INTRODUCTION:The US adopted an individual donor assessment (IDA) policy in 2023 to evaluate blood donor risk, potentially resulting in more eligible donors and first-time donors (FTDs). FTDs are associated with higher transfusion-transmissible infectious disease (TTID) risk. Thus, we compared FTD demographics, characteristics, and return behavior during the first 2 years of the IDA compared to the previous 2 years during the 3-month deferral (3MD) policy. METHODS:FTD donation data from the transfusion-transmissible infections monitoring system (TTIMS) during the initial 2 years of IDA were compared to the preceding 2 years (3MD). Descriptive statistics were used to assess changes in FTD demographics, donation characteristics, state of residence, and return behavior during the IDA policy compared to the 3MD policy. RESULTS:There were slightly over 4 million donations from FTDs during the entire study period, with a 6% increase overall during the IDA period, led mostly by male FTDs (14% increase). Increases were observed in most other demographic/characteristic groups except for a few (female, aged 16-24, or other procedure types). There was a higher absolute number of returning donors and subsequent donations from the FTDs during the IDA period compared to the previous period. The Northeastern US states were found to have the highest increase in FTDs. CONCLUSIONS:There were variable increases in FTDs among most demographic and characteristic groups post-implementation of the IDA policy, notably among men. Although attributability to the new policy is unclear, blood availability may increase with such policies. Continued monitoring will ensure blood safety during donor policy changes.

BACKGROUND:Emerging and re-emerging arboviral infections are a risk to blood safety. We conducted an international survey on how blood establishments respond to current and future arbovirus threats. STUDY DESIGN AND METHODS:A questionnaire on arbovirus donor deferral strategies, pathogen reduction, and donation screening was distributed to members of the International Society of Blood Transfusion working party on transfusion-transmitted infectious diseases. Data from 2024 were gathered and analyzed. RESULTS:A total of 23 survey responses were received from 21 countries. This covered a population of 1.45 billion people and 29.9 million blood donations collected in 2024. All respondents applied travel-based donor deferrals, whereas pathogen reduction, implemented by half of the respondents, was mostly applied for a selection of plasma and platelet donations. West Nile virus (WNV) was the only arbovirus blood donations were screened for by nine respondents from eight countries, with 256 donations confirmed as WNV RNA-positive in 2024. No transfusion-transmitted WNV infections were reported. DISCUSSION:Blood safety measures remain limited and unevenly distributed globally, and in their present form, are unlikely to provide protection against the growing range of emerging arboviruses. Donor deferral may not always be a sustainable blood safety strategy alone for all blood operators, due to large-scale outbreaks associated with these viruses. While pathogen reduction methodologies are being developed to be applied to all blood components, risk assessments for (re)-emerging arboviruses, such as dengue, chikungunya, and Zika viruses, should be performed to determine if additional mitigation, such as blood donation screening, is warranted.

Alpha-gal syndrome (AGS) is an emerging, noninfectious tickborne disease characterized by an allergic reaction to galactose-α-1,3-galactose (alpha-gal), an oligosaccharide found in red (mammalian) meat and other mammalian products such as dairy and gelatin. As of 2022, AGS was estimated to affect up to 450,000 persons in the United States (1). Anaphylactic AGS reactions can be fatal, and AGS allergic reactions encompass a range of symptoms including urticaria, angioedema, wheezing, and gastrointestinal distress. AGS is primarily managed through an avoidance diet. The U.S. geographic distribution of AGS is closely associated with the range of the lone star tick (Amblyomma americanum); bites from this tick introduce alpha-gal through its saliva, which can trigger the allergy. Diagnosis of AGS requires both the presence of clinically compatible symptoms and the detection of serologic immunoglobulin E (IgE) antibodies against alpha-gal. Persons can have alpha-gal-specific IgE antibodies without clinical symptoms. The proportion of persons in the United States who are seropositive for alpha-gal IgE is unknown. To better understand the distribution and seroprevalence of alpha-gal IgE among U.S. adults, 3,000 serum samples collected during November 2024-April 2025 from blood donors living in 10 states were tested for the presence of alpha-gal IgE antibodies. States previously reported to have high numbers of suspected AGS cases were found to have correspondingly high seroprevalences. Among the 10 states, the highest estimated seroprevalences among persons aged ≥16 years were detected in Arkansas (31.2%) and Missouri (26.0%). These findings can guide the development of surveillance systems for AGS and help identify regions at increased risk.

Abstract To understand the impact of blood donor and product characteristics on platelet transfusion outcomes, we linked these variables with recipients of single-unit apheresis-derived platelet products between 1 June 2020 and 31 March 2022. We used multivariable logistic regression to examine associations between donor and product characteristics on posttransfusion platelet counts and 24-hour red blood cell (RBC) transfusion events in 2808 transfusion recipients who received ≥1 platelet transfusions (N = 8207 units). Posttransfusion platelet increments >20 × 109/L and RBC transfusion within 24 hours occurred after 24.9% and 37.7% of platelet transfusion events, respectively. After multivariable adjustment, donor variables, including increasing body mass index (BMI), platelet unit concentration, and elevated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid antibody levels, were associated with increased odds of recipient platelet increments of >20 × 109/L; whereas pathogen reduction, storage in platelet additive solution (PAS), platelet splits, and platelet storage between 5 and 7 days were associated with reduced odds. In parallel, increasing donor BMI and elevated SARS-CoV-2 nucleocapsid antibody levels were associated with lower odds of 24-hour RBC transfusion events. In contrast, pathogen reduction and irradiation were associated with increased odds of RBC transfusion, whereas longer storage, storage in PAS, and platelet unit concentration and splits were not associated with changes in RBC transfusion events. In conclusion, blood donor and product characteristics are predictors of changes in platelet counts and RBC requirements after platelet transfusion. Future studies examining the impact of blood donor and product characteristics on platelet function could be used to optimize platelet transfusion practice.

Transfusion medicine generates enormous volumes of data across the vein-to-vein continuum, spanning donor characteristics, laboratory testing, component manufacturing, logistics and recipient outcomes. The emergence of big data infrastructures, coupled with artificial intelligence (AI), offers a transformative opportunity to harness this information for safer, more efficient and better personalized transfusion practices. This narrative review outlines current and potential applications of AI and machine learning (ML) at each phase of the big data pipeline in transfusion medicine, including data collection, wrangling and harmonization, validation, feature engineering, analysis, publication and knowledge mobilization. We discuss how AI-enabled methods-such as natural language processing to extract variables, anomaly detection for product quality, supervised models to predict risks, federated analysis for collaboration, and forecasting algorithms to optimize inventory and logistics-may address longstanding challenges related to data fragmentation, unstructured documentation and labour-intensive manual validation. We emphasize critical risks and limitations of applying AI to big data analytics and discuss mitigation through robust governance, performance monitoring, fairness audits, cybersecurity measures and transparent human oversight. We end by offering key recommendations and future directions, highlighting that strategic, equitable and ethically sound implementation will be essential to realizing benefits and ensuring trust in an increasingly data-driven transfusion ecosystem.

Sickle cell disease (SCD) is a hereditary disorder characterized by HBB variants, leading to chronic hemolytic anemia and vaso-occlusion. Hepatobiliary complications, including cholelithiasis, are common but underreported. This study investigated the rates and risk factors for cholelithiasis, cholecystitis, and cholecystectomy in a large Brazilian SCD cohort. Data from 2,778 individuals across six referral centers in the REDS-III Brazilian SCD cohort were analyzed. Clinical, laboratory, and genetic data were obtained retrospectively at enrollment and prospectively during follow-up. Gallbladder-related outcomes were assessed through medical records and imaging. Whole-genome sequencing was performed via the TOPMed program. Genome-wide association analyses used logistic mixed models adjusted for age, sex, genotype, and the first 10 principal components. Cholelithiasis, cholecystitis, and cholecystectomy occurred in 35.9%, 25.1%, and 10.6% of participants, respectively. Indirect bilirubin was consistently associated with all outcomes, while associations with other laboratory variables varied by genotype. Genetic analyses confirmed associations between UGT1A1 variants and bilirubin levels and identified genome-wide associations with cholecystectomy. Novel loci, including FER1L6, LRFN5, and SDK2, were also implicated. These findings indicate a high burden of gallbladder-related disease in Brazilian individuals with SCD and highlight both established and novel genetic pathways that may inform risk stratification and preventive strategies.

Importance:Few studies have evaluated whether modifiable aspects of red blood cell (RBC) transfusions are associated with recipient outcomes in very-low-birth-weight (VLBW) infants. Objective:To determine whether blood donor, RBC modifications and storage, or transfusion thresholds and characteristics are associated with serious adverse outcomes in VLBW infants undergoing transfusion. Design, Setting, and Participants:Transfusion in Preterm Infants was a prospective birth cohort study that recruited VLBW infants (<1500 g at birth) between April 1, 2019, and December 31, 2023, at 5 university-affiliated and 3 community birth hospitals in the US. Electronic medical record data linking blood donor and component data to infants were obtained and linked with Vermont Oxford Network outcome data, with additional outcome review by site. The analysis was completed in January 2026. Exposures:RBC transfusion and transfusion characteristics, evaluated up to the first outcome event. Main Outcomes and Measures:The primary outcome was a composite outcome of severe intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), late-onset sepsis, severe bronchopulmonary dysplasia (BPD), retinopathy of prematurity, or death (and secondary individual outcomes), with follow-up through 90 days or death. Blood donor characteristics (sex, age, and hemoglobin), anticoagulant preservative solution and/or unit characteristics, transfused volumes, transfusion number, and infants' pretransfusion hemoglobin values were evaluated using multivariable generalized estimating equation regression models to account for correlation within hospital, adjusted for illness severity. Results:The study enrolled 2605 VLBW infants, and 1283 (586 [45.7%] female; 713 [55.6%] <27 weeks' gestational age) received RBC transfusion. Median pretransfusion hemoglobin level was associated with higher odds of the composite outcome (odds ratio [OR] per 1 g/dL increase, 1.15; 95% CI, 1.07-1.25; P < .001). In contrast, use of additive solution (AS)-1 or AS-5 vs the reference of citrate phosphate dextrose adenine or citrate phosphate dextrose as the anticoagulant preservative solution was associated with lower odds of the composite outcome (OR, 0.72; 95% CI, 0.53-0.97; P = .03). There were no significant associations with other examined modifiable factors and the composite outcome. Among secondary outcomes, anticoagulant preservative solution was associated with lower risk of BPD (AS-1 and AS-5, OR, 0.48; 95% CI, 0.33-0.69; AS-3, OR, 0.65; 95% CI, 0.56-0.77) and higher risk of NEC (AS-3, hazard ratio [HR], 5.33; 95% CI, 1.22-23.29). Transfusion dose was associated with higher risk of mortality (HR per 5 mL/kg, 1.25; 95% CI, 1.17-1.35), and donor age was associated with a lower risk of mortality (HR for age ≥60 years, 0.63; 95% CI, 0.44-0.92). Shorter postirradiation storage duration (<1 day) was associated with lower risk of NEC (HR, 0.44; 95% CI, 0.22-0.89). Female donor sex was associated with lower risk of IVH (HR, 0.60; 95% CI, 0.36-0.99). Conclusions and Relevance:In this cohort study of VLBW infants, pretransfusion hemoglobin and anticoagulant preservative solution were associated with a composite of morbidities and mortality, unlike other modifiable blood banking practices. For individual outcomes, select donor and blood banking factors were identified that may be modifiable targets for further evaluation.

BACKGROUND:Oropouche virus (OROV) re-emerged in Brazil in 2023, causing over 26 000 confirmed cases through December 2025. A reassortant lineage was linked to neurologic complications and congenital infections due to vertical transmission. Although transfusion transmission has not been reported, asymptomatic viremia in blood donors could represent an unrecognized route of infection. METHODS:We conducted nucleic acid testing (NAT), genomic, and serological surveillance among blood donors in Manaus, Brazil, during the 2023-2024 OROV outbreak. Minipools (MPs) of 18 donations from November 2023 to May 2024 were tested using a validated RT-qPCR assay. A subset of NAT-reactive pools underwent whole genome sequencing and phylogenetic analysis. Serosurveys in November 2023 and June 2024 assessed changes in population immunity. The RNA-detectable window was estimated by integrating NAT yield with seroincidence. RESULTS:Among 661 MPs, representing 11 898 donations, 43 (6.5%) were OROV RNA-reactive, peaking in January 2024. About half contained viral RNA concentrations above the limit of quantification. Donor-derived viral genomes clustered with the reassortant lineage circulating in Brazil. Donor seropositivity increased from 13.0% to 29.7%, corresponding to approximately 390 000 estimated infections in Manaus, substantially higher than reported case numbers. The estimated MP RNA-detectable window was 5.4 days (95% CI: 3.8-7.0). CONCLUSIONS:OROV RNA detection in donor samples, together with high-titer viremia, phylogenetic identity to the outbreak strain, and postoutbreak seroconversion, raises questions about blood safety. Continued donor and recipient surveillance will be vital to determine transfusion-transmission risk and inform transfusion safety policies.

BACKGROUND AND OBJECTIVES:In 2020, Brazil implemented individual donor assessment (IDA), expanding eligibility to include individuals previously deferred, such as men who have sex with men (MSM). We assessed human immunodeficiency virus (HIV) incidence and correlates of incident infection among blood donors following this policy change. MATERIALS AND METHODS:We analysed donation data from five Brazilian blood centres from 2020 to 2024. Routine HIV screening included fourth-generation antigen/antibody (Ag/Ab) assays and nucleic acid testing (NAT). Additional testing (limiting antigen [LAg] avidity, viral load) was used to identify recent infections. Incidence was estimated separately for first-time donors (FTD) and repeat donors (RD), and multivariable Poisson regression was used to assess correlates of incident infection. RESULTS:Among 1.66 million screened donations, 2598 (0.16%) were HIV-reactive on routine screening. Residual serum was available for 74% (n = 1927), and following additional testing, 98 were classified as recent HIV infections. HIV incidence was higher among FTD (20.9/100,000 person-years) than RD (18.3/100,000). Higher incidence was observed among male and younger donors as well as those identifying as Black or multiracial (Pardo). Incidence varied between blood centres, with overall incidence stable across the study period. No increase in the residual risk (RR) of HIV transfusion-transmission was observed. CONCLUSION:Our findings indicate that the adoption of IDA in Brazil did not change blood safety. HIV incidence remained stable, with varying HIV infection patterns reflecting known disparities in the epidemiology of HIV in Brazil.

INTRODUCTION:SARS-CoV-2 infection is associated with hypercoagulability in patients with Coronavirus disease (COVID-19). We used a vein-to-vein database to examine the impact of transfusion of plasma units from blood donors with recent SARS-CoV-2 infection. STUDY DESIGN AND METHODS:We linked donor SARS-CoV-2 serology data with plasma transfusions occurring between 6/1/2020 and 3/31/2022. Using multivariable regression, we examined changes in the international normalized ratio (INR) and subsequent transfusion requirements following plasma transfusion relative to the timing of donor SARS-CoV-2 nucleocapsid antibody (anti-N Ab) positivity. RESULTS:We identified 2350 adults who received 5397 plasma units with donor SARS-CoV-2 serology data as part of 3721 plasma transfusion events. 8.1% (436/5397) of plasma units were from anti-N Ab positive donors, and median time from index seropositivity to donation was 89 days (interquartile range [IQR] 0-210). In recipients of plasma units from recently SARS-CoV-2 infected donors (<120 days), the adjusted odds of a 0.25 per unit lowering of the INR were increased (aOR 1.6 [1.1-2.5]; p = .03) and the odds of additional plasma transfusions within 24 h were decreased (aOR 0.6 [0.4-0.9]; p = .04). CONCLUSION:Recipients of plasma units from blood donors with recent SARS-CoV-2 infection were more likely to have post-transfusion reductions in the INR and less likely to require additional plasma transfusions.

BACKGROUND AND OBJECTIVES:Previous studies have shown clinicians' knowledge and practice are suboptimal across all major steps in the clinical transfusion process. Like other settings, limited information is available in Ethiopia. Therefore, we conducted a study to assess clinicians' transfusion medicine knowledge and clinical practice. MATERIALS AND METHODS:A cross-sectional study was conducted at two academic hospitals to examine the correlation between transfusion medicine knowledge and clinical use of blood. Clinicians (n = 232), selected using a random sampling technique, completed a self-administered, structured knowledge assessment. A sampled (n = 152) subset of these clinicians was assessed for appropriate clinical use of blood using a predefined checklist. Student's t-test, one-way analysis of variance (ANOVA) and chi-square test were used. Statistical significance was assessed by 95% confidence intervals (CIs) and p values <0.05. RESULTS:Clinicians' mean knowledge score increased significantly by level of specialization. Out of a maximum score of 80, the mean ± standard deviation (SD) score for general practitioners was 38.1 (SD: ±6.2) while the score for specialists was 45.1 (SD: ±5.8), p = 0.001. Clinicians trained on transfusion guidelines had higher scores (46.6, SD: ±7.2) compared to untrained clinicians (40.3, SD: ±7.0), p = 0.001. Clinical use of blood was deemed appropriate in 41.4% [95% CI: 33.6%-49.2%] of cases. Appropriate clinical use of blood was associated with a higher mean knowledge (43.7, SD: ±7.1) than observed in inappropriate clinical use (40.7, SD: ±8.3) in 58.6%, p = 0.02. CONCLUSION:Better knowledge of transfusion medicine is associated with better transfusion medicine practice. This underscores the importance of implementing transfusion medicine training in Ethiopia.

BACKGROUND AND OBJECTIVES:Recruiting blood donors among a population with a high human immunodeficiency virus (HIV) burden requires detailed information on HIV risks. We studied demographic and behavioural risk factors for incident HIV infection among blood donors in South Africa. MATERIALS AND METHODS:We conducted a case-control study. Incident HIV was defined as HIV antibody negative and RNA positive, or concordant serology and RNA positive with a limiting antigen avidity assay optical density of <1.5. Cases were matched to infection-negative controls (ratio 1:3) on race, age and geography. Risk factors in the 6 months before donation were ascertained by audio computer-assisted self-interview. Data were fitted using separate multivariable logistic regression models for males and females. RESULTS:From April 2014 to March 2017, we enrolled 323 people with incident HIV and 877 controls. Among women, incident HIV was associated with sex with a person living with HIV (PLWH) or unknown HIV status, multiple male sex partners, never or occasional condom use, anal preparation before sex, first-time donor status and referral to donation by a healthcare worker. Among men, incident HIV was associated with being aged 31-40 years, sex with a PLWH or unknown HIV status, multiple sex partners, more than four lifetime male sex partners, gay/bisexual identity, marriage or stable partnership, lower education, penetrative injury, occasional condom use and first-time or lapsed donor status. Some novel or indirect risks for incident HIV were also observed. CONCLUSION:We confirmed the known sexual behaviours asked on the donor screening questionnaire. The findings highlight ongoing challenges in donor disclosure during selection and the importance of donor education.

BACKGROUND:The implementation of revised blood donor deferral policies may change factors associated with HIV infection in donors. Here, we assessed factors associated with HIV in the U.S. blood donor population between 2015 and 2023. STUDY DESIGN AND METHODS:Using exposure data obtained from interviews of HIV cases and matched controls, we investigated sociodemographic and behavioral factors associated with any HIV infection or recently acquired HIV infection, overall and by strata of deferral policy period (lifetime, 12-month and 3-month), for men who have sex with men and other potential risk groups using conditional logistic regression. RESULTS:Multivariable analyses showed that several sociodemographic and behavioral factors were significantly associated with HIV infection, but with no clear evidence of changes in these factors across deferral policy periods. Similarly, several factors were significantly associated with recent HIV infection, with odds ratios similar to those observed for any HIV infection. An association between non-heterosexual orientation and HIV infection remained stable across deferral periods included in the study after adjustment for potential confounders. We found no evidence that non-heterosexual orientation is more strongly associated with recent than with any HIV infection among blood donors. DISCUSSION:Our findings suggest no major impact of revised deferral policies on HIV risk factors among blood donors, nor among risk factors for any HIV and recent HIV infection in this population. These findings should be reassessed after sufficient accrual of data from the individual donor assessment deferral policy period.

OBJECTIVE:To evaluate if hematologic thresholds for red blood cell (RBC) and platelet transfusions changed over time following publication of new evidence from randomized trials in a multicenter cohort of extremely low birth weight (ELBW) infants. STUDY DESIGN:We analyzed data from the National Heart Lung and Blood Institute Recipient Epidemiology and Donor Evaluation Study-IV-Pediatrics study from April 2019 through December 2023. We compared pretransfusion hemoglobin and platelet counts closest to each transfusion within 24 hours by year using linear mixed models and used model interaction terms to determine if trends over time differed by postnatal weeks. RESULTS:We evaluated 981 ELBW infants. For trends in RBC transfusion thresholds, 785 infants (80%) received 5182 RBC transfusions, of which 4835 (93%) had a pretransfusion hemoglobin value. Pretransfusion hemoglobin declined over time (P < .0001), with trends differing by postnatal week (interaction P = .005). The greatest year-over-year decline in pretransfusion hemoglobin was in the third postnatal week or later. For platelet transfusions, 221 infants (23%) received 934 platelet transfusions, of which 900 (96%) had a corresponding pretransfusion platelet count. There was no change in pretransfusion platelet count over time (P = .24). These trends did not differ by postnatal week (interaction P = .14), although pretransfusion platelet counts were lower after the first postnatal week (P < .001). CONCLUSIONS:In this cohort of US centers, we observed declines in pretransfusion hemoglobin but not pretransfusion platelet counts from 2019 to 2023. These findings suggest evidence from recent RBC and platelet transfusion threshold trials may have been differentially translated into clinical practice for ELBW infants.

Increasing syphilis infection rates are a concerning issue worldwide. Blood donation screening is an opportunity to monitor the burden of asymptomatic infections, providing information on contemporary factors associated with infection and public health insights into transmission. Blood donations collected at five Brazilian blood centers between January 2020 and February 2022 were screened with treponemal or non-treponemal assays according to local protocols, followed by alternate Enzyme-Linked Immunosorbent Assay (ELISA); samples with reactive or indeterminate results in the alternate ELISA were further tested with the rapid plasma reagin (RPR), and categorized as RPR-positive or RPR-negative. RPR-positive donations were also grouped according to RPR titers (< 1:8 or ≥ 1:8). We report the prevalence of syphilis in first-time donors (FTD) and repeat donors (RD), as well as incidence in RD. Multivariable models were used to assess factors associated with RPR-positive syphilis. Additionally, we explored the relationship between syphilis positivity in FTD and syphilis cases registered by the Brazilian public health surveillance system from 2012 to 2022. Of 862,146 donations, 10,771 (1.3

INTRODUCTION:Most US blood donations are from donors living in urban areas. Demographics and infectious disease prevalence may vary in urban versus rural areas. We assessed demographic and transfusion-transmissible infection (TTI) prevalence among donors living in urban versus rural areas. METHODS:Blood donation data from the Transfusion-Transmissible Infections Monitoring System were categorized as urban or rural based on donor residential zip code for a three-year period (October 2020-September 2023). Demographics and TTI prevalence (HBV, HCV, HIV consensus positive (CP) and recent infection (RI), and syphilis CP and active infection (ASI)) were compared between the two geographies. Regression analysis determined the odds of TTIs among donors while controlling for demographic characteristics. RESULTS:From 21,941,910 donations, 83.9% were categorized as urban and 16.1% as rural. Donations from urban versus rural donors were more likely to be from men, between the ages of 25 and 54, non-White, and first-time. HBV CP, HIV CP, syphilis CP, and ASI were more prevalent in donations from urban versus rural donors. Significantly higher seroconversion rates also occurred in donors with syphilis CP and ASI. When adjusting for differences in donor demographics and characteristics, only prevalence in HBV CP remained more likely to occur among urban donors (odds ratio (OR): 1.28, 95% CI: 1.03, 1.6) and HCV CP less likely to occur among urban donors (OR: 0.8, 95% CI: 0.71, 0.9). DISCUSSION:Blood donor demographics and TTI prevalence differ in urban areas compared to rural; however, the differences in demographics may explain some of the TTI prevalence trends.

Background: Individuals with sickle cell disease (SCD) face an elevated risk of myeloid leukemias. Recently, myelodysplastic syndrome and acute myeloid leukemia have emerged as complications of curative SCD therapies, including gene therapy and allogeneic hematopoietic cell transplantation (HCT). Leukemias arising in SCD have been reported to harbor somatic TP53 mutations, and post-HCT TP53-mutant leukemias have been traced to low-level TP53 clones detectable pre-HCT. These findings suggest that SCD itself may predispose patients to high-risk clonal hematopoiesis (CH). Prior studies of CH in SCD used sequencing methods with limited sensitivity, yielding conflicting conclusions and potentially missing small, clinically relevant clones. In this multinational cohort, we defined CH prevalence, age distribution, and mutational profiles in SCD relative to non-SCD controls and other hemoglobinopathies. Methods: We analyzed archived blood DNA from 7,283 individuals across 17 cohorts in 4 countries: 3,885 with SCD (SS, SC, Sꞵ0, Sꞵ+), 3,398 without SCD (AA, AS, AC), and 188 with beta-thalassemia. Using duplex sequencing, we identified somatic CH variants at ≥0.001 variant allele fraction (VAF), germline variants in leukemia predisposition genes, and HBB genotypes. CH was analyzed by gene and in pre-specified biological groups: DNMT3A/TET2 (DT-CH) and DNA damage response (DDR-CH: TP53, PPM1D, CHEK2, ATM). We used binomial logistic regression (age- and sex-adjusted) to compare the prevalence of CH in SCD vs non-SCD controls. Results: We detected 6,661 CH variants in 2,673 individuals (median VAF=0.002). CH occurred earlier in SCD and was more prevalent in SCD cases compared to non-SCD controls among those aged 0-19 years [10.6% (95% CI: 9.1, 12.2) vs 3.5% (2.4, 5.0); p <0.0001]. This was driven by a selectively increased prevalence of DDR-CH in SCD [SCD: 3.3% (2.5, 4.3) vs non-SCD: 0.6% (0.2, 1.5), p = 0.0012] which extended across adult age groups (20-29 years: 3.5% vs 0.9%; 30-39 years: 7.7% vs 1.8%; 40-49 years: 15.1% vs 5.5%). Within DDR-CH, PPM1D was enriched in SCD compared to controls (36.4% vs 21.8%; p<0.0001); ATM (4.9% vs 9.5%; p=0.016) and CHEK2 (26.7% vs 34.1%; p=0.03) were underrepresented; and TP53 was similar (32.0% vs. 34.7%; p=0.45). To further evaluate the onset of CH in children with SCD, we performed serial sequencing of 148 participants enrolled in the BabyHUG trial (age 0.6 to 1.4 years) with follow-up samples obtained between 3 and 11 years of age. We detected CH, including DDR-CH, in 4.7% of children at baseline, all of which persisted in subsequent samples. Among those without CH at baseline, 3.9% developed incident CH during follow-up. In contrast to DDR-CH, DT-CH prevalence was higher in SCD among the youngest population [0-19: 6.4% (5.2, 7.7) vs 2.5 (1.5, 3.9), p<0.0001] but progressively decreased with advancing age relative to non-SCD controls. Among older individuals, (age ≥50 years), the prevalence of DT-CH was significantly lower in those with SCD than in those without SCD [54.4% (47.7, 61.0) vs 76.9% (74, 79.6), p<0.0001]. To determine whether sickle cell trait also had increased CH prevalence, we compared individuals with AA to those with AS/AC genotypes. CH prevalence was not higher in AS/AC compared to AA: overall CH (OR 1.01, p=0.95), DDR-CH (OR 0.99, p=0.50), DT-CH (OR 0.92, p=0.38). Then, to evaluate whether the association of SCD with early-onset CH was generalizable to other beta hemoglobinopathies, we analyzed the CH prevalence in pediatric beta-thalassemia patients (n=166). CH prevalence in beta-thalassemia was similar to AA controls (OR 1.37, p=0.49) and lower than SCD (OR 0.41, p=0.027). We observed no DDR-CH in beta-thalassemia. The prevalence of pathogenic/likely pathogenic germline variants in leukemia predisposition genes, such as DDX41, TERT, GATA2, and RUNX1 was similar across all evaluated HBB genotypes.Conclusions: Using deep targeted sequencing, we demonstrate that SCD is associated with a predisposition to early onset high-risk CH. Individuals with SCD exhibit markedly increased prevalence of DDR pathway mutations compared to controls, with the earliest clones detectable in infancy. This precocious DDR-CH is specific to SCD and not observed in individuals with sickle cell trait or beta-thalassemia. These findings provide a plausible mechanistic basis for the elevated relative risk of myeloid leukemias in SCD and therapy-related leukemias as a complication of curative therapies.