Newly produced platelets acquire a low activation state, but whether the megakaryocyte plays a role in this outcome has not been fully uncovered. Mesenchymal stem cells (MSCs) were previously shown to promote platelet production and lower platelet activation. We found that healthy megakaryocytes transfer mitochondria to MSCs, which is mediated by connexin 43 (Cx43) gap junctions on MSCs and leads to platelets at a low energetic state with increased LYN activation, characteristic of resting platelets with increased LYN activation, characteristic of resting platelets. On the contrary, MSCs have a limited ability to transfer mitochondria to megakaryocytes. Sickle cell disease (SCD) is characterized by hemolytic anemia and results in heightened platelet activation, contributing to numerous disease complications. Platelets in SCD mice and human samples had a heightened energetic state with increased glycolysis. MSC exposure to heme in SCD led to decreased Cx43 expression and a reduced ability to uptake mitochondria from megakaryocytes. This prevented LYN activation in platelets and contributed to increased platelet activation at steady state. Altogether, our findings demonstrate an effect of hemolysis in the microenvironment leading to increased platelet activation in SCD. These findings have the potential to inspire new therapeutic targets to relieve thrombosis-related complications of SCD and other hemolytic conditions.

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H (CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.

longitudinal ABCD study, will collect multifactorial brain health data over ten years.Therefore, this research team is now poised to generate a ten-year longitudinal study of the uptake of the MIND diet in adolescents, further delineating the uptake of the MIND diet on vulnerable groups of adolescents.Drawing on data from the ongoing ABCD study, future studies could also describe the longitudinal impact of the MIND diet on brain health in adolescents.These findings could, in turn, give rise to opportunities for clinically meaningful nutritional interventions for at-risk adolescents.

Sickle cell disease (SCD) arises from beta-globin gene mutations, with global estimates indicating around 500 000 affected neonates in 2021. In the United States, it is considered rare, impacting fewer than 200 000 individuals. The key pathogenic flaw lies in mutant haemoglobin S, prone to polymerization under low oxygen conditions, causing erythrocytes to adopt a sickled shape. This leads to complications like vascular occlusion, haemolytic anaemia, inflammation and organ damage. Beyond erythrocyte abnormalities however, there is a body of literature highlighting the hypercoagulable state that is likely a contributor to many of the complications we see in SCD. The persistent activation of the coagulation cascade results in thromboembolic events, notably venous thromboembolism (VTE) which is independently associated with increased mortality in both adults and children with SCD. While the increased risk of VTE in the SCD population seems well established, there is a lack of guidelines for thromboprophylaxis in this population. This Wider Perspective will describe the hypercoagulable state and increased thrombosis risk in the SCD population, as well as advocate for the development of evidence-based guidelines to aid in the prevention of VTE in SCD.

Objectives: This study investigated whether patients with sickle cell disease (SCD) had elevated risk of worse long-term clinical outcomes and healthcare utilization 2.5 years post-SARS-CoV-2 infection.Methods: This study consisted of 178 patients with SCD who tested positive for COVID-19 between February 1, 2020 and January 30, 2022 in a major academic health system in New York City. The control cohort consisted of two-to-one matches of 356 SCD patients without a COVID-19 positive test. The last follow-up was July 18, 2022. The primary outcome was mortality. Secondary outcomes were annualized emergency department visits due to pain, pain hospital admission, length of stay due to pain, acute chest syndrome, episodic transfusion, and episodic exchange transfusion.Results: There was no significant difference in mortality between SCD patients with and without COVID-19 (p > .05). There were no significant differences in secondary outcomes between pre- and postpandemic (p > .05). There were also no significant differences in these outcomes between SCD patients with and without COVID-19 (p > .05). SCD care utilization was not significantly associated with COVID-19 hospitalization status (p > .05).Conclusions: SCD patients with SARS-CoV-2 infection incurred no additional risk of worse long-term outcomes compared to matched controls of SCD patients not infected by SARS-CoV-2.

Background: The coronavirus disease pandemic of 2019 (COVID-19) has been associated with coagulopathy and an increased rate of thrombosis in adults. Medical practitioners have been prompted to consider prophylactic anticoagulation in special populations diagnosed with COVID-19. Patients with sickle cell disease (SCD) are predisposed to a hypercoagulable state. Despite the concern for development of venous thromboembolism (VTE) in these patients, there are no standardized guidelines for routine thromboprophylaxis in either adults or children with SCD. Thus, VTE management options are often extrapolated from guidelines for the general population. Methods: A cross-sectional electronic survey was distributed to pediatric and adult hematology oncology practitioners through 7 SCD specific interest groups. Pediatric and adult practitioners were defined as those who medically manage patients 0-21 years of age and >21 years of age respectively. We examined responses to survey questions focused on routine thromboprophylaxis practices in children and adults with SCD prior to the pandemic and in patients with SCD admitted with COVID-19. Chi-square analyses or Fisher’s exact tests for small samples were used to compare proportions as needed. Results: The survey was distributed to approximately 2,550 providers. Of 93 total responses, 14% (N=13) only treat patients >21yo; 38.7% (N=36) only treat patients 0-21yo and 47.3% (N=44) treat both. Nearly all adult practitioners (96.6%) would recommend pharmacologic prophylaxis, mechanical prophylaxis or both for hospitalized adults, but only 76% of pediatric treaters would recommend any prophylaxis (PPX) in hospitalized children (p<0.0001, Figure 1). Only 16% would recommend pharmacologic PPX only for patients 0-21yo, with 36% preferring non-pharmacologic only methods and 24% preferring both forms. In contrast, for the >21yo patients, 51% preferred to use both pharmacologic and non-pharmacologic PPX, 25% preferred pharmacologic alone, with just 5.3% preferring non-pharmacologic PPX only. Enoxaparin was the most frequently used anticoagulant among both pediatric and adult practitioners [78% vs 89% respectively] (Figure 2). Direct oral anticoagulants (DOACS) were infrequently recommended (3.8% for SCD children and 10.9% for adults); of these, rivaroxaban was used most often. The most common indication for starting thromboprophylaxis for both 0-21yo and >21yo patients was history of prior VTE [81% and 81% respectively], followed by hip replacement [57% and 75% respectively]. In patients admitted with COVID-19, prophylactic anticoagulation was recommended for adults by 94% of treaters. There was a significant increase in the use of prophylactic anticoagulation in children with COVID-19 vs. those without (84% vs. 40%; p=.0001). Figure 3 shows extended thromboprophylaxis practices upon discharge for COVID related admissions. Almost half of respondents (46%) would not recommend any thromboprophylaxis for children on discharge; 37% would recommend either 2-4 weeks or >4weeks of post-discharge PPX. The majority of adult providers would recommend discharge thromboprophylaxis for adults with 2 weeks post discharge (33%), and 2-4 weeks (30%) being the most common regimens. Conclusion: This pilot survey describes the thromboprophylaxis practices used for adult and pediatric SCD patients by specialty practitioners. In general, practitioners were likely to prescribe pharmacologic thromboprophylaxis for adults while mechanical PPX was preferred for children. However, in the high-risk setting of COVID-19 infection, pediatric practitioners would modify their practice to include pharmacologic thromboprophylaxis. Interestingly, despite the long-term availability of direct oral anticoagulants in adults, and recent completion of pediatric studies, the most commonly used pharmacologic agent pre-COVID in adults and children was enoxaparin. Of note, this survey was conducted prior to release of the International Society on Thrombosis and Haemostasis guidelines regarding discharge PPX in COVID-19. (Spyropoulos AC, J Thromb Haemost, 2020) These results highlight the influence of COVID-19 on the use of pharmacologic thromboprophylaxis, specifically in the pediatric population. Due to frequent hospitalization, studies are needed to guide decision making surrounding VTE PPX for the adult and pediatric inpatient SCD population. Disclosures Davila: Spire Learning: Speakers Bureau; ATHN: Other: Grant Funding. Minniti: Bluebird bio: Consultancy, Research Funding; TauTona: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; CLS Bering: Consultancy; Novartis: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Desai: Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ironwood Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Rockpointe Continuing Medical Education Company: Consultancy. O'Brien: Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Enoxaparin used as a form of thromboprophylaxis in children.

BackgroundDegree of cerebrovascular stenosis in pediatric patients with sickle cell anemia (SCA) informs need for chronic transfusion therapy, which has significant risks. Flow artifact, intrinsic to magnetic resonance angiography (MRA), is dependent on technical parameters and can lead to overinterpretation of stenosis. The primary objective of this study was to document any change in stroke prevention therapy that could be attributed to the implementation of a standardized MRA scanning protocol for patients with SCA. MethodsA standardized MRA scanning protocol with an echo time of less than 5 ms was implemented at Montefiore Medical Center (MMC), NY in May 2016. Retrospective chart review identified 21 pediatric patients with SCA, with an MRA head both pre- and post-May 2016. Arterial stenosis on MRA, machine parameters, and treatment plans were compared pre- and post-implementation. ResultsTen of the 21 patients met inclusion criteria. Previously seen stenosis was re-classified to a lower degree in six of the 10 patients, leading to discontinuation of transfusions in five patients. No patients required escalation of therapy to chronic transfusions. ConclusionOptimizing flow artifact by decreasing echo time to less than 5 ms can improve accurate interpretation of cerebrovascular disease, and ensure appropriate treatment plans are in place for stroke prevention. This is especially important for implementing "TCD With Transfusions Changing to Hydroxyurea (TWiTCH)" clinical trial results in the real-world setting.

The Bronx was an early epicenter of the COVID-19 pandemic in the United States. We conducted temporal genomic surveillance of 104 SARS-CoV-2 genomes across the Bronx from March to October 2020. Although the local structure of SARS-CoV-2 lineages mirrored those of New York City and New York State, temporal sampling revealed a dynamic and changing landscape of SARS-CoV-2 genomic diversity. Mapping the trajectories of mutations, we found that although some became “endemic” to the Bronx, other, novel mutations rose in prevalence in the late summer/early fall. Geographically resolved genomes enabled us to distinguish between cases of reinfection and persistent infection in two pediatric patients. We propose that limited, targeted, temporal genomic surveillance has clinical and epidemiological utility in managing the ongoing COVID pandemic.

Individuals with sickle cell disease (SCD) and sickle cell trait (SCT) have many risk factors that could make them more susceptible to COVID-19 critical illness and death compared to the general population. With a growing body of literature in this field, a comprehensive review is needed. We reviewed 71 COVID-19-related studies conducted in 15 countries and published between January 1, 2020, and October 15, 2021, including a combined total of over 2000 patients with SCD and nearly 2000 patients with SCT. Adults with SCD typically have a mild to moderate COVID-19 disease course, but also a 2- to 7-fold increased risk of COVID-19-related hospitalization and a 1.2-fold increased risk of COVID-19-related death as compared to adults without SCD, but not compared to controls with similar comorbidities and end-organ damage. There is some evidence that persons with SCT have increased risk of COVID-19-related hospitalization and death although more studies with risk-stratification and properly matched controls are needed to confirm these findings. While the literature suggests that most children with SCD and COVID-19 have mild disease and low risk of death, some children with SCD, especially those with SCD-related comorbidities, are more likely to be hospitalized and require escalated care than children without SCD. However, children with SCD are less likely to experience COVID-19-related severe illness and death compared to adults with or without SCD. SCD-directed therapies such as transfusion and hydroxyurea may be associated with better COVID-19 outcomes, but prospective studies are needed for confirmation. While some studies have reported favorable short-term outcomes for COVID-19 patients with SCD and SCT, the long-term effects of SARS-CoV-2 infection are unknown and may affect individuals with SCD and SCT differently from the general population. Important focus areas for future research should include multi-center studies with larger sample sizes, assessment of hemoglobin genotype and SCD-modifying therapies on COVID-19 outcomes, inclusion of case-matched controls that account for the unique sample characteristics of SCD and SCT populations, and longitudinal assessment of post-COVID-19 symptoms.

As mentioned in the January 2022 Pediatrics in Review Commentary, we now present three patients who have a common chief complaint followed by 5 questions for CME credit. All three cases have discussions on presentation, the differential diagnosis, and management that collectively serve as a Review article. The common theme here is that all three patients have difficulty breathing. We hope you will enjoy this review format.

Gross S, Melhorn D. Exchange transfusion with citrated whole blood for disseminated intravascular coagulation. J Pediatr 1971;78:415-9. In 1971, Gross and Melhorn reported successful use of whole blood exchange transfusion for neonatal disseminated intravascular coagulation (DIC). Exchange transfusion was introduced in the 1940s for the treatment of hemolytic disease of the newborn. By 1970, exchange transfusion also had been adapted to treat hyperbilirubinemia. At that time, DIC in neonates was an evolving disease entity that was challenging to both diagnose and treat. Limited information was available about normal coagulation in the neonate and about neonatal coagulation during DIC. The mortality rate was high, and treatment relied heavily on treating the underlying illness, which in contemporary reports was largely idiopathic respiratory distress syndrome or sepsis. In that context, this series of 4 neonates and one 4-year-old child who had survived DIC after receiving exchange transfusions of citrated whole blood was remarkable. However, this was a small retrospective study that would need to be validated in a randomized controlled study. Eleven years later, a randomized controlled trial compared exchange transfusion vs plasma and platelets vs no coagulation-directed therapy. No differences were noted in survival between the 3 groups. The results were not supportive of any benefit of using exchange transfusion (or plasma and platelet transfusion) in neonatal DIC. However, there were only 11 patients in each arm, and no power calculation was reported. It remains unclear whether the study was powered to show any difference between the treatment arms.1Gross S.J. Filston H.C. Anderson J.C. Controlled study of treatment for disseminated intravascular coagulation in the neonate.J Pediatr. 1982; 100: 445-448Abstract Full Text PDF PubMed Scopus (53) Google Scholar Fifty years later, whole blood has fallen out of favor as a transfusion product, to be replaced by separated blood components (packed red blood cells, plasma, platelets, cryoprecipitate). Currently, whole blood exchange transfusion does not have a role in managing neonatal DIC. In addition, exchange transfusions for approved indications are now carried out with blood components rather than with whole blood. Separated and processed blood components (plasma, cryoprecipitate, and platelets) as replacement products are used for treating neonatal DIC. In this regard, although we possess much more knowledge about neonatal coagulation, management of neonatal DIC still relies on resolving the underlying illness and replacement of blood products as needed.

We report the clinical and laboratory coagulation characteristics of 27 pediatric and young adult patients (2 months to 21 years) treated for symptomatic COVID-19 at a children’s hospital in the Bronx, New York between March 1 and May 31, 2020. D-Dimer was > 0.5 ug/mL (upper limit of normal) in 25 (93%) patients at admission; 11 (41%) developed peak D-Dimer > 5 ug/mL during admission. Seven (26%) patients developed venous thromboembolism: three with deep vein thrombosis and four with pulmonary embolism. Requirement of increased ventilatory support was a risk factor for thrombosis (p=0.006). Three of eight (38%) patients on prophylactic anticoagulation developed thrombosis, however no patients developed VTE on low molecular weight heparin prophylaxis titrated to anti-Xa level. Manifestation of COVID-19 disease was severe or critical in 16 (59%) patients. Four (15%) patients died of COVID-19 complications: all had comorbidities. Elevated D-dimer and increased VTE rate were observed in this young cohort, particularly in those with severe respiratory complications suggesting thrombotic coagulopathy. More data is needed to guide thromboprophylaxis in this age group.

Background and Purpose: Magnetic Resonance Angiography (MRA) is performed on pediatric patients with sickle cell disease (SCD) to classify degree of cerebrovascular stenosis, informing stroke risk and treatment plan for stroke prevention. Flow artifact intrinsic to MRA with technician dependent factors can lead to over-interpretation of stenosis. The primary objective of this study was to document any change in stroke prevention therapy that could be attributed to the implementation of a standardized MRA scanning protocol. Methods: A standardized MRA scanning protocol with an echo time (TE) of <5msec based on the SWiTCH (Stroke With Transfusions Changing to Hydroxyurea) study protocol for patients with SCD was implemented at Montefiore Medical Center, NY (MMC) in May 2016. This project included a retrospective chart review of patients at MMC ≤ 21 years of age with SCD who had one MRA head pre-May 2016 AND one MRA post-May 2016. Of the 81 patients that met inclusion criteria, 29 patients were found to have cerebral vasculopathy on pre-May 2016 imaging and included in the analysis. Level of arterial stenosis on MRA, TE, and treatment plans were documented both pre- and post-May 2016. McNemar analysis was used to determine the significance of change in treatment plans before and after implementation of the standardized MRA scanning protocol. Results: 24/29 (83%) patients were on chronic transfusion therapy for cerebrovascular disease pre-May 2016 whereas 18/29 (62%) required chronic transfusion therapy post May 2016. Notably, 6 patients had a resolution of cerebral vasculopathy leading to discontinuation of chronic transfusion therapy whereas 0 patients required escalation of therapy to chronic transfusions. McNemar analysis showed this difference to be statistically significant (p = 0.042). Conclusion: Implementing a standardized MRA scanning protocol allowed for chronic transfusion therapy, which has potentially significant side effects, to be discontinued in 6 out of 24 patients. Minimizing flow artifact with TE <5msec can improve accurate interpretation of true cerebrovascular disease and ensure appropriate treatment plans are in place for stroke prevention.

HaemophiliaVolume 26, Issue 3 p. e134-e137 LETTER TO THE EDITOR Rapid desensitization and subsequent immune tolerance induction in a patient with hypersensitivity and inhibitor to factor VIII William Beauregard Mitchell, Corresponding Author William Beauregard Mitchell beau.mitchell13@gmail.com orcid.org/0000-0001-7018-0885 Division of Pediatric Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Correspondence William Beauregard Mitchell, Division of Pediatric Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Email: beau.mitchell13@gmail.comSearch for more papers by this author William Beauregard Mitchell, Corresponding Author William Beauregard Mitchell beau.mitchell13@gmail.com orcid.org/0000-0001-7018-0885 Division of Pediatric Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Correspondence William Beauregard Mitchell, Division of Pediatric Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Email: beau.mitchell13@gmail.comSearch for more papers by this author First published: 20 March 2020 https://doi.org/10.1111/hae.13958Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume26, Issue3May 2020Pages e134-e137 RelatedInformation

We report the clinical and laboratory coagulation characteristics of 27 pediatric and young adult patients (2 months to 21 years) treated for symptomatic COVID-19 at a children's hospital in the Bronx, New York between March 1 and May 31, 2020. D-Dimer was > 0.5 ug/mL (upper limit of normal) in 25 (93%) patients at admission; 11 (41%) developed peak D-Dimer > 5 ug/mL during admission. Seven (26%) patients developed venous thromboembolism: three with deep vein thrombosis and four with pulmonary embolism. Requirement of increased ventilatory support was a risk factor for thrombosis (p=0.006). Three of eight (38%) patients on prophylactic anticoagulation developed thrombosis, however no patients developed VTE on low molecular weight heparin prophylaxis titrated to anti-Xa level. Manifestation of COVID-19 disease was severe or critical in 16 (59%) patients. Four (15%) patients died of COVID-19 complications: all had comorbidities. Elevated D-dimer and increased VTE rate were observed in this young cohort, particularly in those with severe respiratory complications suggesting thrombotic coagulopathy. More data is needed to guide thromboprophylaxis in this age group.