ABSTRACT:Managing patients with suspected heparin-induced thrombocytopenia (HIT) poses significant clinical challenges. Limited evidence exists on how management decisions impact clinical outcomes, leading to treatment recommendations based on low-certainty evidence. This study aimed to evaluate the treatment strategies and clinical outcomes of patients with suspected HIT in a contemporary multicenter cohort. We conducted a prospective, multicenter cohort study including consecutive patients with suspected HIT from 11 centers. Patients were stratified into 3 groups: (1) HIT confirmed, (2) HIT-negative but heparin/platelet factor 4 (PF4) antibody-positive, and (3) HIT-negative without antibodies. Clinical and laboratory data were systematically collected. HIT was diagnosed using the washed-platelet heparin-induced platelet activation test as the reference standard. Among 1393 patients (46% female, median age 67 years), HIT was confirmed in 119 (8.5%). Most patients were in intensive care (37%), or had undergone cardiac surgery (32%). Argatroban was the predominant treatment (70%), and platelet recovery occurred in 77% of patients with HIT. Among patients with HIT, subsequent venous thromboembolism occurred in 23%, arterial thromboembolism in 9%, major bleeding in 12.6%, and mortality in 18%, with no significant differences between anticoagulants. Treatment with argatroban, bivalirudin, or direct oral anticoagulants (DOACs) significantly reduced arterial thromboembolism risk. Outcomes did not differ between patients who were HIT-negative with or without heparin/PF4 antibodies. HIT, as well as the mere suspicion of HIT, remains a serious condition with a high risk of adverse outcomes, including death. Our findings provide further evidence supporting the effectiveness of DOACs, argatroban, and bivalirudin in reducing arterial thromboembolism risk.

Background: Following the current guidelines, immunoassays for the diagnosis of heparin-induced thrombocytopenia (HIT) are interpreted dichotomously, with test results categorized as either positive or negative. However, the extent to which test results hold diagnostic significance across the entire dynamic range remains unclear. Objectives: We utilized data from the prospective towards precise and rapid diagnosis of heparin-induced thrombocytopenia study, comprising 1393 consecutive patients with suspected HIT, to assess the diagnostic significance of 2 heparin/platelet factor 4 immunoassay test results across their respective dynamic ranges: HemoSil Acustar HIT IgG (chemiluminescence immunoassay [CLIA]) and Lifecodes PF4 immunoglobulin G (enzyme-linked immunosorbent assay [ELISA]). Methods: HIT diagnosis was determined by a washed platelet heparin-induced platelet activation assay. For each measurement point in the dataset, we computed likelihood ratios (LRs), sensitivities, and specificities. To provide posttest probabilities for indi- vidual test results, we calculated interval-specific LRs and integrated them into a web- based calculator. Results: The prevalence of HIT was 8.5% (n = 119). An LR of >= 10 was first achieved at 0.3% of the dynamic range (0.4 U/mL; CLIA) and then at 16% (0.64 optical density; ELISA). An LR of >= 100 was present at 9.4% (12 U/mL; CLIA) and 75.0% (3.0 optical density; ELISA). The slope of the linear regression line (LR ti dynamic range) was 9.5 (CLIA) and 0.9 (ELISA). Conclusion: Despite both immunoassays showing an association between results and diagnostic significance, the strength of the association varies by assay. CLIA has a larger increase per measurement unit. Posttest probabilities for individual patients can be estimated using a web-based calculator: https://pcd-research.shinyapps.io/Bayesian Calculator/.

Aims: Pooled platelets concentrates were prepared at WBS measuring between (833-1045 × 10⁹/L) on automated cell counters.27 sites received aliquots plus FFP in temperature regulated transport boxes, to arrive within 24 hours.Sites were required to adjust the platelet count, by diluting with FFP.LTA was performed on days 1, 2 or 3 using 4 aggregation platforms.Methods: The platelet count at 27 sites was adjusted to 299-408 × 10⁹/L prior to aggregation with agonists: ADP, arachidonic acid, collagen, epinephrine, ristocetin, TRAP and U46619.Sites were split on wether they could perform agonist concentrations of BSH or ISTH recommendations.Results: Table 1 includes details of agonist used, concentrations of agonists and interpretations of LTA.

Abstract Background Transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) are the reference treatments for aortic stenosis. Conflicting data exist on late survival results of these two techniques. While randomised controlled trials (with highly selected patients) assert the non-inferiority of TAVR, real-world data from large registries (with potential uncorrected confounders) suggest the opposite. Comparing the survival rates of SAVR and TAVR with those of a matched reference population could help circumvent potential biases of direct procedural comparisons and quantify the impact of frailty on post-operative survival. Purpose Our study aims to compare the 5-year overall survival rates of SAVR, non-frail TAVR, and frail TAVR patients with the survival of their demographically matched reference population. Methods This study included all consecutive patients undergoing either SAVR or TAVR at a tertiary hospital between January 2010 and December 2021. Each patient underwent a comprehensive geriatric assessment by an experienced geriatric team, from which a Clinical Frailty Scale (CFS) was derived using a validated classification tree. Frailty was defined as a CFS ≥ 6, in accordance with ESC guidelines. The patients were stratified into 3 subgroups: SAVR, non-frail TAVR, and frail TAVR patients. For each subgroup, a corresponding reference population was generated using national actuarial tables to ensure individual-level matching based on age, gender, and year of observation. Survival of each subgroup was then compared to its corresponding reference population over a 5-year period using standardized mortality ratios (SMR) and one-sample logrank tests. Results Our cohort included 1183 SAVR, 254 non-frail TAVR, and 151 frail TAVR patients, with mean ages of 74.1, 85.4, and 85.7 years, and median EuroSCORE II of 2.0%, 4.2%, and 5.4%, respectively. Survival of SAVR patients was equivalent to the reference population (80.1 vs 80.9% survival; SMR = 1.06 [0.89 – 1.25]; p = 0.454; Figure 1A). Similarly, non-frail TAVR patients also achieved survival rates comparable to those of the reference population (50.9 vs 54.0% survival; SMR = 0.94 [0.76 – 1.18]; p = 0.549; Figure 1B). However, frail TAVR patients faced a significantly reduced survival rate (41.7% vs 54.0% survival; SMR = 1.48 [1.15 – 1.90]; p < 0.001; Figure 1C). The frailty of this subgroup could therefore explain a 48% increase in mortality risk compared with their reference population after 5 years. Conclusions Treating non-frail patients with aortic stenosis through TAVR or SAVR restores life expectancy to levels comparable with their reference population, challenging results from other real-world registries. In contrast, TAVR in frail patients is associated with worse survival, raising the question of treatment futility in this specific subgroup. Refining the selection of frail patients who may benefit from TAVR remains an important clinical challenge.

Abstract Background For chronic and severe aortic regurgitation (AR), both European and American guidelines recommend surgery in the setting of dilated left ventricle (LV). However, normal LV volumes are described according to age and gender (1) and differences in remodeling according to gender have been described in AR (2) and late referral bias has been suggested as a cause for outcome penalty in female patients with AR (3). Objective and methods To clarify the interactions of age and gender on LV volumes in the setting of AR with cardiac magnetic resonance (CMR). This is a single-center study performed in a referral center for cardiac surgery and aortic valve repair. Patients were adults identified or referred for an at least moderate AR (grade II) by transthoracic echocardiogram (TTE) and were invited to perform a CMR. Exclusion criteria were acute AR caused by bacterial infection or dissection, dilated cardiomyopathy from another identified cause, concomitant more than moderate left heart valve disease or intra-cardiac devices. Results Among 296 patients included (51+/-16 years, 56 (19%) females and 129 (44%) bicuspid), mean regurgitant fraction (RF) was 33%. Age was similar among men and women (50+/-16 vs 54+/-16; p=0.142) but RF was higher among men (35+/-18 vs 25+/-15%, p<0.001). Both LV end-diastolic (iLVEDV) and end-systolic (iLVESV) were moderately correlated to regurgitant fraction (Pearson R of respectively 0.605 and 0.569). Women had lower iLVEDV and iLVESV than men after correction for AR severity (respectively 105+/-24 vs 136+/-43ml/m²; p<0.001 and 48+/-17 vs 66+/-30ml/m²; p=0.007). Female gender was associated with a significantly lower susceptibility to dilate both iEDV and iESV in the setting of an increasing AR severity (p for interaction of respectively 0.048 and 0.041). Similarly, advancing age was associated with a continuous decrease in iEDV and iESV dilatation ability (p for interaction of respectively 0.006 and 0.048). Conclusion Sex and age are significant determinants for LV volumes in AR. Furthermore, both female sex and aging independantly lead to a decreased capability of LV dilatation, suggesting sex and aged-based CMR thresholds for LV dilatation should be further developed to avoid possible late referral bias for surgery in female or elderly population.Gender interaction on LV dilatationLV volumes prediction models

Abstract Background Until 2021, the strongest guidelines on surgical correction of severe aortic regurgitation (AR) focused on the left ventricular systolic function (LVEF) and the presence of symptoms. However, those situations lead to an outcome penalty, even after surgical correction. Left ventricle end-systolic diameter (LVESD) gained in strength in 2021 European guidelines. Moreover, more inclusive cut-off values are now recommended (class IIb) in patients at low surgical risk, reflecting the will to recommend surgery before developing heart failure and its consequences on post-operative outcome. Purpose We sought to evaluate the impact of guidelines triggers and their recent changes on postoperative survival of patients with severe AR from a large multicentric international registry. Method and results Postoperative overall survival of 1899 patients operated for severe and chronic AR (mean age 49±15 years, 85% male) in the international multicenter surgery registry for aortic valve surgery, AVIATOR, was evaluated over a median of 37 months. Twelve patients (0.6%) died postoperatively, and 68 within 10 years. By multivariable Cox analysis, presence of heart failure symptoms (HR 2.60; 95% CI [1.20–5.66]; p=0; 016), and either LVESD >50 mm or >25 mm/m2 (HR 1.64; 95% CI [1.05–2.55]; p=0.029) predicted survival independently over and above age (HR 2.25 per SD, 95% CI [1.67–3.03], p<0.001), female gender and bicuspid phenotype. Therefore, patients operated on when meeting either old or new 2021 class I triggers had worse adjusted survival (respectively 86±2% and 87±2%) than patients operated on without meeting triggers (97±2%, p<0.01). However asymptomatic patients operated on while meeting new 2021 ESC class IIb triggers (ie LVESD >20 mm/m2 or LVEF between 50–55%, 10-year survival 97±3%). Moreover, the sub-group of patients having a dilated LVESD >50 mm or >25 mm/m2 but a preserved LVEF >50% had excellent survival (10-year survival 95±3%). Conclusions In severe AR, patients operated on when meeting any class I trigger have postoperative survival penalty. Asymptomatic patients operated on earlier have better survival. This supports early surgery in AR as encouraged by the recent ESC/EACTS guidelines. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fondation Nationale de la Recherche Scientifique of the Belgian Government

Abstract Background Over the last decade, a new paradigm for heart failure with preserved ejection (HFpEF) development has been proposed. High burden of comorbidities would lead to a systemic inflammatory state and enhanced platelet activation. High platelet reactivity could be associated with higher mean platelet volume (MPV) due increased circulating immature platelets. Moreover, neutrophil-to-lymphocyte (NLR) reflects systemic inflammation. Both parameters have been associated with morbidity and mortality in heart failure (HF). However, data in HFpEF are limited. Purpose We aim to investigate the use of MPV and NLR to predict clinical outcome in HFpEF patients. Methods We prospectively enrolled 228 patients with HFpEF (79±9 years, 66% female patients) and 38 controls of similar age and gender (78±5, 63% female patients). All subjects underwent a complete two-dimensional echocardiography. Mean platelet volume and NLR were measured at baseline. Patients were followed over time for a primary end point of all-cause mortality or first HF hospitalization. The prognosis impact of MPV and NLR were determined with Cox proportional hazard models. Results Mean MPV and median NLR were significantly higher in HFpEF patients compared to controls (MPV: 11.7±1.1 fL vs 10.0±1.1 fL, p=0.005; NLR: 3.3 [2.2; 5.0] vs 2.2 [1.9; 2.9], p<0.001). HFpEF patients with MPV >75th percentile (n=56) had more frequently a history of ischemic cardiomyopathy (46%, p=0.04). HFpEF patients with NLR >75th percentile (n=57) were more frequently in New York Heart Association functional (NYHA) III or IV class (58%, p=0.02) and had higher levels of NT-proBNP (2152 [1336; 6397] pg/mL vs 1690 [705; 3304] pg/mL, p=0.02). Over a median follow-up of 26 months [11.5–56.7 months], 136 HFpEF patients (60%) reached the composite end point (87 deaths and 107 hospitalizations for HF). In univariate Cox regression analysis for the primary end point, MPV >75th percentile (HR: 1.45 [0.99; 2.13], p=0.05) and NLR >75th percentile (HR: 1.59 [1.11; 2.28], p=0.01) were predictors of the primary composite endpoint. In multivariate Cox regression analysis, mean platelet volume >75th percentile (χ2=8.11, P=0.004), continuous MPV (χ2=4.64, P=0.03) provided significant additional prognostic value over a baseline model created using independent predictors of the primary composite end point: body mass index (BMI), NYHA class III or IV, chronic obstructive pulmonary disease (COPD), loop diuretics, estimated glomerular filtration rate (eGFR) and NT-proBNP. By contrast, NLR did not provide any additional information (Figure 1 and 2). Conclusion MPV level and NLR were significantly higher in HFpEF patients compared with controls of similar age and gender. Elevated MPV offers an additional prognostic indication for clinicians and more interestingly it supports the hypothesis that of platelet activation could be involved in disease pathophysiology in HFpEF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Fondation Saint-Luc

INTRODUCTION:Little is known about the prognostic value of increased urine protein to creatinine ratios (UPC) comparing different underlying diseases in dogs. Therefore, between 2014 and 2015, dogs with a UPC of 2,0 or higher measured were retrospectively analysed at least once. They were divided into groups of the most common underlying diseases, namely primary glomerulopathy, Cushing's disease, leishmaniasis and in a group of different diseases. Possible prognostic factors, like UPC at time of diagnosis, creatinine, urine specific gravity, albumin and haematocrit, were assessed. Eighty-nine dogs with severe proteinuria were included in the study. Median time of survival was 42 days. UPC and time of survival did not differ significantly between the groups. Among the dogs with primary glomerulopathy, identified significant risk factors for death included increased UPC (p=0,03), increased creatinine (p.

Abstract Background Up to 40% of patients with severe aortic stenosis (SAS; indexed aortic valve area (AVAi) <0.6 cm2/m2) present with low transvalvular mean gradient (MG) despite a normal left ventricular ejection fraction (EF). There is intense debate about the prognostic significance of such entity, with some referring to it as an advanced form of the disease, others as an intermediate form between a moderate and a severe form. Objectives To compare outcome of patients with paradoxical low gradient SAS (PLG-SAS; i.e., mean gradient <40 mmHg and AVAi <0.6 cm2/m2) vs. moderate aortic stenosis (MAS; i.e. mean gradient <40 mmHg and AVAi >0.6 cm2/m2) and high gradient SAS (HG-SAS; i.e. mean gradient >40 mmHg and AVAi <0.6 cm2/m2). Methods 2582 consecutive patients with aortic stenosis (PLG-SAS, n=933; MAS, n=876 and HG-SAS, n=773) and a preserved EF (>50%) from an international multicentric registry were studied. Five years mortality between groups was compared using Kaplan Meier analysis. Inverse probability weighting was used to adjust for clinical and imaging baseline characteristics. Additionally, to explore the impact of MG (<40 mmHg vs. >40 mmHg) in patients with AVAi <0.6 cm2/m2 (PLG-SAS vs. HG-SAS) and to explore the impact of AVAi (<0.6 cm2/m2 vs. >0.6 cm2/m2) in patients with MG <40 mmHg (PLG-SAS vs MAS) we performed 2 different propensity score analyses. Patients were censored at the time of surgery. Results Overall, during 23 [IQR,10–47] months of follow-up 1003 patients died and 770 patients underwent aortic valve replacement. IPW-adjusted natural history was significantly better in patients with MAS, intermediate for patients with PLG-SAS and worst in patients with HG-SAS (59 vs. 47 vs. 41%, p<0.001, see Figure 1A). Furthermore, at equal MG (448 pairs), survival was significantly better in patients with MAS compared with PLG-SAS (54% vs. 39% p<0.001, see Figure 1B) and at equal AVAi (377 pairs), survival was significantly better in patients with PLG-SAS compared with HG-SAS (43% vs. 32% p<0.001, see Figure 1C). Conclusions In this large multicentric cohort, survival of PLG-SAS patients was better than that of HG-SAS patients and worse than that of MAS patients. Furthermore, with a comparable mean gradient, the smaller the calculated AVAi, the worse the prognosis whereas with a comparable AVAi, the higher the mean gradient, the worse the prognosis. Taking together, these data demonstrate that PLG-SAS is an intermediate form in the disease continuum, HG-SAS being the most malignant form of AS. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fonds National de la Recherche Scientifique (F.R.S.–FNRS)

Introduction: Current prognostic models of classic Hodgkin lymphoma (cHL) incorporate pre-treatment clinical and laboratory parameters, but have low discrimination capacity and limited clinical utility. Circulating tumor DNA (ctDNA) is a sensitive cancer biomarker, but its clinical validity in cHL is unknown. Here we tested whether pre-treatment ctDNA qualification and quantification is prognostic in cHL. Methods: The IOSI-EMA-003 (NCT03280394) is a prospective, observational, multicentric, international, non-interventional trial in which liquid biopsy samples were collected from newly diagnosed cHL patients at the following time points: baseline, interim and end of treatment PET/CT assessments. The LyV4.0 ctDNA CAPP-seq assay (sensitivity: 0.1%) was used to qualify and quantify ctDNA. Clinical data quality was assured through remote medical monitoring. Baseline, interim and end of treatment PET/CT are undergoing central review. Results: A total of 135 patients were recruited. Baseline characteristics were those expected in unelected, previously untreated cHL. After a median follow-up of 33 months, 25 patients had progression events, accounting for 3-year progression free survival (PFS) of 80.0%. At baseline, ctDNA was detected in 90% of patients, with an average of 27 somatic mutation reporters per case. A summary of genes affected by nonsynonymous, synonymous, and noncoding somatic mutations is shown in Figure A. Median ctDNA load was 358.5 hGE/mL of plasma (range 0-16572.4), and correlated (p = 0.004) with clinical proxies of the tumor volume (Figure B). None of the genes mutated in ≥5% of patients, including TP53, stratified PFS (Figure C). By recursive partitioning, ctDNA load in baseline samples stratified PFS with an optimized threshold of 1500 hGE/mL of plasma (Figure D). Patients with high pre-treatment levels of ctDNA had significantly inferior rates of 3-year PFS (44.4% vs 86.9% p = 0.000006) than those with low levels (Figure E). High pre-treatment levels of ctDNA occurred: i) in 0% of early, 12.2% of intermediate and 15.9% of advanced cHL; and ii) in 6.0% of 0-2 international prognostic score (IPS) and 27.3% of >3 IPS cHL. Levels of pre-treatment ctDNA marked patients’ outcome, irrespective of whether they presented in intermediate or advanced stage. The combination of high pre-treatment ctDNA and poor IPS risk >3 allowed to sort out upfront poor risk cHL showing a 3-year PFS of only 33.3% (Figure F). In multivariable analysis, the interaction between pre-treatment ctDNA and IPS remained prognostic for PFS (HR 7.3, 95% CI 3.0-17.5, p = 0.00009) when controlling for GHSG risk. PFS prediction metrics (c-index) were 64.9% for ctDNA, 66.2% for IPS and 69.8% for IPS combined to ctDNA. The research was funded by: -Fond’Action, Lausanne, Switzerland; -Translational Research Program, No. 6594-20, The Leukemia & Lymphoma Society, New York Keywords: Diagnostic and Prognostic Biomarkers, Hodgkin lymphoma Conflicts of interests pertinent to the abstract A. Moccia Consultant or advisory role: Roche, Janssen and Takeda D. Rossi Honoraria: AbbVie, AstraZeneca, Janssen Research funding: AbbVie, AstraZeneca, Janssen.

Background: Overall, ten independent retrospective studies addressed the question of the tolerability of ibrutinib in the real-world setting. Discontinuation rates ranged from 5% to 29%. Such heterogeneity may reflect differences in the case mix, follow up and accessibility to next treatments. Dose reduction/transient interruption rates ranged from 22% to 32%. The impact of intolerance on ibrutinib effectiveness according to baseline CLL biology is largely unknown. We assessed whether outcomes of patients with high-risk CLL is affected by ibrutinib discontinuation, interruption, or dose reduction due to intolerance. Methods: The IOSI-EMA-001 and the IOSI-EMA-003 observational prospective studies (NCT02827617; NCT03280394) enrolled patients with CLL treated with ibrutinib according to prescribing indications in Switzerland and Italy. Pre-treatment demographics, disease data, mutation analysis by LyV4.0 CAPP-seq assay, information on treatment discontinuation, interruption and dose reduction, and efficacy outcomes were collected. Results: In stotal, 90 patients were included in the per protocol population. Baseline features include age >65 years in 71% of cases, male gender in 61%, previous treatment in 47%, beta-2-microglobulin >5 mg/L in 40%, lactate dehydrogenase >ULN in 55%, TP53 disruption in 83%, and unmutated IGHV in 78%. Baseline mutations of SF3B1 (30%), NOTCH1 (28%), ATM (15%), EGR2 (13%), MGA (11%), POT1 (11%), and BIRC3 (10%) were reported in ≥10% of cases. The median follow-up of patients was 2.8 years. Median time on ibrutinib was 29 months. Discontinuation of ibrutinib due to any reason except progressive disease (PD) was reported in 21% of patients and their median time on ibrutinib was 17 months. Median time to discontinuation due to any reason except PD was 16 months. At least 1 interruption was reported in 31% of patients, and 6% interrupted treatment >1 time. The median consecutive days of interruption was 28 and the median total days of interruption was 38. Dose reduction was required by 25% of patients, including 5% who reduced to 140 mg/d. Median dose intensity (proportion of administered vs planned doses of ibrutinib 420 mg/d) was 93.4%. Three-years PFS of the per protocol cohort was 80.3% (CI 69.9-92.2). Early discontinuation due to any reason except PD, treatment interruption, regardless of duration (≥1, ≥8, ≥14 and ≥21 consecutive days), and dose reduction had no impact on PFS. By recursive partitioning, PFS stratification based on the best cut-off for dose intensity did not show a negative outcome, indicating no compounded effect of both dose reduction and interruption. Conclusions: Ibrutinib treatment modifications seem not to have major impact on PFS in patients with high-risk CLL. The impact of ibrutinib dose intensity during the first months of therapy on PFS, and the impact of ibrutinib tolerability on time to next treatment will be explored in this dataset. Keywords: Tumor Biology and Heterogeneity, Diagnostic and Prognostic Biomarkers, Ongoing Trials Conflicts of interests pertinent to the abstract E. Zucca Honoraria: AbbVie; AstraZeneca; Janssen Research funding: AbbVie; AstraZeneca; Janssen D. Rossi Honoraria: AstraZeneca; AbbVie; Janssen Research funding: AstraZeneca; AbbVie; Janssen

Objective Rapid and accurate measurement of direct oral anticoagulant drug level is critical in emergency situations. The diagnostic performance of anti-Xa assays in routine clinical practice is however not well established. We aimed to study the accuracy of the STA®-Liquid anti-Xa assay for the determination of rivaroxaban, apixaban, and edoxban in a large prospective cross-sectional study in clinical practice.