Trace Levels of Innate Immune Response Modulating Impurities (IIRMIs) Synergize to Break Tolerance to Therapeutic Proteins

Therapeutic proteins such as monoclonal antibodies, replacement enzymes and toxins have significantly improved the therapeutic options for multiple diseases, including cancer and inflammatory diseases as well as enzyme deficiencies and inborn errors of metabolism. However, immune responses to these products are frequent and can seriously impact their safety and efficacy. Of the many factors that can impact protein immunogenicity, this study focuses on the role of innate immune response modulating impurities (IIRMIs) that could be present despite product purification and whether these impurities can synergize to facilitate an immunogenic response to therapeutic proteins. Using lipopolysaccharide (LPS) and CpG ODN as IIRMIs we showed that trace levels of these impurities synergized to induce IgM, IFNγ, TNFα and IL-6 expression. In vivo, trace levels of these impurities synergized to increase antigen-specific IgG antibodies to ovalbumin. Further, whereas mice treated with human erythropoietin showed a transient increase in hematocrit, those that received human erythropoietin containing low levels of IIRMIs had reduced response to erythropoietin after the 1st dose and developed long-lasting anemia following subsequent doses. This suggests that the presence of IIRMIs facilitated a breach in tolerance to the endogenous mouse erythropoietin. Overall, these studies indicate that the risk of enhancing immunogenicity should be considered when establishing acceptance limits of IIRMIs for therapeutic proteins

Clinical and echocardiographic risk factors for device-related thrombus after left atrial appendage closure: an analysis from the multicenter EUROC-DRT registry

BACKGROUND Data on Device-related Thrombus (DRT) after left atrial appendage closure (LAAC) remain scarce. This study aimed to investigate risk factors for DRT from centers reporting to the EUROC-DRT registry. METHODS We included 537 patients (112 with DRT and 425 without DRT) who had undergone LAAC between 12/2008 and 04/2019. Baseline and implantation characteristics, anti-thrombotic treatment and clinical outcomes were compared between both groups in uni- and multivariate analyses. Additional propensity-score matching (PSM) was conducted to focus on the role of implantation characteristics. RESULTS Patients with DRT showed higher rates of previous stroke/transient ischemic attack (TIA) (49.1% vs. 34.7%, p < 0.01), spontaneous echocardiographic contrast (SEC) (44.9% vs. 27.7%, p < 0.01) and lower left atrial appendage (LAA) peak emptying velocity (35.4 ± 18.5 vs. 42.4 ± 18.0 cm/s, p = 0.02). Occluders implanted in DRT patients were larger (25.5 ± 3.8 vs. 24.6 ± 3.5 mm, p = 0.03) and implanted deeper in the LAA (mean depth: 7.6 ± 4.7 vs. 5.7 ± 4.7 mm, p < 0.01). Coverage of the appendage ostium was achieved less often in DRT patients (69.5% vs. 81.5%, p < 0.01), while DRT patients were less frequently on oral anticoagulation (7.1% vs. 16.7%, p < 0.01). Multivariate analysis identified age, prior stroke/TIA and SEC as independent risk factors for DRT. After PSM, implantation depth was found to be predictive. Rates of stroke/TIA were higher in DRT patients (13.5% vs. 3.8%, Hazard Ratio: 4.21 [95%-confidence interval: 1.88-9.49], p < 0.01). CONCLUSIONS DRT after LAAC is associated with adverse outcome and appears to be of multifactorial origin, depending on patient characteristics, anticoagulation regimen and device position

Assessment of LAA Strain and Thrombus Mobility and Its Impact on Thrombus Resolution—Added-Value of a Novel Echocardiographic Thrombus Tracking Method

Purpose—The mobility of left atrial appendage (LAA) thrombi and changes hereof under anticoagulation may serve as a marker of both risk of embolism and efficacy of treatment. In this study, we sought to evaluate thrombus mobility and hypothesized that LAA dynamics and thrombus mobility could serve as a baseline marker of thrombus dissolvability. Methods—Patients with two-dimensional transesophageal echocardiographic images of the LAA, and with evidence of LAA thrombus were included in this study. Using a speckle tracking algorithm, functional information from the LAA and thrombi of different patients was computed. While the LAA motion was quantified through the longitudinal strain, thrombus mobility was evaluated using a novel method by directly tracking the thrombus, isolated from the global cardiac motion. Baseline characteristics and echocardiographic parameters were compared between responders (thrombus resolution) and non-responders (thrombus persistence) to anticoagulation. Results—We included 35 patients with atrial fibrillation with evidence of LAA thrombi. Patients had a mean age of 72.9 ± 14.1 years, exhibited a high risk for thromboembolism (CHA2DS2-VASc-Score 4.1 ± 1.5) and had moderately reduced LVEF (41.7 ± 14.4%) and signs of diastolic dysfunction (E/E¢ = 19.7 ± 8.5). While anticoagulation was initiated in all patients, resolution was achieved in 51.4% of patients. Significantly higher LAA peak strain ( 3.0 ± 1.3 vs. 1.6 ± 1.5%, p < 0.01) and thrombus mobility (0.33 ± 0.13 mm vs. 0.18 ± 0.08 mm, p < 0.01) were observed in patients in whom thrombi resolved (i.e. responders against non-responders). Receiver operating characteristic (ROC) analysis revealed a high discriminatory ability for thrombus mobility with regards to thrombus resolution (AUC 0.89). Conclusion—Isolated tracking of thrombus mobility from echocardiographic images is feasible. In patients with LAA thrombus, higher thrombus mobility appeared to be associated with thrombus resolution. Future studies should be conducted to evaluate the role of the described technique to predict LAA thrombus resolution or persistence

Clinical outcomes and thrombus resolution in patients with solid left atrial appendage thrombi: results of a single-center real-world registry

Background: Data on thrombus resolution and clinical outcome data after a therapy of LAA thrombus with novel oral anticoagulants (NOACs) are scarce. Methods: In this single-center study, we retrospectively analyzed 78 patients diagnosed with a solid LAA thrombus by transesophageal echocardiography (TEE). We assessed baseline clinical and echocardiographic characteristics, the anticoagulatory regimens and outcomes of patients with (responders) and without (non-responders) thrombus resolution. Results Mean age was 76.1±8.3 years, patients were male in 57.7% and presented with a high risk for thromboembolism (CHA2DS2-VASc: 4.3±1.1). At thrombus diagnosis, 44.9% patients were treated with a NOAC, while 41.0% were under therapy with a VKA. Complete thrombusresolution was achieved after a mean of 116±79 days in a total of 51.3% of patients, 35.9% showed a reduction of thrombus size, whereas 12.8% showed no changes in thrombus dimensions. There was no statistically signifcant diference in the rate of LAA thrombus resolution between VKA and NOACs (41.2 vs. 57.1%, p=0.18). However, in cases in which only the therapy with a NOAC led to complete thrombus resolution, the time needed was signifcantly shorter than with VKA (81±38 vs. 129±46 days, p=0.03). Regarding safety outcomes, no diferences in bleeding or thromboembolism were observed between patients with and without thrombus resolution. Conclusions: In this registry, approximately 85% of LAA thrombi were diagnosed in patients with ongoing OAC. Thrombus resolution was observed in nearly 50% of cases. Although there was no diference in the rate of LAA thrombus resolution between VKA and NOACs, the resolution time was shorter in patients prescribed a NOAC

Incidence, predictors, and relevance of acute kidney injury in patients undergoing left atrial appendage closure with Amplatzer occluders: a multicentre observational study.

AIMS Acute kidney injury (AKI) remains a frequent complication after cardiac interventions, such as left atrial appendage closure (LAAC), yet limited data are available on the incidence and clinical implication of AKI in this setting. We sought to assess incidence, predictors and relevance of AKI after LAAC. METHODS AND RESULTS We retrospectively analyzed 95 LAAC patients in three European centers. AKI was defined according to the Acute Kidney Injury Network (AKIN) classification. The incidence of AKI was 13.7% with mild AKI in 92.3% and AKI stage > II in 7.7%. Total contrast volume was not linked to the occurrence of AKI (AKI: 127 ± 83 vs. no AKI: 109 ± 92 ml, p = 0.41), however increasing contrast volume (CV) to glomerular filtration rate (GFR) ratio (CV/GFR ratio) was associated with an increased risk of AKI (OR, per unit increase: 1.24, 95% CI 0.97-1.58, p = 0.08). ROC-analysis revealed a moderate predictive value of CV/GFR ratio for the prediction of AKI (AUC: 0.67, 95% CI 0.50-0.84, p = 0.05). Furthermore, AKI was associated with significantly increased mortality 6 months and 1 year after LAAC. No significant difference in the incidence of AKI was observed between patients with mere fluoroscopic and additional echocardiographic guidance (16.3% vs. 11.5%, p = 0.56). CONCLUSION Whereas mild AKI is common in patients after LAAC, severe AKI is rare. AKI after LAAC is associated with poor baseline renal function, increased doses of contrast (CV/GFR ratio) and impaired outcome. Future studies will be needed to elaborate the benefit of reducing or avoiding contrast volume regarding this endpoint

Symptomatic vs. non-symptomatic device-related thrombus after LAAC: a sub-analysis from the multicenter EUROC-DRT registry.

BACKGROUND Device-related thrombus (DRT) after left atrial appendage closure (LAAC) is associated with adverse outcomes, i.e. ischemic stroke or systemic embolism (SE). Data on predictors of stroke/SE in the context of DRT are limited. AIMS This study aimed to identify predisposing factors for stroke/SE in DRT patients. In addition, the temporal connection of stroke/SE to DRT diagnosis was analyzed. METHODS The EUROC-DRT registry included 176 patients, in whom DRT after LAAC were diagnosed. Patients with symptomatic DRT, defined as stroke/SE in the context of DRT diagnosis, were compared against patients with non-symptomatic DRT. Baseline characteristics, anti-thrombotic regimens, device position, and timing of stroke/SE were compared. RESULTS Stroke/SE occurred in 25/176 (14.2%) patients diagnosed with DRT (symptomatic DRT). Stroke/SE occurred after a median of 198 days (IQR 37-558) after LAAC. In 45.8% stroke/SE occurred within one month before/after DRT diagnosis (DRT-related stroke). Patients with symptomatic DRT had lower left ventricular ejection fractions (50.0 ± 9.1% vs. 54.2 ± 11.0%, p = 0.03) and higher rates of non-paroxysmal atrial fibrillation (84.0% vs. 64.9%, p = 0.06). Other baseline parameters and device positions were not different. Most ischemic events occurred among patients with single antiplatelet therapy (50%), however, stroke/SE was also observed under dual antiplatelet therapy (25%) or oral anticoagulation (20%). CONCLUSION Stroke/SE are documented in 14.2% and occur both in close temporal relation to the DRT finding and chronologically independently therefrom. Identification of risk factors remains cumbersome, putting all DRT patients at substantial risk for stroke/SE. Further studies are necessary to minimize the risk of DRT and ischemic events

Device-Related Thrombus After Left Atrial Appendage Closure: Data on Thrombus Characteristics, Treatment Strategies, and Clinical Outcomes From the EUROC-DRT-Registry

International audienceBackground: Left atrial appendage closure is an established therapy in patients with atrial fibrillation. Although device-related thrombosis (DRT) is relatively rare, it is potentially linked to adverse events. As data on DRT characteristics, outcome, and treatment regimen are scarce, we aimed to assess these questions in a multicenter approach. Methods: One hundred fifty-six patients with the diagnosis of DRT after left atrial appendage closure were included in the multinational EUROC-DRT registry. Baseline characteristics included clinical and echocardiographic data. After inclusion, all patients underwent further clinical and echocardiographic follow-up to assess DRT dynamics, treatment success, and outcome. Results: DRT was detected after a median of 93 days (interquartile range, 54–161 days) with 17.9% being detected >6 months after left atrial appendage closure. Patients with DRT were at high ischemic and bleeding risk (CHA 2 DS 2 -VASc 4.5±1.7, HAS-BLED 3.3±1.2) and had nonparoxysmal atrial fibrillation (67.3%), previous stroke (53.8%), and spontaneous echo contrast (50.6%). The initial treatment regimens showed comparable resolution rates (antiplatelet monotherapy: 57.1%, dual antiplatelet therapy: 85.7%, vitamin K antagonists: 80.0%, novel oral anticoagulants: 75.0%, and heparin: 68.6%). After intensification or switch of treatment, complete DRT resolution was achieved in 79.5% of patients. Two-year follow-up revealed a high risk of mortality (20.0%) and ischemic stroke (13.8%) in patients with DRT. Patients with incomplete DRT resolution showed numerically higher stroke rates and increased mortality rates (stroke: 17.6% versus 12.3%, P =0.29; mortality: 31.3% versus 13.1%, P =0.05). Conclusions: A substantial proportion of DRT is detected >6 months after left atrial appendage closure, highlighting the need for imaging follow-up. Patients with DRT appear to be at a high risk for stroke and mortality. While DRT resolution was achieved in most patients, incomplete DRT resolution appeared to identify patients at even higher risk. Optimal DRT diagnostic criteria and treatment regimens are warranted