Al‐Huniti, Ahmad

Background: The objective of this study was to describe thrombin generation in children undergoing cardiac surgery with cardiopulmonary bypass. Change in the endogenous thrombin potential (ETP) across three measurements before and after cardiopulmonary bypass (after protamine and at chest closure) was the primary outcome. Secondary analyses explored an association between thrombin generation and transfusion requirements and predictors of the thrombin generation decline. Methods: Blood samples of children (median age, 6.3 months; 68.5% weighed less than 10 kg) were collected intraoperatively three times: before administration of heparin (baseline), shortly after protamine, and at sternal closure. Platelet-poor plasma obtained after centrifugation of these samples was frozen at −80ºC. Thrombin generation and anti-Xa assays were performed in series on batches of thawed samples to evaluate thrombin generation parameters and functional activity of unfractionated heparin, which could have affected thrombin generation assay results. Results: Between August 2022 and May 2024, 162 plasma samples from 54 patients were collected and analyzed. Compared with baseline, mean ETP decreased by 1,911 nM (95% CI, 1,655 to 2,168) after administration of protamine and by 1,865 nM (95% CI, 1,609 to 2,122) at sternal closure (P < 0.001). Similar changes were observed in secondary thrombin generation parameters. Median unfractionated heparin activity was less than 0.1 U/ml at all three time points. Secondary analyses showed a strong negative correlation between ETP after protamine and volume of transfusion after bypass (ρ = −0.52, P < 0.001). Among five examined factors, only total heparin dose was independently associated with ETP decline, with a higher dose being predictive of greater ETP decline (P = 0.002). Conclusions: In children undergoing cardiac surgery, thrombin generation assay revealed significant and persistent decline in endogenous thrombin potential after cardiopulmonary bypass, despite hemostatic interventions. This reduced thrombin potential correlated with a higher volume of transfusions. Additionally, greater intraoperative heparin requirements could be linked to a more pronounced decline in thrombin generation.

ABSTRACTPatients with vascular anomalies (VAs) require expert multidisciplinary care. No prior studies have characterized the sociodemographic characteristics across multiple VA centers. We collected data on 5783 patients receiving care at 20 VA centers between July 1, 2020 through December 31, 2022. Male patients were underrepresented compared to the state‐level census data at 17/20 centers. Black and Asian patients were underrepresented at 14/20 and 12/20 centers, respectively. The median distance to the hospital was 48 miles, and median age was 12.0 years. These data suggest that race, sex, age, and distance from the hospital could impede the ability to access expert VA care.

Introduction Assessing bleeding symptoms is essential for diagnosing bleeding disorders. Bleeding assessment tools (BATs) were developed to standardize the collection of bleeding symptoms and their severity, thereby enhancing the diagnostic accuracy. However, their diagnostic precision across various inherited bleeding disorders remains unclear. Therefore, we conducted a systematic literature and meta-analysis to evaluate the diagnostic accuracy of BATs in pediatric and adult populations. This systematic review and meta-analysis aimed to evaluate the diagnostic accuracy of BATs in pediatric and adult populations. Objective: To evaluate the diagnostic effectiveness of BATs in identifying laboratory-confirmed inherited bleeding disorders. Methods Literature Search Strategy: A comprehensive systematic literature search was conducted across Scopus, Embase, Web of Science, MEDLINE, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, and the World Health Organization databases from inception until January 27, 2024 Study Selection: Two independent reviewers screened titles and abstracts using Covidence (Covidence systematic review software, Veritas Health Innovation). Data extraction was performed independently by two authors reviewing and collecting data in duplicate from all selected articles. Eligibility Criteria: Included studies reported on the diagnostic accuracy of any BAT in diagnosing inherited bleeding disorders. Exclusion criteria included abstracts, review articles, case reports/series, studies focusing solely on distinguishing specific bleeding disorders, and those lacking sufficient data to assess test accuracy. Quality Assessment: Risk of bias was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Two authors assessed each article independently and each study was categorized as having a low, moderate, or high risk of bias. Results Of 7,009 studies identified, 31 met the inclusion criteria, comprising 6,962 patients (2,152 with bleeding disorders, 4,810 controls). Most studies (74%) were prospective. Studies assessed various bleeding disorders: 39% all types, 32% von Willebrand Disease (VWD), 10% Inherited Platelet Function Disorder (IPFD), 10% both VWD and IPFD, and 10% other rare disorders. The ISTH-BAT was the most frequently used tool (47%), followed by MCMDM-1 VWD (21%) and PBQ (18%). The pooled prevalence of confirmed bleeding disorder in all prospective studies was 32% (range, 3%-71%). The pooled sensitivity for BAT in all included studies (31 studies) was 82% (95% CI, 76.5%-86.7%) and the specificity was 66% (95% CI, 54%-76%). Subgroup analysis revealed that the ISTH-BAT (studies: BD 6, VWD 5, IPFD 3, GT/BSS 2), had a sensitivity of 77% (95% CI, 69%-84%) and a specificity of 70% (95% CI, 58%-80%), the MCMDM-1 VWD (studies: VWD 4, BD 2, GT/BSS 1) had sensitivity of 78% (95% CI, 61%-89%) and a specificity of 79% (95% CI, 54%-92%) , and the Pediatric Bleeding Questionnaire (studies: BD 3, VWD 2, VWD/IPFD 1) had a sensitivity of 93% (95% CI, 85%-97%) and a specificity of 73% (95% CI, 41%-92%) . The sensitivity and specificity of BATs for studies investigating all types of bleeding disorders (12 studies) soley VWD (10 studies), and soley IPFD (3 studies) were 80% (95% CI, 67%-88%) and 50% (95% CI, 34%-67%) , 79% (95% CI, 71%-86%) and 83% (95% CI, 59%-95%), and 85% (95% CI, 79%-89%) and 74% (95% CI, 56%-86%), respectively. Significant heterogeneity was observed across studies in terms of populations, BATs used, and diagnostic methods. This heterogeneity limits the generalizability of the results and suggests that BAT performance may vary depending on the specific clinical context and patient population. Additionally, 26% of studies were classified as having a high risk of bias, potentially affecting the reliability of some findings. Conclusion Despite heterogeneity, this meta-analysis supports the use of BATs as valuable screening tools for inherited bleeding disorders, demonstrating generally high sensitivity across various patient populations. However, the variability in specificity across different disorders and tools underscores the need for careful selection and interpretation of BATs in clinical practice. Further standardization of BATs and diagnostic criteria could improve their utility in diverse clinical settings.

Introduction Establishment of reference intervals (RI) for quantitative assays requires a minimum of 120 qualified normal donor (ND) samples for each partition of an analyte. Based on CLSI EP28 A3C guideline [CLSI. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline-Third Edition. CLSI document EP28-A3c. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.], verification of previously established and/or published RI can be performed with a minimum of 20 NDs, especially given complexities of finding qualified NDs. Reagent manufacturers typically provide adult RI, thus facilitating RI verification as a viable option. NDs for the Pediatric (Peds) (&lt;18 years of age) population are difficult to obtain, published RIs are performed with sample cohorts less than the suggested number or only performed with specific instrument/reagent combinations. Herein, we report our experiences with Peds RI. Methods After IRB approval, healthy pediatric outpatients ages 0-18yrs were recruited and consented. Plasma obtained from umbilical cord, finger/heel/ear stick, or venipuncture blood samples (no more than 50 mL or 3 mL per kg) and collected in 3.2% sodium citrate. Assays included Protein (P) C antigen (PCAG) and chromogenic activity (PCFX); P S total (PST), free (PSF) antigen, and functional (SFX); antithrombin antigen (ATAG) and chromogenic activity (ATFX); plasminogen (PLGN) and alpha-2-plasmin inhibitor (A2PI). Assay kits were PCFX - HemosIL® (Werfen, Beford, MA) Protein C, PST - LIATEST® (Diagnostica Stago S.A.S., Asnières sur Seine, France) Protein S, PSF - HemosIL® Free Protein S, SFX - HemosIL® Protein S Activity, ATAG - LIATEST® AT III , ATFX - HemosIL® Liquid Antithrombin, PLGN - HemosIL® Plasminogen, and A2PI - HemosIL® Plasmin Inhibitor performed on the ACL TOP 700 (Werfen) instrument. PCAG - REAADS® Protein C Antigen Test Kit (Corgenix, Inc. Broomfield, CO) was performed on the Janus G3 liquid handler (Revvity, Waltham, MA) and Synergy Neo2 microplate reader (Agilent, Santa Clara, CA). Assay mean and range were calculated. Results Insufficient numbers of patients &lt;1yr were collected. Type of assay, age range in yr and number of samples (n), assay mean in % and range results respectively were as follows: PCAG 1-5 (n=15) 87(46-146); 5-10 (n=82) 81 (45-158); 10-15 (n=169) 84 (44-157); 15-18 (n=107) 91 (57-149). PCFX 1-5 (n=20) 97 (56-140); 5-10 (n=84) 89 (62-135); 10-15 (n=188) 91 (55-140); 15-18 (n=124) 96 (54-138). PST (males): 1-5 (n=10) 120 (96-145); 5-10 (n=46) 108 (75-150); 10-15 (n=91) 111 (80-168); 15-18 (n=63) 113 (72-184). PST (females): 1-5 (n=9) 104 (67-146); 5-10 (n=37) 111 (81-159); Ages 10-15 (n=94) 107 (78-153); 15-18 (n=63) 101 (65-148). PSF (males): 1-5 (n=10) 94 (74-109); 5-10 (n=47) 101 (66-141); 10-15 (n=93) 101 (69-151); 15-18 (n=62) 111 (74-187). PSF (females): 1-5 (n=9) 78 (9-124); 5-10 (n=37) 107 (79-137); 10-15 (n=95) 99 (63-138); 15-18 (n=63) 97 (60-132). SFX (males): 1-5 (n=9) 100 (85-128); 5-10 (n=48) 104 (66-144); 10-15 (n=93) 103 (66-168); 15-18 (n=59) 109 (72-157). SFX (females): 1-5 (n=8) 94 (18-121); 5-10 (n=37) 107 (81-143); 10-15 (n=90) 101 (65-147); 15-18 (n=60) 97 (53-135). ATAG 1-5 (n=19) 104 (80-121); 5-10 (n=83) 104 (78-121); 10-15 (n=188) 104 (66-126); 15-18 (n=126) 101 (67-126). ATFX 1-5 (n=20) 112 (94-135); 5-10 (n=84) 107 (87-123); 10-15 (n=188) 105 (84-138); 15-18 (n=126) 101 (84-129). PLGN 1-5 (n=17) 96 (76-124); 5-10 (n=85) 88 (65-125); 10-15 (n=183) 90 (49-151); 15-18 (n=119) 94 (64-151). A2PI: 1-5 (n=17) 134 (118-151); 5-10 (n=85) 126 (107-139); 10-15 (n=183) 121 (104-140); 15-18 (n=118) 116 (91-143). Conclusions Based on CLSI EP28 A3C criteria for verification, no more than 10% of results should fall outside of established/published RI, for example adult RI. Thus, compared to the SCL adult RI, PLGN assay meets criteria in all age ranges and no additional ND are needed. For the remaining assays, additional ND for ages 1-5 are needed. For ages 5-18 criteria for verification are satisfied for all analytes except PCAG. PCAG has 27, 61, and 19 patients falling below lower RI for ages 5-10, 10-15, and 15-18, respectively.

ABSTRACTAthletes are at high risk of iron deficiency even without anemia. In this systematic review and meta‐analysis that included 17,519 athletes in 122 references from 23 countries, participating in 62 unique sports over a 41‐year timeframe, approximately 53.9% of student‐athletes were found to be hypoferritinemic (ferritin concentration below 50 mcg/L) with 23.0% percent showing absolute iron deficiency based on current definitions (ferritin concentration below 20 mcg/L). These findings strongly suggest that changes in clinical practice guidelines are warranted to enable routine screening for iron deficiency among adolescent and collegiate athletes.

ABSTRACTObjectiveIron and other biologically important metals are essential to mitochondrial function but are not routinely evaluated. Their equilibrium is critical to the optimal performance of cells with high metabolic activity such as neurons, cardiomyocytes, and skeletal myocytes. Teenagers are at a high risk of iron deficiency even without anemia. Metal ion imbalances can cause cognitive impairments, muscle weakness, and sudden cardiac death. We aim to assess the current prevalence of iron deficiency among collegiate athletes in the Upper Midwest.MethodsOur study is a multicenter, retrospective chart review of outpatient clinics in a regional healthcare system between January 2012 and December 2023, and a national public database between 2017 and March 2020. We reviewed the ferritin concentrations of regional collegiate athletes having preparticipation sport evaluations and nationally in the NHANES database.ResultsWe identified 643 unique individuals aged 16–21 years with 253 having ferritin screening. Iron deficiency (ferritin <20 mcg/L) was present in 24.5% and hypoferritinemia (ferritin <50 mcg/L) was present in 66.7% of collegiate athletes. From the NHANES database, 12.7% of active sampled participants aged 16–21 years were iron deficient.ConclusionOur study findings suggest the need for universal screening for iron deficiency among collegiate athletes given the high prevalence of iron deficiency in both the retrospective chart review and NHANES database analysis. Given the critical role of metal ion homeostasis to optimal mitochondrial function, these findings may warrant the inclusion of ferritin testing in cardiac, neurological, and skeletal muscle evaluations.

Thrombopoietin receptor agonists (TPO-RAs) induce trilineage hematopoiesis under conditions with acquired hematopoietic failure. We evaluated safety, tolerability, and preliminary efficacy of a TPO-RA, romiplostim (Nplate), with or without standard-of-care immunosuppressive therapy (±IST) for children (ages <21 y) with newly diagnosed and relapsed/refractory severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS). Data were collected from an observational study and a single arm interventional pilot study. The safety outcome was treatment-related adverse events (AEs). Efficacy was evaluated by complete hematopoietic response (CHR) at week 24. Romiplostim was commenced at 5 µg/kg/week, with dose escalation of 2.5 µg/kg/week (maximum, 20 µg/kg/dose) based on platelet response. Romiplostim was continued until CHR was observed. Ten subjects (SAA, 9 [IST, 4; without IST, 5]; MDS, 1) completed the study (median age: 9.2 y). Median romiplostim dose was 10 µg/kg/week (range: 5 to 17.5 µg/kg/week). The cumulative incidence of CHR was 70.4% (95% CI, 20.2%-92.6%). Among 21 AEs (Grade 1 to 3), 3 were attributed to romiplostim. At a median posttherapy follow-up of 10.9 months (range: 0.7 to 77.5), no clonal evolution, bone marrow fibrosis or mortality was reported. This proof-of-concept study provides data about short-term safety, tolerability, and preliminary efficacy of romiplostim (±IST) for treatment of pediatric SAA/MDS.

AbstractBackgroundΕ‐Aminocaproic acid oral solution (EACA OS) is the only commercially available antifibrinolytic for patients who cannot swallow tablets. Insurance denials and high costs remain barriers to its use.ObjectivesTo determine the safety and efficacy of crushed tranexamic acid tablets in water (cTXAw) for children with bleeding disorders.MethodsWe retrospectively reviewed records of children (<10 years) with bleeding disorders who received cTXAw or EACA OS from 1 December 2018, through 31 July 2022, at Mayo Clinic (Rochester, Minnesota). Bleeding outcomes were defined according to ISTH criteria.ResultsThirty‐two patients were included (median age, 3 years; male, n = 23). Diagnoses were VWD (n = 17), haemophilia (n = 5), FVII deficiency (n = 3), inherited platelet disorder (n = 4), ITP (n = 2), and combined FV and FVII deficiencies (n = 1). Thirty‐two courses of cTXAw (monotherapy 24/32; mean duration 6 days) and fifteen courses of EACA (monotherapy 12/15; mean duration 5 days) were administered. No surgical procedures (n = 28) were complicated by bleeding. Of the 19 bleeding events, 16 had effective haemostasis, two had no reported outcome, and one had no response. cTXAw and EACA were equally effective in preventing and treating bleeding (p value > .1). No patients had adverse effects. Eight of 19 patients (42%) who were initially prescribed EACA OS did not receive it because of cost or insurance denial.The estimated average wholesale price of one treatment was $94 for cTXAw and $905 for EACA OS.ConclusionsCTXAw appears to be an effective, safe, and low‐cost alternative option to EACA OS for young children with bleeding disorders.