Schaefer, Jordan K.

Abstract Systems-based hematology (SBH) is an emerging discipline focused on optimizing care delivery for patients with hematologic disorders within complex health care systems. Despite its growing importance, the field lacks a formal definition, standardized curriculum, and clear career pathway, hindering widespread adoption and training of future SBH experts. We sought to define core principles, competencies, challenges, and future directions of SBH to identify foundational components for a potential educational curriculum. Semistructured interviews were conducted with 8 SBH experts. Expert participants were identified through their committee involvement with the American Society of Hematology. Five overarching themes emerged: (1) The accidental expert: SBH careers have developed organically and reactively in response to pressing institutional needs, not through formal training; (2) Defining the unseen: experts define the field pragmatically by its function and roles; (3) The SBH toolkit: success requires a hybrid skillset combining clinical hematology expertise with health systems science (HSS) principles; (4) The architect's dilemma: the field's growth is hindered by interdependent challenges of building a curriculum, awareness, and securing resources; and (5) Charting the future: the discipline is poised for growth, driven by increasing health care complexity and specialization. SBH represents the nexus of HSS principles and hematology care. Formalizing SBH requires a multipronged approach, including developing a standardized curriculum that equips learners with a hybrid skillset, creating clear value for health systems and patients, and fostering a community of practice through professional societies. These findings provide a foundational framework for developing educational resources and institutional support necessary to continue advancing SBH.

Introduction: Systems-based hematology (SBH) is an emerging field focused on improving hematology care delivery through quality improvement (QI) and health systems science (HSS). However, a universal definition and standardized training curriculum are lacking. This study aimed to explore experts' perspectives on defining SBH, identify core knowledge and skills, and discuss challenges and opportunities in developing a curriculum. Methods: Semi-structured interviews were conducted with eight hematologists who have expertise in SBH through practical experience, scientific publications, and serve on related committees for the American Society of Hematology. These interviews were automatically transcribed through Microsoft Teams. Thematic analysis, using both inductive and deductive coding, was employed to identify themes and subthemes from the verbatim interview transcripts. This was accomplished with a large language model (LLM; Google Gemini Advanced, June 2024). Results: In combination, these semi-structured interviews lasted approximately 400 minutes and generated 231 pages of transcript text with 63117 words for analysis. Five main themes and associated subthemes were identified. (1) Defining SBH: experts highlighted the lack of a universal definition for SBH, emphasizing the reason it is often defined by its functions, such as improving healthcare delivery, ensuring appropriate use of resources, and addressing disparities in care. They often compared SBH to other fields like antimicrobial stewardship or implementation science to illustrate its expansive role and scope. (2) The Role and Scope of SBH: experts described SBH as encompassing a broad range of activities, including improving healthcare delivery, implementing QI initiatives, conducting pragmatic research, and advocating for policy changes at various levels. They emphasized the importance of data-driven approaches and collaboration with other healthcare professionals. (3) Training and Education in SBH: the lack of formal training programs and curricula for SBH was a recurring theme. Experts suggested that a comprehensive curriculum should include QI methodologies, implementation science, clinical informatics, health economics, leadership skills, and hematology-specific examples and case studies. They proposed various delivery methods, including asynchronous online modules, virtual workshops, and in-person sessions, targeting hematology fellows, junior faculty, and other healthcare professionals involved in hematology care. They unanimously agreed that a SBH curriculum could borrow heavily from an established HSS curriculum but should incorporate hematology-specific examples. (4) Challenges and Barriers to Implementing SBH: experts identified several challenges, including the lack of awareness and recognition of SBH among healthcare professionals and administrators, resource constraints, and the need for institutional buy-in. They also highlighted the technical difficulty of measuring and demonstrating the value of SBH interventions, particularly in terms of cost savings and improved patient outcomes. (5) The Future of SBH: despite the challenges, experts expressed optimism about the future of SBH, predicting its growing importance and expanding scope, including malignant hematology, community practice, and pediatrics. They envisioned SBH playing a crucial role in addressing rising healthcare costs, quality concerns, and disparities in care. They also anticipated the integration of new technologies like artificial intelligence, “virtual” care delivery, and molecular genetics into SBH practice. Conclusions: This study provides valuable insights into the current state of SBH and the need for a standardized curriculum. The findings can inform the development of educational resources and training programs to equip future practitioners with the necessary knowledge and skills to effectively practice SBH and improve hematology care delivery. This study also sheds light on the utility of qualitative research within SBH and the emerging analytical tools that will require further exploration and standardization (e.g., LLM prompt engineering).

The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease provide strategies for the prevention, diagnosis, and treatment of venous thromboembolism (VTE) in adult patients with cancer. VTE is a common and life-threatening condition in patients with cancer, and its management often requires multidisciplinary efforts. The NCCN panel is comprised of specialists spanning various fields, including cardiology, hematology, medical oncology, internal medicine, interventional radiology, and pharmacology. The content featured in this issue specifically addresses the evaluation and recommended treatment options outlined in the NCCN Guidelines for the diverse subtypes of cancer-associated VTE.

ObjectiveWhile thrombosis and pregnancy loss are the best‐known clinical features of antiphospholipid syndrome (APS), many patients also exhibit “extra‐criteria” manifestations, such as thrombocytopenia. The mechanisms that drive APS thrombocytopenia are not completely understood, and no clinical biomarkers are available for predicting antiphospholipid antibody (aPL)–mediated thrombocytopenia. Calprotectin is a heterodimer of S100A8 and S100A9 that is abundant in the neutrophil cytoplasm and released upon proinflammatory neutrophil activation. Here, we sought to evaluate the presence, clinical associations, and potential mechanistic roles of circulating calprotectin in a cohort of primary APS and aPL‐positive patients.MethodsLevels of circulating calprotectin were determined in plasma by the QUANTA Flash chemiluminescent assay. A viability dye‐based platelet assay was used to assess the potential impact of calprotectin on aPL‐mediated thrombocytopenia.ResultsCirculating calprotectin was measured in 112 patients with primary APS and 30 aPL‐positive (without APS criteria manifestations or lupus) patients as compared to patients with lupus (without APS), patients with unprovoked venous thrombosis (without aPL), and healthy controls. Levels of calprotectin were higher in patients with primary APS and aPL‐positive patients compared to healthy controls. After adjustment for age and sex, calprotectin level correlated positively with absolute neutrophil count (r = 0.41, P < 0.001), positively with C‐reactive protein level (r = 0.34, P = 0.002), and negatively with platelet count (r = −0.24, P = 0.004). Mechanistically, we found that calprotectin provoked aPL‐mediated thrombocytopenia by engaging platelet surface toll‐like receptor 4 and activating the NLRP3‐inflammasome, thereby reducing platelet viability in a caspase‐1‐dependent manner.ConclusionThese data suggest that calprotectin has the potential to be a functional biomarker and a new therapeutic target for APS thrombocytopenia.image

Abstract Introduction Heparin induced thrombocytopenia (HIT) is often not considered as a potential etiology of thrombocytopenia. The gradual 5 to 14 day decline in platelet count (PC) may not be easily recognized by busy clinicians. The life-threatening complications of HIT are potentially preventable with prompt recognition and management. Implementation of computer-based clinical decision support systems (CDSS) may aid in addressing these issues. Such systems have shown promise in increasing provider recognition, appropriate testing, and management of a variety of conditions. Methods We developed, implemented and evaluated a CDSS designed to identify patients at risk for HIT. The CDSS was integrated into the electronic medical record (Centricity Enterprise, GE) at Mayo Clinic Rochester. The CDSS identified inpatients with recent or active use of heparin medications, who experienced a 50% PC drop. For such patients, the system generated an electronic message alerting their care team of the 50% PC drop and asked them to consider the possibility of HIT. A link to a website with recommendations for the diagnosis and management of HIT was included with the alert. Providers were encouraged to assess for HIT using the 4Ts Score and, if indicated, the anti-heparin/platelet factor 4 (PF4) antibody assay. We performed a retrospective chart review of consecutive patients identified by the system and equal number of randomly generated controls that did not trigger alerts. The accuracy of the algorithm was assessed and errors were analyzed for clinical significance. Patient risk of HIT was evaluated by using the 4Ts Score and the HIT Expert Probability (HEP) Score. Alert effect was classified as: Results Over the study period, 2,785 patients had a total of 37,060 PC (13.31 PC/patient) and the CDSS triggered a total of 124 alerts. About 10% of alerted clinicians reviewed the website with recommendations on the management of HIT. A total of 117 patients generating alerts were compared to 124 controls. Demographics between the two groups were similar. The CDSS had a 95% sensitivity for accurately detecting a 50% platelet drop for inpatients on heparin. The specificity was 74%. The Objective alert effect was found in 21% of the cases (16% of providers changed their management and 5% documented that HIT was felt to be unlikely). The most common actions taken after receiving the alert were obtaining a HIT antibody assay, withholding heparin, consulting a subspecialty service, and/or changing anticoagulants. The Probable alert effect was 14% of the cases. HIT had been considered before the alert was sent in 11% of patients. Alert effect was classified as None for the remaining 54% of patients. Anti-heparin/PF4 testing for HIT was ordered for 25% of the intervention patients compared to 3% of controls. For the intervention group, PF4 was negative for 86% of tested patients, equivocal for 10%, and positive in 3%. All PF4 tests were negative in the control group. 4Ts score was greater than or equal to 4 in 38% of patients and averaged 3.1 (range 7 to 0). HEP score averaged 4 (range 14 to -4). Risk calculations showed a trend to higher risk with therapeutic heparin compared to prophylactic heparin preparations. HIT risk scores were comparable by admitting service and diagnosis. Conclusions Our CDSS successfully identified upwards of 95% of inpatients at risk for HIT. However, approximately 26% of the alerts were false positives. Only a small proportion of clinicians accessed the website with recommendations for the diagnosis and management of HIT but patients with a suspected HIT were managed appropriately. Of the patients triggering a HIT alert, 38% had an intermediate or high clinical probability of HIT based on the 4Ts Score that would be an indication for further testing. This result highlights the success of the CDSS in identifying patients needing further evaluation but also the difficulties of a computer-based CDSS in representing all the important clinical criteria for the diagnosis of HIT. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Ex-vivo analysis of platelet inhibition by aspirin (ASA) suggests that an optimal decrease in platelet function occurs when 90-95% of platelets are inhibited with ASA. In patients with known vascular disease a daily aspirin decreases the probability of a future vascular event by about 25%. However, platelets from patients with diabetes mellitus (DM) are highly reactive with an increased turnover rate, and prophylaxis with a daily aspirin is not nearly as effective. Because platelet response among individuals is highly variable, we developed a light aggregation based assay that measures platelet function with 100% blockade of an individual’s platelet thromboxane A2 receptor (100% “aspirinated” platelets). This assay is utilized to determine the percentage of platelets inhibited by aspirin, “aspirinated” platelets (ASA-PLTS). Methods Platelet prostaglandin agonist (PPA), (Analytical Control Systems, Fishers IN) an agonist known to be sensitive to the amount of platelet inhibition with aspirin, was used to develop a light aggregometry based technique that measures ASA-PLTS. A specific inhibitor of the thromboxane A2 receptor SQ 29,548(S.Q.)(Cayman Chemicals, Ann Arbor, Mi.) was used to verify that maximal (100%) inhibition of platelets by aspirin was present 2 hrs after ingestion of 325mg ASA. In separate experiments platelets obtained 2 hrs after 325mg ASA (100% ASA-PLTS) were mixed with platelets from the same subject obtained just before aspirin ingestion (0% ASA-PLTS) so that the PPA light aggregation slopes could be measured with 95%, 90%, 85% and 80% ASA-PLTS. The slope of the PPA-AGG curve measured 24 hours after 325mg ASA was compared to the slopes obtained with known concentrations of ASA-PLTS using the formula T24-T2/ T0-T2. (T24= slope 24 hrs post ASA; T2=slope 2 hrs post ASA; T0=slope off ASA). Results Two hours after ingestion of 325mg ASA the slopes of the PPA-AGG curves with and without S.Q. were identical in 7 normal subjects reflecting the aspirin response with 100% ASA-PLTS. Because of the large range of response among individuals, eac subject served as their own control to develop an aspirin response curve for the different percentages of ASA-PLTS. 24 hours after 325mg ASA the percentage of ASA-PLTS in 6 of 7 normal subjects was greater than 90%. Conclusion 1. The slope of the PPA stimulated light aggregation curve with and without S.Q. obtained 2 hrs after 325mg of aspirin in normal subjects can be used as a measure of 100% ASA-PLTS response. 2. Platelet response in most normal subjects 24 hours after aspirin shows that at least 90% of their platelets are “aspirinated”. Comment This technique can identify patients, like those with DM whose percentage of ASA-PLTS may fall below 90% at the end of the dosing interval. A shorter aspirin dosing interval in these patients may result in a higher percentage of ASA-PLTS at the end of the dosing period and possibly decrease the patient’s probability of a subsequent vascular event, but these questions can only be answered with clinical studies. Disclosures: No relevant conflicts of interest to declare.