Analysis of influencing factors and construction of risk prediction model for postoperative thrombocytopenia in critically ill patients with heart disease.

OBJECTIVE: To analyze the influencing factors of postoperative thrombocytopenia in critically ill patients with heart disease and construct a nomogram prediction model. METHODS: From October 2022 to October 2023, 319 critically ill patients with heart disease who visited our hospital were collected and separated into postoperative thrombocytopenia group (n = 142) and no postoperative thrombocytopenia group (n = 177) based on their postoperative thrombocytopenia, Logistic regression analysis was applied to screen risk factors for postoperative thrombocytopenia in critically ill patients with heart disease; R software was applied to construct a nomogram for predicting postoperative thrombocytopenia in critically ill patients with heart disease, and ROC curves, calibration curves, and Hosmer-Lemeshow goodness of fit tests were applied to evaluate nomogram. RESULTS: A total of 142 out of 319 critically ill patients had postoperative thrombocytopenia, accounting for 44.51%. Logistic regression analysis showed that gender (95% CI 1.607-4.402, P = 0.000), age ≥ 60 years (95% CI 1.380-3.697, P = 0.001), preoperative antiplatelet therapy (95% CI 1.254-3.420, P = 0.004), and extracorporeal circulation time > 120 min (95% CI 1.681-4.652, P = 0.000) were independent risk factors for postoperative thrombocytopenia in critically ill patients with heart disease. The area under the ROC curve was 0.719 (95% CI: 0.663-0.774). The slope of the calibration curve was close to 1, and the Hosmer-Lemeshow goodness of fit test was χ2 = 6.422, P = 0.491. CONCLUSION: Postoperative thrombocytopenia in critically ill patients with heart disease is influenced by gender, age ≥ 60 years, preoperative antiplatelet therapy, and extracorporeal circulation time > 120 min. A nomogram established based on above multiple independent risk factors provides a method for clinical prediction of the risk of postoperative thrombocytopenia in critically ill patients with heart disease.

Somatic RAP1B gain-of-function variant underlies isolated thrombocytopenia and immunodeficiency.

The ubiquitously expressed small GTPase Ras-related protein 1B (RAP1B) acts as a molecular switch that regulates cell signaling, cytoskeletal remodeling, and cell trafficking and activates integrins in platelets and lymphocytes. The residue G12 in the P-loop is required for the RAP1B-GTPase conformational switch. Heterozygous germline RAP1B variants have been described in patients with syndromic thrombocytopenia. However, the causality and pathophysiological impact remained unexplored. We report a boy with neonatal thrombocytopenia, combined immunodeficiency, neutropenia, and monocytopenia caused by a heterozygous de novo single nucleotide substitution, c.35G>A (p.G12E) in RAP1B. We demonstrate that G12E and the previously described G12V and G60R were gain-of-function variants that increased RAP1B activation, talin recruitment, and integrin activation, thereby modifying late responses such as platelet activation, T cell proliferation, and migration. We show that in our patient, G12E was a somatic variant whose allele frequency decreased over time in the peripheral immune compartment, but remained stable in bone marrow cells, suggesting a differential effect in distinct cell populations. Allogeneic hematopoietic stem cell transplantation fully restored the patient's hemato-immunological phenotype. Our findings define monoallelic RAP1B gain-of-function variants as a cause for constitutive immunodeficiency and thrombocytopenia. The phenotypic spectrum ranged from isolated hematological manifestations in our patient with somatic mosaicism to complex syndromic features in patients with reported germline RAP1B variants.

[Developments of high-throughput sequencing-based diagnosis of congenital thrombocytopenia/platelet disorders in a registry study].

Congenital thrombocytopenia/platelet disorders are heterogeneous disorders of platelet number and/or function. Pathogenic variants in the genes implicated in megakaryocyte differentiation and platelet formation cause thrombocytopenia in these patients. Recent advances have elucidated several causative genes for these disorders, but identifying the underlying causative genes remains challenging. Patients with these disorders often receive inappropriate treatments, including glucocorticoids and splenectomy, for chronic immune thrombocytopenia (ITP). In Japan, we have developed a diagnostic system using high-throughput DNA sequencing with a multigene panel and established a registry. Between 2018 and 2023, 245 patients were enrolled and analyzed. Pathogenic variants in 17 genes (42 MYH9, 19 ANKRD26, 17 ITGA2B/ITGB3, 8 ACTN1, 8 WAS, 6 ETV6, 6 VWF, 5 CYCS, and 14 others) were identified in 125 patients (51.0%). An additional 29 patients (11.8%) had suspected pathogenic variants under investigation. We also found that immature platelet fraction (IPF%) is useful in the differential diagnosis because the median IPF% in MYH9 disorders, 48.7%, was significantly higher than in all other groups (chronic ITP, 13.4%; controls, 2.6%). The results of this study provide new insight into congenital thrombocytopenia/platelet disorders.

Hematological abnormality and associated factors in newborns with hyperbilirubinemia before and after phototherapy at University of Gondar Comprehensive Specialized Hospital.

This study aimed to assess the magnitude of hematological toxicity and associated factors in newborns with hyperbilirubinemia. A cross-sectional study was conducted from April to December 2023. A total of 247 newborns were included. The data were collected using questionnaires and a data extraction sheet. Four 4 ml of blood was collected. A Sysmex KX-21 analyzer was used for blood analysis, and a Mindray BS-240 analyzer was used for bilirubin measurement. The data were entered into Epi-data and analyzed by SPSS. The logistic regression was used. The P value was set at 0.05. Before phototherapy, the hematological toxicities, such as anemia, leucopenia, and thrombocytopenia, were 45.7%, 22.2%, and 6.1%, respectively, whereas after phototherapy, anemia and thrombocytopenia, significantly increased, but the leucopenia, significantly decreased. The risk of developing anemia increased, 3.5, 2.7, and 2.1-fold among newborns with bilirubin > 18 mg/dl, with Rh blood group incompatibility, and treated with intensive phototherapy, respectively. Both low birth weight and intensive phototherapy increased the incidence of thrombocytopenia by 2 and 3.4-fold, respectively. Hematological toxicity was found to be a severe public health issue in newborns. Thus, strict follow-up and early detection of toxicity by considering aggravation factors are necessary.

Eighty-six cases of clinical characteristics and outcomes of systemic lupus erythematosus-associated macrophage activation syndrome: A meta-analysis study.

OBJECTIVE: To improve our understanding of systemic lupus erythematosus (SLE)-macrophage activation syndrome (MAS). METHODS: A systematic review was performed, to retrieve all those papers on patients with SLE-MAS, in individual or aggregated form. The data in each of these medical records were extracted and analyzed to identify the characteristics of SLE-MAS. RESULTS: A total of 86 SLE-MAS patients were included (25 males and 61 females. The mean (±standard error of the mean) age was 31.21 ± 1.694 years. MAS occurred as the initial presentation of SLE in 47 people (54.65%) and during the course of SLE in 39 (45.35%). A coinfection was reported in 23 (26.74%) patients. The mean Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score was 16.54 ± 0.9462. Overall, 10 patients (11.63%) died. The SLEDAI-2K score was higher in patients with MAS as an initial manifestation of SLE than in those where MAS occurred during the course of SLE. The proportion of patients receiving steroid pulse therapy was lower in patients with coinfections. The deceased group demonstrated lower platelet and ferritin levels. Multiple regression analysis revealed that age and thrombocytopenia were independent factors associated with poor prognosis. In receiver operating characteristic analysis, a platelet count cutoff value of ≤47 × 109/L was a predictor of poor outcome. CONCLUSIONS: SLE-MAS patients demonstrated high lupus activity, and lupus activity was especially higher in patients with MAS as an initial manifestation. Lupus activity was the predominant trigger of lupus MAS. Thrombocytopenia was an independent factor for poor prognosis.

Heparin Induced Thrombocytopenia Testing.

This article provides a comprehensive overview of Heparin-Induced Thrombocytopenia (HIT) with an emphasis on laboratory testing and advantages of automation. HIT is a critical condition arising from heparin exposure, leading to a contradictory combination of thrombocytopenia with an increased thrombosis risk. The article discusses HIT's history, clinical presentation, laboratory diagnosis, and management strategies. It highlights the importance of interdisciplinary collaboration for effective diagnosis and treatment, underscoring advancements in technology and targeted therapies that are shaping future approaches to HIT management.

Familial autoimmunity and risk of developing immune thrombocytopenia and Evans syndrome.

BACKGROUND: Immune thrombocytopenia (ITP) and Evans syndrome (ES) are manifestations of immune dysregulation. Genetic variants in immune-related genes have been identified in patients with ITP and especially ES. We aimed to explore familial autoimmunity in patients with ITP and ES to understand possible contributions to chronicity. PROCEDURE: We assessed family history in two ways: via patient report for ITP and ES and by population-based analysis using the Utah Population Database (UPDB) for ITP. A total of 266 patients with ITP and 21 patients with ES were identified via chart review, and 252 of the 266 patients with ITP were also identified in the UPDB. RESULTS: Chart review showed familial autoimmunity in 29/182 (15.9%) and 25/84 (29.8%) of patients with newly diagnosed+persistent (nd+p) ITP and chronic ITP (cITP), respectively, (p = .009). The UPDB analysis revealed that autoimmunity in relatives of patients with nd+pITP was higher than in relatives of controls (odds ratio [OR]: 1.69 [1.19-2.41], p = .004), but was not significantly increased in relatives of patients with cITP (OR 1.10 [0.63-1.92], p = .734). Incomplete family history in medical records likely contributed to the observed discrepancy. CONCLUSIONS: The findings suggest that familial autoimmunity may have a stronger association with the development of ITP rather than its duration. Twelve (57.1%) patients with ES reported autoimmunity in their relatives. UPDB analysis was omitted due to the small number of patients with ES. The use of population databases offers a unique opportunity to assess familial health and may provide clues about contributors to immune dysregulation features within families.

Romiplostim in chemotherapy-induced thrombocytopenia: A review of the literature.

Chemotherapy-induced thrombocytopenia (CIT) is a common challenge of cancer therapy and can lead to chemotherapy dose reduction, delay, and/or discontinuation, affecting relative dose intensity, and possibly adversely impacting cancer care. Besides changing anticancer regimens, standard management of CIT has been limited to platelet transfusions and supportive care. Use of the thrombopoietin receptor agonist romiplostim, already approved for use in immune thrombocytopenia, has shown promising signs of efficacy in CIT. In a phase 2 prospective randomized study of solid tumor patients with platelet counts <100 × 109/L for ≥4 weeks due to CIT, weekly romiplostim corrected the platelet count to >100 × 109/L in 93% (14/15) of patients within 3 weeks versus 12.5% (1/8) of untreated patients (p < 0.001). Including patients treated with romiplostim in an additional single-arm cohort, 85% (44/52) of all romiplostim-treated patients responded with platelet count correction within 3 weeks. Several retrospective studies of CIT have also shown responses to weekly romiplostim, with the largest study finding that poor response to romiplostim was predicted by tumor invasion of the bone marrow (odds ratio, 0.029; 95% CI: 0.0046-0.18; p < 0.001), prior pelvic irradiation (odds ratio, 0.078; 95% CI: 0.0062-0.98; p = 0.048), and prior temozolomide treatment (odds ratio 0.24; 95% CI: 0.061-0.96; p = 0.043). Elsewhere, lower baseline TPO levels were predictive of romiplostim response (p = 0.036). No new safety signals have emerged from romiplostim CIT studies. Recent treatment guidelines, including those from the National Comprehensive Cancer Network, now support consideration of romiplostim use in CIT. Data are expected from two ongoing phase 3 romiplostim CIT trials.

Effective and safe use of intramuscular clozapine in a patient presenting with catatonia and thrombocytopenia.

Clozapine is the most effective medication for the management of treatment-resistant schizophrenia and schizoaffective disorder, and its discontinuation can pose significant challenges in treatment. We present a patient with a diagnosis of schizoaffective disorder who was stable on clozapine for a decade until discontinuation due to thrombocytopenia. She experienced a relapse of her illness, presenting with psychotic and catatonic features with poor oral intake and physical health complications requiring a lengthy admission to the hospital. There was a poor response to alternative antipsychotics and a full course of electroconvulsive therapy. Intramuscular (IM) clozapine was initiated due to catatonia and refusal to accept oral medications. After receiving 10 doses of IM clozapine, she started accepting oral clozapine and made a full recovery within a few weeks. The low platelet count was persistent, and a bone marrow biopsy showed results consistent with immune thrombocytopenia being the cause of that low platelet count.

Injuries and deaths following Covid-19 vaccination: The ethical and legal case for compensation.

In April 2024, in a class action suit for compensation to families of persons suffering injury or death after vaccination with AstraZeneca's (AZ) Covid-19 vaccine [1], the manufacturer admitted in a UK court that the Oxford-AZ Covid-19 vaccine could cause a rare and potentially fatal blood clotting disorder ("thrombosis with thrombocytopenia syndrome" or TTS, which when triggered by a vaccine is called "vaccine induced thrombocytopenia and thrombosis, or VITT) [2]. The AZ Covid-19 vaccine is a chimpanzee adenovirus vectored vaccine encoding the SARS-CoV2 spike protein (ChAdOx1-S) marketed under the names Covishield and Vaxzevria.

Identification of Active Molecules against Thrombocytopenia through Machine Learning.

Thrombocytopenia, which is associated with thrombopoietin (TPO) deficiency, presents very limited treatment options and can lead to life-threatening complications. Discovering new therapeutic agents against thrombocytopenia has proven to be a challenging task using traditional screening approaches. Fortunately, machine learning (ML) techniques offer a rapid avenue for exploring chemical space, thereby increasing the likelihood of uncovering new drug candidates. In this study, we focused on computational modeling for drug-induced megakaryocyte differentiation and platelet production using ML methods, aiming to gain insights into the structural characteristics of hematopoietic activity. We developed 112 different classifiers by combining eight ML algorithms with 14 molecule features. The top-performing model achieved good results on both 5-fold cross-validation (with an accuracy of 81.6% and MCC value of 0.589) and external validation (with an accuracy of 83.1% and MCC value of 0.642). Additionally, by leveraging the Shapley additive explanations method, the best model provided quantitative assessments of molecular properties and structures that significantly contributed to the predictions. Furthermore, we employed an ensemble strategy to integrate predictions from multiple models and performed in silico predictions for new molecules with potential activity against thrombocytopenia, sourced from traditional Chinese medicine and the Drug Repurposing Hub. The findings of this study could offer valuable insights into the structural characteristics and computational prediction of thrombopoiesis inducers.

Hantavirus Cardiopulmonary syndrome: Another Reason to Avoid Mice.

Hantavirus cardiopulmonary syndrome is a severe illness transmitted by rodent excretions. We describe a case of a 24-year-old man who presented to the emergency department with cough, shortness of breath, chills, myalgias, nausea, and diarrhea. Physical examination and laboratory analysis revealed signs of respiratory distress and thrombocytopenia. The trajectory of his illness led to acute respiratory distress syndrome (ARDS) and hemodynamic instability. Serum testing was positive for hantavirus IgM and IgG antibodies. The patient was managed with supportive care and improved. This case highlights the importance of considering hantavirus when managing patients who develop thrombocytopenia, ARDS, and hemodynamic instability in the appropriate clinical setting.

Delayed diagnosis of TAFRO syndrome: A case report.

RATIONALE: TAFRO syndrome is a systemic inflammatory disorder, manifesting as thrombocytopenia (t), anasarca (a), fever (f), reticulin myelofibrosis/renal insufficiency (r), and organomegaly (o), and considered as a unique clinical subtype of idiopathic multicentric Castleman disease (iMCD). Such syndrome gave rise to a clinical picture similar to that of either a connective tissue disease or an autoimmune disease. PATIENT CONCERNS: A Chinese young female initially presenting with arthralgia, Raynaud phenomenon, generalized edema, and a positive anti-small nuclear ribonucleoprotein particle antibody was diagnosed as mixed connective tissue disease. The kidney biopsy showed thrombotic microangiopathy. Bone marrow smear showed bone marrow hyperplasia and biopsy revealed suspected light chain restricted expression, megakaryocyte proliferation, and moderate to severe bone marrow fibrosis. A lymph node biopsy was conducted and the histopathological findings were consistent with the subtype of mixed Castleman disease. The clinical symptoms were relieved after regular chemotherapy. DIAGNOSES: After above examination results and clinical manifestations, the final diagnoses was TAFRO syndrome. INTERVENTION: The she was started on chemotherapy with bortezomib, cyclophosphamide, and dexamethasone. OUTCOME: After chemotherapy, symptoms such as thrombocytopenia, hematuria and proteinuria disappeared, lymphadenopathy and VEGF level decreased, and bone marrow fibrosis relieved. LESSONS: Our case illustrated the first cases of shared characteristics of mixed connective tissue disease and iMCD-TAFRO syndrome. Cytokines may play a role in the shared pathogenicity of the iMCD-TAFRO syndrome and systemic autoimmune diseases. Therapy directly against inflammatory factors such as corticosteroids or chemotherapy have an important therapeutic implication.

Complete Blood Count Values Over Time in Young Children During the Dengue Virus Epidemic in the Dominican Republic From 2018 to 2020.

Background: Dengue fever (DF) is a mosquito-borne illness with substantial economic and societal impact. Understanding laboratory trends of hospitalized Dominican Republic (DR) pediatric patients could help develop screening procedures in low-resourced settings. We sought to describe laboratory findings over time in DR children with DF and DF severity from 2018 to 2020. Methods: Clinical information was obtained prospectively from recruited children with DF. Complete blood count (CBC) laboratory measures were assessed across Days 1-10 of fever. Participants were classified as DF-negative and DF-positive and grouped by severity. We assessed associations of DF severity with demographics, clinical characteristics, and peripheral blood studies. Using linear mixed-models, we assessed if hematologic values/trajectories differed by DF status/severity. Results: A total of 597 of 1101 with a DF clinical diagnosis were serologically evaluated, and 574 (471 DF-positive) met inclusion criteria. In DF, platelet count and hemoglobin were higher on earlier days of fever (p < = 0.0017). Eighty had severe DF. Severe DF risk was associated with thrombocytopenia, intraillness anemia, and leukocytosis, differing by fever day (p < = 0.001). Conclusions: In a pediatric hospitalized DR cohort, we found marked anemia in late stages of severe DF, unlike the typically seen hemoconcentration. These findings, paired with clinical symptom changes over time, may help guide risk-stratified screenings for resource-limited settings.

Impact of thrombocytopenia-associated c.-118C>T and c.-140C>G ANKRD26 5'UTR variants in three-generational pedigree.

Inherited thrombocytopenias (ITs) encompass a group of rare disorders characterized by diminished platelet count. Recent advancements have unveiled various forms of IT, with inherited thrombocytopenia 2 (THC2) emerging as a prevalent subtype associated with germline variants in the critical 5' untranslated region of the ANKRD26 gene. This region is crucial in regulating the gene expression of ANKRD26, particularly in megakaryocytes. THC2 is an autosomal dominant disorder presenting as mild-to-moderate thrombocytopenia with minimal symptoms, with an increased risk of myeloproliferative malignancies. In our study of a family with suspected IT, three affected individuals harbored the c.-118C>T ANKRD26 variant, while four healthy members carried the c.-140C>G ANKRD26 variant. We performed a functional analysis by studying platelet-specific ANKRD26 gene expression levels using quantitative real-time polymerase-chain reaction. Functional analysis of the c.-118C>T variant showed a significant increase in ANKRD26 expression in affected individuals, supporting its pathogenicity. On the contrary, carriers of the c.-140C>G variant exhibited normal platelet counts and no significant elevation in the ANKRD26 expression, indicating the likely benign nature of this variant. Our findings provide evidence confirming the pathogenicity of the c.-118C>T ANKRD26 variant in THC2 and suggest the likely benign nature of the c.-140C>G variant.

What is the context?Inherited thrombocytopenias (ITs) are rare conditions characterized by low platelet counts. Inherited thrombocytopenia 2 (THC2) is caused by ANKRD26 gene changes leading to increased ANKRD26 expression as the main reason for subsequent thrombocytopenia. THC2 results in a mild-to-moderate decrease in platelet count and increases blood cancer risk. We focused on understanding two ANKRD26 variants in a family with a history of thrombocytopenia.What is new?We conducted functional analysis to understand the effect of variants on platelet function and gene expression. We identified three thrombocytopenic family members as carriers of ANKRD26 variant c.-118C>T. This variant is linked to increased expression of the ANKRD26 gene and confirmed as the likely cause of THC2. Another variant, c.-140C>G, was present in four healthy family members. Although it was considered causal for THC2 in the past, our study suggests that the c.-140C>G variant does not elevate ANKRD26 expression and does not cause thrombocytopenia.What is the impact?Understanding the genetic and functional implications of ANKRD26 gene variants is crucial for THC2 diagnosis and management. Our study emphasizes the necessity of conducting functional analyses to precisely evaluate the clinical significance of variants linked to inherited blood disorders. Carriers of the c.-118C>T variant should undergo vigilant monitoring for THC2 and potential cancer development. Conversely, the c.-140C>G variant does not pose a risk of THC2 or heightened cancer susceptibility.

Safety of Antiplatelet Therapy in Noncardioembolic Ischemic Stroke With Thrombocytopenia: The CASE II Study.

BACKGROUND: There is scant evidence regarding the safety of antiplatelet therapy in acute ischemic stroke (AIS) patients with thrombocytopenia. Our study aims to address this concern by examining AIS patients with thrombocytopenia from a large database in real-world settings. METHODS AND RESULTS: We included patients with AIS with a platelet count <100×109/L who had complete records of antiplatelet drug use. Those requiring anticoagulation or having contraindications to antiplatelet therapy were excluded. Short-term safety outcomes were in-hospital bleeding events, while the long-term safety outcome was 1-year all-cause mortality. A good clinical outcome was defined as functional independence, indicated by a modified Rankin Scale score of 0 to 2 at discharge. Propensity score matched analyses were used. We screened 169 423 patients with AIS from 90 stroke centers in the CASE II register, ultimately enrolling 2808 noncardioembolic patients with thrombocytopenia. In the propensity score matched analyses, no significant difference was observed between the antiplatelet and nonantiplatelet groups in terms of intracranial hemorrhage (odds ratio=0.855 [95% CI, 0.284-5.478]; P=0.160) or gastrointestinal bleeding (odds ratio=2.034 [95% CI, 0.755-5.478]; P=0.160). Antiplatelet therapy was associated with improved functional outcomes at discharge (odds ratio=1.405 [95% CI, 1.028-1.920]; P=0.033), and showed a trend towards reducing 1-year mortality (odds ratio=0.395 [95% CI, 0.152-1.031]; P=0.058). CONCLUSIONS: The use of antiplatelet therapy lessened as platelet count decreased in patients with AIS with thrombocytopenia. However, our findings suggest that antiplatelet medications remain safe and effective for this population.

Subphenotypes of platelet count trajectories in sepsis from multi-center ICU data.

Although thrombocytopenia on admission to the ICU is associated with increased in-hospital mortality in septic patients, the role of longitudinally measured platelet counts, which are dynamically changing, is unclear. We aimed to identify patterns of dynamic platelet count trajectories and evaluate their association with outcomes and thrombocytopenia in septic patients. We tested the longitudinal platelet trajectory patterns of sepsis patients within the first four days of ICU admission in the MIMIC-IV database and their association with 28-day mortality, and independently validated our findings in the eICU-CRD database. Statistical methods used included multivariate regression, propensity score analysis, doubly robust estimation, gradient boosting model, and inverse probability weighting to ensure the robustness of our findings. A total of 22,866 septic patients were included in our study. The trajectory analysis categorizes patients into ascending (AS), stable (ST), or descending (DS) patterns. The risk of 28-day mortality was increased in the DS patients (OR = 2.464, 95%CI 1.895-3.203, p < 0.001) and ST patients (OR = 1.302, 95%CI 1.067-1.589, p = 0.009) compared to AS patients. The AS patients had lower ICU length of stay (2.36 vs. 4.32, p < 0.001) and 28-day maximum SOFA scores (5.00 vs. 6.00, p < 0.001) than the DS patients, but had more ventilator-free days within 28 days than the DS group (26.00 vs. 24.00, p < 0.001). The mediating effect of thrombocytopenia was significant (p < 0.001 for the average causal mediation effect (ACME)). Longitudinal platelet trajectory was associated with risk-adjusted 28-day mortality among patients with sepsis and was proportionally mediated through thrombocytopenia.

Outcomes and prognostic factors for survival of children with oesophageal atresia.

INTRODUCTION: Oesophageal atresia (EA) is a life-threatening congenital oesophageal deformity that causes considerable newborn morbidity and death. Many prognostic variables have been linked to the survival of infants with EA, although the results of the studies are still conflicting. Furthermore, studies on EA effects in developing countries still need to be included. Here, we aimed to determine the survival of children with EA and link it to prognostic variables in a particular developing country. MATERIALS AND METHODS: A cross-sectional observational retrospective study was conducted using medical records of paediatric patients with EA at our institution from January 2014 to December 2020. RESULTS: A total of 53 children with EA were included in the study. Log-rank analysis showed that definitive surgery and thrombocytopenia were significantly associated with the survival of children with EA, with a p-value of 0.007 and 0.002, respectively, whereas, sex, EA type, pneumonia and sepsis were not (p = 0.898, 0.919, 0.255, and 0.499, respectively). Multivariate analysis revealed that thrombocytopenia and definitive surgery were strongly associated with the survival of children with EA with a pvalue of 0.014 (hazard ratio (HR) = 2.67 [95% confidence interval (CI) = 1.22-5.85]) and 0.022 (HR =0.39 [95% CI = 0.17- 0.87]), respectively. CONCLUSION: Our study shows that thrombocytopenia might increase mortality, while definitive surgery might be beneficial for the survival of paediatric patients with EA. It implies that definitive surgery should be performed as early as necessary to prevent further morbidity and mortality. Our study comprehensively provides the survival of children with EA and links it to prognostic variables in a particular developing country. It serves as a potential research project that can be applied to the clinical setting to help clinicians manage EA better.

Two delayed-diagnosis case reports of long-lasting thrombocytopenia with splenomegaly.

RATIONALE: Gaucher disease (GD) is a rare hereditary lysosomal storage disorder disease progression and inappropriate treatment. However, not all patients with GD receive timely diagnosis and treatment. PATIENT CONCERNS: Early diagnosis is important for initiating proper treatment and preventing complications. DIAGNOSES: Two patients were diagnosed as GD in this study. INTERVENTIONS AND OUTCOMES: These 2 patients received the imiglucerase enzyme replacement and symptoms significantly improved by the follow-up. LESSONS: Herein, we report 2 patients with a delayed diagnosis of GD to increase awareness and improve education regarding rare diseases. However, noninvasive ß-glucocerebrosidase activity or GBA gene testing had not been done before bone marrow aspiration, which are the noninvasive and reliable tests that indicate the diagnosis of GD.

Exploring the Genotype-Phenotype Correlations in a Child with Inherited Seizure and Thrombocytopenia by Digenic Network Analysis.

Understanding the correlation between genotype and phenotype remains challenging for modern genetics. Digenic network analysis may provide useful models for understanding complex phenotypes that traditional Mendelian monogenic models cannot explain. Clinical data, whole exome sequencing data, in silico, and machine learning analysis were combined to construct a digenic network that may help unveil the complex genotype-phenotype correlations in a child presenting with inherited seizures and thrombocytopenia. The proband inherited a maternal heterozygous missense variant in SCN1A (NM_001165963.4:c.2722G>A) and a paternal heterozygous missense variant in MYH9 (NM_002473.6:c.3323A>C). In silico analysis showed that these two variants may be pathogenic for inherited seizures and thrombocytopenia in the proband. Moreover, focusing on 230 epilepsy-associated genes and 35 thrombopoiesis genes, variant call format data of the proband were analyzed using machine learning tools (VarCoPP 2.0) and Digenic Effect predictor. A digenic network was constructed, and SCN1A and MYH9 were found to be core genes in the network. Further analysis showed that MYH9 might be a modifier of SCN1A, and the variant in MYH9 might not only influence the severity of SCN1A-related seizure but also lead to thrombocytopenia in the bone marrow. In addition, another eight variants might also be co-factors that account for the proband's complex phenotypes. Our data show that as a supplement to the traditional Mendelian monogenic model, digenic network analysis may provide reasonable models for the explanation of complex genotype-phenotype correlations.