Frequency, characteristics, antithrombotic therapies, and outcomes of thromboembolism in paediatric patients with CHD undergoing cardiac surgery: a single centre retrospective study.

INTRODUCTION: Thromboembolism is a complication in paediatric patients with CHD requiring cardiac surgery. Previous research has focused on post-operative thromboembolism. This study aimed to describe thromboembolism frequency before or after cardiac surgery in children with CHD. METHODS: We performed a single-centre retrospective study from October 2020 to June 2023 (inclusive). Patients were eligible for inclusion if they were <21 years of age and underwent cardiac surgery. Outcomes of interest included the occurrence and characteristics of thromboembolism in the 12 months before and after surgery, antithrombotic therapies, recurrent thromboembolism, and clinically significant bleeding. RESULTS: Among 260 patients included, 35 (13.5%) developed an index thromboembolism. Twelve (34.3%) patients had an index thromboembolism <12 months before surgery and 23 (65.7%) had an index thromboembolism <12 months after surgery, including 8 (22.9%) patients who had thromboembolism during both exposure periods. The median interquartile range (IQR) time of thromboembolism relative to cardiac surgery was -26 (-4 to -140) days and 15 (4 to 41) days, respectively. Seven (20%) patients had arterial, 18 (51.4%) venous, and 3 (8.6%) had both arterial and venous thromboembolism. Median (IQR) antithrombotic therapy duration was 49 (24-84) days. Nine (25.7%) patients developed recurrent thromboembolism and five (14.3%) patients experienced clinically significant bleeding. CONCLUSIONS: The risk of thromboembolism and recurrence is high both before and after cardiac surgery among paediatric patients with CHD. Prospective multi-centre studies should seek to identify risk factors for preoperative and postoperative thromboembolism to inform the design of future risk-stratified thromboembolism prevention trials in children with CHD.

Endoscopic Assessment and Serial Balloon Dilatation in a Toddler With Dyskeratosis Congenita-Hoyeraal-Hreidarsson Syndrome Following Bone Marrow Transplant: A Case Report.

We report a 3-year-old patient with suspected oropharyngeal graft-versus-host disease (GVHD) who developed progressive dysphagia to solids and liquids. The patient has a history of Dyskeratosis Congenita-Hoyeraal-Hreidarsson Syndrome with associated bone marrow failure requiring a nonmyeloablative matched sibling hematopoietic stem cell transplant. Esophagram revealed significant narrowing in the cricopharyngeal region. Subsequent esophagoscopy showed a proximal, high-grade pinhole esophageal stricture that was very difficult to visualize and cannulate. High-grade esophageal strictures are uncommon in very young children with GVHD. We believe the patient's underlying Dyskeratosis Congenita-Hoyeraal-Hreidarsson Syndrome in the setting of inflammatory changes seen in GVHD following hematopoietic stem cell transplant set the stage for a high-grade esophageal obstruction. The patient's symptoms improved with serial endoscopic balloon dilation.

What can the plasma proteome tell us about platelets and (vice versa)?

Multi-omics approaches are being used increasingly to study physiological and pathophysiologic processes. Proteomics specifically focuses on the study of proteins as functional elements and key contributors to, and markers of the phenotype, as well as targets for diagnostic and therapeutic approaches. Depending on the condition, the plasma proteome can mirror the platelet proteome, and hence play an important role in elucidating both physiologic and pathologic processes. In fact, both plasma and platelet protein signatures have been shown to be important in the setting of thrombosis-prone disease states such as atherosclerosis and cancer. Plasma and platelet proteomes are increasingly being studied as a part of a single entity, as is the case with patient-centric sample collection approaches such as capillary blood. Future studies should cut across the plasma and platelet proteome silos, taking advantage of the vast knowledge available when they are considered as part of the same studies, rather than studied as distinct entities.

Platelets are key cellular elements of blood with plasma constituting the liquid component. Both platelets and proteins found in plasma rapidly work in unity to prevent/limit blood loss in response to blood vessel damage. Proteomics is the analysis of the entire protein complement of a cell, tissue, or organism under a specific, defined set of conditions. Of note, research to date has shown that platelet and plasma proteomes share many common proteins. In some disease scenarios, plasma proteomes can be used to identify platelet function or dysfunction, while in other scenarios, platelet-specific proteins are needed for physiological assessment. Thus, it may be beneficial to simultaneously study the plasma and platelet proteomes, thereby exploiting the considerable wealth of information provided under such circumstances.

Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with thrombotic complications in adults, but the incidence of COVID-19-related thrombosis in children and adolescents is unclear. Most children with acute COVID-19 have mild disease, but coagulopathy has been associated with multisystem inflammatory syndrome in children (MIS-C), a postinfectious complication. We conducted a multicenter retrospective cohort study to determine the incidence of thrombosis in children hospitalized with COVID-19 or MIS-C and evaluate associated risk factors. We classified patients into 1 of 3 groups for analysis: COVID-19, MIS-C, or asymptomatic SARS-CoV-2. Among a total of 853 admissions (COVID-19, n = 426; MIS-C, n = 138; and asymptomatic SARS-CoV-2, n = 289) in 814 patients, there were 20 patients with thrombotic events (TEs; including 1 stroke). Patients with MIS-C had the highest incidence (9 [6.5%] of 138) vs COVID-19 (9 [2.1%] of 426) or asymptomatic SARS-CoV-2 (2 [0.7%] of 289). In patients with COVID-19 or MIS-C, a majority of TEs (89%) occurred in patients age ≥12 years. Patients age ≥12 years with MIS-C had the highest rate of thrombosis at 19% (9 of 48). Notably, 71% of TEs that were not present on admission occurred despite thromboprophylaxis. Multivariable analysis identified the following as significantly associated with thrombosis: age ≥12 years, cancer, presence of a central venous catheter, and MIS-C. In patients with COVID-19 or MIS-C, hospital mortality was 2.3% (13 of 564), but it was 28% (5 of 18) in patients with TEs. Our findings may help inform pediatric thromboprophylaxis strategies.

Thrombosis in Children: Approach to Anatomic Risks, Thrombophilia, Prevention, and Treatment.

Pediatric venous thromboembolism (VTE) is increasing in incidence but minimal data exist for best practices regarding therapy, use of thrombophilia testing, and management of long-term complications. Classification schema use anatomic location and presence of clinical or thrombophilic inciting factors. There are a small number of risk-assessment and risk-modeling systems for incident VTE, but all suffer from low numbers, single-institution design, and lack of prospective validation. Acute treatment is limited to heparin products and thrombolysis may be indicated in specific situations. In addition, chronic postthrombotic comorbidities are expected to increase in incidence and lack evidence-based treatment paradigms.

Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia.

Acquired aplastic anemia (aAA) results from the T cell-mediated autoimmune destruction of hematopoietic stem cells. Factors predicting response to immune suppression therapy (IST) or development of myelodysplastic syndrome (MDS) are beginning to be elucidated. Our recent data suggest most patients with aAA treated with IST develop clonal somatic genetic alterations in hematopoietic cells. One frequent acquired abnormality is copy-number neutral loss of heterozygosity on chromosome 6p (6p CN-LOH) involving the human leukocyte antigen (HLA) locus. We hypothesized that because 6p CN-LOH clones may arise from selective pressure to escape immune surveillance through deletion of HLA alleles, the development of 6p CN-LOH may affect response to IST. We used single nucleotide polymorphism array genotyping and targeted next-generation sequencing of HLA alleles to assess frequency of 6p CN-LOH, identity of HLA alleles lost through 6p CN-LOH, and impact of 6p CN-LOH on response to IST. 6p CN-LOH clones were present in 11.3% of patients, remained stable over time, and were not associated with development of MDS-defining cytogenetic abnormalities. Notably, no patient with 6p CN-LOH treated with IST achieved a complete response. In summary, clonal 6p CN-LOH in aAA defines a unique subgroup of patients that may provide insights into hematopoietic clonal evolution.

Pluripotent stem cells reveal erythroid-specific activities of the GATA1 N-terminus.

Germline GATA1 mutations that result in the production of an amino-truncated protein termed GATA1s (where s indicates short) cause congenital hypoplastic anemia. In patients with trisomy 21, similar somatic GATA1s-producing mutations promote transient myeloproliferative disease and acute megakaryoblastic leukemia. Here, we demonstrate that induced pluripotent stem cells (iPSCs) from patients with GATA1-truncating mutations exhibit impaired erythroid potential, but enhanced megakaryopoiesis and myelopoiesis, recapitulating the major phenotypes of the associated diseases. Similarly, in developmentally arrested GATA1-deficient murine megakaryocyte-erythroid progenitors derived from murine embryonic stem cells (ESCs), expression of GATA1s promoted megakaryopoiesis, but not erythropoiesis. Transcriptome analysis revealed a selective deficiency in the ability of GATA1s to activate erythroid-specific genes within populations of hematopoietic progenitors. Although its DNA-binding domain was intact, chromatin immunoprecipitation studies showed that GATA1s binding at specific erythroid regulatory regions was impaired, while binding at many nonerythroid sites, including megakaryocytic and myeloid target genes, was normal. Together, these observations indicate that lineage-specific GATA1 cofactor associations are essential for normal chromatin occupancy and provide mechanistic insights into how GATA1s mutations cause human disease. More broadly, our studies underscore the value of ESCs and iPSCs to recapitulate and study disease phenotypes.

Immune hemolytic anemia with drug-induced antibodies to carboplatin and vincristine in a pediatric patient with an optic pathway glioma.

BACKGROUND: Drug-induced immune hemolytic anemia (DIIHA) is a rare, but important condition requiring specialized laboratory testing for diagnosis. We report a case of DIIHA with antibodies against carboplatin and vincristine (VCR) in a child with an optic pathway glioma. Platinum-based drugs are established to cause DIIHA; to our knowledge, this is the first report implicating VCR. STUDY DESIGN AND METHODS: A 35-month-old girl with an optic pathway glioma developed hemolytic anemia while receiving carboplatin and VCR. Specialized blood bank testing was performed to determine the presence of drug-dependent antibodies and thus DIIHA. RESULTS: Initial direct antiglobulin test (DAT) was negative. A repeat DAT 3 days later was positive, 3+ with polyspecific-antiglobulin sera, weak+ with anti-immunoglobulin (Ig)G, and 2+ with anti-C3d. An eluate from the DAT-positive red blood cells (RBCs) was nonreactive. The patient's serum reacted without specificity to all RBC tested using papain-IgG-antiglobulin test (AGT) and polyethylene glycol-IgG-AGT. No alloantibodies to common RBC antigens were detected. When the serum was evaluated for the presence of drug-specific antibody, reactivity was shown with VCR and carboplatin using the drug addition solution method, but only with carboplatin using the drug-coating method. CONCLUSION: The patient developed hemolytic anemia during chemotherapy. Initial detection of a panagglutinin suggested a warm-type autoimmune process. However, since DIIHA could not be excluded, chemotherapy was discontinued and further work-up was initiated. The findings confirmed the presence of antibodies to carboplatin and VCR. This case highlights the importance for clinicians to maintain a high index of suspicion for DIIHA in patients with unexplained hemolysis and the importance of specialized serologic testing.