Prothrombin Knockdown Protects Podocytes and Reduces Proteinuria in Glomerular Disease.

Chronic kidney disease (CKD) is a leading cause of death, and its progression is driven by glomerular podocyte injury and loss, manifesting as proteinuria. Proteinuria includes urinary loss of coagulation zymogens, cofactors, and inhibitors. Importantly, both CKD and proteinuria significantly increase the risk of thromboembolic disease. Prior studies demonstrated that anticoagulants reduced proteinuria in rats and that thrombin injured cultured podocytes. Herein we aimed to directly determine the influence of circulating prothrombin on glomerular pathobiology. We hypothesized that (pro)thrombin drives podocytopathy, podocytopenia, and proteinuria. Glomerular proteinuria was induced with puromycin aminonucleoside (PAN) in Wistar rats. Circulating prothrombin was either knocked down using a rat-specific antisense oligonucleotide or elevated by serial intravenous infusions of prothrombin protein, which are previously established methods to model hypo- (LoPT) and hyper-prothrombinemia (HiPT), respectively. After 10 days (peak proteinuria in this model) plasma prothrombin levels were determined, kidneys were examined for (pro)thrombin co-localization to podocytes, histology, and electron microscopy. Podocytopathy and podocytopenia were determined and proteinuria, and plasma albumin were measured. LoPT significantly reduced prothrombin colocalization to podocytes, podocytopathy, and proteinuria with improved plasma albumin. In contrast, HiPT significantly increased podocytopathy and proteinuria. Podocytopenia was significantly reduced in LoPT vs. HiPT rats. In summary, prothrombin knockdown ameliorated PAN-induced glomerular disease whereas hyper-prothrombinemia exacerbated disease. Thus, (pro)thrombin antagonism may be a viable strategy to simultaneously provide thromboprophylaxis and prevent podocytopathy-mediated CKD progression.

Increasing optimal coagulation factor dosing in the paediatric emergency department: Update to a quality improvement study.

INTRODUCTION: Prompt, appropriate coagulation factor replacement according to injury and bleeding severity in persons with haemophilia is required to prevent acute and long-term complications. AIMS: Increase proportion of persons with haemophilia A (HA) and B (HB) treated appropriately for an acute injury and bleeding episode at a tertiary children's emergency department (ED) from 65% to 85% and sustain for one year. Secondary aim: increase time interval between patient ED encounters with out-of-range factor dosing. METHODS: Utilizing quality improvement methodology and plan-do-study-analyze cycles, ED encounters for individuals with HA/HB receiving coagulation factor replacement for injuries were audited for in-range coagulation factor dosing. Goal factor dose defined as 50% correction for minor bleeds and 100% correction for major bleeds. Optimal dosing range defined as 90%-120% of the calculated goal dose to account for vial size variability. Interventions targeted communication via the EMR problem list and optimization of physician education. RESULTS: Our previous publication demonstrated 33.3% of ED encounters with out-of-range factor replacement. Following several interventions, the cumulative rate of encounters with out-of-range dosing decreased to 18%. Overall, there was an increase in the mean percent of encounters receiving optimal factor dosing for both HA/HB compared to baseline (82.2% vs. 71.1%), though this was not a statistically significant difference. CONCLUSION: Despite implementation of multiple interventions, out-of-range factor dosing continues to occur. Our team plans to reinstate simulation center education for ED staff and continue education efforts of pharmacists and hematology trainees with the goal of further reducing out-of-range dosing in our ED.

CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience.

BACKGROUND: Approximately 10% of pediatric malignancies are secondary to germline alterations in cancer-predisposing genes. Checkpoint kinase 2 (CHEK2) germline loss-of-function variants have been reported in pediatric cancer patients, but clinical phenotypes and outcomes are poorly described. We present our single-institution experience of pediatric oncology patients with CHEK2 germline alterations, including clinical presentations and outcomes. METHODS: Pediatric oncology patients with CHEK2 germline alterations were identified among those assessed by clinical or translational research at the Institute for Genomic Medicine at Nationwide Children's Hospital. A chart review of disease course was conducted on identified patients. RESULTS: We identified 6 patients with germline CHEK2 variants from a cohort of 300 individuals, including 1 patient with concurrent presentation of Burkitt lymphoma and neuroblastoma, 3 patients with brain tumors, 1 patient with Ewing sarcoma, and 1 patient with myelodysplastic syndrome. Three patients had a family history of malignancies. Four patients were in remission; one was undergoing treatment; one patient had developed treatment-related meningiomas. We review prior data regarding CHEK2 variants in this population, challenges associated with variant interpretation, and genetic counseling for individuals with CHEK2 variants. CONCLUSIONS: CHEK2 germline loss-of-function alterations occur in patients with a variety of pediatric tumors. Larger multicenter studies will improve our understanding of the incidence, phenotype, and molecular biology of CHEK2 germline variants in pediatric cancers.

Exploring the Role of Antithrombin in Nephrotic Syndrome-Associated Hypercoagulopathy: A Multi-Cohort Study and Meta-Analysis.

BACKGROUND: Nephrotic syndrome is associated with an acquired hypercoagulopathy that is thought to drive its predisposition for venous thromboembolism. Previous studies have suggested that urinary antithrombin (AT) loss leading to acquired AT deficiency is the primary mechanism underlying this hypercoagulopathy, but this hypothesis has not been directly tested. The objectives of this study were to test the influence of AT levels on hypercoagulopathy in nephrotic syndrome patient samples and perform meta-analyses to evaluate the likelihood of AT deficiency in patients with nephrotic syndrome. METHODS: Samples from three independent nephrotic syndrome cohorts were analyzed. AT antigen and activity assays were performed using ELISA and amidolytic assays, respectively. Plasma thrombin generation, albumin, and urine protein-to-creatinine ratios were determined using established methods. Meta-analyses were performed by combining these new data with previously published data. RESULTS: AT levels were not consistently related to either plasma albumin or proteinuria. AT was quantitatively related to hypercoagulopathy in adult nephrotic syndrome, whereas AT activity was inconsistently associated with hypercoagulopathy in childhood nephrotic syndrome. Notably, hypercoagulopathy did not differ between patients with normal AT levels and those with levels below the threshold used to define clinical AT deficiency (<70%). Moreover, ex vivo AT supplementation did not significantly alter hypercoagulopathy in AT-deficient plasma samples. The meta-analyses demonstrated that AT deficiency was not a uniform feature of nephrotic syndrome and was more common in children than adults. CONCLUSIONS: These data suggest that AT deficiency plays only a limited role in the mechanisms underlying the acquired hypercoagulopathy of nephrotic syndrome. Moreover, AT deficiency was not present in all patients with nephrotic syndrome and was more likely in children than adults despite the higher risk for venous thromboembolism in adults than children.

Intracardiac thrombi in pediatrics: anticoagulation approach and treatment outcomes.

Background: Intracardiac thrombi (ICT) are associated with significant morbidity and mortality. Anticoagulation is the first line of treatment and may be complemented by thrombectomy or thrombolysis. However, optimal anticoagulant duration remains ill-defined. High-risk features of ICT that may warrant long-term anticoagulation therapy have not been established. Objectives: To describe anticoagulation duration and patterns of ICT resolution. To identify potential risk factors for persistent ICT despite anticoagulation. Methods: A single-institution retrospective chart review identified patients diagnosed with ICT by echocardiogram between January 2014 and March 2022. Descriptive statistics and logistic regression were used. Results: Fifty-one patients with ICT were identified. Median age at diagnosis was 9.2 years (IQR, 0.4-15.2). The most common underlying diagnoses were congenital heart disease (41%), infection (25%), and malignancy (24%). The majority of ICT were in the right atrium (n = 30). The median longest ICT dimension was 1.5 cm (range, 0.4-4.0). The median duration of anticoagulation was 4.3 months (IQR, 2.2-9.1). Among 48 patients who received anticoagulation as first-line treatment, 32 had partial or complete response with 3 to 6 months of anticoagulation, while remaining 16 patients had no response to anticoagulation. Patients with a central venous line had a delayed resolution of ICT [hazards ratio = 0.45 (95% CI, 0.22-0.93)]. Conclusion: Our study demonstrates the wide variability in duration of anticoagulation for children with ICT. Majority of the individuals benefit from 3-to-6 month treatment; however, individuals with a central venous line may benefit from a longer course of anticoagulation. Further large-scale studies are recommended to validate our findings.

Oncology patients' perception of physicians who use an integrated electronic health record (EHR) during clinic visits: PRIME-EHR double-blind, randomized controlled trial.

BACKGROUND: Patients with cancer prefer and positively perceive physicians who communicate face-to-face without the use of a computer. However, the use of electronic health records (EHRs) in the examination room remains a practical necessity. On the basis of existing literature, the authors developed and tested an integration model, PRIME-EHR, that focuses on the best-practice guidelines. To their knowledge, no randomized controlled trials (RCTs) have been conducted to test the effectiveness of such models. METHODS: In this double-blind, crossover RCT, 120 eligible patients with cancer were enrolled between April 1, 2019 and February 15, 2020 at The University of Texas MD Anderson Cancer Center. The objectives were to compare patients' perceptions of physicians' skills and their overall preference after they watched 2 standardized, scripted video vignettes of physicians: 1 portraying the use of a standard EHR and the other portraying the use of a PRIME-EHR. Actors and patients were blinded to the purpose of the study. Investigators were blinded to the sequence of videos watched by the patients. Validated questionnaires to rate physicians' compassion (0 = best, 50 = worst), communication skills (14 = poor, 70 = excellent), and professionalism (4 = poor, 20 = very good) were used. RESULTS: PRIME-EHR, compared with the standard EHR, resulted in better scores for physician compassion (median score, 5 [interquartile range, 0-10] vs 12 [interquartile range, 4-25]; P = .0009), communication skills (median score, 69 [interquartile range, 63-70] vs 61 [interquartile range, 50-69]; P = .0026), and professionalism (median score, 20 [interquartile range, 18-20] vs 18 [interquartile range, 14-20]; P = .0058). The majority of patients preferred physicians who used PRIME-EHR (n = 70 [77%] vs n = 21 [23%]; P < .0001). CONCLUSIONS: The PRIME-EHR approach significantly improved patients' perceptions of and preference for the physicians. This integrated model of health care delivery has the potential to improve communication and compassion in cancer care.

Thrombosis Prevention and Anticoagulation Management in the Pediatric Patient with Congenital Heart Disease.

Thrombosis is one of the most frequent complications affecting children with congenital heart disease (CHD). Palliative and reparative cardiac surgeries are some of the main players contributing to the thrombosis risk in this patient population. Additional risk factors related to the CHD itself (e.g., cardiac dysfunction, arrhythmias, and polycythemia in cyanotic cardiac disorders) can contribute to thrombogenicity alone or combined with other factors. Thrombotic complications have been recognized as a significant cause of morbidity and mortality in this patient population. Here, we provide an overview of the pathophysiology and risk factors for thrombosis as well as the indications for and use of different anticoagulation, antiplatelet, and thrombolytic agents. In addition, we describe some of most common thrombotic complications and their management in the pediatric CHD population.

Schistosomiasis and liver disease: Learning from the past to understand the present.

To diagnose schistosomiasis, past medical history review should include recent travel to or from an endemic area, a history of elevated liver enzymes as well as contact with contaminated sources of water or farm animals.

Chronic Non-Malignant Pain in Patients with Cancer Seen at a Timely Outpatient Palliative Care Clinic.

Palliative care is seeing cancer patients earlier in the disease trajectory with a multitude of chronic issues. Chronic non-malignant pain (CNMP) in cancer patients is under-studied. In this prospective study, we examined the prevalence and management of CNMP in cancer patients seen at our supportive care clinic for consultation. We systematically characterized each pain type with the Brief Pain Inventory (BPI) and documented current treatments. The attending physician made the pain diagnoses according to the International Association for the Study of Pain (IASP) task force classification. Among 200 patients (mean age 60 years, 69% metastatic disease, 1-year survival of 77%), the median number of pain diagnosis was 2 (IQR 1-2); 67 (34%, 95% CI 28-41%) had a diagnosis of CNMP; 133 (67%) had cancer-related pain; and 52 (26%) had treatment-related pain. In total, 12/31 (39%) patients with only CNMP and 21/36 (58%) patients with CNMP and other pain diagnoses were on opioids. There was a total of 94 CNMP diagnoses among 67 patients, including 37 (39%) osteoarthritis and 20 (21%) lower back pain; 30 (32%) were treated with opioids. In summary, CNMP was common in the timely palliative care setting and many patients were on opioids. Our findings highlight the need to develop clinical guidelines for CNMP in cancer patients to standardize its management.

Enormous haemangioma of the liver.

Haemangiomas are the most common benign tumours of the liver. Their origin lies in the proliferation of the vascular endothelium. Their growth mechanism is by dilation. They are considered giant when they exceed 5 cm at their greatest diameter. Very uncommon presentations surpass 15 cm; these are known as enormous haemangiomas. We present a case of a 54-year-old woman with an enormous haemangioma of 30 cm in diameter. A mass was present in her right upper quadrant along with dull abdominal pain for several years. It is unknown for how long the tumour had been developing. She underwent surgical management due to evident mass effect. Clinicians should be aware of the importance of early diagnosis in these types of tumours. Its erratic growth pattern, mass effect-related complications and the capacity of producing haematological abnormalities makes it an entity to be considered.