Sridharan, Meera

Abstract Objectives Fluorescence resonance energy transfer (FRET)–based ADAMTS13 activity assays are critical for the diagnosis of thrombotic thrombocytopenic purpura. However, these assays are susceptible to interference. As iodide has been suggested to interfere in laboratory testing via fluorophore quenching or promotion, we aimed to determine whether iodinated contrast (Omnipaque) interferes with the ATS-13 ADAMTS13 Activity Assay 2.0. Methods We evaluated the excitation, emission, and absorbance spectrum of Omnipaque alone and spiked in patient plasma with known ADAMTS13 activity and ADAMTS13 activity on Omnipaque alone, an abnormal control of patient plasma previously observed to display elevated baseline relative fluorescent units, and variable concentrations of patient plasma with known ADAMTS13 activity spiked with Omnipaque. Results No atypical fluorescent peaks were observed on any sample (Omnipaque alone or spiked in plasma) between 250 and 700 nm. There was no difference in the mean ADAMTS13 activity among the various concentrations of plasma spiked with Omnipaque or plasma spiked with saline. Conclusions Iodinated contrast does not appear to interfere—either via spectral overlap of the fluorophore or through physiologic inhibition of the ADAMTS13 enzyme—with ADAMTS13 activity FRET-based assays based on the findings from this in vitro analysis. Delaying sample collection for ADAMTS13 activity testing from suspected patients with thrombotic thrombocytopenic purpura following administration of iodinated radiocontrast agents is not necessary, and recent contrast administration should not yield erroneous ADAMTS13 activity results.

Introduction: There are discrepant definitions of both iron deficiency and anemia in pregnancy. It is recognized that iron requirements increase during pregnancy, particularly in the third trimester, and that deficiencies should be corrected to avoid adverse maternal-fetal outcomes. While low dose iron supplementation is recommended for all pregnant persons (ACOG Bulletin 233), dosing through prenatal vitamins varies widely. Additionally, despite the epidemic of iron deficiency in reproductive-age females globally and availability of high-value biomarkers (e.g., ferritin), current guidelines only recommend screening for iron deficiency during pregnancy in the presence of anemia. As anemia is the terminal manifestation of iron deficiency and reference ranges vary by organization, these guidelines and practices warrant further investigation and discussion. Methods: Retrospective review and analysis of the electronic health record at Mayo Clinic (Rochester, MN) was performed for obstetric deliveries between June 2022 and May 2023. Iron deficiency was defined as a ferritin <50 mcg/L and anemia was defined as a hemoglobin <11 g/dL. Results: A total of 2,141 unique deliveries were identified. The median age at delivery was 31 years old (range: 15 - 45) with 82% identifying as white. Anemia was documented in 42% (n=904) of pregnancies at least once throughout gestation, with an increasing frequency of 2% (n=43) in the first trimester, 11% (n=230) in the second trimester, 17% (n=361) in the third trimester, and 38% (n=803) from admission for delivery through the peri-partum period. There were five documented pRBC transfusions prior to admission for delivery; however, from admission for delivery through the peri-partum period, there were a total of 102 documented pRBC transfusions. In total, 15% (n=318) of pregnancies were screened for iron deficiency through ferritin testing. Ferritin levels were measured 415 times with 23% (n=96) occurring between the last menstrual period and 12 weeks gestational age (WGA), 24% (n=100) occurring between 13-27 WGA, 40% (n=164) occurring between 28-40 WGA, and 13% (n=55) occurring post-partum. Iron deficiency was found in 70% (n=67), 79% (n=79), 80% (n=164), and 78% (n=43) of measured ferritin levels, respectively. Despite the paucity of screening, prescriptions for oral iron increased throughout gestation with supplementation in pregnancy for 8% (n=170) prior to 12 WGA, 14% (n=290) for those 13-27 WGA, and 23% (n=489) for those 28-40 WGA. Similarly, intravenous iron infusions increased throughout gestation with supplementation in pregnancy for 0.3% (n=7) prior to 12 WGA, 0.7% (n=16) for those 13-27 WGA, and 4% (n=95) for those 28-40 WGA. Prenatal vitamins were documented in over 90% of pregnancies throughout gestation, although the majority were non-prescription and contained variable amounts of elemental iron. Conclusions: Iron deficiency in pregnancy is underrecognized and undertreated. It follows that the accuracy of current reference ranges for anemia in pregnancy are suspect without rigorous verification of replete iron stores in the reference population. Given potential implications for blood product utilization and prenatal care, additional studies are warranted to better characterize iron deficiency in pregnancy as well as clinical sequelae for both mothers and infants. Simultaneously, discussions are needed around current guidelines and recommendations for both screening and treating iron deficiency in pregnancy. Providers, institutions, and professional societies should pursue pragmatic quality improvement initiatives and equitable healthcare delivery efforts to optimize care for this vulnerable patient population at high risk of iron deficiency.

Background: The term classical hematology (CH), referring to a subspecialty focusing on non-cancer blood disorders, was officially adopted by the American Society of Hematology (ASH) in 2022. There is a perceived shortage of classical hematologists, although data are limited (Winter JN, Hematologist 2022). Prior studies have shown that <6% of hematology-oncology fellows pursue a practice subspecializing in CH after training (Todd RF, Blood 2004; Marshall Al, Blood Adv 2018). Moreover, mentorship is consistently cited as the most important factor guiding fellows' career decisions (Sharma D, Blood Adv 2019; Masselink LE, Blood Adv 2019). To help bridge the CH workforce gap, ASH has supported additional hematology-focused fellowship programs (HFFP) within select hematology-oncology fellowship programs. CH constitutes a large proportion of consults in US National Cancer Institute (NCI)-designated cancer centers (West CV, JCO Oncol Pract 2024). The goals of our study were: 1) to determine the proportion of adult hematologist-oncologists within NCI cancer centers who practice CH; and 2) to describe the physician characteristics of cancer centers with HFFP and compare these centers to those without HFFP. Methods: We included all NCI-designated cancer centers with a clinical program as of April 1, 2024. The only exception was St Jude Children's Hospital due to its pediatric focus. We obtained the practice profile of each internal medicine-trained adult hematologist-oncologist (henceforth, physician) as well as the availability of HFFP from the respective cancer center websites. We also searched the corresponding department of medicine and division of hematology at each affiliated academic institution to ensure inclusion of all physicians practicing CH. Each physician was classified into one of the following categories: classical hematologist (attending to only non-cancer conditions), general hematologist-oncologist (cancer and non-cancer conditions), and oncologist (cancer only). The number of hematology-oncology fellowship programs in the US was obtained from the Accreditation Council for Graduate Medical Education. Results: We included 64 NCI-designated cancer centers, 55 of which were considered as comprehensive cancer centers. There was a total of 4,616 physicians (3,891 oncologists [84.3%], 487 hematologists-oncologists [10.6%], and 238 classical hematologists [5.1%]). The median numbers of physicians, oncologists, general hematologist-oncologists, and classical hematologists per center were 55 (range, 16-275), 45 (range, 12-270), 5 (range, 0-48), and 3 (range, 0-13), respectively. The median proportions of classical hematologists and physicians practicing CH (general hematologist-oncologists plus classical hematologists) were 5.1% (range, 0-20.0) and 14.9% (range, 0-55.6%), respectively. There were 12 HFFP within NCI-designated cancer centers (18.8%). Most (11/12) centers with HFFP had >50 physicians (median 95 [range, 38-185]) and >5% classical hematologists (median 6% [range, 3.8-13.5%]); 11 centers with similar characteristics did not have HFFP. Centers with HFFP have significantly higher numbers of physicians (median 95.0 [range, 38-185] vs 49.5 [range, 16-275]; P=0.001) and classical hematologists (median 6.0 [range, 3-13] vs 2.0 [range, 0-11]; P<0.001) but similar proportions of classical hematologists (median 6.0% [range, 3.8-13.5] vs 4.5% [range, 0-20.0]; P=0.078) and physicians practicing CH (median 12.3% [range, 6.5-47.7] vs 15.7% [range, 0-55.6]; P=0.402) compared to those without HFFP. Conclusions: Among adult hematologist-oncologists at NCI-designated cancer centers, only 1 in 20 are classical hematologists, although 1 in 7 have CH as part of their practice. Within NCI-designated cancer centers, only 1 in 5 have an HFFP. These findings suggest that there is an opportunity for NCI-designated cancer centers to encourage and recruit physicians subspecializing in CH and a rationale to create additional HFFPs. These measures may help further alleviate CH workforce shortages and expand CH mentorship to meet the needs of an increasingly complex subspecialty within hematology.

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: Thrombotic thrombocytopenic purpura (TTP) has been previously described in pregnancy, however there is limited data available on the impact of TTP in this subset of patients. In this analysis, we evaluate the maternal and fetal morbidity outcomes of TTP in hospitalized pregnant patients. Methods: We used retrospective data from the National Inpatient Sample (NIS) to identify all hospital admissions of pregnant patients with and without TTP from 2012 to 2021 using ICD-9/10 codes. To describe the impact of TTP on maternal and fetal morbidity, we identified different morbidity indicators using standard Centers for Disease Control and Prevention (CDC) definitions with a particular focus on preeclampsia/eclampsia, thromboembolic events (venous and arterial), other organ failure, maternal morbidity and fetal outcomes including intrauterine growth restriction (IUGR) and fetal loss. To account for the effects of acute TTP during pregnancy versus a history of TTP, we separately analyzed hospitalizations that included plasma therapeutic plasma exchange (TPE). Predictors of maternal/fetal morbidities in pregnant TTP patients were determined using multivariable logistic regression analysis. Results: We identified 7,514,304 pregnancy hospitalizations with a mean age of 29 years. Of these, 234 women had a diagnosis of TTP, with 74 receiving TPE during admission (acute TTP during pregnancy). Compared to pregnancy-related hospitalizations in women without TTP, those with TTP were more likely to be African American, admitted to urban teaching hospitals, have lower income, and have a higher Charlson Comorbidity Index (CCI). Most maternal morbidity outcomes were significantly higher in hospitalizations with TTP as compared to those without TTP including increased eclampsia (2.1% vs 0.08%), acute myocardial infarction (1.7% vs 0.01%, p<0.001), puerperal cerebrovascular disorders (8.1% vs 0.7%, p<0.001), cardiac arrest (0.9% vs 0.01%), acute renal failure (35% vs 0.2%, p<0.001), adult respiratory distress syndrome (ARDS) (6.4% vs 0.06%, p<0.001), disseminated intravascular coagulation (DIC) (18% vs 0.2%, p<0.001), pulmonary edema/acute heart failure (5.1% vs 0.1%, p<0.001), sepsis (9% vs 0.22%, p<0.001), shock (6.4% vs 0.1%, p<0.001), air/thrombotic embolism (3.0% vs 0.05%, p<0.001), blood transfusion requirement (25.6 vs 1.28%, p<0.001), and ventilation requirement (6.4% vs 0.06%, p<0.001). There was also a higher need for cesarean sections in TTP hospitalizations compared to non-TTP (57.1% vs 36.9%). For fetal morbidity outcomes, intrauterine growth restriction (IUGR) was more common in TTP hospitalizations (6.8% vs 2.4%, p<0.001), while there was no statistical difference between the two groups in the rates of preterm delivery (3.9% vs 3.3%, p=0.651). In-hospital mortality (1.7% vs 0.02%, p<0.001), and length of stay (11 vs 3 days, p<0.001) were also significantly higher in hospitalizations with TTP. Patients with TTP who received TPE during the hospital stay had worse maternal morbidity outcomes than those who did not, likely reflecting the active nature of the disease in this cohort. In the multivariate analysis, CCI ≥ 1 (OR 3.52, 95% CI, 1.64-7.54) and receipt of TPE (OR 2.99, 95% CI, 1.52-5.86) were associated with higher likelihood of maternal/fetal morbidity in TTP hospitalizations. Conclusion: In conclusion, TTP has a significant impact on hospitalized pregnant patients, both on maternal and fetal outcomes. Further studies are needed to assess risk factors associated with TTP in pregnancy and ideal treatment regimens for these patients.

Background The American Society of Clinical Oncology (ASCO) launched the Diversity in Oncology initiative in 2017 to address the need for increased minority representation in the hematology-oncology workforce. A recent series of reports, titled “State of the Oncology Workforce in America,” published in JCO Oncology Practice in 2021 and 2022, focused on this issue. Notably, these reports did not include any data regarding the representation of Asian minorities in the field. Therefore, our objective was to assess the proportion of Asian professionals within the hematology-oncology workforce, encompassing both practitioners and trainees. Methods We conducted a comprehensive search for publicly available data regarding Asian representation among US hematology-oncology practitioners and trainees in both adult and pediatric fields. Our primary data sources included the 2020 US Census, the Association of American Medical Colleges, the Accreditation Council for Graduate Medical Education, and various professional societies. We defined practitioners to include hematologist-oncologists, gynecologic oncologists, radiation oncologists, surgical oncologists, hematopathologists, hematology-oncology nurse practitioners, hematology-oncology physician assistants, and nurses specializing in hematology-oncology. Trainees encompassed fellows and residents. Additionally, we gathered comparable data on the US population, medical students, adult internal medicine residents, gynecology residents, pediatric residents, pathology residents, surgery residents, nurses, nurse practitioners, and physician assistants. To provide a comprehensive overview of the hematology-oncology workforce, we utilized data from 2020 to 2022, and whenever possible, we collected longitudinal data on trainees over the years. Results As of 2020, Asians represented 6.2% of the US population. Among hematology-oncology physician practitioners, the percentage of Asian individuals ranges from 14.7% to 32.1%, including 32.1% of adult hematologist-oncologists, 20.4% of pediatric hematologist-oncologists, 25.9% of radiation oncologists, 14.7% of gynecologic oncologists, and 7.0% of hematology-oncology physician assistants. In the realm of physician trainees, Asian representation is between 17.9% and 35.3%, with 35.3% of adult hematology-oncology fellows, 20.0% of pediatric hematology-oncology fellows, 26.4% of radiation oncology residents, and 17.9% of gynecologic oncology fellows. Additionally, the proportion of Asian residents from which hematology-oncology fellows are drawn ranges from 14.9% to 35.9%. Specifically, 35.9% of internal medicine residents, 22.0% of pediatric residents, 14.9% of gynecology residents, 26.6% of pathology residents, and 19.2% of surgical residents are Asian. Furthermore, 26.7% of medical students identify as Asian. Notably, the proportions of Asian hematology-oncology trainees and medical students have remained relatively stable from 2005 to 2022. Data on hematopathologists, surgical oncologists, and non-physician practitioners are limited, although Asian representation among hematology-oncology physician assistants is 7.0% and among nurses is 7.2%. Conclusions Asians comprise a large segment of the hematology-oncology workforce in the US. While only 1 in 20 people in the US are Asians, between 1 in 3 and 1 in 5 hematology-oncology physician practitioners and trainees, are Asians. Data are limited for non-physician practitioners. Asian minority representation should be highlighted and considered as an example of success in diversity in hematology-oncology workforce. This framework should be embraced moving forward to continue advancing minority representation throughout the field of hematology-oncology.

Abstract Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing disorder caused by autoantibody-mediated deficiency of ADAMTS13. Rituximab is frequently administered to prevent relapses, but whether the durability of rituximab effect is maintained with subsequent treatment courses has not been studied. Using the United States Thrombotic Microangiopathy Consortium (USTMA) retrospective iTTP registry, we evaluated clinical relapse-free survival (RFS) with subsequent courses of rituximab treatment in multiply relapsing patients. Separately, we evaluated overall RFS (composite of time to clinical relapse, ADAMTS13 relapse, or preemptive rituximab) in a prospective iTTP cohort from the Johns Hopkins University and the University of Minnesota. In the USTMA registry, median clinical RFS was shorter after the second or subsequent rituximab-treated episode than the first (2.1 vs 6.0 years; P = .04). White patients’ clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared with the first (hazard ratio [HR], 1.86; 95% confidence interval [CI], 0.22-15.80; P = .57), whereas for Black patients, clinical relapse risk was significantly higher after the second or subsequent courses (HR, 2.82; 95% CI, 1.52-5.24; P = .001). In the prospective cohort, overall RFS progressively shortened after each episode of rituximab treatment with the first episode having the longest RFS (2.8 years; interquartile range, 2.0-6.0) and this loss of response durability was most pronounced in Black patients. The durability of rituximab’s effect declines with subsequent treatments, which is more pronounced in Black patients, who may benefit from closer monitoring and alternative immunomodulatory approaches such as maintenance rituximab and consideration of other agents.