Organic carbon content and carbon isotope variations across the Permo-Triassic boundary in the Gartnerkofel-1 borehole, Carnic Alps, Austria

The Gartnerkofel borehole is one of the most thoroughly studied and described Permo-Triassic sections in the world. Detailed bulk organic carbon isotope studies show a negative base shift from − 24‰ to − 28‰ in the Latest Permian which latter value persists into the Earliest Triassic after which it decreases slightly to − 26‰. Two strongly negative peaks of > − 38‰ in the Latest Permian and a lesser peak of − 31‰ in the Early Triassic are too negative to be due to a greater proportion of more negative organic matter and must be due to very negative methane effects. The overall change to more negative values across the Bulla/Tesero boundary fits the relative rise in sea level for this transition based on the facies changes. A positive shift in organic carbon isotope values at the Late Permian Event Horizon may be due to an increase in land-derived organic detritus at this level—a feature shown by all Tethyan Permo-Triassic boundary sections though these other sections do not have the same values. Carbonate carbon isotope trends are similar in all sections dropping by 2–3 units across the Permo-Triassic boundary. Gartnerkofel carbonate oxygen values are surprisingly, considering the ubiquitous dolomitization, compatible with values elsewhere and indicate reasonable tropical temperatures of 60 °C in the Latest Permian sabkhas to 20–40 °C in the overlying marine transition beds. Increased land-derived input at the Late Permian Event Horizon may be due to offshore transport by tsunamis whose deposits have been recognized in India at this level

High-throughput microfluidic blood testing to phenotype genetically linked platelet disorders: an aid to diagnosis

Linking the genetic background of patients to a bleeding diathesis and altered platelet function is still challenging. We aimed to assess how the multiparameter microspot-based measurement of thrombus formation under flow can identify patients with a platelet bleeding disorder. For this purpose, we studied 16 patients, presenting with bleeding and/or albinism and a suspected platelet dysfunction, as well as 15 relatives. Genotyping of patients revealed a novel biallelic pathogenic variant in RASGRP2 (splice site c.240-1G>A), abrogating CalDAG-GEFI expression; a compound heterozygosity (c.537del, c.571A>T) in P2RY12, affecting P2Y12 signaling; and heterozygous variants of unknown significance in the P2RY12 and HPS3 genes. Other patients had confirmed Hermansky-Pudlak syndrome type 1 or 3. In 5 patients, no genetic variant was found. Platelet functions were assessed by routine laboratory measurements. Blood samples from all subjects and day controls were screened for blood cell counts and microfluidic outcome on six surfaces (48 parameters), in comparison to a reference cohort of healthy subjects. Differential analysis of the microfluidic data showed that key parameters of thrombus formation were compromised for the 16 index patients. Principal component analysis resulted in separate clusters of patients versus heterozygous family members plus control subjects. Clusters further segregated by inclusion of hematological values and laboratory measurements. Subject ranking indicated an overall impairment in thrombus formation for the patients carrying a (likely) pathogenic variant of the genes, but not for the asymptomatic relatives. Together, our results indicate the advantage of testing for multiparametric thrombus formation in this patient population

A Novel GATA1 Variant in the C-Terminal Zinc Finger Compared with the Platelet Phenotype of Patients with A Likely Pathogenic Variant in the N-Terminal Zinc Finger

The GATA1 transcription factor is essential for normal erythropoiesis and megakaryocytic differentiation. Germline GATA1 pathogenic variants in the N-terminal zinc finger (N-ZF) are typically associated with X-linked thrombocytopenia, platelet dysfunction, and dyserythropoietic anemia. A few variants in the C-terminal ZF (C-ZF) domain are described with normal platelet count but altered platelet function as the main characteristic. Independently performed molecular genetic analysis identified a novel hemizygous variant (c.865C>T, p.H289Y) in the C-ZF region of GATA1 in a German patient and in a Spanish patient. We characterized the bleeding and platelet phenotype of these patients and compared these findings with the parameters of two German siblings carrying the likely pathogenic variant p.D218N in the GATA1 N-ZF domain. The main difference was profound thrombocytopenia in the brothers carrying the p.D218N variant compared to a normal platelet count in patients carrying the p.H289Y variant; only the Spanish patient occasionally developed mild thrombocytopenia. A functional platelet defect affecting αIIbβ3 integrin activation and α-granule secretion was present in all patients. Additionally, mild anemia, anisocytosis, and poikilocytosis were observed in the patients with the C-ZF variant. Our data support the concept that GATA1 variants located in the different ZF regions can lead to clinically diverse manifestations