Proteogenomic analyses identify coagulation factor XI as a thromboinflammatory mediator of long COVID.

SARS-CoV-2 infection can result in long COVID, characterized by post-acute symptoms from multiple organ systems. Current hypotheses on mechanisms underlying long COVID include persistent inflammation and dysregulated coagulation; however, precise mechanisms and causal mediators remain unclear. Here, we tested the associations of genetic instruments for 49 complement and coagulation factors from the UK Biobank ( N =34,557) with long COVID in the Long COVID Host Genetics Initiative ( N =997,600). Primary analyses revealed that genetically predicted higher factor XI increased long COVID risk (odds ratio, 1.17 [95% confidence interval, 1.08-1.27] per standard deviation; P =1.7×10 -4 ). This association was robust to sensitivity analyses using pleiotropy-robust methods and different genetic instruments and was replicated using proteogenomic data from an Icelandic cohort. Genetically predicted factor XI was also associated with venous thromboembolism, but not with acute COVID-19 or long COVID-resembling conditions. Collectively, these findings provide genetic evidence implicating factor XI in the biology of long COVID.

A Prospective, Monocentric Case-Control Study on Uncontrolled Psoriasis as Independent Risk Factor for a Hypercoagulable State.

INTRODUCTION: Chronic inflammatory diseases, including psoriasis, are associated with development of venous thromboembolism (VTE). The clot lysis profile (CLP) provides information on both the clotting tendency and fibrinolysis activity. We hypothesized that CLP in uncontrolled psoriasis patients is disturbed towards more clotting/less lysis compared to healthy controls (HC) and that successful psoriasis treatment could normalize the CLP. In this project, we aim to compare the CLP in patients with uncontrolled psoriasis with age- and sex-matched HC and investigate the effect of anti-inflammatory treatment on CLP. METHODS: Patients with uncontrolled psoriasis [psoriasis area severity index (PASI) or body surface area (BSA) > 10] (n = 87) and HC (n = 87) were recruited at a tertiary dermatology department. Samples from patients were obtained before treatment and when disease control was obtained (PASI < 3). Amplitude, area under the curve (AUC) and 50% clot lysis time were determined. RESULTS: At baseline, psoriasis patients had higher median amplitude and AUC compared with HC (p < 0.0001). After correction for possible confounders (BMI, smoking behavior, psoriatic arthritis, arterial hypertension, diabetes and coronary artery disease), the increased amplitude in psoriasis patients compared to HC remained significant. Successful anti-inflammatory treatment resulted in a significant decrease in amplitude (p = 0.0365). CONCLUSION: This is the first prospective study comparing the CLP of psoriasis patients with that of HC. A significant increase in both amplitude and area under the curve, indicative of a hypercoagulable CLP, was observed in psoriasis patients compared to HC. After successful anti-inflammatory treatment, amplitude significantly decreased.

The Relevance of Arterial Blood Pressure in the Management of Glaucoma Progression: A Systematic Review.

BACKGROUND: Glaucoma is one of the leading causes of global blindness and is expected to co-occur more frequently with vascular morbidities in the upcoming years, as both are aging-related diseases. Yet, the pathogenesis of glaucoma is not entirely elucidated and the interplay between intraocular pressure, arterial blood pressure (BP) and ocular perfusion pressure is poorly understood. OBJECTIVES: This systematic review aims to provide clinicians with the latest literature regarding the management of arterial BP in glaucoma patients. METHODS: A systematic search was performed in Medline, Embase, Web of Science and Cochrane Library. Articles written in English assessing the influence of arterial BP and systemic antihypertensive treatment of glaucoma and its management were eligible for inclusion. Additional studies were identified by revising references included in selected articles. RESULTS: 80 Articles were included in this systemic review. A bimodal relation between BP and glaucoma progression was found. Both high and low BP increase the risk of glaucoma. Glaucoma progression was, possibly via ocular perfusion pressure variation, strongly associated with nocturnal dipping and high variability in the BP over 24 h. CONCLUSIONS: We concluded that systemic BP level associates with glaucomatous damage and provided recommendations for the management and study of arterial BP in glaucoma. Prospective clinical trials are needed to further support these recommendations.

Therapy and guideline adherence at a multidisciplinary hypertension clinic: A prospective, observational study.

BACKGROUND: Hypertension is highly prevalent and remains one of the most frequent and preventable causes of cardiovascular morbidity and mortality. Yet, suboptimal blood pressure control is common. Hypertension clinics might play an important role in improving target attainment, by targeting drug therapy adherence, improving guideline compliance and by involving pharmacists. OBJECTIVES: We aimed to characterize patient drug therapy adherence, prescriber guideline compliance and pharmacist interventions at the hypertension clinic. METHODS: A prospective observational study was performed at the hypertension clinic of a large, academic hospital. Adult Dutch-speaking patients were eligible for inclusion. Following data were collected: patient demographics, medication use, patient adherence to prescribed antihypertensive drug therapies according to the BAASIS tool and prescriber compliance to the 2018 European Society of Cardiology (ESC) hypertension guidelines. RESULTS: A cohort of 108 patients was included with 51.9% male and aged 65 (IQR: 52-75) years. In total, 104 patients took at least 1 antihypertensive drug and 46 patients (44.2%) were classified as non-adherent with regard to their antihypertensive treatment; 82 patients (78.8%) had suboptimal blood pressure control. Compliance with the ESC guidelines was 66.3% prior to the consultation at the clinic and significantly increased to 77.9% thereafter (p = 0.0015). The clinical pharmacist performed a medication review for 27 patients with a total of 44 recommendations and an acceptance rate of 59.1%. CONCLUSION: A visit to the multidisciplinary hypertension clinic improved prescriber guideline compliance and the use of single pill combinations. Involvement of a clinical pharmacist could be beneficial to further improve patient drug therapy adherence and guideline compliance.

Heparin dosing in patients with Impella-supported cardiogenic shock.

BACKGROUND: Impella™ is increasingly used in cardiogenic shock. However, thromboembolic and bleeding events are frequent during percutaneous mechanical circulatory support (pMCS). OBJECTIVE: Therefore, we aimed to explore the optimal anticoagulation regime for pMCS to prevent thromboembolism and bleedings. METHODS: This hypothesis-generating multi-center cohort study investigated 170 patients with left-Impella™ support. We (A) compared bleeding/thrombotic events in two centers with therapeutic range (TR-aPTT) activated partial thromboplastin time (60-80s) and (B) compared events of these centers with one center with intermediate range aPTT (40-60s). RESULTS: After matching, there were no differences in patients' characteristics. In centers aiming at TR-aPTT, major bleeding was numerically lower with aPTT <60s within 48 h of left-Impella™ support, versus patients that achieved the aimed aPTT of ≥60s [aPTT ≥60s: 22 (37.3%) vs. aPTT<60s 14 (23.7%); Hazard ratio [HR], 0.62 (95%) CI, 0.28-1.38; p = 0.234]. Major cardiovascular and cerebrovascular adverse events (MACCE) did not differ between groups. In comparison of centers, TR-aPTT strategy showed higher major bleeding rates [TR: 8 (47.1%) vs. intermediate range: 1 (5.9%); HR, 0.06 (95%) CI, 0.01-0.45; p = 0.006]. MACCE were lower in the intermediate range aPTT group as well [TR 12 (70.6%) vs. intermediate range 5 (29.4%) HR, 0.32 (95%) CI, 0.11-0.92; p = 0.034]. CONCLUSION: This pilot analysis showed that lowering UFH-targets in left-Impella™ supported CS patients seems to be a safe and promising strategy for reducing major bleedings without increasing MACCE. This needs to be validated in larger, randomized clinical trials.

Protective Effect of Ticagrelor Against Infective Endocarditis Induced by Virulent Staphylococcus aureus in Mice.

In addition to its potent antiplatelet activity, ticagrelor possesses antibacterial properties against gram-positive bacteria. We wondered whether the typical clinical dosage of ticagrelor could prevent the development of infective endocarditis caused by highly virulent Staphylococcus aureus. Ticagrelor prevented vegetation formation in a mouse model of inflammation-induced endocarditis. The dosage achieved in patients under ticagrelor therapy altered bacterial toxin production and adherence on activated endothelial cells, thereby mitigating bacterial virulence. Besides the previously described bactericidal activity at high doses, ticagrelor at typical clinical doses possesses antivirulence activity against S aureus. Ticagrelor antiplatelet activity further interferes with the interplay between platelets and bacteria.

Management of edoxaban therapy and clinical outcomes in patients undergoing major or nonmajor surgery: a subanalysis of the EMIT-AF/VTE study.

BACKGROUND: Optimising periprocedural management of direct oral anticoagulation in patients with atrial fibrillation on chronic treatment undergoing major surgeries is an important aspect of balancing the risk of surgery-related bleeding with the risk of thromboembolic events, which may vary by surgery type. METHODS: This subanalysis of the prospective EMIT-AF/VTE programme assessed periprocedural-edoxaban management, according to physicians' decisions, and bleeding and thromboembolic event rates in patients who underwent major vs. nonmajor surgeries. Edoxaban interruption and clinical outcomes were compared between major vs. nonmajor surgeries and between renal function subgroups (creatinine clearance [CrCL] ≤ 50 mL/min vs. > 50 mL/min). RESULTS: We included 276 major and 512 nonmajor surgeries. The median pre- and postprocedural duration of edoxaban interruption in major vs. nonmajor surgeries was 4 vs. 1 days, whereas median duration of interruption for those with preprocedural-only and postprocedural-only interruption was 2 vs. 1 days and 2 vs. 0 days, respectively (P < 0.0001). Rates of all bleeding and clinically relevant nonmajor bleeding were numerically higher in major vs. nonmajor surgeries. Event rates (number of events per 100 surgeries) were low overall (< 6 events per 100 surgeries), independent of renal function subgroups. CONCLUSION: In this subanalysis of the EMIT-AF/VTE programme, periprocedural-edoxaban interruption was significantly longer in patients undergoing major vs. nonmajor surgery. This clinician-driven approach was associated with low rates of bleeding and thromboembolic events following both major and nonmajor surgeries. TRIAL REGISTRATION: NCT02950168, registered October 31, 2016; NCT02951039, registered November 1, 2016.

Peptidylarginine deiminase 4 and ADAMTS13 activity in Staphylococcus aureus bacteraemia.

Staphylococcus aureus infection is associated with increased levels of neutrophil extracellular traps (NETs) and von Willebrand factor (VWF), and with reduced activity of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Peptidylarginine deiminase 4 (PAD4) contributes to NET formation and inactivates ADAMTS13 in vitro. The role of PADs in the dynamics of NETs, VWF and ADAMTS13 has not yet been studied. We thus aimed to assess the longitudinal evolution of NETs, PADs, VWF and ADAMTS13 activity in S. aureus infection. Plasma samples from S. aureus bacteraemia patients were longitudinally collected and analysed for NETs, PAD4/PAD2, VWF and ADAMTS13 activity. Correlation analyses with clinical data were performed. Recombinant PAD4 and S. aureus were assessed in vitro for their potential to modulate ADAMTS13 activity. Sixty-seven patients were included. Plasma levels of NETs, VWF, PAD4 and PAD2 were increased and ADAMTS13 activity was decreased. Levels of PADs were negatively correlated with ADAMTS13 activity. NETs were positively correlated with PADs, and negatively with ADAMTS13 activity. In vitro, recombinant PAD4 but not S. aureus reduced ADAMTS13 activity in plasma. Levels of PAD4 and PAD2 correlate with reduced ADAMTS13 activity, with neutrophils as the likely source of PAD activity in S. aureus bacteraemia. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.

Serum proteomic profiling of carotid arteriopathy: A population outcome study.

BACKGROUND AND AIMS: Circulating proteins reflecting subclinical vascular disease may improve prediction of atherosclerotic cardiovascular disease (ASCVD). We applied feature selection and unsupervised clustering on proteomic data to identify proteins associated with carotid arteriopathy and construct a protein-based classifier for ASCVD event prediction. METHODS: 491 community-dwelling participants (mean age, 58 ± 11 years; 51 % women) underwent carotid ultrasonography and proteomic profiling (CVD II panel, Olink Proteomics). ASCVD outcome was collected (median follow-up time: 10.2 years). We applied partial least squares (PLS) to identify proteins linked to carotid intima-media thickness (cIMT). Next, we assessed the association between future ASCVD events and protein-based phenogroups derived by unsupervised clustering (Gaussian Mixture modelling) based on proteins selected in PLS. RESULTS: PLS identified 19 proteins as important, which were all associated with cIMT in multivariable-adjusted linear regression. 8 of the 19 proteins were excluded from the clustering analysis because of high collinearity. Based on the 11 remaining proteins, the clustering algorithm subdivided the cohort into two phenogroups. Compared to the first phenogroup (n = 177), participants in the second phenogroup (n = 314) presented: i) a more unfavorable lipid profile with higher total cholesterol and triglycerides and lower HDL cholesterol (p ≤ 0.014); ii) higher cIMT (p = 0.0020); and iii) a significantly higher risk for future ASCVD events (multivariable-adjusted hazard ratio (95 % CI) versus phenogroup 1: 2.05 (1.26-3.52); p = 0.0093). The protein-based phenogrouping supplemented ACC/AHA 10-year ASCVD risk scoring for prediction of a first ASCVD event. CONCLUSIONS: Focused protein-based phenogrouping identified individuals at high risk for future ASCVD and may complement current risk stratification strategies.

Effect of 24-h blood pressure dysregulations and reduced ocular perfusion pressure in open-angle glaucoma progression.

BACKGROUND: Low ocular perfusion pressure (OPP), which depends on the mean arterial pressure (MAP) and intraocular pressure (IOP), is associated with glaucoma. We studied 24-h MAP dysregulations and OPP in relation to the progression of glaucoma damage. METHODS: We retrospectively analyzed 155 normal-tension glaucoma (NTG) and 110 primary open-angle glaucoma (POAG) patients aged 18 years old followed at the University Hospital Leuven with repeated visual field tests ( n  = 7000 measures, including both eyes) who underwent 24-h ambulatory blood pressure monitoring. Twenty-four-hour MAP dysregulations were variability independent of the mean (VIM), and the five lowest dips in MAP readings over 24 h. OPP was the difference between 2/3 of the MAP and IOP. Glaucoma progression was the deterioration of the visual field, expressed as decibel (dB) changes in mean deviation analyzed by applying multivariable linear mixed regression models. RESULTS: The mean age was 68 years (53% were women). High 24-h VIMmap was associated with glaucoma progression in POAG ( P  < 0.001) independently of the 24-h MAP level. The estimated changes in mean deviation in relation to dip MAP measures ranged from -2.84 dB [95% confidence interval (CI) -4.12 to -1.57] to -2.16 dB (95% CI -3.46 to -0.85) in POAG. Reduced OPP along with high variability and dips in MAP resulted in worse mean deviation deterioration. CONCLUSION: The progression of glaucoma damage associates with repetitive and extreme dips in MAP caused by high variability in MAP throughout 24 h. This progression exacerbates if 24-h MAP dysregulations occur along with reduced OPP.

Predictive Factors and Clinical Events Associated with Edoxaban Interruption and Heparin Bridging Strategy: EMIT-AF/VTE.

Patients treated with edoxaban may require diagnostic and therapeutic procedures that involve edoxaban interruption. Although heparin bridging strategies are not recommended, heparin is frequently used in clinical practice. However, whether heparin use decreases thromboembolic risk remains unclear, and the potential for increased periprocedural bleeding remains a concern. Here, we report factors predicting edoxaban interruption and the use of heparin bridging strategies and associated clinical events from Global EMIT-AF/VTE, a multicenter, prospective, noninterventional study (Clinicaltrials.gov NCT02950168). Eligible patients are adults with atrial fibrillation or venous thromboembolism treated with edoxaban who underwent a diagnostic or therapeutic procedure. Edoxaban interruption, heparin bridging strategies, and clinical event data were collected from 5 days before procedure through 29 days afterwards. Edoxaban was interrupted in 1222/2089 procedures (58.5%); a heparin bridging strategy was used during 178 (14.6%) of these interruptions. Patients who received periprocedural heparin had higher baseline HAS-BLED (2.4±1.0 vs 1.9±1.1, P <0.0001) scores and similar CHA2DS2-VASc (3.6±1.6 vs 3.4±1.6, P = 0.09) scores versus patients who did not. HAS-BLED score >3 and high EHRA procedural risk predicted both edoxaban interruption and the use of a heparin bridging strategy, whereas CHA2DS2-VASc scores did not predict either. Bleeding and ischemic event rates were low; the all-bleeding rate was higher with the use of a heparin bridging strategy versus without (6.2% vs 3.1%, P = 0.04). Periprocedural heparin use was associated with higher bleeding rates, but not with lower thromboembolic risk. Individual patient and procedural bleeding risks appear to contribute more than stroke risk to clinicians' consideration of a heparin bridging strategy.

The 2023 Belgian clinical guidance on anticoagulation management in hospitalized and ambulatory COVID-19 patients.

COVID-19 is associated with an increased risk for thrombotic complications. The trials investigating the optimal thromboprophylactic dose are performed in challenging times and seemingly produce conflicting evidence. The burdensome circumstances, divergent endpoints, and different analytical approaches hamper comparison and extrapolation of available evidence. Most importantly, clinicians should provide thromboprophylaxis in hospitalized COVID-19 patients while (re)assessing bleeding and thrombotic risk frequently. The COVID-19 Thromboprophylaxis Working Group of the BSTH updated its guidance document. It aims to summarize the available evidence critically and to guide clinicians in providing the best possible thromboprophylaxis.

Edoxaban use in the context of dental procedures: analysis from the EMIT-AF/VTE database.

INTRODUCTION: Literature reviews support continuing anticoagulation during dental procedures. However, studies often present grouped anticoagulation data, and information on individual anticoagulant management would be helpful to dentists. The Edoxaban Management in Diagnostic and Therapeutic Procedures (EMIT-AF/VTE) programme (NCT02950168; NCT02951039) demonstrated low periprocedural bleeding and thrombotic event rates in patients with atrial fibrillation receiving edoxaban. AIMS: To report periprocedural edoxaban interruption and clinical events in patients from EMIT-AF/VTE who underwent dental procedures. METHODS: Dental procedures were categorised by type (cleaning/noncleaning). Edoxaban interruption, bleeding events, and thrombotic events were observed 5 days preprocedure through 29 days postprocedure. RESULTS: Overall, 196 patients underwent 350 cleaning and/or noncleaning procedures; most patients (171/196 [87.2%]) underwent noncleaning procedures (282/350 [80.6%]), whereas 48/196 (24.5%) underwent 68/350 (19.4%) cleaning procedures. Edoxaban was uninterrupted for most cleanings (53/68 [77.9%]). Preprocedural interruption was common for single and multiple tooth extractions (single, 67/100 [67.0%]; multiple, 16/30 [53.3%]). The only major bleeding occurred after an unrelated cleaning. Minor bleeding occurred in 1/68 (1.5%) cleaning and 4/282 (1.4%) noncleaning procedures. There were no thrombotic events. CONCLUSIONS: For most cleanings, edoxaban was not interrupted, whereas preprocedural interruption was more common for tooth extractions. Overall, bleeding rates were low, and no thrombotic events occurred.

Management of Bleeding and Hemolysis During Percutaneous Microaxial Flow Pump Support: A Practical Approach.

Percutaneous ventricular assist devices (pVADs) are increasingly being used because of improved experience and availability. The Impella (Abiomed), a percutaneous microaxial, continuous-flow, short-term ventricular assist device, requires meticulous postimplantation management to avoid the 2 most frequent complications, namely, bleeding and hemolysis. A standardized approach to the prevention, detection, and treatment of these complications is mandatory to improve outcomes. The risk for hemolysis is mostly influenced by pump instability, resulting from patient- or device-related factors. Upfront echocardiographic assessment, frequent monitoring, and prompt intervention are essential. The precarious hemostatic balance during pVAD support results from the combination of a procoagulant state, due to critical illness and contact pathway activation, together with a variety of factors aggravating bleeding risk. Preventive strategies and appropriate management, adapted to the impact of the bleeding, are crucial. This review offers a guide to physicians to tackle these device-related complications in this critically ill pVAD-supported patient population.

Emicizumab for acquired haemophilia A: A case series.

BACKGROUND: Emicizumab is approved to prevent bleeding in patients with congenital haemophilia A with or without inhibitors. However, no randomized trials addressed the efficacy of emicizumab in acquired haemophilia A (AHA). AIMS: To report the clinical and biochemical response of emicizumab in AHA. METHODS: This single-centre retrospective study included seven adults with AHA between November 2020 and May 2022. We collected patient characteristics, laboratory coagulation parameters, the use of haemostatic agents, bleeds and thrombotic events. Treatment was monitored using chromogenic FVIII assays. The assay with human reagents assesses both the emicizumab FVIII-like-activity and native patient FVIII-activity. The assay with bovine reagents only measures the patients' native FVIII-activity as emicizumab does not bind to bovine reagents. RESULTS: Patients presented with spontaneous hematoma (n = 7), intramuscular bleeding (n = 2), haematuria (n = 2) and/or gastro-intestinal bleeding (n = 2). Six patients had major bleedings. At diagnosis, APTT was prolonged (91 seconds, IQR 73-103), FVIII activity was 0% (IQR 0-1) and FVIII inhibitor 182 BU/mL (IQR 104-228). Emicizumab was administered weekly (3 mg/kg) for 4 weeks, and thereafter every 2 weeks until regression of the inhibitor. Three patients received activated FVIIa (cumulative dose of 1.7 mg/kg, IQR 1.2-2.2). All bleedings were controlled after treatment initiation, without further bleeds. After starting emicizumab, FVIII-like activity reached ≥5% at 12 days (IQR 7-14), whereas recovery of the intrinsic FVIII-activity ≥5% occurred at 128 days (IQR 88-173), coinciding with the disappearance of the FVIII inhibitor. There were no safety issues. CONCLUSION: In this AHA case series, no new clinically relevant bleeds were observed after initiation of emicizumab in conjunction with standard immunosuppressive therapy.

Pharmacokinetic drug-drug interactions with direct anticoagulants in the management of cancer-associated thrombosis.

Drug-drug interactions (DDIs) are common in cancer management and complicate the choice of anticoagulation in cancer-associated thrombosis. Cancer confers an increased risk of thrombotic events. Also, more bleeding events are observed in those who receive anticoagulation compared to those without cancer. In the treatment of cancer-associated thrombosis, direct oral anticoagulants (DOACs) have been found to be at least as effective as low-molecular weight heparins, which became the standard of care after several trials demonstrated superiority over vitamin K antagonists. Non-inferiority compared to low-molecular weight heparins has been shown for rivaroxaban, edoxaban and apixaban with a signal of fewer recurrent thrombotic events, albeit with an increase in bleeding events. Yet, potentially major pharmacokinetic drug-drug interactions have been identified as a reason to withhold DOACs and to rather choose an alternative. Practical guidance on what constitutes a major pharmacokinetic interaction and/or how to deal with these interactions in clinical practice is limited. Hence, here we have provided a framework to allow clinicians to better deal with pharmacokinetic drug-drug interactions between DOACs and cancer therapies in the management of cancer-associated thrombosis. In this review we have discussed the current literature, how the pharmacokinetic profile links to the label information on DDI, and have provided a practical proposal, applied to a clinical case.

Inhibition of thrombin-activatable fibrinolysis inhibitor via DS-1040 to accelerate clot lysis in patients with acute pulmonary embolism: a randomized phase 1b study.

BACKGROUND: The optimal treatment of intermediate-risk pulmonary embolism (PE) in hemodynamically stable patients remains unknown. Fibrinolytics reduce the risk of hemodynamic deterioration but increase bleeding risk. DS-1040, an inhibitor of thrombin-activatable fibrinolysis inhibitor, enhanced endogenous fibrinolytic activity without increasing bleeding risk in preclinical studies. OBJECTIVES: To evaluate the tolerability and explore the efficacy of DS-1040 in patients with acute PE. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study, ascending doses of intravenous DS-1040 (20-80 mg) or placebo were added to enoxaparin (1 mg/kg twice daily) in patients with intermediate-risk PE. The primary endpoint was the number of patients with major or clinically relevant nonmajor bleeding. The percentage change in thrombus volume and right-to-left ventricular dimensions, assessed using quantitative computed tomography pulmonary angiography, at baseline and after 12 to 72 hours were used to explore the efficacy of DS-1040. RESULTS: Of 125 patients with all available data, 38 were randomized to placebo and 87 to DS-1040. The primary endpoint occurred in 1 patient in the placebo group (2.6%) and 4 patients who received DS-1040 (4.6%). One subject experienced major bleeding (DS-1040 80 mg group); no fatal or intracranial bleeding occurred. Thrombus volume was 25% to 45% lower after infusion, with no differences between the DS-1040 and placebo groups. There was no difference in the change from baseline right-to-left ventricular dimensions between the DS-1040 and placebo groups. CONCLUSION: In patients with acute PE, adding DS-1040 to standard anticoagulation was not associated with an increase in bleeding but did not improve thrombus resolution or right ventricular dilation.