Uncommon BK polyomaviruses detected in allogeneic hematopoietic cell transplant recipients.

The role of viral diversity in the pathogenesis of BK polyomavirus (BKPyV)-associated disease is poorly understood. Here, we report near full-length BKPyV genome sequences from two allogeneic hematopoietic cell transplant recipients infected with BKPyV genotype II, which is uncommon in the USA.

A prospective multi-institutional study of eculizumab to treat high-risk stem cell transplantation-associated TMA.

ABSTRACT: High-risk, complement mediated, untreated transplant-associated thrombotic microangiopathy (hrTMA) has dismal outcomes due to multi-organ dysfunction syndrome (MODS). The complement C5 blocker eculizumab shows promising results in hrTMA, but has not been prospectively studied in hematopoietic stem cell transplant (HCT) recipients. We performed the first multi-institutional prospective study in children and young adults to evaluate eculizumab as an early targeted intervention for hrTMA/MODS. We hypothesized that eculizumab would more than double survival in HCT recipients with hrTMA, compared to our prior study of prospectively screened, untreated hrTMAs serving as historical controls. HrTMA features (elevated terminal complement (sC5b-9) and proteinuria measured by random urine protein/creatinine ratio (≥1mg/mg)) were required for inclusion. The primary endpoint was survival at 6 six-months from hrTMA diagnosis. Secondary endpoints were cumulative incidence of MODS 6 months after hrTMA diagnosis and 1-year posttransplant survival. Eculizumab dosing included intensive loading, induction, and maintenance phases for up to 24 weeks of therapy. All 21 evaluated study subjects had MODS. Primary and secondary study endpoints were met by demonstrating survival of 71% (P < .0001) 6 months after hrTMA diagnosis and 62% 1 year after transplant. Of fifteen survivors, 11 (73%) fully recovered organ function and are well. Our study demonstrates significant improvement in survival and recovery of organ function in hrTMA using an intensified eculizumab dosing and real time biomarker monitoring. This study serves as a benchmark for planning future studies that should focus on preventative measures or targeted therapy to be initiated prior to organ injury. This trial was registered at www.clinicaltrials.gov as #NCT03518203.

Pediatric transplant-associated thrombotic microangiopathy health care utilization and implications of eculizumab therapy.

ABSTRACT: The health care use (HCU) burden of transplant-associated thrombotic microangiopathy (TA-TMA) and its treatments are unknown. The objective of this study was to investigate inpatient costs associated with meeting criteria for TA-TMA in the first year after hematopoietic cell transplant (HCT). This institutional review board-approved retrospective multicenter study included serial children who underwent HCT from 1 January 2015 to 1 July 2019. A standardized unit cost (adjusted for geographic location, differences in cost of living, and inflation) for inpatient hospitalization was extracted from the Pediatric Health Information System data and linked to clinical data. Both total cost and cost per day from 15 days before stem cell infusion to 1-year after HCT were calculated. Among allogeneic (allo) transplant recipients, after adjusting for severe grade 3/4 acute graft-versus-host disease (GVHD), infections, and HLA mismatch, costs were not different in TA-TMA (n = 137) vs no TA-TMA (n = 238). Severe GVHD was significantly associated with increased costs. Among allo high-risk (HR) TMA-TMA, unadjusted costs were significantly higher in the eculizumab-treated cohort (n = 19) than in the supportive care group (n = 36). However, after adjusting for gastrointestinal bleeding that occurred disproportionately in the eculizumab (n = 6) vs supportive care (n = 0) cohort, eculizumab treatment was not associated with increased total costs. More studies are needed to determine the etiology of increased HCU costs in those with HR-TA-TMA and predict those more likely to benefit from eculizumab, reducing HCU and improving outcomes.

Diffuse alveolar hemorrhage after hematopoietic cell transplantation- response to treatments and risk factors for mortality.

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of hematopoietic cellular therapy (HCT). This study aimed to evaluate the effect of DAH treatments on outcomes using data from consecutive HCT patients clinically diagnosed with DAH from 3 institutions between January 2018-August 2022. Endpoints included sustained complete response (sCR) defined as bleeding cessation without recurrent bleeding, and non-relapse mortality (NRM). Forty children developed DAH at a median of 56.5 days post-HCT (range 1-760). Thirty-five (88%) had at least one concurrent endothelial disorder, including transplant-associated thrombotic microangiopathy (n=30), sinusoidal obstructive syndrome (n=19), or acute graft versus host disease (n=10). Fifty percent had a concurrent pulmonary infection at the time of DAH. Common treatments included steroids (n=17, 25% sCR), inhaled tranexamic acid (INH TXA,n=26, 48% sCR), and inhaled recombinant activated factor VII (INH fVIIa, n=10, 73% sCR). NRM was 56% 100 days after first pulmonary bleed and 70% at 1 year. Steroid treatment was associated with increased risk of NRM (HR 2.25 95% CI 1.07-4.71, p=0.03), while treatment with INH TXA (HR 0.43, 95% CI 0.19- 0.96, p=0.04) and INH fVIIa (HR 0.22, 95% CI 0.07-0.62, p=0.005) were associated with decreased risk of NRM. Prospective studies are warranted to validate these findings.

Increased Body Mass Index Augments Endothelial Injury and Clinical Outcomes after Hematopoietic Stem Cell Transplantation.

Higher body mass index (BMI) is characterized as a chronic inflammatory state with endothelial dysfunction. Endothelial injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT) puts patients at risk for such complications as transplantation-associated thrombotic microangiopathy (TA-TMA) and acute graft-versus-host-disease (aGVHD). To evaluate the impact of increased BMI on endothelial injury after allo-HSCT in pediatric and young adult patients, we conducted a retrospective cohort study evaluating 476 consecutive allo-HSCT children and young adult recipients age 0 to 20 years. Our analysis was subdivided based on distinct age categories (<2 years and 2 to 20 years). BMI was considered as a variable but was also expressed in standard deviations from the mean adjusted for age and sex (z-score), based on established criteria from the World Health Organization (age <2 years) and the Centers for Disease Control and Prevention (age 2 to 20 years) to account for differences associated with age. Primary endpoints included the incidences of TA-TMA and aGVHD. Increased BMI z-score was associated with TA-TMA after allo-HSCT in patients age <2 years (median, 18.1; IQR, 17 to 20; P = .006) and in patients age 2 to 20 years (median, 18.7; IQR, 16 to 21.9; P = .02). Higher BMI z-score correlated with TA-TMA risk in both age groups, with a BMI z-score of .9 in the younger cohort and .7 (IQR, -.4 to 1.6; P = .04) in the older cohort. Increased BMI z-score was associated with an increased risk of TA-TMA in a multivariate analysis of the entire cohort (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.05 to 1.37; P = .008). Multivariate analysis also demonstrated that patients with BMI in the 85th percentile or greater had an increased risk of developing TA-TMA compared to those with a lower BMI percentile (OR, 2.66; 95% CI, 1.62 to 4.32; P < .001). Baseline and day +7 ST2 levels were elevated in subjects with TA-TMA compared to those without TA-TMA in both age groups. Baseline sC5b-9 concentration was not correlated with BMI z-score, but sC5b-9 concentration was increased markedly by 7 days post-allo-HSCT in patients age <2 years who later developed TA-TMA compared to those who never developed TA-TMA (P = .001). The median BMI z-score was higher for patients with aGVHD compared to patients without aGVHD (.7 [range, -3.9 to 3.9] versus .2 [range, -7.8 to 5.4]; P = .03). We show that high BMI is associated with augmented risk of endothelial injury after HSCT, specifically TA-TMA. These data identify a high-risk population likely to benefit from early interventions to prevent endothelial injury and prompt treatment of established endothelial injury.

Optimized vitamin D repletion with oral thin film cholecalciferol in patients undergoing stem cell transplant.

Vitamin D deficiency is common in childhood, pervasive before and after bone marrow transplant, and is associated with increased incidence of graft-versus-host disease (GVHD) and decreased survival in patients undergoing hematopoietic stem cell transplant (HSCT). Numerous barriers impede replacement, including malabsorption secondary to gut GVHD, mucositis, inability to take capsules, kidney disease, liver disease, and infection; many patients remain refractory despite vitamin D therapy. We hypothesized that a different formulation of cholecalciferol, administered on the tongue as a readily dissolving oral thin film (OTF), would ease administration and facilitate therapeutic vitamin D levels (>35 ng/mL) in patients who are refractory. In this prospective pilot study, we evaluated 20 patients after HSCT (range, day +21 - day +428 at enrollment) with serum vitamin D levels ≤35 ng/mL. Cholecalciferol OTF strips were administered for 12 weeks. Dosing was based on patient body weight and titrated per individual pharmacokinetics. Wilcoxon matched-pairs signed-rank test demonstrated marked improvement in all 20 patients who were formerly refractory, increasing from a median baseline vitamin D level of 29.2 ng/mL to 58 ng/mL at end of study (P < .0001). All patients demonstrated improvement in serum vitamin D level by week 4 on study, some of whom had been refractory for years prior. Median dose was 1 OTF strip (40 000 IU) per week. No toxicity was observed. This formulation proved to be safe, effective, efficient, and well received. We are eager to explore other patient populations, which might benefit from this promising development, and other therapeutics that might be optimized using this mode of delivery. This trial was registered at www.clinicaltrials.gov as #NCT04818957.

BK Polyomavirus Diversity After Hematopoietic Stem Cell Transplantation.

BK polyomavirus (BKPyV) infection is common after hematopoietic stem cell transplantation (HSCT) and is associated with the development of hemorrhagic cystitis (HC). The role that BKPyV plays in the pathogenesis of HC is not well characterized. We investigated the impact of BKPyV diversity on the development of HC using a previously established cohort of pediatric HSCT patients. There were 147 urine samples with quantifiable BKPyV at month 1 after HSCT; 137 (93.2%) were amplified using our in-house polymerase chain reaction approach and sent for next-generation sequencing. Subtype Ia was most frequent (61.3%), followed by subtype Ib1 (31.4%). The median viral load of subtype Ia samples was higher than for subtype Ib1 at month 1. Across the protein coding regions, APOBEC-induced mutations and signature patterns associated with HC were identified. This is the largest sequencing study of a single cohort of HSCT patients, providing a vast resource of sequence data for future analyses.

Intestinal permeability in patients undergoing stem cell transplantation correlates with systemic acute phase responses and dysbiosis.

Intestinal permeability may correlate with adverse outcomes during hematopoietic stem cell transplantation (HSCT), but longitudinal quantification with traditional oral mannitol and lactulose is not feasible in HSCT recipients because of mucositis and diarrhea. A modified lactulose:rhamnose (LR) assay is validated in children with environmental enteritis. Our study objective was to quantify peri-HSCT intestinal permeability changes using the modified LR assay. The LR assay was administered before transplant, at day +7 and +30 to 80 pediatric and young adult patients who received allogeneic HSCT. Lactulose and rhamnose were detected using urine mass spectrometry and expressed as an L:R ratio. Metagenomic shotgun sequencing of stool for microbiome analyses and enzyme-linked immunosorbent assay analyses of plasma lipopolysaccharide binding protein (LBP), ST2, REG3α, claudin1, occludin, and intestinal alkaline phosphatase were performed at the same timepoints. L:R ratios were increased at day +7 but returned to baseline at day +30 in most patients (P = .014). Conditioning regimen intensity did not affect the trajectory of L:R (P = .39). Baseline L:R ratios did not vary with diagnosis. L:R correlated with LBP levels (r2 = 0.208; P = .0014). High L:R ratios were associated with lower microbiome diversity (P = .035), loss of anaerobic organisms (P = .020), and higher plasma LBP (P = .0014). No adverse gastrointestinal effects occurred because of LR. Intestinal permeability as measured through L:R ratios after allogeneic HSCT correlates with intestinal dysbiosis and elevated plasma LBP. The LR assay is well-tolerated and may identify transplant recipients who are more likely to experience adverse outcomes.

Reeling in complement in transplant-associated thrombotic microangiopathy: You're going to need a bigger boat.

Over the last decade there have been numerous advances in both the diagnosis and treatment of transplant-associated thrombotic microangiopathy (TA-TMA). These are largely the result of an improved understanding of complement activation in TA-TMA and the ability to prevent end organ injury and death with timely initiation of complement-blocking therapies. In this article, we review our current understanding of the pathophysiology of TA-TMA, particularly as it pertains to complement activation, endothelial injury, and clinical management. We then review novel complement-blocking therapies that are currently under investigation for use in TA-TMA, as well as discuss special considerations for complement-blocking therapy in hematopoietic stem cell transplant recipients. Through these reviews we aim to answer or at least provide an educated discussion on the most commonly posed TA-TMA management questions and dilemmas.

Reduced-Intensity Conditioning Mitigates Risk for Primary Ovarian Insufficiency but Does Not Decrease Risk for Infertility in Pediatric and Young Adult Survivors of Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for many pediatric malignant and nonmalignant conditions. Gonadal insufficiency or infertility is present in almost all HSCT survivors who received a myeloablative conditioning (MAC) regimen. Reduced-intensity conditioning (RIC) regimens are being increasingly used in medically fragile patients or in patients with nonmalignant diagnoses to limit the toxicities associated with HSCT; however, the short-term and long-term gonadal toxicity of RIC regimens in pediatric and young adult survivors remains unknown. In this study, we compared the prevalence of gonadal insufficiency and infertility among pubertal and postpubertal pediatric and young adult survivors of HSCT who received a RIC regimen versus those who received a MAC regimen. Twenty-three females (RIC, n = 8; MAC, n = 15) and 35 males (RIC, n = 19; MAC, n = 16) were included in this single-center, retrospective cross-sectional study. Eligible patients were those with available laboratory results who were ≥1 year post-HSCT, age <40 years, and pubertal or postpubertal as assessed by an endocrinologist. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and anti-Müllerian hormone (AMH) levels were measured in females, and FSH, LH, total testosterone, and inhibin B (InhB) levels were measured in males. Twenty-one males (RIC, n = 11; MAC, n = 10) underwent semen analysis through a separate consent. Parametric and nonparametric analyses were undertaken to compare the RIC and MAC groups. Female patients who received RIC were less likely than those who received MAC to develop primary ovarian insufficiency, as demonstrated by elevated FSH (P = .02) and low estradiol (P = .01) or elevated LH (P = .09). Most females in the RIC (75%) and MAC (93%) groups had low AMH levels, indicating low or absent ovarian reserve, with no significant difference between the groups (P = .53). In males, there were no significant differences between the 2 groups in the prevalence of abnormal FSH, LH, testosterone, or InhB levels. Ten of 11 RIC males (91%) and 10 of 10 MAC males (100%) had azoospermia or oligospermia, at a median time to semen analysis from HSCT of 3.7 years (range, 1.3 to 12.2 years). RIC may pose less risk than MAC for primary ovarian insufficiency among female survivors of HSCT; however, both female and male recipients of either RIC or MAC regimens are at high risk for infertility. In the largest reported series of semen analyses of pediatric and young adult male recipients of RIC, azoospermia or oligospermia was found in nearly all (91%) RIC survivors. All patients undergoing HSCT should receive counseling about the high risk of gonadal toxicity, and efforts should be made to preserve fertility in patients undergoing either RIC or MAC.

What complements complement in transplant-associated thrombotic microangiopathy?

Transplant-associated thrombotic microangiopathy remains a lethal complication of haematopoietic stem cell transplant and not all patients respond to terminal complement inhibitors. Qi et al. show that hypoxia-inducible factor-1α (HIF-1α) may be a previously unrecognized driver of this endothelial injury syndrome. Commentary on Qi et al. Upregulation of HIF-1α contributes to complement activation in transplantation-associated thrombotic microangiopathy. Br J Haematol. 2022 199:603-615.

The Role of Complement in HSCT-TMA: Basic Science to Clinical Practice.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a common complication occurring post-HSCT and is associated with substantial morbidity and mortality if not promptly identified and treated. Emerging evidence suggests a central role for the complement system in the pathogenesis of HSCT-TMA. The complement system has also been shown to interact with other pathways and processes including coagulation and inflammation, all of which are activated following HSCT. Three endothelial cell-damaging "hits" are required for HSCT-TMA genesis: a genetic predisposition or existing damage, an endothelial cell-damaging conditioning regimen, and additional damaging insults. Numerous risk factors for the development of HSCT-TMA have been identified (including primary diagnosis, graft type, and conditioning regimen) and validated lists of relatively simple diagnostic signs and symptoms exist, many utilizing routine clinical and laboratory assessments. Despite the relative ease with which HSCT-TMA can be screened for, it is often overlooked or masked by other common post-transplant conditions. Recent evidence that patients with HSCT-TMA may also concurrently present with these differential diagnoses only serve to further confound its identification and treatment. HSCT-TMA may be treated, or even prevented, by removing or ameliorating triggering "hits", and recent studies have also shown substantial utility of complement-targeted therapies in this patient population. Further investigation into optimal management and treatment strategies is needed. Greater awareness of TMA post-HSCT is urgently needed to improve patient outcomes; the objective of this article is to clarify current understanding, explain underlying complement biology and provide simple tools to aid the early recognition, management, and monitoring of HSCT-TMA.

Cerebral vascular injury in transplant-associated thrombotic microangiopathy.

Transplant-associated thrombotic microangiopathy (TA-TMA) and atypical hemolytic uremic syndrome (aHUS) are complement-mediated TMAs. The central nervous system (CNS) is the most common extrarenal organ affected by aHUS, and, despite mechanistic overlap between aHUS and TA-TMA, CNS involvement is rarely reported in TA-TMA, suggesting that CNS involvement in TA-TMA may be underdiagnosed and that these patients may benefit from complement blockers. In addition, there are no widely used histologic or radiologic criteria for the diagnosis of TMA in the brain. Thirteen recipients of pediatric hematopoietic cell transplants (HCTs) who had TA-TMA and who underwent autopsy were studied. Seven of 13 brains had vascular injury, and 2 had severe vascular injury. Neurologic symptoms correlated with severe vascular injury. Classic TMA histology was present and most often observed in the cerebellum, brainstem, and cerebral white matter. Abnormalities in similar anatomic regions were seen on imaging. Brain imaging findings related to TMA included hemorrhages, siderosis, and posterior reversible encephalopathy syndrome. We then studied 100 consecutive HCT recipients to identify differences in neurologic complications between patients with and those without TA-TMA. Patients with TA-TMA were significantly more likely to have a clinical concern for seizure, have an electroencephalogram performed, and develop altered mental status. In summary, our study confirms that TA-TMA involves the brains of recipients of HCT and is associated with an increased incidence of neurologic symptoms. Based on these findings, we propose that patients with low- or moderate-risk TA-TMA who develop neurologic complications should be considered for TA-TMA-directed therapy.

Transplantation-Associated Thrombotic Microangiopathy Risk Stratification: Is There a Window of Opportunity to Improve Outcomes?

Transplantation-associated thrombotic microangiopathy (TA-TMA) can range from a self-limiting condition to a lethal transplantation complication. It is important to identify TA-TMA patients at risk for severe multiorgan endothelial injury to implement targeted therapies in a timely manner. Current therapeutic approaches with complement blockade have improved survival markedly in high-risk TA-TMA patients, yet one-third of these patients respond inadequately to eculizumab therapy. Poor response may indicate that substantial endothelial injury has already occurred and raises the possibility that earlier intervention may improve outcomes. The goal of this study was to identify additional TA-TMA patients who would benefit from early targeted intervention and update TA-TMA risk stratification methods to reflect these findings. We studied 130 HSCT recipients with a diagnosis of TA-TMA who were screened prospectively and stratified into 3 TA-TMA risk groups (high-risk, n = 64; moderate-risk, n = 48; 18 low-risk, n = 18). We specifically examined TA-TMA biomarkers and clinical outcomes in subjects who were not offered complement blocking therapy (moderate-risk and low-risk TA-TMA subjects) and compared them with those who received TA-TMA-targeted therapy (high-risk TA-TMA subjects). One-year post-HSCT survival for subjects with untreated moderate-risk TA-TMA was similar to those with high-risk TA-TMA receiving eculizumab therapy (71% versus 66%; P = .40), indicating that a subset of moderate-risk patients may benefit from therapy. A detailed analysis of moderate-risk subjects highlighted the importance of relative as well as absolute complement pathway activation in determining organ injury. We demonstrated that activated terminal complement (measured by elevated blood sC5b-9) alone is a valuable indicator of reduced survival. Moderate-risk TA-TMA subjects with elevated sC5b-9 levels had a nearly 3-fold higher risk of mortality that was statistically significant in multivariant analyses (P = .01). A "dose effect" also was observed, and higher sC5b-9 levels were associated with worse outcomes. Furthermore, all moderate-risk patients with sustained sC5b-9 elevation for >2 weeks ultimately developed multiorgan dysfunction syndrome (MODS). This indicates that scheduled sC5b-9 measurements could promptly identify patients at risk for poor outcomes and would facilitate early TA-TMA-directed therapy to prevent organ injury. Untreated low-risk TA-TMA patients had a 1-year post-HSCT survival of 94% and should be observed without targeted interventions. Routine TA-TMA screening and complement-blocking therapies have markedly improved the outcomes for high-risk TA-TMA patients, and our study suggests that additional patients may benefit from TA-TMA treatment. This study provides further support for prospective TA-TMA screening as an integral tool for identifying patients at greatest risk for organ injury and death from TA-TMA. An updated TA-TMA risk algorithm that incorporates relevant laboratory biomarkers, clinical findings, and comorbid conditions was generated using this study's findings, and we propose clinical implementation of this algorithm for the management of TA-TMA.

Abnormal Maximal and Submaximal Cardiopulmonary Exercise Capacity in Pediatric Stem Cell Transplant Recipients Despite Normal Standard Echocardiographic Parameters: A Pilot Study.

Left ventricular systolic dysfunction is a known complication of stem cell transplantation (SCT). There has been minimal research to determine whether subclinical cardiac dysfunction exists in SCT patients using tools other than standard echocardiography, such as maximal and submaximal effort cardiopulmonary exercise testing (CPET) and vascular function studies. The objective of this study was to determine the rate of subclinical cardiac dysfunction in patients with normal ejection fraction after SCT, identified by abnormal values by CPET, tissue-Doppler imaging, and arterial stiffness measurements and to further describe submaximal exercise test measures in this population. A prospective cohort study of SCT survivors who were at least 3 years after SCT without prior anthracycline or radiation exposure and with preserved systolic function (left ventricular ejection fraction > 50%) was performed to evaluate for abnormalities in exercise, vascular function, and diastolic function in an effort to detect subclinical dysfunction in SCT patients. Eleven patients (12.4 ± 3.8 years old) were included in the study. No patients had diastolic dysfunction. All patients completed a maximal effort exercise test, and 73% (8/11) had abnormal peak oxygen consumption (Vo2 peak), which is a measure of aerobic fitness. However, during submaximal effort CPET, 45% (5/11) had an abnormal Vo2 at anaerobic threshold (i.e., the point in exercise where aerobic transitions to anaerobic metabolism and fatigue starts), and 64% (7/11) had an abnormal oxygen uptake efficiency slope (a measure that relates Vo2 peak to total ventilation). Eighty-six percent (6/7) of the patients with an abnormal oxygen uptake efficiency slope ultimately had an abnormal Vo2 peak. There were no vascular function abnormalities. Pediatric survivors of SCT often have abnormal maximal and submaximal exercise capacity without vascular or cardiac dysfunction.

BK Polyomavirus Subtypes II and IV in Hematopoietic Cell Transplant Recipients.

Symptomatic BK polyomavirus (BKPyV) infections are common and relevant in immunocompromised patients. Here, we present full-length BKPyV genomes from samples from patients who received hematopoietic cell transplants in the United States. These individuals had non-subtype I BKPyV, as determined by amplification, next-generation sequencing, and phylogenetic analysis.

Eculizumab precision-dosing algorithm for thrombotic microangiopathy in children and young adults undergoing HSCT.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal posttransplant complication of hematopoietic stem cell transplantation. We recently reported that survival for TA-TMA has been improved by early intervention with eculizumab, a complement C5 inhibitor, guided by pharmacokinetic/pharmacodynamic (PK/PD) model-informed precision dosing. However, patients with gastrointestinal bleeding showed poor survival, even when treated with more frequent doses. Our objective was to develop separate models in bleeding and nonbleeding patients with TA-TMA and to propose precision dosing algorithms. Eculizumab PK/PD was analyzed in 19 bleeding and 38 nonbleeding patients (0.5-29.9 years of age). A complement activation biomarker (sC5b-9) and body weight were identified as significant determinants of eculizumab clearance regardless of bleeding. Eculizumab clearance after the first dose was higher in bleeding than in nonbleeding patients (83.8 vs 61.3 mL/h per 70 kg; P = .07). The high clearance was maintained over treatment doses in bleeding patients, whereas nonbleeding patients showed a time-dependent decrease in clearance. sC5b-9 levels were highest before the first dose and decreased over time, regardless of bleeding complications. A Monte Carlo Simulation analysis showed that the current dosing protocols recommended for atypical hemolytic uremic syndrome had <15% probability of attaining the target concentration of >100 µg/mL eculizumab in nonbleeding patients. We identified an intensified loading protocol to reach 80% target attainment. Our data clearly showed the need for individualized dosing for patients with significant bleeding and for ongoing dose adjustments to optimize outcomes. The developed models will be incorporated into a clinical decision guideline for precision dosing to improve outcomes in children and young adults with TA-TMA.