Padrnos, Leslie

Abstract Background Congenital hemophilias affect about 30,000 US individuals (0.01% of the population) and atrial fibrillation (AF) about 10.5 million US individuals (4.5% of the population). Stroke prevention in this population is limited to expert opinion with formal guideline development hindered by a lack of clinical trials. Herein, we correlate outcomes of major bleeding and ischemic stroke with CV risk factors and antithrombotic management in our patient cohort. Methods This is a retrospective review (minimal risk study) of patients with hemophilia A, B, or C and concomitant AF diagnosed between 2000 and 2025. Patients were identified through a Mayo Clinic Rochester database using key terms. All cases were manually reviewed in the electronic medical record for appropriateness. Major bleeding was defined per International Society on Thrombosis and Haemostasis (ISTH) criteria. Stroke and bleeding risk were based on CHA₂DS₂-VASc and HAS-BLED scores. Analyses were performed using BlueSky Statistics software, with chi-square tests for categorical variables and Mann-Whitney U tests for continuous variables. Results A total of 21 patients were identified. Of these, 18 (86%) were male. Common comorbidities included type 2 diabetes (T2DM) in 14 (67%), hyperlipidemia in 18 (86%), hypertension in 18 (86%), and coronary artery disease in 12 (57%). Fifteen (71%) were never smokers. One patient (5%) had HIV on antiretroviral therapy, and five (24%) had a history of localized, resected cancer. Congenital hemophilia A was present in 12 patients (57%), hemophilia B in 5 (24%), and hemophilia C in 5 (24%). The median age at hemophilia diagnosis was 55.3 years. Hemophilia severity was mild in 17 (81%) and moderate in 4 (19%). Median factor level was 33% (SD=12.77%). Most were diagnosed with hemophilia from accumulation of minor bleeding events and family history. Six (29%) had major bleeds prior to AF diagnosis. The median age at AF diagnosis was 65.6 years. Paroxysmal AF was the most common subtype (11 patients; 52%), followed by permanent (5; 24%) and persistent (5; 24%). Median CHA₂DS₂-VASc and HAS-BLED scores at AF diagnosis were 2 and 1, respectively. At AF diagnosis, 2 patients (10%) were already on antithrombotic therapy (aspirin 81 mg [ASA]), both for recent transcatheter aortic valve replacement (TAVR). For AF-related stroke prevention, 5 patients (24%) were started on ASA and 5 others (24%) were started on apixaban. Cardioversion was performed in 5 patients (24%) and ablation in 2 (10%)). Five (24%) underwent procedural interventions (3 Watchman devices, 2 Maze procedures). Three patients (14%) had at least one major bleed following AF diagnosis. Bleed locations included traumatic intracranial, severe epistaxis, and spontaneous intracranial (one each). At the time of bleed, one patient was on ASA and two were on no antithrombotic or anticoagulation. One patient (5%) had a second major bleed – a muscle hematoma. He was not on antithrombotic or anticoagulation at the time. Two bleeds were fatal. Patient 1 was an 83-year-old male with moderate hemophilia A, a history of major GI bleed prior to AF diagnosis, a CHA₂DS₂-VASc score of 7 on ASA (taken for 11.5 years), and a HAS-BLED score of 3 who died of complications from severe epistaxis.Patient 2 was a 56-year-old male with moderate hemophilia B, a CHA₂DS₂-VASc score of 1, and a HAS-BLED score of 1 that died from a spontaneous intracranial bleed. One patient experienced an ischemic stroke: a 71 year old male with moderate Hemophilia A, a CHA₂DS₂-VASc score of 7, and a HAS-BLED score of 5 who was anticoagulated on apixaban. Conclusion: Despite the relatively low use of anticoagulation and antithrombotic, nearly 15% of this cohort experienced major bleeding after AF diagnosis, including two fatal events. Ischemic stroke was rare but occurred in a high-risk patient that was anticoagulated with apixaban. These findings demonstrate limitations of existing risk-stratification tools in this unique population, and support the need for larger studies and evidence based guidelines for patients with bleeding disorders and AF.

Abstract Background: Recombinant activated factor VIIa (rFVIIa, NovoSeven®) is an FDA-approved medication for managing bleeding in patients with hemophilia A or B with inhibitors and for those with congenital factor VII deficiency. Its use has expanded off-label in the perioperative context to manage unexpected bleeding complications. However, there is still a gap in real-world data regarding institutional practices, dosing, and outcomes associated with rFVIIa. Methods: With IRB approval, we identified patients who received rFVIIa in the perioperative period between 2020 to 2024 at Mayo Clinic. A detailed chart review was conducted to gather demographic data, comorbid conditions, bleeding disorders, timing, and dosing of perioperative rFVIIa (pre-, intra-, and postoperative), along with postoperative outcomes. We focused on thrombotic and bleeding events, hospital readmissions, and return to the operating room (OR). Descriptive statistics were used for patient characteristics, rFVIIa dosing patterns, and postoperative complications. Type of surgical interventions were stratified based on UCLA perioperative risk stratifications, with a risk score of 5 equating to very high risk surgery and a score of 1 equating to very low risk surgery. Results: Of the 55 patients included, the median age at surgery was 42.3 years (SD 27.4), and 69% were male. The majority were non-Hispanic white (91%). The most common bleeding diatheses were Factor VII deficiency (54.6%), Factor VIII inhibitor (12.7%), and Glanzmann thrombasthenia (7.3%). Less frequent conditions included Hemophilia A (3.6%) and Hemophilia A with inhibitors (3.6%). Among patients with Factor VII deficiency, mild deficiency accounted for 65.9% of cases, followed by severe (19.5%) and moderate (14.6%) forms. Adjunctive medications to control bleeding included emicizumab, FEIBA, and rituximab. Mean estimated blood loss was 136 mL (SD 211 mL), and mean length of stay was 5.7 days (SD 6.4). Surgical risk strongly correlated with perioperative outcomes: blood loss increased from 19 mL in very low-risk surgeries to 352 mL in very high-risk surgeries, while mean length of stay increased from 4.5 days (risk 1) to 19 days (risk 4) and 11 days (risk 5). Actual rFVIIa dosing ranged from 7.2 to 7211.5 mcg/kg per dose, with a median of 67.4 mcg/kg and a mean of 852.8 mcg/kg, reflecting variability in clinical practice. When stratified by surgical risk, the highest median doses were observed in very low- and low-risk surgeries (84.4 and 86.8 mcg/kg, respectively), while very high-risk surgeries had the lowest median dose (30.0 mcg/kg). In the postoperative period, thrombotic events did not occur in the first 90 days but were documented in 1.8% of patients between 90 and 365 days and in 1.8% after 365 days. Bleeding complications were frequent and demonstrated predominance in the immediate post-op period. Within the first 30 days after surgery, 18.2% of patients experienced bleeding complications, with 3.6% classified as major and 14.5% classified as minor, based on ISTH criteria. Between 30 and 90 days, bleeding complications occurred in 9.1% of patients (3.6% major and 5.5% minor), between 90 and 365 days, bleeding was observed in 10.9% of patients, all of which were minor, and beyond one year, bleeding complications were documented in 23.6% of patients, with 3.6% major and 21.8% minor. Readmissions were also common and followed a similar time distribution. In the first 30 days, 7.3% of patients had readmissions related to the prior surgery, and 3.6% had unrelated readmissions. Between 30 and 90 days, 3.6% of readmissions were related and 3.6% were unrelated. Between 90 and 365 days, 3.6% were related and 14.5% were unrelated to the initial procedure. Returns to the OR occurred in 1.8% of patients between 30 and 90 days and in 1.8% between 90 and 365 days. Conclusions: In conclusion, perioperative rFVIIa was most frequently used for Factor VII deficiency but was also administered to patients with Factor VIII inhibitor and Glanzmann's thrombasthenia, as well as several rare congenital and acquired bleeding disorders. Postoperative thrombotic events were rare, while ISTH-defined bleeding complications and readmissions were common. Most bleeding complications were minor, but their frequency was highest in the early postoperative period and again beyond one year. High-risk surgeries were associated with greater blood loss, prolonged hospitalization, and a higher burden of postoperative complications.

Abstract Gentically driven classical hematological disorders have variable prevelance in the general population, sickle cell disease (SCD) being the most common at 30 per 100,000 people, hemophilia (hem) 12 per 100,000 people for hemophilia A, 4 per 100,000 people for hemophilia B, and thalassemia (thal) at 18 per 100,000 people, with regional and racial-ethnic variation across US. There has been a dramatic change in the therapeutic landscape for these diseases in the past decade. Several new drugs and biological therapies including gene therapies have been approved for each of these disorders. Clinicians utilize different information sources to assimilate this rapid influx of knowledge into their practice; in the era of social media, the readership is not limited to original publications. As research visibility influences clinical adoption and patient awareness, it is vital to understand the modalities of engagement of gene therapy studies by clinicians and patients. An altmetric score is a simple and effective way of understanding engagement with research across platforms. It. measures digital attention received by research output, allowing us to gauge the social impact of an article. We sought to compare the impact and scientific dissemination of publications of gene therapy trials in these 3 diseases by capturing the number of traditional citations and Altmetric assessment score. Methods: A PubMed search was conducted for gene therapy trials in SCD, Hem and Thal between 2015 to 2025 and citations were captured using metrics from Google Scholar. The Altmetric assessment score for each article was determined using www.altmetric.com which includes any mention by news outlets, blogs, Twitter (X), Facebook, and Mendeley reader counts. Descriptive statistics are reported for the number of citations as well as the Altmetric assessment score in each of the disease categories. Median and range were reported due to the skewed distribution of the data. Comparison across groups for significance was done using the Kruskal-Wallis test. Results: The number of qualifying studies for SCD (n=7) were lower than hem (n=21) and thal (n=12). Median PubMed citations were highest for SCD (147, range 4-436), followed by hem (26, range 0-828) and thal (42, range 0-801), though the difference was not statistically significant (p=0.4) Altmetric scores demonstrated differences that approached statistical significance with p=0.08: SCD had the highest median (422, range 4-770), driven by exceptional Twitter engagement, while hem and thal medians were 20 (range 0-2038) and 49 (range 0-825) respectively. Twitter/X was the leading social platforms for all diseases. Scholarly interest measured by Mendeley readers was also highest for SCD (median 195, range 11-542), with thal and hem medians at 50 (range 0-773) and 64 (range 8-646) respectively. Conclusion: We observed substantial variability in both academic and social media dissemination of practice-changing SCD, Hem and thal gene therapy studies, though not statistically significant likely due to the limited number of studies overall. Higher citation count and Altmetric score in SCD studies may reflect recent robust dissemination efforts by ASH and patient advocacy groups. Intentional promotion across academic and media platforms increases awareness, helping with early dissemination of updated information that could have significant impact on patient outcomes.

Abstract Introduction A 2017 survey by the American Society of Hematology found a widespread perceived shortage of classical hematologists in the US, which was compounded by a low trainee interest in the field (<5%) (Masselink LE, Blood Adv 2019). Recently, we reported that among hematologist/oncologists at the 64 National Cancer Institute (NCI)-designated cancer centers with clinical programs, only ~5% identify as classical hematologists, despite 15% of them including classic hematology (CH) patients in their practice (Go LT, Blood Adv, in press). However, there remains limited data on CH consult volumes at NCI-designated cancer centers (West CV, JCO Oncol Pract 2023). This study aimed to evaluate the volume and nature of CH outpatient consults at the Mayo Clinic Comprehensive Cancer Center (MCCC). Methods We reviewed electronic medical records to identify all completed outpatient consults in CH, malignant hematology (MH), and solid tumor oncology at MCCC in Rochester, Minnesota from January 1 to December 31, 2024. Consults were defined as either external or internal referrals for new patients seen in CH outpatient clinic. CH consults were further categorized by referral reasons and the type of physician (CH, MH, or fellow) performing the consultations. CH physicians were defined as those whose clinical practice primarily focuses on non-malignant hematologic conditions; one advanced practice provider (APP) was included in this group. Inpatient consults, electronic consults, and return visits were excluded. Results In 2024, a total of 17,153 outpatient consults were completed. Of these, 13.4% were CH, 30.5% were MH and 56.1% were solid tumor oncology. Among CH consults, the most common referral reasons were abnormal blood counts (68.3%), bleeding disorders (10.6%), thrombosis (11.8%), and other hematologic diagnoses (9.3%). Within abnormal blood counts, the leading indications were anemia (50.7%), thrombocytopenia (15.3%), leukopenia (11.0%), leukocytosis (9.1%), and pancytopenia (7.0%). Among bleeding disorders, the top reasons included suspected bleeding diathesis (49.4%), von Willebrand disease (24.5%), Hemophilia A (4.1%), Factor VII deficiency (3.7%), and platelet qualitative defect (3.4%). Thrombosis-related consults were most often for pulmonary embolism or deep vein thrombosis (43.2%), antiphospholipid syndrome (17.7%), thrombophilia (16.2%), portal vein thrombosis (4.1%), and splenic infarct (2.6%). The top ten referrals for a specific hematologic diagnosis were iron deficiency anemia (29.2%), pulmonary embolism or DVT (13.5%), immune thrombocytopenic purpura (10.3%), von Willebrand disease (6.9%), hemoglobinopathy (5.5%), antiphospholipid syndrome (5.5%), thrombophilia (5.1%), anemia of chronic kidney disease (2.4%), aplastic anemia (1.5%), and hereditary spherocytosis (1.4%). Of the 114 physicians at MCCC during the study period, 55 (48.2%) were medical oncologists, 54 (47.4%) primarily practiced MH, and only 5 (4.4%) were dedicated CH physicians. Despite comprising only 4.4% of the hematology/oncology workforce, CH physicians or fellows completed the majority (86.1%) of CH consults; MH physicians completed 13.8%. Conclusion CH consults represent a substantial portion of outpatient hematology referrals at MCCC, primarily for diagnostic evaluation of cytopenias or thrombotic/bleeding symptoms. However, a striking mismatch exists between CH physician representation (4.4%) and CH consult volume (13.4%). This imbalance has implications for quality, timeliness, and continuity of care for patients with non-malignant hematologic conditions. Our findings underscore the urgent need to expand recruitment and career development pathways in CH to address a huge clinical demand.

Abstract Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome resulting from immune dysregulation. While diagnostic and therapeutic guidelines (e.g., HLH-2004) are established for pediatric HLH, adult-onset HLH remains both a diagnostic and therapeutic challenge, with limited characterization and sparse outcome data. Here, we conduct a single-institution retrospective cohort study to evaluate clinical features, causes, and prognostic markers associated with outcomes. Methods: We performed a retrospective chart review of all adult patients (≥18 years) first diagnosed with HLH across all Mayo Clinic sites between January 1, 2006 and July 1, 2025. Diagnosis was based on hematologist adjudication at time of care. Patients with prior diagnoses of HLH or HLH related to T-cell therapy (CAR-T) were excluded. Clinical and laboratory variables were extracted from electronic health records. The primary outcome was overall survival (OS), defined as time from diagnosis of HLH to death or last follow-up. OS was estimated using the Kaplan-Meier method. Multivariable analysis to identify independent predictors of mortality was performed using a Cox proportional hazards regression model, adjusting for age at diagnosis, sex, HLH etiology, and relevant clinical and laboratory parameters. Model discrimination was assessed using Harrell's concordance index (c-index). Descriptive statistics were summarized using median and interquartile range (IQR) for continuous variables and frequency with percentages for categorical variables. Results: A total of 203 patients diagnosed with HLH were included. The median age at diagnosis was 55 years (range 18-86). The cohort was predominantly male (n=130, 64%) and White (n=163, 80%). The majority of diagnoses occurred in more recent years, with 75 patients (36.9%) diagnosed between 2021–2025, 61 (30.0%) between 2016–2020, and 43 (21.2%) between 2011–2015. Prior to HLH diagnosis, 86 patients (42.4%) had a history of malignancy, 55 (27.1%) had a history of autoimmune disease, and 28 (13.8%) had a history of transplant. The most common HLH etiologies were malignancy-associated (n=99, 49%), infectious (n=51, 25%), and autoimmune (n=24, 12%), in addition to idiopathic (n=6, 3%), post-transplant lymphoproliferative disease or graft-vs-host disease (n=3, 1%), drug-induced (n=3, 1%), or primary HLH (n=1, 0.5%). The most common malignancies included T-cell (n=35, 17.2%) and diffuse large B-cell lymphoma (n=24, 11.8%). Forty-four cases (21.7%) were associated with Epstein-Barr virus (EBV), either through overt viremia or malignancies with EBV positivity on pathology report. Five patients (2.5%) had COVID-19–associated HLH and 2 (1.0%) were attributed to immune checkpoint inhibitors. Overall, 164 patients (80.8%) met the HLH-2004 diagnostic threshold of ≥5 out of 8 criteria, while 196 (96.6%) met the HLH-2024 ≥4 of 7 modified criteria. Among patients with available information, elevated ferritin was present in 197 of 198 (99.5%), fever in 185 of 202 (91.6%), cytopenias involving ≥2 lineages in 184 of 199 (92.5%), hemophagocytosis in 156 of 182 (85.7%), elevated sCD25 in 117 of 121 (96.7%), hypertriglyceridemia in 117 of 186 (62.9%), hypofibrinogenemia in 118 of 196 (60.2%), splenomegaly in 125 of 188 (66.5%), and impaired NK cell activity in 16 of 25 (64.0%). In addition, hepatomegaly was noted in 57 of 195 patients (29.2%). After a median follow-up of 58.3 months, median OS was 62 days (95% CI 40-110) from day of diagnosis. In a multivariable Cox proportional hazards model with moderate discrimination (c-index=0.75), after adjusting for age at diagnosis and sex, T-cell lymphoma–driven HLH (HR 1.78, 95% CI 1.05–3.00, p = 0.03) and elevated blood urea nitrogen (median 51.0 mg/dL, IQR 27.9–99.1; HR 2.07, 95% CI 1.37–3.13, p < 0.005) were independently associated with shorter OS Conclusions: In this cohort of adult patients with HLH, malignancy was found to be the most common trigger for HLH. T-cell malignancies in particular were strongly correlated with poor survival. Elevated blood urea nitrogen at diagnosis also identified patients at significantly higher risk of death, consistent with other critical illnesses that can present with multi-organ failure. These findings emphasize the need for adult-specific prognostic tools incorporating disease etiology and organ dysfunction markers to better stratify risk and guide clinical management in adult-onset HLH.

Abstract Background: In 2022, Medicare alone spent $42.1 billion on prescription drugs, with antineoplastic and classical hematology drugs accounting for 44% and 8% of the total, respectively (2024 MedPAC Data Book). While antineoplastic drugs have been extensively studied, classical hematology drugs have received comparatively little attention. We analyzed US Food and Drug Administration (FDA) approvals of classical hematology drugs over the past 30 years and examined their per-patient costs and annual total US sales. Methods: We identified all classical hematology drugs (those prescribed by hematologist/oncologists for non-malignant indications) approved by the FDA from January 1, 1995 to December 31, 2024, including novel pharmaceuticals (synthesized from chemical compounds), biologics (derived from living organisms), and biosimilars (highly similar, but not identical, to biologics previously approved). Cost estimates for 2024 were based on wholesale acquisition costs (WAC), using annual WAC for continuous-duration treatments and typical course WAC for fixed-duration treatments. WAC and US gross sales data for 2024 were obtained from IPD Analytics (Aventura, FL). Results: A total of 98 classical hematology drugs were approved over the past 30 years—11% in 1995–2004, 26% in 2005–2014, and 63% in 2015–2024. These included pharmaceuticals (36%), biologics (54%), and biosimilars (10%). Six gene therapies received approval: 3 for hemophilia and 1 each for sickle disease, beta thalassemia, and sickle cell disease/beta thalassemia (dual indication). Common categories of indications included bleeding (31%), anemia (30%), neutropenia (9%), and thrombocytopenia (9%). Leading diagnoses were hemophilia (25%), chemotherapy-induced neutropenia (9%), thromboembolism (8%), paroxysmal nocturnal hemoglobinuria (PNH; 7%), anemia of chronic kidney disease (6%), iron deficiency anemia (6%), and immune thrombocytopenia (5%). The median cost for gene therapies was $2.9 million per treatment (range: $2.2 million–$3.5 million). Among non-gene therapies, median costs were $3,000 per course for fixed-duration treatments (range: $64–$378,000) and $467,000 annually for continuous-duration treatments (range: $2,400–$1.8 million). The most expensive fixed-duration treatments targeted hemophagocytic lymphohistiocytosis ($378,000/8-week course), while the most expensive continuous-duration treatments were for hemophilia (median: $630,000/year; range: $270,000–$853,000). Estimated 2024 US gross sales across all drugs exceeded $70 billion. Top-selling indications included thromboembolism ($43.5 billion), hemophilia ($6.9 billion), immune thrombocytopenia ($4.9 billion), PNH ($4.7 billion), chemotherapy-induced neutropenia ($2.8 billion), anemia of chronic kidney disease ($2.0 billion), and iron deficiency anemia ($1.8 billion). Total sales for all gene therapies combined were $143 million. Six drugs have been discontinued (year approved/year discontinued/reason): betrixaban (2017/2020/business), daprodustat (2023/2024/business), fidanacogene elaparvovec (2024/2025/business), oprelvekin (1997/2011/business), peginesatide (2012/2013/safety), and voxelotor (2019/2024/safety). There are limitations to our study. Some drugs have non-classical hematology indications (anticoagulants in atrial fibrillation; luspatercept in myelodysplastic neoplasm) and/or may also be prescribed by non-classical hematologists (erythropoiesis stimulating agents by nephrologists and medical oncologists). We were unable to disaggregate the sales data in these situations. Therefore, the annual sales for certain indications may be overestimated. Conclusions: Classical hematology drugs contribute substantially to US prescription drug spending, with over $70 billion in annual sales and medications for thromboembolism accounting for over half of the costs. Approvals have accelerated over the past three decades, doubling each decade. Biologics and biosimilars now represent two-thirds of approvals. Continuous-duration treatments, particularly for rare hereditary diseases like hemophilia, carry significant financial burden, with annual costs per patient often exceeding $0.5 million. In these conditions, if gene therapies demonstrate durable efficacy, they may prove to be cost-effective alternatives. As more gene therapies are developed, evaluating their long-term value relative to chronic high-cost treatments will be essential for shaping future reimbursement and access strategies.