Exploration of rotational thromboelastometry (ROTEM) to characterize the coagulation profiles of newly diagnosed pediatric leukemia patients.

BACKGROUND: Viscoelastic testing has been used in adult hematologic malignancies in conjunction with conventional coagulation tests (CCTs) to predict coagulopathies and tailor blood product replacement. However, there is a paucity of similar pediatric studies. OBJECTIVES: Analyze and correlate leukemia-associated coagulopathy in newly diagnosed pediatric leukemia patients using CCT's and Rotational Thromboelastometry (ROTEM). METHODS: Pediatric patients with newly diagnosed acute leukemia underwent testing with ROTEM and CCTs on days 0, 15 and 29 of induction chemotherapy. RESULTS: Sixty-two patients were enrolled. At presentation, 54.8 % of patients had platelets <50 K/µL, 73 % had prolonged PT, 1.6 % had fibrinogen <150 mg/dL. Fifteen patients (24.2 %) had WHO grade 1 bleeding and two patients (3 %) had WHO grade 4 bleeding. EXTEM/INTEM values at presentation (day 0) reflected hypocoagulability, however FIBTEM revealed hypercoagulability. Patients showed a progressive hypocoagulability in all ROTEM assays by day 15 (day 0 vs day 15, p < 0.001), with improvement by day 29 (day 15 vs day 29, p < 0.001). Day 0 ROTEM parameters were comparable to day 29. Fibrinogen strongly correlated with ROTEM at all three time points (p < 0.0001), along with platelet count with moderate correlations (p < 0.001). CONCLUSION: Fibrinogen and platelets appear to be the drivers of leukemia associated coagulopathy in the pediatric population, suggesting the utility of using CCTs and ROTEM in this population to better evaluate hemostatic function and guide blood product replacement.

Prolonged prothrombin time does not correlate with clinical bleeding symptoms in newly diagnosed paediatric leukaemia patients.

Prolonged prothrombin time (PT) and/or activated partial thromboplastin time (aPTT) are frequently seen in newly diagnosed paediatric leukaemia patients (NDPLP), which can lead to delayed diagnostic and therapeutic procedures due to concern for bleeding. A single-centre retrospective chart review of NDPLP between 2015 and 2018 aged 1-21 years. We analysed 93 NDPLP of whom 33.3% had bleeding symptoms within 30 days of presentation, predominantly mucosal bleeding (80.6%) and petechiae (64.5%). Median laboratory values: white blood cell count 15.7, haemoglobin 8.1, platelets 64, PT 13.2 and a PTT 31. Red blood cells were administered in 41.2%, platelets in 52.9%, fresh frozen plasma in 7.8% and vitamin K in 21.6% of patients. Prolonged PT was found in 54.8% of patients, while aPTT was prolonged in 5.4%. Anaemia and thrombocytopenia did not correlate with prolonged PT ( P  = 0.73 and P  = 0.18, respectively), or prolonged aPTT ( P  = 0.52 and 0.42). Leukocytosis showed significant correlation with elevated PT ( P  < 0.001), but not aPTT ( P  = 0.3). Bleeding symptoms upon presentation did not correlate with prolonged PT ( P  = 0.83), prolonged aPTT ( P  = 1) or anaemia ( P  = 0.06) but had a significant correlation with thrombocytopenia ( P  ≤ 0.0001). Therefore, a prolonged PT in NDPLP may not necessitate the reflexive use of blood product replacement, in the absence of significant bleeding, which is likely related to leukocytosis than to a true coagulopathy.

An Introduction to Structural Competency for Haitian-Identified Patients: History, Culture, and Access to Care.

INTRODUCTION: The Haitian population within the US represents the largest diaspora outside of Haiti, with most Haitians residing in major urban communities. Despite clear differences in health outcomes specific to Haitians, the community has traditionally been aggregated into the general Black population. To address specific health disparities, this workshop was designed to distinguish and elaborate on the health care problems affecting Haitians. METHODS: We created an interactive 60-minute workshop including a PowerPoint presentation, two case presentations, and a 5-minute informational video to bring awareness of the historical perspectives impacting Haitian/Haitian American health, access to care, and health care disparities to providers. Knowledge was assessed by pre- and postworkshop evaluation forms. The module was aimed at health care professional learners. RESULTS: Seventy-four people with diverse ethnoracial identities, including medical students, residents, academic faculty, physicians, nonmedical graduate students, and health care staff and administrators, attended three workshops. All learning objectives were met, with pre- and postworkshop data indicating a statistically significant increase in participants' reported confidence. Workshop attendees commented positively on the group discussion component, the workshop's interactive nature, the opportunity to apply taught knowledge to case presentations, and the historical context provided. DISCUSSION: As the number of Haitian immigrants continues to rise throughout US urban communities, providers must increase their culture competency in training and delivery to improve care for a major population. This module can help better prepare health care providers and trainees to offer competent care to Haitian/Haitian American patients.

MEIS2 sequence variant in a child with intellectual disability and cardiac defects: Expansion of the phenotypic spectrum and documentation of low-level mosaicism in an unaffected parent.

Deletions and pathogenic sequence variants in Myeloid Ecotropic Insertion Site 2 (MEIS2) gene have been reported to cause a recognizable triad of intellectual disability, congenital heart malformations, and palatal defects. To date, 18 individuals with de novo pathogenic sequence variants in MEIS2 have been reported in the literature, most with all three cardinal features. We recently saw a young boy, almost 3 years of age, who was known to have mosaic XYY syndrome (47,XYY [23]/46,XY[7]). He presented with atrial and ventricular septal defects, developmental delay, facial dysmorphism, gastroesophageal reflux, undescended testicle, a buried penis with penoscrotal transposition, primary neutropenia, and a branchial cleft sinus. Whole-exome sequencing identified a previously reported in-frame pathogenic deletion (c.998_1000delGAA; p.R333del; NM_170674.4) in MEIS2. His unaffected father was confirmed to have low-level mosaicism for the same MEIS2 variant. The proband represents the 19th reported individual with a pathogenic sequence variant in MEIS2 and expands the phenotypic spectrum to include primary neutropenia, branchial anomalies, and complex genital anomalies. Furthermore, to our knowledge this is the first reported case of mosaicism for a variant in this gene in an apparently unaffected parent. This finding would have implications for recurrence risk counseling for families.

Taking Care of the Puerto Rican Patient: Historical Perspectives, Health Status, and Health Care Access.

Introduction: Hispanics are the largest minority group in the US at 18% of the population, of which Puerto Ricans are the second largest subgroup. Puerto Ricans have poorer health status than other US Hispanic and non-Hispanic populations. Thus, health care providers need to know about and distinguish the health care problems of Puerto Ricans to improve their health. Although there are some published curricula addressing how to provide health care to Hispanic populations, none address the specific needs of Puerto Ricans. Methods: We developed a 60-minute interactive workshop consisting of a PowerPoint presentation and case discussion aimed at increasing health care providers' knowledge and understanding of the historical perspective that led to Puerto Rican identity, health issues and disparities, and the health care access problems of mainland and islander Puerto Ricans. Evaluation consisted of pre- and postworkshop questionnaires. Results: There were a total of 64 participants with diverse ethnoracial identities including medical students, residents, faculty, physicians, researchers, administrators, and students/faculty from nursing, occupational therapy, genetic counseling, biomedical sciences, and social work programs. A comparison of pre- and postworkshop data showed a statistically significant increase in participants' confidence in meeting all learning objectives. Participants positively commented on the interactive nature of the workshop, the case discussion, and the historical perspective provided. Discussion: With the increasing migration of Puerto Ricans to the US mainland this module can uniquely improve the preparation of current and future health care providers to provide competent care to Puerto Rican patients.

The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3.

Many long non-coding RNAs (lncRNAs) affect gene expression, but the mechanisms by which they act are still largely unknown. One of the best-studied lncRNAs is Xist, which is required for transcriptional silencing of one X chromosome during development in female mammals. Despite extensive efforts to define the mechanism of Xist-mediated transcriptional silencing, we still do not know any proteins required for this role. The main challenge is that there are currently no methods to comprehensively define the proteins that directly interact with a lncRNA in the cell. Here we develop a method to purify a lncRNA from cells and identify proteins interacting with it directly using quantitative mass spectrometry. We identify ten proteins that specifically associate with Xist, three of these proteins--SHARP, SAF-A and LBR--are required for Xist-mediated transcriptional silencing. We show that SHARP, which interacts with the SMRT co-repressor that activates HDAC3, is not only essential for silencing, but is also required for the exclusion of RNA polymerase II (Pol II) from the inactive X. Both SMRT and HDAC3 are also required for silencing and Pol II exclusion. In addition to silencing transcription, SHARP and HDAC3 are required for Xist-mediated recruitment of the polycomb repressive complex 2 (PRC2) across the X chromosome. Our results suggest that Xist silences transcription by directly interacting with SHARP, recruiting SMRT, activating HDAC3, and deacetylating histones to exclude Pol II across the X chromosome.