bleeding diathesis.

Conclusions: The GATA-1 p.His289Tyr variant resulted in mild anemia, impaired platelet aggregation and secretion in hemizygous carriers. This is the first variant located in the GATA-1 C-terminal Zn-finger associated with platelet dysfunction and bleeding.

To cite this abstract in AMA style:

Bastida JM, Boeckelmann D, Palma-Barqueros V, Wolter M, L Lozano M, Glonnegger H, Benito R, H Schilling F, Morgan N, Freson K, Rivera J, Zieger B. A Novel Hemizygous Variant in GATA1 Associated with Bleeding Diathesis and Platelet Dysfunction in Two Unrelated Patients [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/a-novel-hemizygous-variant-in-gata1-associated-with-bleeding-diathesis-and-platelet-dysfunction-in-two-unrelated-patients/. Accessed August 16, 2022.

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