Increased Risk Of Bleeding Research Articles

Risk of death, thromboembolic events, and bleeding in elderly patients with Atrial Fibrillation and Clinical Complexity who are not taking oral anticoagulation

Abstract Background Patients with Atrial Fibrillation (AF) often exhibit Clinical Complexity (CC), defined as ≥2 features, i.e. patients aged ≥75 years plus a body mass index (BMI) < 23/kg/m2 and/or bleeding history and/or chronic kidney disease. No data are available about the clinical course of patients with Atrial Fibrillation (AF) and CC who are not taking oral anticoagulation (OAC). Purpose To assess the risk of thrombotic and hemorrhagic events in patients with Atrial Fibrillation (AF) and CC who are not taking OAC. Methods Retrospective study with a health care research network (TriNetX). Based on the ICD-10-CM codes entered between 2011-2022 from 85 health care organizations mainly located in the United States, AF patients ≥75 years with CC were categorized into two groups based on the use of OAC during the last year before the study period. The primary outcomes were the one-year risk of death, major cardiovascular events ([MACE]: heart failure, stroke, and myocardial infarction), and major bleeding (central nervous system, gastrointestinal, internal bleeding, and hypovolemic shock). Secondary outcomes were each component of the primary outcome and catheter ablation. Cox regression analyses were used to calculate hazard ratios (HRs) and 95% CIs following propensity score matching 1:1. Results Overall, we identified 271,402 AF CC patients not on OAC (80.1±6.8 years, 46.5% females) and 87,101 AF CC patients on OAC (79.8±6.5 years, 47.6% females). Before PSM, AF CC patients not on OAC showed no significant differences in cardiovascular and bleeding risk factors but were less treated with pharmacological treatment than AF CC patients on OAC. After PSM, no significant differences were found between the two groups, but AF CC not on OAC were at higher risk of all-cause death (HR 1.54, 95%CI 1.50-1.57), MACE (HR 1.13, 95%CI 1.11-1.16), and major bleeding (HR 1.34, 95%CI 1.31-1.38), when compared to AF CC on OAC. AF CC patients not on OAC were associated with a higher risk of each component of the primary outcome and with a lower use of catheter ablation procedures (HR 0.48, 95%CI 0.43-0.54) (Table 1). The risk of the composite outcomes was the highest in those with all the three CC components. A progressive increase in OAC prescription was observed during the follow-up period, with increasing of NOACs and lower use of warfarin being observed. There was a clear temporal relationship between increasing OAC prescription and incidence of bleeding in CC patients (Figure 1) Conclusions AF CC patients not on OAC have a high risk of all-cause death, thrombotic and hemorrhagic events. Over time, increasing NOAC use was associated with more bleeding in CC patients. New antithrombotic approaches aimed at reducing thrombotic risk without increasing bleeding risk are needed in these patients.Figure 1 OAC new prescriptions

Preclinical characterisation and first-in-human results on the tolerability and pharmacodynamic effect of REGN9933, a monoclonal antibody targeting the factor XI/activated factor XI apple 2 domain

Abstract Background/Introduction Standard-of-care anticoagulants are associated with increased bleeding risk. Genetic/pharmacological data suggest coagulation factor XI (FXI) inhibition can prevent thrombosis with minimal increased bleeding risk. We present preclinical and first-in-human (FIH) data on REGN9933, a FXI-binding monoclonal Ab. Purpose To characterise REGN9933 epitope binding sites, affinities for FXI and activated FXI (FXIa), and effect on high molecular weight kininogen (HMWK)’s interaction with FXI. Also, to assess safety, tolerability and pharmacodynamics in healthy human participants (pts). Methods Epitope binding sites mapped with cryogenic electron microscopy, binding affinities determined with plasmon resonance techniques, effect on thrombin generation assessed with a thrombin generation assay, and impact on HMWK:FXI interaction analysed using ELISAs. In the FIH, Ph 1, randomised, double-blind, single-centre study, pts received a single dose of REGN9933 intravenously (IV; 3–300 mg) or subcutaneously (SC; 100 mg & 300 mg), or placebo (PBO). Primary endpoint: incidence and severity of treatment-emergent AEs (TEAEs). Other endpoints: effect of REGN9933 on activated partial thromboplastin time (aPTT) and prothrombin time (PT) to assess intrinsic and extrinsic pathway-triggered coagulation, respectively; and FXI activity. Results REGN9933 was found to bind the FXI apple 2 domain, with subnanomolar binding affinities for FXI and FXIa at 37°C, resulting in reduced thrombin generation from the intrinsic (not extrinsic) pathway. REGN9933 competed with HMWK for FXI binding in a dose-related manner. In the Ph 1 study, 56 pts received REGN9933 (IV, n=30; SC, n=12) or PBO (n=14); 42.9% and 21.4% had ≥1 TEAE, respectively (most common with REGN9933: headache, 12%; oropharyngeal pain, 5%). No serious/severe TEAEs, or TEAEs of special interest (inc. moderate/severe bleeding) reported. Laboratory tests revealed no clinically meaningful differences in the number/type of treatment-emergent potentially clinically significant values with REGN9933 vs PBO. REGN9933 resulted in dose-dependent prolongation of aPTT; aPTT mean fold change from baseline was highest with IV 300 mg after 8 hrs (2.7) and remained >2 for 36 days (Fig 1). There was no detectable effect on PT or clinically meaningful effect on bleeding time. REGN9933 supressed FXI activity in a dose-dependent manner, with suppression to approx. the lower limit of assay quantification (5%) with IV ≥30 mg (Fig 2). Conclusion(s) REGN9933 binds the FXI apple 2 domain and inhibits HMWK:FXI interaction, preventing intrinsic pathway-triggered FXI activation. FIH data showed dose-dependent inhibition of the intrinsic coagulation pathway by REGN9933, without affecting the extrinsic or common pathways. Pharmacodynamic and safety findings support continued development of REGN9933 as an anticoagulant that may carry less bleeding risk than currently approved agents.

Low rates of haemorrhagic stroke, not increased by age, renal/hepatic impairment, concomitant anti-platelet use and high CHA2DS2-VASc scores, in the 4-year follow-up of ETNA-AF-Europe

Abstract Background Balancing the risks of stroke and bleeding is necessary to optimise oral anticoagulation use in clinical practice. Concerns remain over the increased bleeding risk in patients receiving NOACs, and long-term safety data in this population are limited. Purpose To report annualised rates of haemorrhagic stroke in various sub-populations of patients with atrial fibrillation (AF) treated with edoxaban during the 4-year follow-up of ETNA-AF-Europe. Methods ETNA-AF-Europe, a post-authorisation, observational study conducted across 776 sites from 10 European countries, assessed the risks and benefits of edoxaban use in patients with AF. Here, we present the annualised event rates of haemorrhagic stroke during the 4-year follow-up, that occurred overall (on-/off-edoxaban) and on-edoxaban, including sub-populations stratified by age, renal impairment, hepatic impairment, chronic concomitant antiplatelet use and CHA2DS2-VASc score. Patient characteristics were collected at baseline and annualised event rates were reported for outcomes. Results A total of 13,164 patients were included in the full analysis set. Baseline characteristics are reported in Table 1. The overall and on-edoxaban annualised haemorrhagic stroke rates were low (number of events, % [95% confidence interval]: 36, 0.1 [0.05;0.11] and 31, 0.1 [0.05;0.10] respectively). The overall haemorrhagic stroke rates remained low in subgroups stratified by age (<65 years: 4, 0.1 [0.00;0.11]; ≥65–75 years: 13, 0.1 [0.04;0.13]; ≥75 years: 19, 0.1 [0.05;0.12]), renal impairment (yes: 23, 0.1 [0.05;0.13]; no: 12, 0.1 [0.03;0.11]), hepatic impairment (yes: 0, 0.0 [0.00;0.00]; no: 35, 0.1 [0.06;0.11]), concomitant antiplatelet use (yes: 2, 0.1 [0.00;0.16]; no: 34, 0.1 [0.05;0.11]) and CHA2DS2-VASc score (low [0–1]: 0, 0.0 [0.00;0.00]; moderate [2–4]: 28, 0.1 [0.06;0.12]; high [>4]: 7, 0.1 [0.03;0.18]) (Figure). Likewise, on-edoxaban haemorrhagic stroke rates were low irrespective of age (<65 years: 3, <0.1 [0.00;0.010; ≥65–75 years: 12, 0.1 [0.04;0.13]; ≥75 years: 16, 0.1 [0.04;0.12]); renal impairment (yes: 20, 0.1 [0.05;0.12]; no: 10, 0.1 [0.02;0.10]); hepatic impairment (yes: 0, 0.0 [0.00;0.00]; no: 30, 0.1 [0.05;0.11]); chronic concomitant antiplatelet use (yes: 2, 0.1 [0.00;0.18; no: 29, 0.1[0.05;0.10]) or CHA2DS2-VASc score (low [0–1]: 0, 0.0 [0.00;0.00]; moderate [2–4]: 25, 0.1 [0.05;0.12]; High [>4]: 6, 0.1 [0.02;0.17]) (Figure). Conclusions The overall and on-edoxaban annualised rates of haemorrhagic stroke were low and were not increased by non-modifiable risk factors such as age, renal/hepatic impairment, concomitant antiplatelet use and high CHA2DS2-VASc scores during the 4-year follow-up. The overall annualised rates on-edoxaban in ETNA-AF-Europe registry are quite comparable with incidence rates reported in the literature in age-stratified populations (incidence/100 person-years: 55-64 years: 0.06 [0.04-0.07]; 65-74 years: 0.1 [0.09-0.1]; 75-84 years 0.2 [0.1-0.2]).Baseline Characteristics

An analysis of the virtual cardio-oncology research initiative (VICORI) resource: bleeding risk among cancer patients beyond 1-year post-myocardial infarction

Abstract Introduction Cardiovascular disease (CVD) and cancer are common causes of morbidity and mortality. Advancements in treatment strategies for both diseases have resulted in a growing population who live with both conditions. Myocardial infarction (MI) represents approximately 20% of all CVD admissions in cancer patients and 10% of patients who present with an acute MI have cancer. Managing MI patients with cancer require careful balancing of their ischaemic and bleeding risks. While dual antiplatelet therapy (DAPT) increases a patient’s bleeding risk, cancer patients are at further increased risk due to a range of direct and indirect cancer effects. While our recent studies demonstrated an increased bleeding risk in cancer patients in the 1st year after MI (the period of intensive APT), it is currently not known if this risk is sustained beyond this period. VICORI is the world’s first whole-country cardio-oncology research platform, linking data from the National Cancer Registration and Analysis Service, National Institute for Cardiovascular Outcomes Research and Hospital Episode Statistics [1]. We investigated the risk of bleeding among MI patients in the 2nd year post-MI, where a large majority of patients would have completed a course of DAPT, stratified by the presence or absence of cancer. Methods In this retrospective observational study, we investigated the risk of bleeding following an MI between 2006-2019, in patients with and without cancer. Cancer was defined as a diagnosis of cancer in the 1-year preceding MI. Patients who lived past the 1st year after MI were followed-up from 12 to 24 months after their MI. We used inverse probability weighting based on propensity scores to produce a balanced cohort of patients with and without cancer. Cox proportional hazard and flexible parametric modelling were used to investigate cancer as a predictor of bleeding. Subgroup analyses were performed on stent status, MI and cancer type. Results Of 506280 patients presenting with MI, 5666 (1.1%) had cancer while 500614 (98.9%) did not. Prostate (n=1377), colorectal (n=1024), lung (n=490), breast (n=448) and bladder (n=334) cancers were among the most common types of cancers. The rate (hazard) of bleeding in MI was higher in patients with cancer in the 2nd year post-MI (HR:1.42, 95%CI 1.29-1.56) compared to those without. From the flexible parametric survival analysis, the risk of bleeding in cancer patients in the 2nd year post-MI was lower compared to the 1st year but remained statistically significant compared to non-cancer patients. Conclusion In this large real-world study, cancer patients have a persistent, increased bleeding risk beyond the 1-year post-MI period, compared to those without cancer, and this risk differed by type of cancer. Further work is needed to identify specific patient characteristics in each patient sub-group which alters one’s ischaemic or bleeding risk so they can be balanced favourably with personalised strategies.

Polygenic risk, aspirin and primary prevention of coronary artery disease.

Recent aspirin primary prevention trials failed to identify a net benefit of aspirin for preventing cardiovascular disease versus the harms of bleeding. This study aimed to investigate whether a high-risk subgroup, individuals with elevated genetic predisposition to coronary artery disease (CAD), might derive more benefit than harm with aspirin, compared to those with lower genetic risk. We performed genetic risk stratification of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized controlled trial using a CAD polygenic risk score (GPSMult). For 12,031 genotyped participants (5,974 aspirin, 6,057 placebo) overall, we stratified them by GPSMult quintiles (q1-5), then examined risk of CAD (composite of myocardial infarction and coronary heart disease death) and bleeding events using Cox models. During a median 4.6 years of follow-up with randomization to 100 mg/day aspirin versus placebo, 234 (1.9%) participants had CAD and 373 (3.1%) had bleeding events. In the overall cohort, aspirin resulted in higher bleeding risk (adjusted Hazard Ratio [aHR]=1.30 [1.06-1.61], P=0.01) but no significant CAD reduction (aHR=0.84 [0.64-1.09], P=0.19). However, among the highest quintile of polygenic risk (q5, top 20% of the GPSMult distribution), there was a 47% reduction in risk of CAD events with aspirin (aHR=0.53 [0.31-0.90], P=0.02) without increased bleeding risk (aHR=1.05 [0.60-1.82], P=0.88). Interaction between the GPSMult and aspirin was significant for CAD (q5 versus q1, P=0.02) but not bleeding (P=0.80). The balance between net benefit and harm on aspirin in the primary prevention setting shifts favourably in individuals with an elevated genetic predisposition.

Optimal antithrombotic therapy in ischemic stroke patients with non-valvular atrial fibrillation and atherothrombosis: study protocol for a randomized controlled trial

BackgroundThe addition of antiplatelet therapy to anticoagulant therapy in patients with stroke with non-valvular atrial fibrillation (NVAF) and atherothrombotic disease may increase bleeding risk without reducing recurrent stroke risk.AimsTo evaluate the clinical benefits of anticoagulant monotherapy compared to combination therapy with anticoagulants and antiplatelet agents.Methods and designThis is an investigator-initiated prospective multicenter, randomized, open-label, parallel-group clinical trial. Patients with NVAF and atherothrombotic disease who have had a recent ischemic stroke or transient ischemic attack will be eligible to participate in this trial.Study outcomesThe primary outcome is a composite of ischemic cardiovascular events, including cardiovascular death, ischemic stroke, myocardial infarction, systemic embolism, ischemic events requiring urgent revascularization, and major bleeding events within 2 years after randomization.Sample size estimatesThis study will enroll 400 patients, 200 receiving anticoagulant monotherapy and 200 receiving combination therapy. This sample size will provide 90% power (one-sided p = 0.025) to detect a risk reduction in outcome events within 2 years, assuming event rates of 13 and 27% for each group, respectively, and a 10% loss to follow-up at a 2.5% significance level with one-sided log-rank tests at an interim analysis and a final analysis.DiscussionThis will be the first study to assess the net clinical benefit of oral anticoagulant monotherapy in ischemic stroke patients with NVAF and atherothrombosis.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT03062319, NCT03062319; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000029222, UMIN000025392; https://jrct.niph.go.jp/latest-detail/jRCTs051180202, jRCTs051180202.

Effect of mild hypothermia vs normothermia cardiopulmonary bypass on postoperative bleeding in patients undergoing coronary artery bypass grafting: protocol of a multi-center, randomized, controlled trial

BackgroundCoronary artery bypass grafting (CABG) is often performed with hypothermic cardiopulmonary bypass (CPB) to reduce metabolic demands and protect the myocardium. However, hypothermia can increase bleeding risks and other complications.MethodsThis is a prospective, multi-center, randomized controlled trial. From September 2023 to December 2024, a total of 336 eligible patients planning to undergo on-pump CABG will be enrolled. All participants will be randomly divided into mild hypothermia CPB group (target oxygenator arterial outlet blood temperature at 32–33℃) or normothermia CPB group (target oxygenator arterial outlet blood temperature at 35–36℃). The primary endpoint is Universal Definition of Perioperative Bleeding (UDPB) class 2–4. Secondary endpoints are class of UDPB, levels of coagulation and inflammatory factors, in-hospital mortality, perioperative related complications, ICU length of stay, and hospital length of stay.DiscussionThis clinical trial aims to compare the effects of different target temperature during CPB on postoperative bleeding and to explore optimal temperature strategy to provide new clinical evidence.Trial registrationChictr.org.cn: ChiCTR2300075405. The trial was prospectively registered on 4 September 2023.

Impact of Thrombocytopenia on Bleeding and Thrombotic Outcomes in Adults with Cancer-associated Splanchnic Vein Thrombosis

Malignancy is a risk factor for splanchnic vein thrombosis (SpVT). Data on the natural history of cancer-associated SpVT are limited. This was a single-center retrospective cohort study of 581 adult patients with cancer and SpVT. We aimed to characterize the impact of thrombocytopenia on major bleeding and progression or recurrence of SpVT within one year of initial cancer-associated SpVT diagnosis. Baseline thrombocytopenia (platelet < 100,000/uL within 15 days of SpVT diagnosis) was present in 39.5% of patients. A total of 39.2% of patients received therapeutic anticoagulation within two weeks of SpVT diagnosis. The cumulative once-year incidence of major bleeding was 10.7% (95% CI: 8.2–13.2), and for SpVT recurrence/progression was 16.2% (95% CI: 13.2–19.2). In multivariable regression analysis, therapeutic anticoagulation was associated with increased major bleeding (aRR: 1.74, 95% CI: 1.08-2.81) and decreased progression/recurrence of SpVT (aRR: 0.55, 95% CI: 0.35-0.86). Baseline thrombocytopenia was not independently associated with either major bleeding (aRR: 0.76, 95% CI: 0.43-1.34) or progression/recurrence of SpVT (aRR: 1.14, 95% CI: 0.73–1.78). A secondary analysis using inverse probability of treatment weighting with propensity scores for baseline thrombocytopenia corroborated that patients with thrombocytopenia did not have increased bleeding risk (aHR: 0.81, 95% CI: 0.48–1.39). Multivariable analysis treating platelets as a time varying covariate also did not reveal an association with major bleeding (aHR: 0.89, 95% CI: 0.55–1.45). Bleeding and thrombosis progression were frequent in patients with cancer-associated SpVT. Anticoagulation was associated with increased major bleeding and decreased thrombotic progression; thrombocytopenia did not impact outcomes.

Drug-drug-interactions in patients with atrial fibrillation admitted to the emergency department

IntroductionPolypharmacy is a growing concern in healthcare systems. While available data on potential drug-drug interactions (pDDI) from emergency department (ED) patients is derived from heterogenous populations, this study specifically focused on patients with atrial fibrillation (AF). We hypothesized that patients with AF have similar comorbidities, receive similar drugs, and have similar pDDIs. The overarching aim was to highlight frequent pDDIs, providing practical guidance for treating healthcare professionals and consequently reduce the risk of adverse drug reactions.MethodsTwo hundred patients ≥18 years with AF, who received rate- or rhythm-controlling medication at the ED of the University Hospital Vienna, and who were on long-term medication before admission, were eligible. Long-term medication alone, as well as in combination with medication administered at the ED were analyzed for pDDIs using the Lexicomp® Drug interactions database.ResultsWithin the long-term medication of patients’, we identified 664 pDDIs. Drugs administered at the ED increased pDDIs more than 3-fold to 2085. Approximately, every fifth patient received a contraindicated drug combination (on average 0.24 per patient), while 70% received drug combinations for which therapy modifications are recommended (on average 1.59 per patient). The most frequently involved drugs included amiodarone, propofol, bisoprolol, enoxaparin, and acetylsalicylic acid. Increased risk of bleeding, QTc prolongation, and myopathy were among the most relevant potential consequences of these interactions.DiscussionIn conclusion, an optimization of medication would be advisable in almost every AF patient. Treating healthcare professionals should be cautious of drugs that increase bleeding risk, prolong QTc, or bear a risk for myopathy.

A Systematic Review of Safety and Efficacy of Factor XI/XIa Inhibitors in Patients With ESKD on Hemodialysis

IntroductionFactor XI/XIa (FXI/XIa) has emerged as a potential target for antithrombotic therapy, driven by preclinical evidence showing a role of FXI/XIa inhibition for preventing thrombosis without impeding hemostasis. This is particularly promising for patients at high risk of both thromboembolic events and bleeding, such as patients with end-stage kidney disease (ESKD) on hemodialysis (HD). MethodsWe systematically searched Embase, MEDLINE, and ClinicalTrials.gov for randomized controlled trials evaluating FXI/XIa inhibitors in patients with ESKD on HD, without restricting inclusion to specific comparators or indications. Interventional treatment arms were pooled, and study results were synthesized by fitting random-effects models, calculating odds ratios (OR) and 95% confidence intervals (CI). ResultsFive phase II studies encompassing 1,270 participants were identified, investigating gruticibart, IONIS-FXIRx, osocimab, or fesomersen in the general HD population and using placebo as a comparator. Four studies were fully published and included in the meta-analysis. Use of FXI/XIa inhibitors was associated with an OR of 0.80 (95% CI, 0.47-1.35) for clinically relevant bleeding, 0.51 (95% CI, 0.21-1.28) for major bleeding, and 0.90 (95% CI, 0.49-1.68) for clinically relevant non-major bleeding. The ORs for thromboembolic events and all-cause mortality were 0.66 (95% CI, 0.28-1.56) and 0.46 (95% CI, 0.15-1.40), respectively. ConclusionCurrently available evidence does not indicate a significantly increased bleeding risk of FXI/XIa inhibitors in patients with ESKD on HD compared to placebo. Their efficacy and their association with all-cause mortality need to be investigated in sufficiently powered, randomized controlled phase III trials.

Platelet P2Y12 Receptor Inhibition and Perioperative Patient Management.

P2Y12 receptor inhibitor use increases bleeding risk in surgical patients by inhibiting platelet aggregation. Preoperative monitoring, platelet transfusion, and targeted reversal strategies with novel therapies may help to optimize patient management.

Effects of selective serotonin reuptake inhibitors on platelet functions: a literature review.

Many epidemiological studies have evidenced an increased bleeding risk associated with selective serotonin reuptake inhibitors (SSRIs), yet the underlying mechanisms remain unclear. This review summarizes data on SSRIs' effects on platelet functions assessed with assays used in clinical practice and highlights the areas that deserve further investigation. Conflicting results of SSRI effects on platelet aggregation were observed irrespectively of the agonist used, the antidepressant drug or the study type. Alike, discrepant results were reported with flow-cytometry-based assays assessing either platelet surface glycoprotein levels, integrin activation, agonist-induced secretion of intraplatelet granule content or membrane anionic phospholipid exposure. Other tests may have detected a platelet function defect in SSRIs samples, however, results were largely inconsistent. Critical literature examination unveils very low certainty of evidence on potential SSRI effect on platelet functions. Findings are often inconsistent even when similar methods are used, most likely because of differences in study design, included patients (age, comorbid conditions), SSRIs' type and dose, uncontrolled confounding factors, and statistical analysis power. Further studies are needed to disentangle any intrinsic antiplatelet effect of SSRIs and the multiple confounding factors, mainly the depression control itself and the degree of platelet SERT inhibition.

Guideline concordance of aspirin use for primary prevention in adult outpatients

AbstractRecent guidelines have recommended a reduced role for primary prevention aspirin use, which is associated with an increased bleeding risk. This study aimed to characterize guideline-discordant aspirin use among adults in a community care setting. As part of a quality improvement initiative, patients at 1 internal medicine and 1 family medicine clinic affiliated with an academic hospital were sent an electronic survey. Patients were included if they were at least 40 years old, had a primary care provider at the specified site, and were seen in the last year. Patients were excluded if they had an indication for aspirin other than primary prevention. Responses were collected from 15 February to 16 March 2022. Analyses were performed to identify predictors of primary prevention aspirin use and predictors of guideline-discordant aspirin use; aspirin users and nonusers were compared using Fisher exact test, independent samples t tests, and multivariable logistic regression. Of the 1460 patients sent a survey, 668 (45.8%) responded. Of the respondents, 132 (24.1%) reported aspirin use that was confirmed to be for primary prevention. Overall, 46.2% to 58.3% of primary prevention aspirin users were potentially taking aspirin, contrary to the guideline recommendations. Predictors of discordant aspirin use included a history of diabetes mellitus and medication initiation by a primary care provider. In conclusion, primary prevention aspirin use may be overutilized and discordant with recent guideline recommendations for approximately half of the patients, suggesting a need for aspirin deimplementation. These efforts may be best focused at the primary care level.

Analysis of bleeding outcomes in patients with hypoproliferative thrombocytopenia in the A-TREAT clinical trial.

Despite prophylactic platelet transfusions, hypoproliferative thrombocytopenia is associated with bleeding; historical risk factors include hematocrit (HCT) 25%, activated partial thromboplastin time 30 s, international normalized ratio 1.2, and platelets 5000/μL. We performed a post hoc analysis of bleeding outcomes and risk factors in participants with hematologic malignancy and hypoproliferative thrombocytopenia enrolled in the American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (A-TREAT) and randomized to receive either tranexamic acid (TXA) or placebo. World Health Organization (WHO) grade 2+ bleeding occurred in 46% of 330 participants, with no difference between the TXA (44%) and placebo (47%) groups (p = 0.66). Overall, the most common sites of bleeding were oronasal (18%), skin (17%), gastrointestinal (11%), and genitourinary (11%). Among participants of childbearing potential, 28% experienced vaginal bleeding. Platelets ≤5000/μL and HCT < 21% (after adjusting for severe thrombocytopenia) were independently associated with increased bleeding risk (HR 3.78, 95% CI 2.16-6.61; HR 2.67, 95% CI 1.35-5.27, respectively). Allogeneic stem cell transplant was associated with nonsignificant increased risk of bleeding versus chemotherapy alone (HR 1.34, 95% CI 0.94-1.91). The overall rate of WHO grade 2+ bleeding was similar to previous reports, albeit with lower rates of gastrointestinal bleeding. Vaginal bleeding was common in participants of childbearing potential. Platelets ≤5000/μL remained a risk factor for bleeding. Regardless of platelet count, bleeding risk increased with HCT < 21%, suggesting a red blood cell transfusion threshold above 21% should be considered to mitigate bleeding. More investigation is needed on strategies to reduce bleeding in this population.

Platelet integrin αIIbβ3 plays a key role in a venous thrombogenesis mouse model

Venous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. VT is initiated by the accumulation of platelets and neutrophils at sites of endothelial cell activation. A role for platelet αIIbβ3 in VT is not established, a task complicated by the increased bleeding risk caused by partial agonists such as tirofiban. Here, we show that m-tirofiban, a modified version of tirofiban, does not agonize αIIbβ3 based on lack of neoepitope expression and the cryo-EM structure of m-tirofiban/full-length αIIbβ3 complex. m-tirofiban abolishes agonist-induced platelet aggregation while preserving clot retraction ex vivo and, unlike tirofiban, it suppresses venous thrombogenesis in a mouse model without increasing bleeding. These findings establish a key role for αIIbβ3 in VT initiation and suggest that m-tirofiban and compounds with a similar structurally-defined mechanism of action merit consideration as potential thromboprophylaxis agents in patients at high risk for VT and hemorrhage.

Predicting Individual Treatment Effects to Determine Duration of Dual Antiplatelet Therapy After Stent Implantation.

After coronary stent implantation, prolonged dual antiplatelet therapy (DAPT) increases bleeding risk, requiring personalization of DAPT duration. The aim of this study was to develop and validate a machine learning model to predict optimal DAPT duration after contemporary drug-eluting stent implantation in patients with coronary artery disease. The One-Month DAPT, RESET (Real Safety and Efficacy of 3-Month Dual Antiplatelet Therapy Following Endeavor Zotarolimus-Eluting Stent Implantation), and IVUS-XPL (Impact of Intravascular Ultrasound Guidance on Outcomes of Xience Prime Stents in Long Lesion) trials provided a derivation cohort (n=6568). Using the X-learner approach, an individualized DAPT score was developed to determine the therapeutic benefit of abbreviated (1-6 months) versus standard (12-month) DAPT using various predictors. The primary outcome was major bleeding; the secondary outcomes included 1-year major adverse cardiac and cerebrovascular events and 1-year net adverse clinical events. The risk reduction with abbreviated DAPT (3 months) in the individualized DAPT-determined higher predicted benefit group was validated in the TICO (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus-Eluting Stent for Acute Coronary Syndrome) trial (n=3056), which enrolled patients with acute coronary syndrome treated with ticagrelor. The validation cohort comprised 1527 abbreviated and 1529 standard DAPT cases. Major bleeding occurred in 25 (1.7%) and 45 (3.0%) patients in the abbreviated and standard DAPT groups, respectively. The individualized DAPT score identified 2582 (84.5%) participants who would benefit from abbreviated DAPT, which was significantly associated with a lower major bleeding risk (absolute risk difference [ARD], 1.26 [95% CI, 0.15-2.36]) and net adverse clinical events (ARD, 1.59 [95% CI, 0.07-3.10]) but not major adverse cardiac and cerebrovascular events (ARD, 0.63 [95% CI, -0.34 to 1.61]), compared with standard DAPT in the higher predicted benefit group. Abbreviated DAPT had no significant difference in clinical outcomes of major bleeding (ARD, 1.49 [95% CI, -1.74 to 4.72]), net adverse clinical events (ARD, 2.57 [95% CI, -1.85 to 6.99]), or major adverse cardiac and cerebrovascular events (ARD, 1.54 [95% CI, -1.26 to 4.34]), compared with standard DAPT in the individualized DAPT-determined lower predicted benefit group. Machine learning using the X-learner approach identifies patients with acute coronary syndrome who may benefit from abbreviated DAPT after drug-eluting stent implantation, laying the groundwork for personalized antiplatelet therapy.

CLINICAL OUTCOMES OF PRIMARY PERCUTANEOUS CORONARY INTERVENTION USING DES VS BMS In ACUTE CORONARY SYNDROME PATIENTS WITH LEFT ANTERIOR DESCENDING ARTERY INVOLVEMENT: A COMPARATIVE STUDY

Acute coronary syndrome (ACS) with left anterior descending (LAD) artery involvement often leads to more extensive myocardial infarction. Choosing between drug-eluting stents (DES) and bare-metal stents (BMS) for revascularisation in these patients is a topic of clinical relevance. While drug-eluting stents are the gold standard, bare-metal stents remain an essential option for patients with specific considerations such as an inability to complete the recommended duration of DAPT, advanced age, concomitant oral anticoagulation, cancer, affordability issues, increased bleeding risk, and planned noncardiac surgery within the next year. Objective: This study aimed to compare the clinical outcomes of ACS patients with LAD involvement treated with either DES or BMS during primary PCI.Methods: A retrospective cohort study was conducted between January 1, 2021, and December 31, 2023, at a tertiary care center. A total of 200 ACS patients with LAD involvement who underwent primary PCI were included. Patients were grouped based on the type of stent used (DES or BMS). Data on patient demographics, comorbidities, procedural details, and outcomes were collected. Major adverse cardiovascular events (MACE), including all-cause mortality, myocardial infarction (MI), and target lesion revascularisation (TLR), were assessed. Kaplan-Meier survival analysis and Cox proportional hazards models were used to analyse outcomes. Results: MACE occurred in 48 patients (24%) during the one-year follow-up. Patients treated with DES experienced significantly fewer events (p &lt; 0.001) compared to those receiving BMS. Diabetes mellitus and chronic kidney disease were independent predictors of adverse outcomes (p = 0.006 and p &lt; 0.001, respectively).Conclusion: Primary PCI using DES in ACS patients with LAD involvement is associated with better clinical outcomes compared to BMS, particularly in high-risk populations. These findings suggest that DES should be the preferred stent type for this patient group to reduce adverse events and improve long-term survival.

Imaging features of hepatic angiosarcoma: retrospective analysis of two centers

PurposeIdentifying primary hepatic angiosarcoma (PHA) preoperatively is challenging, often relying on postoperative pathology. Invasive biopsy increases bleeding risk, emphasizing the importance of early PHA diagnosis through imaging. However, comprehensive summaries of ultrasound, abdominal computed tomography (CT), magnetic resonance imaging (MRI), and whole- body positron emission tomography-CT (PET-CT) in this context are lacking. This study aimed to investigate the comprehensive imaging characteristics of PHA.Patients and methodsImaging data were collected from 7 patients diagnosed with PHA via pathology between January 2000 and December 2019 in two provincial grade III hospitals. All patients underwent routine color ultrasound examinations before surgery, with 3 patients receiving contrast-enhanced ultrasound (CEUS).CT scans, both plain and enhanced, were performed on 5 patients, and whole-body PET-CT examinations were conducted on 2 patients.ResultsAmong the 7 patients with PHA, 4 presented with a single solid intrahepatic mass (2 of which were large), 1 with a single exophytic macroblock type, 1 with a mixed type featuring multiple masses and nodules, and 1 with a multiple nodule type. Conventional ultrasound of PHA showed uneven echoes within the tumor, potentially accompanied by septal zone echoes, and a blood flow grade of 0-I. CEUS displayed early-stage circular high enhancement, a central non-enhancement area, and a "vascular sign" around the tumor. CT scans revealed low-density shadows in the plain scan stage, high peripheral ring enhancement, and punctate nodular enhancement in the arterial phase, with varying intensities and the presence of a "vascular sign." During the portal vein stage, the interior of the tumor was consistently unfilled and exhibited structural disorder. PET-CT showed low-density lesions in the liver and low fluorodeoxyglucose metabolism.ConclusionsImaging diagnosis plays a crucial role in PHA diagnosis. When liver tumor imaging matches the above characteristics, consider PHA.

Storage properties of platelet concentrates from umbilical cord blood prepared using three different methods.

Thrombocytopenia, common in preterm newborns, may increase bleeding risk and is often treated with transfusions. Recent studies reveal that transfusing platelets at a high threshold worsens outcomes, possibly due to a "developmental mismatch" between adult-derived platelets and neonatal hemostatic system. Cord blood-derived platelet concentrates (CBPCs) could be an alternative for newborns. Our study aims to produce and evaluate the quality parameters of CBPCs during storage. Cord blood was collected from placentas after near-term and full-term pregnancies. Several production methods were attempted to obtain CBPCs, varying centrifugation settings, filtration, and dilution procedures. Adult-derived platelet concentrates (PCs) processed with the same methods, and standard PCs from five buffy-coats were used as controls. Storage tests were performed on days 2, 4-5, 7 from the collection. CBPCs parameters were compared with adult-derived PCs, and no significant differences were found for mean platelet volume (MPV), swirling, morphology, glucose, lactate, pCO2, and pO2. pH and bicarbonate were lower in CBPCs. Some significant differences between methods in CD62P expression and JC-1 ratio were observed. Compared with standard PCs, CBPCs showed lower platelet concentration, pH, and JC-1. Additionally, both in CBPCs as well as in control PCs, the apoptosis marker phosphatidylserine was elevated. CBPCs were of comparable quality to control PCs during storage. However, apoptosis markers in both groups were elevated, suggesting processing and storage of low volumes of PCs require further optimization. Also, filtration of low volumes leads to significant platelet loss, an issue that requires remedy.

Risk of bleeding in patients with essential thrombocythemia and extreme thrombocytosis

AbstractApproximately 25% of patients with essential thrombocythemia (ET) present with extreme thrombocytosis (ExT), defined as having a platelet count ≥1000 × 109/L. ExT patients may have an increased bleeding risk associated with acquired von Willebrand syndrome. We retrospectively analyzed the risk of bleeding and thrombosis in ExT vs non-ExT patients with ET at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2014 to 2022 to inform treatment decisions. We abstracted the first major bleed, clinically relevant nonmajor bleed (CRNMB), and thrombotic events from medical records. We identified 128 ExT patients (28%) and 323 non-ExT patients (72%). Cumulative incidence of bleeding was not different in ExT vs non-ExT patients (21% vs 13% [P = .28] for major bleed; 16% vs 15% [P = .50] for CRNMB). Very low and low thrombotic risk ExT patients were more likely to be cytoreduced than very low- and low-risk non-ExT patients (69% vs 50% [P = .060] for very low risk; 83% vs 53% [P = .0059] for low risk). However, we found no differences in bleeding between ExT and non-ExT patients when restricting the risk of bleed from diagnosis to cytoreduction start date (28% vs 19% [P = .29] for major bleed; 24% vs 22% [P = .75] for CRNMB). Cumulative incidence of thrombosis was also not different between ExT and non-ExT patients (28% vs 25%; P = .98). This suggests that cytoreduction may not be necessary to reduce bleeding risk based only on a platelet count of 1 million. We identified novel risk factors for bleeding in patients with ET including diabetes mellitus and the DNMT3A mutation.