Platelet dysfunction caused by a novel thromboxane A₂ receptor mutation and congenital thrombocytopenia in a case of mild bleeding

Abstract

Chronic hemorrhagic diathesis in patients showing normal levels of plasmatic clotting factors strongly suggests for congenital platelet disorders. We report on a pediatric patient (male, 3 years, D1) with mild bleeding. A sibling (D2), his mother (D3) and father (D4) were included for laboratory investigation. Platelet counts in D1, D2 and D4 indicated mild thrombocytopenia (100 Gpt/L). D1 and D3 platelets showed significantly diminished aggregation response on arachidonic acid and U46619 stimulation. Immunostaining for platelet proteins on blood smears of D1 and D2 indicated defects in ß1-tubulin. Exon sequencing of TBXA2R and TUBB1 revealed heterozygosity for the novel TBXA2R*c.908T>C (p.L303P) mutation in D1 and D3. TUBB1 was either wild type (D2, D3) or heterozygous (D1, D4) for the common polymorphism TUBB1*c.920G>A (rs6070697; p.R307H). In conclusion, the bleeding phenotype of the index patient can be explained by a diminished platelet function caused by the TBXA2R*c.908T>C mutation inherited from the mother and a mild thrombocytopenia with unknown molecular basis that is inherited from the father.

Keywords:

• Aspirin-like defect
• beta1 tubulin
• inherited platelet disorder
• thrombocytopenia
• thromboxane A₂ receptor

Contribution details

P. Bugert designed the study, performed the molecular studies and wrote the manuscript. L. Fischer and R. Knöfler recruited the family, determined bleeding phenotypes and blood counts and performed LTA. K. Althaus performed immmunofluorescence microscopy and wrote the manuscript. T. Bakchoul designed the study and wrote the manuscript.

Declaration of interest

The authors report no conflicts of interest.