Immobility-associated thromboprotection is conserved across mammalian species from bear to human.

Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a major cause of morbidity and mortality. Short-term immobility-related conditions are a major risk factor for the development of VTE. Paradoxically, long-term immobilized free-ranging hibernating brown bears and paralyzed spinal cord injury (SCI) patients are protected from VTE. We aimed to identify mechanisms of immobility-associated VTE protection in a cross-species approach. Mass spectrometry-based proteomics revealed an antithrombotic signature in platelets of hibernating brown bears with heat shock protein 47 (HSP47) as the most substantially reduced protein. HSP47 down-regulation or ablation attenuated immune cell activation and neutrophil extracellular trap formation, contributing to thromboprotection in bears, SCI patients, and mice. This cross-species conserved platelet signature may give rise to antithrombotic therapeutics and prognostic markers beyond immobility-associated VTE.

Review: Sex-related differences in the treatment of cardiac arrhythmia.

Cardiac arrhythmias are a common and potentially serious cardiovascular disorders that affect both men and women. However, there is evidence to suggest that there may be sex-related differences in the prevalence, clinical presentation, and management of cardiac arrhythmias. Hormonal and cellular factors may play a role in these sex-specific differences. In addition, there are differences in the types of arrhythmias that men and women experience, with men more likely to experience ventricular arrhythmias and women more likely to experience supraventricular arrhythmias. The management of cardiac arrhythmias also differs between men and women. For example, some studies have found that women are less likely to receive appropriate treatment for arrhythmias and are more likely to have adverse outcomes following treatment. Despite these sex-related differences, the majority of research on cardiac arrhythmias has been conducted in men, and there is a need for more research to specifically examine the differences between men and women. This is especially important given that the prevalence of cardiac arrhythmia is increasing, and it is essential to understand how to effectively diagnose and treat these conditions in both men and women. In this review, we examine the current understanding of sex-related differences in cardiac arrhythmias. We also review the available data on sex-specific management strategies for cardiac arrhythmias and highlight areas of future research.

Heparin-Induced Thrombocytopenia in Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation.

Background: Heparin-induced thrombocytopenia (HIT) is a serious, immune-mediated adverse drug reaction to unfractionated heparin (UFH) affecting also patients undergoing venoarterial extracorporeal membrane oxygenation (VA-ECMO). Although the association between VA-ECMO support and the development of thrombocytopenia has long been known and discussed, HIT as one underlying cause is still insufficiently understood. Therefore, the purpose of this study was to further investigate the epidemiology, mortality, diagnosis, and clinical management of HIT occurring in VA-ECMO patients treated with UFH. Methods: We conducted a retrospective single-center study including adult patients (≥18 years) with VA-ECMO support in the cardiac intensive care unit (ICU) of the University Hospital of Munich (LMU) between January 2013 and May 2022, excluding patients with a known history of HIT upon admission. Differences in baseline characteristics and clinical outcome between excluded HIT (positive anti-platelet factor 4 (PF4)/heparin antibody test but negative functional assay) and confirmed HIT (positive anti-PF4/heparin antibody test and positive functional assay) VA-ECMO patients as well as diagnosis and clinical management of HIT were analysed. Results: Among the 373 patients included, anti-PF4/heparin antibodies were detected in 53/373 (14.2%) patients. Functional HIT testing confirmed HIT in 13 cases (3.5%) and excluded HIT in 40 cases (10.7%), corresponding to a prevalence of confirmed HIT of 13/373 (3.5%) [1.6, 5.3] and a positive predictive value (PPV) of 24.5% for the antibody screening test. The platelet course including platelet recovery following argatroban initiation was similar between all groups. One-month mortality in patients with excluded HIT was 14/40 (35%) and 3-month mortality 17/40 (43%), compared to 5/13 (38%) (p > 0.999), and 6/13 (46%) (p > 0.999) in patients with confirmed HIT. Neurological outcome in both groups measured by the cerebral performance category of survivors on hospital discharge was similar, as well as adverse events during VA-ECMO therapy. Conclusions: With a prevalence of 3.5%, HIT is a non-frequent complication in patients on VA-ECMO and was not associated with a higher mortality rate. HIT was ultimately excluded by functional essay in 75% of VA-ECMO patients with clinical suspicion of HIT and positive anti-PF4/heparin antibody test. Argatroban seems to be an appropriate and safe therapeutic option for confirmed HIT-positive patients on VA-ECMO support.

Impairment of Quality of Life in Patients with Implanted Subcutaneous Cardioverter Defibrillator (S-ICD) Compared to Implanted Transvenous Cardioverter Defibrillator Therapy.

Background: The subcutaneous cardioverter defibrillator (S-ICD) has been shown to be a viable alternative to transvenous ICDs (TV-ICD) in all patients at risk of sudden cardiac death (SCD) but without pacing indication. Aim: The aim of this study was to examine the impact of therapy with current S-ICD devices on quality of life (QoL) in comparison to patients with TV-ICD devices. Methods: In our single-centre study, 52 consecutive patients with S-ICD and 52 matched patients with TV-ICD were analysed. QoL has been assessed by a standardized questionnaire (EQ-5D-3L, modified). Additionally, clinical baseline and follow-up data were evaluated. Results: Two-thirds of the total study population reported restrictions in daily routine compared to their life before ICD implantation. A total of 27.7% of S-ICD patients stated to expect an improvement of QoL by deactivation or explantation of their defibrillator compared to only 6.4% of patients with TV-ICD (p=0.006), which was mainly caused by discomfort and pain from the S-ICD pocket (relevant discomfort and pain in 32.6% vs 11.5%; p<0.01). Limitations: Main limitation of the study is that quality of life was assessed for one single time point only and time since implantation differed significantly between S-ICD and TV-ICD. Furthermore our collective is younger, and, due to the high proportion of patients without cardiomyopathy, the mean EF is better than usual ICD collective. The absence of heart failure in about the half of our patients might have relevant impact on our QoL analysis. Conclusion: A relevant proportion of S-ICD patients expects an improvement of QoL by explantation of the device. Of note, this impression was not driven by the fear of receiving shocks but mainly by discomfort and pain caused by the pulse generator.

Neutrophil "plucking" on megakaryocytes drives platelet production and boosts cardiovascular disease.

Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils "plucked" intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependent migration towards perisinusoidal megakaryocytes, plucking neutrophils actively pulled on proplatelets and triggered myosin light chain and extracellular-signal-regulated kinase activation through reactive oxygen species. By these mechanisms, neutrophils accelerate proplatelet growth and facilitate continuous release of platelets in steady state. Following myocardial infarction, plucking neutrophils drove excessive release of young, reticulated platelets and boosted the risk of recurrent ischemia. Ablation of neutrophil plucking normalized thrombopoiesis and reduced recurrent thrombosis after myocardial infarction and thrombus burden in venous thrombosis. We establish neutrophil plucking as a target to reduce thromboischemic events.

Prevalence of pathological arrhythmia in patients triaged to "cardiac arrhythmia" in the emergency department: a preliminary study.

BACKGROUND: Symptoms caused by cardiac arrhythmia are common problems that lead to presentation to the emergency department. However, the prevalence of pathological heart rhythm in patients triaged for cardiac arrhythmia in the emergency department remains up to now unknown. METHODS AND RESULTS: In this retrospective study, patients triaged for cardiac arrhythmia admitted to the interdisciplinary emergency department of the Ludwig-Maximilians University Hospital in Munich within 1 year were included. Subsequently, cardiac rhythm in the 12-lead electrocardiogram, clinical presentation, admission rate, and diagnosis at discharge was analyzed. A total of 558 out of 39,798 patients were triaged for cardiac arrhythmia. Of these 42.3% of patients showed a pathological heart rhythm on the initial electrocardiogram (66.9% atrial fibrillation, 16.5% atrial flutter, 16.5% others). About 80% presented in emergency severity index III (many resources are needed without critical vitals) conditions. Sixty-two percent of the pathological electrocardiogram group and 60% of the sinus rhythm group of patients were admitted to the hospital, and 34.7% with pathological electrocardiogram underwent invasive investigations (16.8% in the sinus rhythm group). In 43.4% of patients, the diagnosis of cardiac arrhythmia was already known from previous medical contacts. CONCLUSION: A total of 1.8% of patients who presented to our interdisciplinary emergency department were triaged for cardiac arrhythmia. With 49.5%, the hospital admission rate was quite high but the patients presented to the emergency department in our cohort were rarely in critical condition. As a high percentage of our cohort had a history of cardiac arrhythmia, better outpatient management is needed for these patients to reduce emergency department visits and save resources.

Propofol versus midazolam sedation in patients with cardiogenic shock - an observational propensity-matched study.

PURPOSE: Benzodiazepines are recommended as first line sedative agent in ventilated cardiogenic shock patients, although data regarding the optimal sedation strategy are sparse. The aim of this study was to investigate the hemodynamic effects of propofol versus midazolam sedation in our cardiogenic shock registry. MATERIALS AND METHODS: Mechanically ventilated patients suffering from cardiogenic shock were retrospectively enrolled from the cardiogenic shock registry of the university hospital of Munich. 174 patients treated predominantly with propofol were matched by propensity-score to 174 patients treated predominantly with midazolam. RESULTS: Catecholamine doses were similar on admission but significantly lower in the propofol group on days 1-4 of ICU stay. Mortality rate was 38% in the propofol and 52% in the midazolam group after 30 days (p = 0.002). Rate of ≥BARC3 bleeding was significantly lower in the propofol group compared to the midazolam group (p = 0.008). Sedation with midazolam was significantly associated with ICU mortality. CONCLUSION: In this observational cohort study, sedation with propofol in comparison to midazolam was linked to a reduced dose of catecholamines, decreased mortality and bleeding rates for patients with cardiogenic shock. Based on this study and in contrast to current recommendations, propofol should be given consideration for sedation in cardiogenic shock patients.

Noncanonical Effects of Oral Thrombin and Factor Xa Inhibitors in Platelet Activation and Arterial Thrombosis.

Nonvitamin K oral anticoagulants (NOACs) or direct oral anticoagulants comprise inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban) or factor IIa (dabigatran). Both classes efficiently interfere with the final or penultimate step of the coagulation cascade and showed superior net clinical benefit compared with vitamin K antagonists for prevention of thromboembolic events in patients with AF and for prevention and therapy of deep vein thrombosis and pulmonary embolism. None the less, accumulating data suggested, that there may be differences regarding the frequency of atherothrombotic cardiovascular events between NOACs. Thus, the optimal individualized NOAC for each patient remains a matter of debate. Against this background, some basic and translational analyses emphasized NOAC effects that impact on platelet activity and arterial thrombus formation beyond inhibition of plasmatic coagulation. In this review, we will provide an overview of the available clinical and translational evidence for so-called noncanonical NOAC effects on platelet activation and arterial thrombosis.

Randomized Comparison of Intensified and Standard P2Y12-Receptor-Inhibition Before Elective Percutaneous Coronary Intervention: The SASSICAIA Trial.

BACKGROUND: Even among biomarker-negative patients undergoing elective percutaneous coronary intervention (PCI), periprocedural thrombotic and bleeding complications can lead to increased morbidity and mortality. Whether stronger platelet inhibition by an intensified oral loading strategy (ILS) before PCI impacts on outcomes among these patients in contemporary practice remains unclear. METHODS: This multicenter, randomized, assessor-blinded trial tested the hypothesis that in elective PCI prasugrel 60 mg (ILS) is superior to standard loading strategy with clopidogrel 600 mg regarding a composite primary end point of all-cause death, any myocardial infarction, definite/probable stent thrombosis, stroke, or urgent vessel revascularization. After PCI, all patients were on clopidogrel 75 mg/day and aspirin. The trial was terminated prematurely because of slower-than-expected recruitment and funding discontinuation. RESULTS: Of 781 patients included in the final analysis, 382 were assigned to ILS and 399 to standard loading strategy. At 30 days, the primary end point occurred in 66 patients (17.3%) assigned to ILS and 74 patients (18.6%) assigned to standard loading strategy (odds ratio, 0.92 [95% CI, 0.63-1.32]; P=0.64). Any myocardial infarction and Bleeding Academic Research Consortium ≥2 bleeding rates were similar among ILS and standard loading strategy groups 16.2% versus 17.5%, odds ratio, 0.91 (95% CI, 0.62-1.32), P=0.62 and 4.2% versus 4.8%, odds ratio 0.87 (95% CI, 0.44-1.73), P=0.70, respectively. CONCLUSIONS: In biomarker-negative stable and unstable angina patients undergoing elective PCI, the trial did not find a conclusive difference in efficacy or safety. This observation should be interpreted in the context of wide CIs and premature termination of the trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02548611.

Whole blood platelet aggregation kinetics under cardiopulmonary bypass: A pilot study.

Assessing the platelets' functional status during surgery on cardiopulmonary bypass is challenging. This study used multiple electrode impedance aggregometry (Multiplate®) to create a timeline of platelet aggregation changes as induced by cardiopulmonary bypass in antiplatelet-naive patients undergoing elective surgery for mitral valve regurgitation. We performed six consecutive measurements (T1: pre-operatively, T2: after heparinization, T3: 3 min after establishment of cardiopulmonary bypass, T4: immediately after administration of cardioplegia, T5: 5 min after administration of cardioplegia, and T6: 45 min after administration of cardioplegia). Platelet aggregation was determined after stimulation with 3.2-µg/mL collagen, 6.4-µM adenosine diphosphate, and 32-µM thrombin receptor activating peptide. Five patients were included (age: 64 ± 10 years, one female). We observed a decrease in hematocrit levels by -17.1% ± 3.7% (T1 vs T6) with a drop after establishment of cardiopulmonary bypass (T2 vs T3) and slightly decreasing platelet counts by -6.2% ± 7.7% (T1 vs T6). Immediately after establishment of cardiopulmonary bypass (T2 vs T3), we observed reduced platelet aggregation responses for stimulation with adenosine diphosphate (-19.7% ± 12.8%) and thrombin receptor activating peptide (-19.3% ± 6.3%). Interestingly, we found augmented platelet aggregation for all stimuli 45 min after administration of cardioplegia (T5 vs T6) with the strongest increase for collagen (+83.4% ± 42.8%; adenosine diphosphate: +39.0% ± 37.2%; thrombin receptor activating peptide: +34.5% ± 18.5%). Thus, after an initial drop due to hemodilution upon establishment of cardiopulmonary bypass, platelet reactivity increased over time which was not outweighed by decreasing platelet counts due to mechanical platelet destruction and absorption. These findings have implications for rational transfusion, peri-operative antiplatelet therapy, and for the management of patients on other extracorporeal support, such as extracorporeal life support or extracorporeal membrane oxygenation.

Rivaroxaban Reduces Arterial Thrombosis by Inhibition of FXa-Driven Platelet Activation via Protease Activated Receptor-1.

RATIONALE: A reduced rate of myocardial infarction has been reported in patients with atrial fibrillation treated with FXa (factor Xa) inhibitors including rivaroxaban compared with vitamin K antagonists. At the same time, low-dose rivaroxaban has been shown to reduce mortality and atherothrombotic events in patients with coronary artery disease. Yet, the mechanisms underlying this reduction remain unknown. OBJECTIVE: In this study, we hypothesized that rivaroxaban's antithrombotic potential is linked to a hitherto unknown rivaroxaban effect that impacts on platelet reactivity and arterial thrombosis. METHODS AND RESULTS: In this study, we identified FXa as potent, direct agonist of the PAR-1 (protease-activated receptor 1), leading to platelet activation and thrombus formation, which can be inhibited by rivaroxaban. We found that rivaroxaban reduced arterial thrombus stability in a mouse model of arterial thrombosis using intravital microscopy. For in vitro studies, atrial fibrillation patients on permanent rivaroxaban treatment for stroke prevention, respective controls, and patients with new-onset atrial fibrillation before and after first intake of rivaroxaban (time series analysis) were recruited. Platelet aggregation responses, as well as thrombus formation under arterial flow conditions on collagen and atherosclerotic plaque material, were attenuated by rivaroxaban. We show that rivaroxaban's antiplatelet effect is plasma dependent but independent of thrombin and rivaroxaban's anticoagulatory capacity. CONCLUSIONS: Here, we identified FXa as potent platelet agonist that acts through PAR-1. Therefore, rivaroxaban exerts an antiplatelet effect that together with its well-known potent anticoagulatory capacity might lead to reduced frequency of atherothrombotic events and improved outcome in patients.

Emergency Venous Angioplasty of a Complete Superior Vena Cava Thrombosis.

A patient with a history of colon cancer was admitted to our emergency department due to progressive dyspnea, chest pain, and swelling of the upper limbs and face. A central venous port device had been implanted into the right subclavian vein for administration of systemic chemotherapy several months prior. Thoracic computed tomography scan revealed a 2.8 cm-long thrombus arising from the tip of the venous catheter, which completely occluded the superior vena cava in close proximity to the right atrium.

Hybrid-stenting with metallic and bioresorbable drug-eluting stents 2-year clinical outcomes in KUM ABSORB registry.

AIM AND OBJECTIVE: We sought to investigate and compare outcomes 2 years after Hybrid-stenting with bioresorbable vascular scaffolds (BVS) and contemporary metallic drug-eluting stents (DES) within the same coronary lesion versus BVS alone. METHODS: Between 11/2012 and 7/2015 at our institution, 134 (33.2%) were treated with Hybrid-stenting for complex or long coronary lesions, 270 patients were treated by BVS alone. The primary outcome of interest was target lesion failure (TLF) at 2-years of follow-up. RESULTS: Patients treated by Hybrid-stenting were more frequently men (80% vs. 70%, p = 0.04) had extensive multivessel disease (84% vs. 71%, p < 0.01) including more complex (89% vs. 52%, p < 0.01) and longer lesions (28.9 mm vs 16.4 ± mm, p < 0.01) resulting in longer treated segments (47.3 mm vs 21.5 mm, p < 0.01) and more residual in-segment stenosis (12.3% vs 8.5%, p < 0.01) compared to BVS alone patients. At 2 years, cumulative incidence of TLF was 9.7% of Hybrid-stenting patients and 11.5% of BVS alone patients (p = 0.62), myocardial infarction (3.0% vs 4.1%, p = 0.59) and mortality (1.5% vs 4.1%, p = 0.17), respectively. Target lesion revascularization occurred in 9 Hybrid-stenting patients (2 located in DES) and in 20 BVS alone patients, cumulative incidence 6.7% vs. 7.4% (p = 0.80). Chronic kidney disease and residual in-segment stenosis >30% were identified as independent predictors of TLF at 2-years. CONCLUSION: Despite differences in clinical and angiographic profile, Hybrid-stenting performed similar to BVS alone at 2 years after percutaneous coronary intervention.

Age-dependent impact of the SYNTAX-score on longer-term mortality after percutaneous coronary intervention in an all-comer population.

BACKGROUND: The Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX)-score is a validated tool for risk stratification and revascularization strategy selection in patients with complex coronary artery disease. The aim of this study was to analyse its age-related prognostic value. METHODS: SYNTAX-score was calculated in 1331 all-comer patients undergoing percutaneous coronary intervention (PCI): 463 patients ≥ 75 years and 868 patients < 75 years. Outcomes of interest were all-cause mortality at one and two years. RESULTS: A significant interaction of age and SYNTAX-score for mortality was observed at two-year (P interaction = 0.019) but not at one-year follow-up (P interaction = 0.594). In multivariable analysis, SYNTAX-score independently predicted 1-year mortality in both age groups (< 75 years, hazard ratio (HR): 1.43, 95% confidence intervals (CI): 1.03-2.00, P = 0.034; and ≥ 75 years, HR: 1.37, 95% CI: 1.01-1.85, P = 0.042), but only two-year mortality among younger patients (< 75 years, HR: 1.33, 95% CI: 1.01-1.76, P = 0.041; and ≥ 75 years, HR: 1.11, 95% CI: 0.87-1.41, P = 0.394). SYNTAX-score tertiles were useful to stratify 1-year mortality in both, patients < 75 years (SYNTAX-score < 9, 3.8%; 9-20, 5.3%; ≥ 20, 10.3%; P = 0.004) and ≥ 75 years (SYNTAX-score < 11, 5.7%; 11-22.5, 16.1%; ≥ 22.5, 18.7%; P = 0.003), but two-year mortality only among patients < 75 years (SYNTAX-score < 9, 6.5%; 9-20, 7.6%; ≥ 20, 15%; P < 0.001) and not among ≥ 75 years old patients (SYNTAX-score < 11, 19.4%; 11-22.5, 26.3%; ≥ 22.5, 27.9%; P = 0.138). CONCLUSIONS: Age modifies the impact of the SYNTAX-score on longer-term mortality after PCI. Among patients < 75 years, the SYNTAX-score independently predicts the risk of death at one and two years after PCI, while among patients ≥ 75 years its predictive role is limited to the first year after PCI. Further studies are needed to evaluate the value of SYNTAX-score for selecting the most appropriate revascularization strategy among elderly patients.

Oral thrombin inhibitor aggravates platelet adhesion and aggregation during arterial thrombosis.

In patients with atrial fibrillation, oral anticoagulation with oral thrombin inhibitors (OTIs), in contrast to vitamin K antagonists (VKAs), associates with a modest increase in acute coronary syndromes (ACSs). Whether this observation is causatively linked to OTI treatment and, if so, whether OTI action is the result of a lower antithrombotic efficacy of OTI compared to VKA or reflects a yet undefined prothrombotic activity of OTI remain unclear. We analyzed platelet function in patients receiving OTI or dose-adapted VKA under static and flow conditions. In vivo, we studied arterial thrombosis in OTI-, VKA-, and vehicle-treated mice using carotid ligation and wire injury models. Further, we examined thrombus formation on human atherosclerotic plaque homogenates under arterial shear to address the relevance to human pathology. Under static conditions, aggregation in the presence of ristocetin was increased in OTI-treated blood, whereas platelet reactivity and aggregation to other agonists were only marginally affected. Under flow conditions, firm platelet adhesion and thrombus formation on von Willebrand factor, collagen, and human atherosclerotic plaque were increased in the presence of OTI in comparison to VKA. OTI treatment was associated with increased thrombus formation in injured carotid arteries of mice. Inhibition or ablation of GPIbα-thrombin interactions abolished the effect of OTI on thrombus formation, suggesting a mechanistic role of the platelet receptor GPIbα and its thrombin-binding site. The effect of OTI was also abrogated in the presence of aspirin. In summary, OTI treatment has prothrombotic activity that might contribute to the increase in ACS observed clinically in patients.