Cost-effectiveness of sutimlimab in cold agglutinin disease.

Primary cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by cold-reactive antibodies that bind to red blood cells and lead to complement-mediated hemolysis. Patients with primary CAD experience the burden of increased health resource utilization and reduced quality of life. The standard-of-care (SOC) in patients with primary CAD has included cold avoidance, transfusion support, and chemoimmunotherapy. The use of sutimlimab, a humanized monoclonal antibody that selectively inhibits C1-mediated hemolysis, was shown to reduce transfusion-dependence and improve quality of life across two pivotal phase 3 studies, further supported by 2-year extension data. Using data from the transfusion-dependent patient population that led to sutimlimab's initial FDA approval, we performed the first-ever cost-effectiveness analysis in primary CAD. The projected incremental cost-effectiveness ratio (ICER) in our Markov model was $2 340 000/QALY, significantly above an upper-end conventional US willingness-to-pay threshold of $150 000/QALY. These results are consistent across scenarios of higher body weight and a pan-refractory SOC patient phenotype (i.e., treated sequentially with bendamustine-rituximab, bortezomib, ibrutinib, and eculizumab). No parameter variations in deterministic sensitivity analyses changed our conclusion. In probabilistic sensitivity analysis, SOC was favored over sutimlimab in 100% of 10 000 iterations. Exploratory threshold analyses showed that significant price reduction (>80%) or time-limited treatment (<18 months) followed by lifelong clinical remission off sutimlimab would allow sutimlimab to become cost-effective. The impact of sutimlimab on health system costs with longer term follow-up data merits future study and consideration through a distributional cost-effectiveness framework.

Evaluating the clinical validity of genes related to hemostasis and thrombosis using the Clinical Genome Resource gene curation framework.

BACKGROUND: Inherited bleeding, thrombotic, and platelet disorders (BTPDs) are a heterogeneous set of diseases, many of which are very rare globally. Over the past 5 decades, the genetic basis of some of these disorders has been identified, and recently, high-throughput sequencing has become the primary means of identifying disease-causing genetic variants. OBJECTIVES: Knowledge of the clinical validity of a gene-disease relationship is essential to provide an accurate diagnosis based on results of diagnostic gene panel tests and inform the construction of such panels. The Scientific and Standardization Committee for Genetics in Thrombosis and Hemostasis undertook a curation process for selecting 96 TIER1 genes for BTPDs. The purpose of the process was to evaluate the evidence supporting each gene-disease relationship and provide an expert-reviewed classification for the clinical validity of genes associated with BTPDs. METHODS: The Clinical Genome Resource (ClinGen) Hemostasis/Thrombosis Gene Curation Expert Panel assessed the strength of evidence for TIER1 genes using the semiquantitative ClinGen gene-disease clinical validity framework. ClinGen Lumping and Splitting guidelines were used to determine the appropriate disease entity or entities for each gene, and 101 gene-disease relationships were identified for curation. RESULTS: The final outcome included 68 Definitive (67%), 26 Moderate (26%), and 7 Limited (7%) classifications. The summary of each curation is available on the ClinGen website. CONCLUSION: Expert-reviewed assignment of gene-disease relationships by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel facilitates accurate molecular diagnoses of BTPDs by clinicians and diagnostic laboratories. These curation efforts can allow genetic testing to focus on genes with a validated role in disease.

The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included 4 phases: 1) Phase I, criteria generation by surveys and literature review; 2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; 3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and 4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into 6 clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and 2 laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2 -glycoprotein I antibodies). Patients accumulating at least 3 points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria versus the 2006 revised Sapporo classification criteria had a specificity of 99% versus 86%, and a sensitivity of 84% versus 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

2023 ACR/EULAR antiphospholipid syndrome classification criteria.

OBJECTIVE: To develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR. METHODS: This international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators' consensus as the gold standard. RESULTS: The 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1-7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti-ß2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%. CONCLUSION: These new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.

Impact of Prophylactic Antibacterials on Coagulation Profiles and Bleeding in Patients with Acute Myeloid Leukemia/Myelodysplastic Syndrome.

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often receive antibacterial prophylaxis. Antibacterial agents can cause elevations in the prothrombin time and international normalized ratio (INR). The impact of prophylactic antibacterials on the coagulation profiles and bleeding risk in patients with AML/MDS is unknown. We evaluated patients with AML or MDS who were being admitted to the hospital. The cohort was divided into two groups of patients: (1) those receiving and (2) those not receiving prophylactic antibacterials, at the time of admission. We conducted a retrospective cohort study of adult patients with AML/MDS admitted to Yale-New Haven Hospital between 2015-2019. The study was approved by the Yale Institutional Review Board. Inclusion criteria included patients >18 years old with a diagnosis of AML or MDS admitted to the hospital. We identified 150 individual patient encounters with active AML/MDS admitted to Yale-New Haven of which 32 occurred while on and 118 while off antibacterial prophylaxis. Median duration of pre-admission antibacterial exposure was 2 (range: 0.07-24) months. Patients on antibacterial prophylaxis had higher INR (median 1.14 vs. 1.03, p = 0.0002), and higher partial thromboplastin time prolongation (median 26.5 vs. 24.3, p < 0.0014), than patients without antibacterial prophylaxis. Patients without antibacterial prophylaxis had higher rates of bleeding using the ISTH-defined criteria (24.6% vs. 6.3%, p = 0.043), including higher rates of ISTH major (2 vs. 0) and clinically relevant bleeding (9 vs. 0). Patients with AML/MDS on antibacterial prophylaxis were more likely to have an abnormal coagulation profile when compared with their counterparts not on prophylaxis. Conversely, rates of bleeding were higher in patients not on prophylaxis. These data suggest that prophylactic antibacterials do not increase bleeding risk in patients with AML/MDS.

Consensus recommendations on peripheral blood smear review: defining curricular standards and fellow competency.

Graduate medical education training in hematology in North America is accredited by the Accreditation Council for Graduate Medical Education (ACGME). Trainees routinely review peripheral blood smears (PBS) in providing clinical care. Competency in PBS review at graduation is required by the ACGME. However, there are no consensus guidelines on best practices surrounding PBS review, education, or competency. We describe the generation of proposed theory and the consensus recommendations developed through a multi-institutional focus group, developed using constructivist grounded theory and a modified nominal group technique. Eight academic hematologists, spanning classical and malignant hematology, enrolled and participated in 2 one-hour focus groups. All routinely worked with fellows and half had formally instructed trainees on PBS interpretation. Focus group data were analyzed using mixed-methods techniques. Tenets of emerging theory were identified through inductive coding. Consensus recommendations (CR) were generated. Participants reviewed CR in an iterative fashion until consensus was reached. Strong consensus was reached on multiple aspects of PBS education. All agreed that trainees should learn PBS review through a systematic approach. Group discussion focused on disorders of red and white blood cells. The diagnoses of acute leukemia and thrombotic microangiopathies were most commonly discussed, with specific emphasis on disorders in which prompt recognition was required to avert significant patient morbidity. These CR offer external validity to future research and curricular development for both PBS review and other visuospatial tasks in medical education.

Sex differences in long-term outcomes of patients with deep vein thrombosis.

OBJECTIVE: Sex differences in short-term outcomes of patients with deep vein thrombosis (DVT) have been reported, but differences in long-term outcomes remain poorly characterized. This study aimed to evaluate sex differences in long-term mortality, venous thromboembolism (VTE)-related mortality, and bleeding-related mortality in patients with DVT at a tertiary care center. METHODS: A retrospective chart review from 2012 to 2018 of all consecutive patients diagnosed with DVT was performed. Patients were grouped by sex, and baseline characteristics and treatment modalities were compared. Long-term outcomes of recurrent VTE, bleeding, and related mortalities were analyzed. Multivariable regression analysis was performed to determine factors associated with overall mortality. RESULTS: A total of 1043 (female = 521 and male = 522) patients with DVT were captured in this study period. Female patients were older (64.7 vs 61.6 years old, p = 0.01) and less likely to be obese (68.2% vs. 71.1%, p = 0.04),but had a higher average Caprini score (6.73 vs 6.35, p = 0.04). There was no difference in anatomic extent of DVT, association with PE, and severity of PE between sexes. Most patients (80.5%) were treated with anticoagulation, with no differences in choice of anticoagulant or duration of anticoagulation between females and males. Male patients were more likely to undergo catheter-directed thrombolysis (CDT) for DVT (4.2% vs 1.7%, p = 0.02) and PE (2.7% vs 0.9%, p = 0.04). Female patients were more likely to receive systemic thrombolysis for PE (2.9% vs 1.1%, p = 0.05). After an average 2.3 years follow-up, there was significantly higher bleeding complications among females (22.2% vs 16.7%, p = 0.027). The overall mortality rate was 33.5% and not different between males and females. Females were more likely to experience VTE-related mortality compared to males (3.3% vs 0.6%, p = 0.002). On regression analysis, older age (OR = 1.04 [1.03-1.06]), cancer (OR = 7.64 [5.45-10.7]), and congestive heart failure (OR = 3.84 [2.15-6.86]) were independently associated with overall mortality. CONCLUSIONS: In this study, there was no difference in overall long-term mortality between sexes for patients presenting with DVT. However, females had increased risk of long-term bleeding and VTE-related mortality compared to males.

Association of iron infusion reactions with ABO blood type.

OBJECTIVES: We sought to determine risk factors for iv iron infusion-related reactions (IRR), and identify strategies for iron repletion after IRR. METHODS: We conducted a retrospective chart review of patients treated in the classical hematology clinic at Yale Cancer Center (n = 330 consecutive patients) from 2016 to 2021, who received iv ferumoxytol (60.3%), iron sucrose (14.8%), or iron dextran (10.9%). RESULTS: The iv iron IRR was noted in 58 (17.6%) patients, 62.1% of whom had previously tolerated iv iron. The severity of IRR was mild in 22, moderate in 23, and severe in 11 patients. Most (72.4%) patients who experienced IRR tolerated a subsequent iv iron infusion. On multivariable analysis, a history of non-medication allergies was associated with greater odds of IRR (odds ratio [OR] 2.12, 95% confidence interval (CI): 1.16-3.87, p = .01). No patients with type AB blood, and few with type A blood (n = 6), had IRR; compared to type A or AB together, patients with type B (OR 5.00, 95% CI: 1.56-16.06, p = .007) or type O (OR 3.71, 95% CI: 1.44-9.55, p = .007) blood had greater odds of IRR. CONCLUSIONS: This study highlights a possible association of blood type with iv iron IRR; prospective studies with larger patient numbers are warranted to explore this association.

The case for classical haematology: the impact of a name and the future of a field.

The entirety of haematology not involving blood cancers is variably referred to as benign haematology, non-malignant haematology, and classical haematology. Existential challenges face this broad, diverse, and historically significant field, including a workforce shortage and serious perception issues among trainees. Although the problem has been best documented in the USA, there is evidence to suggest it is more widespread. In this Viewpoint, we argue that use of the terms benign and non-malignant to describe this field dismisses patient suffering, dampens trainee interest, and diminishes the field as a whole. We propose more uniform adoption of the term classical haematology by organisations, academic divisions, and clinical practices, as this term avoids the conscious and unconscious devaluation of the "benign" and "non-malignant" descriptors. Unlike the alternatives, the term classical haematology evokes the field's rich, centuries-long history of numerous scientific advances central to every aspect of medicine, including discoveries by women and people of colour, thereby fostering interest and recruitment among trainees and dignifying patients living with serious non-cancerous haematological diseases.

Association of renalase with clinical outcomes in hospitalized patients with COVID-19.

Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March-June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if <18 years, or opted out of research. The primary composite outcome was intubation or death within 180 days. Secondary outcomes included mortality alone, intensive care unit admission, use of vasopressors, and CPR. Enrolled patients had mean age 64 years (SD±17), were 53% males, and 48% non-whites. Mean renalase levels was 14,108·4 ng/ml (SD±8,137 ng/ml). Compared to patients with high renalase, those with low renalase (< 8,922 ng/ml) were more likely to present with hypoxia, increased ICU admission (54% vs. 33%, p < 0.001), and cardiopulmonary resuscitation (10% vs. 4%, p = 0·023). In Cox proportional hazard model, every 1000 ng/ml increase in renalase decreased the risk of death or intubation by 5% (HR 0·95; 95% CI 0·91-0·98) and increased survival alone by 6% (HR 0·95; CI 0·90-0·98), after adjusting for socio-demographics, initial disease severity, comorbidities and inflammation. Patients with high renalase-low IL-6 levels had the best survival compared to other groups (p = 0·04). Renalase was independently associated with reduced intubation and mortality in hospitalized COVID-19 patients. Future studies should assess the pathophysiological relevance of renalase in COVID-19 disease.

Impact of COVID-19 on Hematology-Oncology Fellowship Programs: A Quantitative and Qualitative Survey Assessment of Fellowship Program Directors.

PURPOSE: The COVID-19 pandemic led to unprecedented challenges in medical training, and we sought to assess the specific impact of COVID-19 on hematology-oncology (HO) fellowship programs. METHODS: We conducted a cross-sectional anonymous online survey of 103 HO program directors (PDs) in conjunction with the American Society of Hematology (ASH) and ASCO. We sought to assess the specific impact of COVID-19 on HO fellowship programs' clinical, educational, and research activities, evaluate perceptions regarding PD and trainee emotional and mental health, and identify ways to support programs. Data were analyzed using descriptive statistics, parametric and nonparametric tests, and multivariable logistic regression models. Responses to open-ended questions were analyzed with thematic analysis. RESULTS: Significant changes to fellowship activities included transitioning fellow training from outpatient clinics to telehealth (77.7%), shifting to virtual education (94.2%), and moving to remote research work (63.1%). A minority (21.4%) of PDs reported that their fellows were redeployed to cover non-HO services. Most PDs (54.4%) believed COVID-19 had a slight negative impact on fellowship training. PD self-reported burnout increased significantly from 15.5% prepandemic to 44.7% during the pandemic, and most PDs witnessed minor signs of fellow burnout (52.4%). Common PD concerns included inadequate supervision for telehealth activities, reduced opportunities for fellow advancement and promotion, lack of professional development activities, limited research operations and funding, program financial constraints, and virtual recruitment. CONCLUSION: We encourage institutions and national societies to allocate resources and develop programs that can support fellowships and mitigate the potential negative effects of COVID-19 on trainee and PD career development.

Clinical characteristics, time course, and outcomes of major bleeding according to bleeding site in patients with venous thromboembolism.

BACKGROUND: Bleeding is the most dreaded complication of anticoagulant therapy for acute venous thromboembolism (VTE). Limited data exist about patient characteristics, time course and outcomes of major bleeding, according to the bleeding site. METHODS: We used the data from the Registro Informatizado Enfermedad TromboEmbólica (RIETE) registry (03/2001-07/2018) and identified patients who suffered from major bleeding during anticoagulation. We assessed patient characteristics, time course, and 30-day outcomes including mortality, re-bleeding, and VTE recurrences, according to bleeding site. RESULTS: Among 78,136 patients with VTE receiving anticoagulation, 2244 (2.9%) suffered from major bleeding (gastrointestinal in 800, intracranial in 417, hematoma in 410, genitourinary in 222, retroperitoneal in 145; other sites in 250). There were variations in baseline characteristics, including older age (P < 0.001) and predominance of women (70.2% [95% confidence interval [CI]]: 65.6-74.6% versus 50.5%, 95% CI: 48.2-52.9, P < 0.001) in patients with hematoma, compared with other patients. Overall, 82.7% of hematomas and 81.4% of retroperitoneal bleeds occurred in the first 90 days after the diagnosis of the VTE event, compared with only 50.6% of intracranial bleeds. Across the bleeding subgroups, 30-day all-cause mortality rates were highest in patients who suffered from intracranial bleeding (41.0%; 99% confidence interval [CI]: 34.8-47.4%), and lowest in patients who suffered from hematoma (17.8%; 99% CI: 13.2-23.2%). Patients who suffered from a major bleeding event in the first 30 days after VTE had significantly higher odds at 90-day follow-up to develop mortality (including from bleeding), recurrent VTE, and recurrent major bleeding (all Ps < 0.001). Variations were observed in the results according to the bleeding site. CONCLUSIONS: Major bleeding is a serious complication in VTE patients. Patient characteristics, time course and outcomes varied substantially according to the bleeding site. Additional studies are needed to tease out the impact of patient risk factors, treatment regimens, and a potential distinct effect from the site of bleeding. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02832245 (RIETE registry).

A guide to molecular and functional investigations of platelets to bridge basic and clinical sciences.

Platelets have been shown to be associated with pathophysiological process beyond thrombosis, demonstrating critical additional roles in homeostatic processes, such as immune regulation, and vascular remodeling. Platelets themselves can have multiple functional states and can communicate and regulate other cells including immune cells and vascular smooth muscle cells, to serve such diverse functions. Although traditional platelet functional assays are informative and reliable, they are limited in their ability to unravel platelet phenotypic heterogeneity and interactions. Developments in methods such as electron microscopy, flow cytometry, mass spectrometry, and 'omics' studies, have led to new insights. In this Review, we focus on advances in platelet biology and function, with an emphasis on current and promising methodologies. We also discuss technical and biological challenges in platelet investigations. Using coronavirus disease 2019 (COVID-19) as an example, we further describe the translational relevance of these approaches and the possible 'bench-to-bedside' utility in patient diagnosis and care.

SARS-CoV-2 vaccination and ITP in patients with de novo or preexisting ITP.

Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post-SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.

Challenges in interpreting cytokine data in COVID-19 affect patient care and management.

Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic.

Association of obesity with venous thromboembolism and myocardial injury in COVID-19.

INTRODUCTION: Although both obesity and coronavirus disease 2019 (COVID-19) independently induce inflammation and thrombosis, the association between obesity class and risk of thrombosis in patients with COVID-19 remains unclear. METHODS: This retrospective cohort study included consecutive patients hospitalized with COVID-19 at a single institution. Patients were categorized based on obesity class. The main outcomes were venous thromboembolism (VTE) and myocardial injury, a marker of microvascular thrombosis in COVID-19. Adjustments were made for sociodemographic variables, cardiovascular disease risk factors and comorbidities. RESULTS: 609 patients with COVID-19 were included. 351 (58%) patients were without obesity, 110 (18%) were patients with class I obesity, 76 (12%) were patients with class II obesity, and 72 (12%) were patients with class III obesity. Patients with class I and III obesity had significantly higher risk-adjusted odds of VTE compared to patients without obesity (OR = 2.54, 95% CI: 1.05-6.14 for class I obesity; and OR = 3.95, 95% CI: 1.40-11.14 for class III obesity). Patients with class III obesity had significantly higher risk-adjusted odds of myocardial injury compared to patients without obesity (OR = 2.15, 95% CI: 1.12-4.12). Both VTE and myocardial injury were significantly associated with greater risk-adjusted odds of mortality. CONCLUSION: This study demonstrates that both macrovascular and microvascular thromboses may contribute to the elevated morbidity and mortality in patients with obesity and COVID-19.