Platelet Aggregation, Spontaneous

To characterize bleeding phenotype in Noonan Syndrome, to test the utility of following national guidelines in detecting this phenotype, to evaluate thromboelastography (TEG) as a diagnostic tool and to evaluate the cohort for genotype-phenotype correlations.

Participants with a clinical diagnosis NS or related RASopathy were enrolled in a cohort study. Study procedures included clinical bleeding assessment, coagulation testing per guidelines and hematology consultation. TEG was completed in a subset and genetic testing was conducted for those without a molecular diagnosis. International Society of Haemostasis and Thrombosis Bleeding Assessment Tool (ISTH-BAT) scores were calculated with hematology consultation. Bleeding phenotype was defined as abnormal bleeding score.

Twenty participants enrolled; 12completed clinical and laboratory evaluation, five of whom met the definition for bleeding phenotype. Four of the five participants with a bleeding phenotype had platelet aggregation defects and at least one additional coagulation defect. TEG was performed in nine participants, four with bleeding phenotype and five without, and results were normal in all cases. No genotype-phenotype correlation was found.

Five of 20 participants had a bleeding phenotype identified. Based on available data we do not recommend incorporating TEG into clinical practice for NS patients. Platelet aggregation defects were the most common abnormalities, which would not be detected on Tier 1 testing of current guidelines, therefore we propose a new algorithm.

Hyphema, that is, massive anterior chamber hemorrhage, is one of the major complications after a recent minimally invasive glaucoma surgery. Hyphema along with high intraocular pressure increases the risk of corneal bloodstaining.

A 71-year-old female was receiving 0.1% fluorometholone drops in both eyes for severe dry eye. She was also receiving antiplatelet agents for platelet aggregation hyperactivity and prednisolone for interstitial pneumonia internally. Her right eye was suffering from increased intraocular pressure.

We diagnosed her right eye as steroid-induced glaucoma.

We performed microhook trabeculotomy.

At postoperative day 10, she had total anterior chamber hemorrhage and high intraocular pressure, and subsequently developed corneal blood staining at postoperative day 15, for which we performed anterior chamber cleaning. After that, we did not perform additional anterior chamber cleaning, and during the 1-year follow-up, a gradual improvement was noted in the entire cornea with reddish-brown opacity, from the periphery to the center. However, almost the entire pupil was still covered with opacity, and her visual acuity was at the light perception at the final visit.

Corneal bloodstaining takes a considerable time to resolve and causes severe vision loss. Special attention should be given to persistent corneal blood staining when hyphema and high intraocular pressure are observed after minimally invasive glaucoma surgeries.

GATA1 is an essential transcription factor for both polyploidization and megakaryocyte (MK) differentiation. The polyploidization defect observed in GATA1 variant carriers is not well understood.

To extensively phenotype two pedigrees displaying different variants in the GATA1 gene and determine if GATA1 controls MYH10 expression levels, a key modulator of MK polyploidization.

146 unrelated propositi with constitutional thrombocytopenia were screened on a multigene panel. We described the genotype-phenotype correlation in GATA1 variant carriers and investigated the effect of these novel variants on MYH10 transcription using luciferase constructs.

The clinical profile associated with the p.L268M variant localized in the C terminal Zinc finger was unusual in that the patient displayed bleeding and severe platelet aggregation defects without early-onset thrombocytopenia. p.N206I localized in the N terminal Zinc finger was associated, on the other hand, with severe thrombocytopenia (15G/L) in early life. High MYH10 levels were evidenced in platelets of GATA1 variant carriers. Analysis of MKs anti-GATA1 ChIP-sequencing data revealed two GATA1 binding sites, located in the 3' untranslated region and in intron 8 of the MYH10 gene. Luciferase reporter assays showed their respective role in the regulation of MYH10 gene expression. Both GATA1 variants significantly alter intron 8 driven MYH10 transcription.

The discovery of an association between MYH10 and GATA1 is a novel one. Overall, this study suggests that impaired MYH10 silencing via an intronic regulatory element is the most likely cause of GATA1-related polyploidization defect.