Impact of left atrial appendage flow velocity on thrombus resolution and clinical outcomes in patients with atrial fibrillation and silent left atrial thrombi: insights from the LAT study.

AIMS: Blood stasis is crucial in developing left atrial (LA) thrombi. LA appendage peak flow velocity (LAAFV) is a quantitative parameter for estimating thromboembolic risk. However, its impact on LA thrombus resolution and clinical outcomes remains unclear. METHODS AND RESULTS: The LAT study was a multicentre observational study investigating patients with atrial fibrillation (AF) and silent LA thrombi detected by transoesophageal echocardiography (TEE). Among 17 436 TEE procedures for patients with AF, 297 patients (1.7%) had silent LA thrombi. Excluding patients without follow-up examinations, we enrolled 169 whose baseline LAAFV was available. Oral anticoagulation use increased from 85.7% at baseline to 97.0% at the final follow-up (P < 0.001). During 1 year, LA thrombus resolution was confirmed in 130 (76.9%) patients within 76 (34-138) days. Conversely, 26 had residual LA thrombi, 8 had thromboembolisms, and 5 required surgical removal. These patients with failed thrombus resolution had lower baseline LAAFV than those with successful resolution (18.0 [15.8-22.0] vs. 22.2 [17.0-35.0], P = 0.003). Despite limited predictive power (area under the curve, 0.659; P = 0.001), LAAFV ≤ 20.0 cm/s (best cut-off) significantly predicted failed LA thrombus resolution, even after adjusting for potential confounders (odds ratio, 2.72; 95% confidence interval, 1.22-6.09; P = 0.015). The incidence of adverse outcomes including ischaemic stroke/systemic embolism, major bleeding, or all-cause death was significantly higher in patients with reduced LAAFV than in those with preserved LAAFV (28.4% vs. 11.6%, log-rank P = 0.005). CONCLUSION: Failed LA thrombus resolution was not rare in patients with AF and silent LA thrombi. Reduced LAAFV was associated with failed LA thrombus resolution and adverse clinical outcomes.

Balloon-Assisted Endovascular Thrombectomy for Tibial Thromboembolism.

We present a novel approach to endovascular thrombectomy using the Penumbra Indigo® Aspiration System with balloon assistance for a thromboembolic occlusion to the tibioperoneal trunk and tibial arteries causing acute limb ischemia. This technique allows for effective suction thrombectomy of distal vessels into a shorter, large-diameter aspiration catheter, thereby overcoming the limitations of the longer but smaller aspiration catheters.

Combined anticoagulant and antiplatelet therapy is associated with an improved outcome in hospitalised patients with COVID-19: a propensity matched cohort study.

BACKGROUND: COVID-19 is a respiratory disease that results in a prothrombotic state manifesting as thrombotic, microthrombotic and thromboembolic events. As a result, several antithrombotic modalities have been implicated in the treatment of this disease. This study aimed to identify if therapeutic anticoagulation (TAC) or concurrent use of antiplatelet and anticoagulants was associated with an improved outcome in this patient population. METHODS: A retrospective observational cohort study of adult patients admitted to a single university hospital for COVID-19 infection was performed. The primary outcome was a composite of in-hospital mortality, intensive care unit (ICU) admission or the need for mechanical ventilation. The secondary outcomes were each of the components of the primary outcome, in-hospital mortality, ICU admission, or the need for mechanical ventilation. RESULTS: 242 patients were included in the study and divided into four subgroups: Therapeutic anticoagulation (TAC), prophylactic anticoagulation+antiplatelet (PACAP), TAC+antiplatelet (TACAP) and prophylactic anticoagulation (PAC) which was the reference for comparison. Multivariable Cox regression analysis and propensity matching were done and showed when compared with PAC, TACAP and TAC were associated with less in-hospital all-cause mortality with an adjusted HR (aHR) of 0.113 (95% CI 0.028 to 0.449) and 0.126 (95% CI 0.028 to 0.528), respectively. The number needed to treat in both subgroups was 11. Furthermore, PACAP was associated with a reduced risk of invasive mechanical ventilation with an aHR of 0.07 (95% CI 0.014 to 0.351). However, the was no statistically significant difference in the occurrence of major or minor bleeds, ICU admission or the composite outcome of in-hospital mortality, ICU admission or the need for mechanical ventilation. CONCLUSION: The use of combined anticoagulant and antiplatelet agents or TAC alone in hospitalised patients with COVID-19 was associated with a better outcome in comparison to PAC alone without an increase in the risk of major and minor bleeds. Sufficiently powered randomised controlled trials are needed to further evaluate the safety and efficacy of combining antiplatelet and anticoagulants agents or using TAC in the management of patients with COVID-19 infection.

On-admission versus in-hospital thromboembolism due to COVID-19 infection. What is the particular characteristic of those with early thrombotic events?

INTRODUCTION: Increasing evidence has declared a hypercoagulable state in the coronavirus 2019 infection (COVID-19), while the etiology has remained a question. For the first time, the current study has aimed to compare the contributors of thromboembolism among those whose primary manifestations of COVID-19 were thrombosis vs the patients with a thrombotic event during the period of hospitalization. MATERIAL AND METHODS: This case-control study has been conducted on 267 COVID-19 patients, including 59, 48, and 160 ones with an on-admission, in-hospital, and without a thrombotic event, respectively. The events were defined as deep vein thrombosis (DVT), ischemic cerebrovascular accidents (CVA), pulmonary thromboembolism (PTE), or acute myocardial infarction (AMI). The demographic, physical examination, clinical and laboratory assessments of the groups were compared. RESULTS: The DVT (OR: 5.18; 95% CI: 1.01-26.7), AMI (OR: 11.1; 95% CI: 2.36-52.3), and arterial thrombosis (OR: 5.93; 95% CI: 0.63-55.8) were significantly associated with an on-admission thrombosis compared to those who presented in-hospital events. Lower levels of oxygen saturation were the only significant predictor index inversely associated with on-admission thrombosis compared to those with an event during the hospital admission period. CONCLUSION: PTE development was the most common in-hospital thrombotic event, whereas other thromboembolism types were remarkably more often among cases with on-admission events. Oxygen saturation was the only predictor of premature thrombosis that was inversely associated with outpatient events.

Risk Factors of Thromboembolism in Lymphoma Patients Undergoing Chemotherapy and its Clinical Significance.

This study investigated the risk factors of thromboembolism (TE) in lymphoma patients undergoing chemotherapy and its clinical significance. A total of 304 lymphoma patients who received chemotherapy from January 2012 to July 2019 were retrospectively analyzed, including 111 patients with and 193 patients without TE. The clinical characteristics and related laboratory test results were compared between the 2 groups using univariate analysis, while the risk factors for TE in lymphoma patients undergoing chemotherapy were analyzed using multivariate logistic regression analysis. Univariate analysis revealed an increase in the risk of TE among lymphoma patients with chemotherapy in the following categories: female patients, patients with body mass index <18.5 or > 24, patients aged ≥60 years, those with platelet abnormality before chemotherapy, single hospital-stay patients, and Ann Arbor stage III/IV patients. Multivariate logistic regression analysis revealed that for platelet count abnormality before chemotherapy, Ann Arbor stage III/IV and female patients represented independent risk factors for TE among lymphoma patients after chemotherapy (P < .05). For lymphoma patients treated with chemotherapy, the risk of TE occurring in women, patients with platelet abnormalities before chemotherapy, and patients at Ann Arbor stage III/IV was significantly higher compared with other patients. For these patients, we recommend prophylactic anticoagulant therapy.

Reverse remodeling of tricuspid valve morphology and function in chronic thromboembolic pulmonary hypertension patients following pulmonary thromboendarterectomy: a cardiac magnetic resonance imaging and invasive hemodynamic study.

BACKGROUND: To investigate changes in tricuspid annulus (TA) and tricuspid valve (TV) morphology among chronic thromboembolic pulmonary hypertension (CTEPH) patients before and 12 months after pulmonary thromboendarterectomy (PEA) and compare these findings to normal control subjects. METHODS: 20 CTEPH patients and 20 controls were enrolled in the study. The patients were examined with echocardiography, right heart catherization and cardiac magnetic resonance imaging prior to PEA and 12 months after. RESULTS: Right atrium (RA) volume was significantly reduced from baseline to 12 months after PEA (30 ± 9 vs 23 ± 5 ml/m2, p < 0.005). TA annular area in systole remained unchanged (p = 0.11) and was comparable to controls. The leaflet area, tenting volume and tenting height in systole were significantly increased at baseline but decreased significantly with comparable values to controls after 12 months (p < 0.005). There was correlation between the changes of right ventricular-pulmonary artery coupling and changes of TV tenting height (r = - 0.54, p = 0.02), TV tenting volume (r = - 0.73, p < 0.001) and TV leaflet area (- 0.57, p = 0.01) from baseline to 12 months after PEA. Tricuspid regurgitation jet area/RA area was significantly (p < 0.01) reduced from baseline (30 ± 13%) to 12 months after PEA (9 ± 10%). CONCLUSION: In CTEPH patients selected for PEA, TV tenting height, volume and valve area are significantly increased whereas annulus size and shape are less affected. The alterations in TV morphology are fully reversed after PEA and correlates to improvements of right ventricular-pulmonary arterial coupling.

Optimizing cerebral perfusion and hemodynamics during cardiopulmonary bypass through cannula design combining in silico, in vitro and in vivo input.

Cardiopulmonary bypass (CPB) is a standard technique for cardiac surgery, but comes with the risk of severe neurological complications (e.g. stroke) caused by embolisms and/or reduced cerebral perfusion. We report on an aortic cannula prototype design (optiCAN) with helical outflow and jet-splitting dispersion tip that could reduce the risk of embolic events and restores cerebral perfusion to 97.5% of physiological flow during CPB in vivo, whereas a commercial curved-tip cannula yields 74.6%. In further in vitro comparison, pressure loss and hemolysis parameters of optiCAN remain unaffected. Results are reproducibly confirmed in silico for an exemplary human aortic anatomy via computational fluid dynamics (CFD) simulations. Based on CFD simulations, we firstly show that optiCAN design improves aortic root washout, which reduces the risk of thromboembolism. Secondly, we identify regions of the aortic intima with increased risk of plaque release by correlating areas of enhanced plaque growth and high wall shear stresses (WSS). From this we propose another easy-to-manufacture cannula design (opti2CAN) that decreases areas burdened by high WSS, while preserving physiological cerebral flow and favorable hemodynamics. With this novel cannula design, we propose a cannulation option to reduce neurological complications and the prevalence of stroke in high-risk patients after CPB.

Optimizing indices of atrial fibrillation susceptibility and burden to evaluate atrial fibrillation severity, risk and outcomes.

Atrial fibrillation (AF) has heterogeneous patterns of presentation concerning symptoms, duration of episodes, AF burden, and the tendency to progress towards the terminal step of permanent AF. AF is associated with a risk of stroke/thromboembolism traditionally considered dependent on patient-level risk factors rather than AF type, AF burden, or other characterizations. However, the time spent in AF appears related to an incremental risk of stroke, as suggested by the higher risk of stroke in patients with clinical AF vs. subclinical episodes and in patients with non-paroxysmal AF vs. paroxysmal AF. In patients with device-detected atrial tachyarrhythmias, AF burden is a dynamic process with potential transitions from a lower to a higher maximum daily arrhythmia burden, thus justifying monitoring its temporal evolution. In clinical terms, the appearance of the first episode of AF, the characterization of the arrhythmia in a specific AF type, the progression of AF, and the response to rhythm control therapies, as well as the clinical outcomes, are all conditioned by underlying heart disease, risk factors, and comorbidities. Improved understanding is needed on how to monitor and modulate the effect of factors that condition AF susceptibility and modulate AF-associated outcomes. The increasing use of wearables and apps in practice and clinical research may be useful to predict and quantify AF burden and assess AF susceptibility at the individual patient level. This may help us reveal why AF stops and starts again, or why AF episodes, or burden, cluster. Additionally, whether the distribution of burden is associated with variations in the propensity to thrombosis or other clinical adverse events. Combining the improved methods for data analysis, clinical and translational science could be the basis for the early identification of the subset of patients at risk of progressing to a longer duration/higher burden of AF and the associated adverse outcomes.

The Inflammatory Profile of CTEPH-Derived Endothelial Cells Is a Possible Driver of Disease Progression.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension characterized by the presence of fibrotic intraluminal thrombi and causing obliteration of the pulmonary arteries. Although both endothelial cell (EC) dysfunction and inflammation are linked to CTEPH pathogenesis, regulation of the basal inflammatory response of ECs in CTEPH is not fully understood. Therefore, in the present study, we investigated the role of the nuclear factor (NF)-κB pro-inflammatory signaling pathway in ECs in CTEPH under basal conditions. Basal mRNA levels of interleukin (IL)-8, IL-1ß, monocyte chemoattractant protein-1 (MCP-1), C-C motif chemokine ligand 5 (CCL5), and vascular cell adhesion molecule-1 (VCAM-1) were upregulated in CTEPH-ECs compared to the control cells. To assess the involvement of NF-κB signaling in basal inflammatory activation, CTEPH-ECs were incubated with the NF-κB inhibitor Bay 11-7085. The increase in pro-inflammatory cytokines was abolished when cells were incubated with the NF-κB inhibitor. To determine if NF-κB was indeed activated, we stained pulmonary endarterectomy (PEA) specimens from CTEPH patients and ECs isolated from PEA specimens for phospho-NF-κB-P65 and found that especially the vessels within the thrombus and CTEPH-ECs are positive for phospho-NF-κB-P65. In summary, we show that CTEPH-ECs have a pro-inflammatory status under basal conditions, and blocking NF-κB signaling reduces the production of inflammatory factors in CTEPH-ECs. Therefore, our results show that the increased basal pro-inflammatory status of CTEPH-ECs is, at least partially, regulated through activation of NF-κB signaling and potentially contributes to the pathophysiology and progression of CTEPH.

Effect of Supervised Training Therapy on Pulmonary Arterial Compliance and Stroke Volume in Severe Pulmonary Arterial Hypertension and Inoperable or Persistent Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Pulmonary arterial compliance (PAC) is a prognostic parameter in pulmonary arterial hypertension (PAH) reflecting the elasticity of the pulmonary vessels. OBJECTIVES: The objective of this post hoc analysis of a prospective randomized controlled trial (RCT) was to assess the effect of exercise training on PAC and stroke volume (SV) in patients with PAH and persistent/inoperable chronic thromboembolic pulmonary hypertension (CTEPH). METHOD: From the previous RCT, 43 out of 87 patients with severe PAH (n = 29) and CTEPH (n = 14) had complete haemodynamic examinations at baseline and after 15 weeks by right heart catheterization and were analysed (53% female, 79% World Health Organization functional class III/IV, 58% combination therapy, 42% on supplemental oxygen therapy, training group n = 24, and control group n = 19). Medication remained unchanged for all patients. RESULTS: Low-dose exercise training at 4-7 days/week significantly improved PAC (training group 0.33 ± 0.65 mL/mm Hg vs. control group -0.06 ± 1.10 mL/mm Hg; mean difference 0.39 mL/mm Hg, 95% confidence interval [CI] 0.15-0.94 mL/mm Hg; p = 0.004) and SV (training group 9.9 ± 13.4 mL/min vs. control group -4.2 ± 11.0 mL/min; mean difference 14.2 mL, 95% CI 6.5-21.8 mL; p < 0.001) in the training versus control group. Furthermore, exercise training significantly improved cardiac output and pulmonary vascular resistance at rest, peak oxygen consumption, and oxygen pulse. CONCLUSIONS: Our findings suggest that supervised exercise training may improve right ventricular function and PAC at the same time. Further prospective studies are needed to evaluate these findings.

Thromboembolic Complications in Severe COVID-19: Current Antithrombotic Strategies and Future Perspectives.

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS- CoV-2) is our latest pandemic and has turned out to be a global public health crisis. One of the special characteristics of this disease is that it may predispose patients to thrombotic disease both in the venous and arterial circulation. We review arterial and venous thromboembolic complications in patients with COVID-19, epidemiology, pathogenesis, hematologic biomarkers, and current antithrombotic strategies. Future perspectives and clinical trials are ongoing to determine the best thromboprophylaxis strategies in the hospitalized patients with severe COVID-19.

Irreversible Limb Ischemia Due to Embolizing Aneurysm of the Superficial Femoral Artery.

BACKGROUND: Degenerative superficial femoral artery aneurysms are rare and can lead to catastrophic complications; among these, rupture is the most usual, whereas peripheral embolization is less common. METHOD: We report a patient with a large superficial femoral artery aneurysm presenting with irreversible limb ischemia, due to multiple distal embolization as demonstrated with urgent computed tomography angiography. Due to local and systemic consequences primary limb amputation was performed. Unfortunately, the patient died from cardiac arrest on the 2nd postoperative day. CONCLUSION: Delayed diagnosis of true superficial femoral artery aneurysms can result in life-threatening consequences. Peripheral embolization is an uncommon event, but can lead to irreversible ischemia and limb loss.

MANAGEMENT OF ENDOCRINE DISEASE: Cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing's syndrome: a practical approach.

Cushing's syndrome (CS) is associated with increased mortality that is driven by cardiovascular, thromboembolic, and infection complications. Although these events are expected to decrease during disease remission, incidence often transiently increases postoperatively and is not completely normalized in the long-term. It is important to diagnose and treat cardiovascular, thromboembolic, and infection complications concomitantly with CS treatment. Management of hyperglycemia/diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with clinical care standards. Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism, and treatment adjustments can be made based on disease pathophysiology and drug-drug interactions. Thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding. Pneumocystis jiroveci pneumonia prophylaxis should be considered for patients with high urinary free cortisol at the initiation of hypercortisolism treatment.

Nonatrial Fibrillation Patients With Complete P Wave Disappearance: An Overlooked Population With High Stroke Risk.

BACKGROUND AND PURPOSE: Complete P wave disappearance (CPWD) in patients without atrial fibrillation is an uncommon clinical phenomenon. We aimed to study the relationship between CPWD and thromboembolism. METHODS: Between July 2007 and December 2018, consecutive patients with CPWD on surface ECG and 24-hour Holter recording were recruited into the study from 4 centers in China. All recruited patients underwent transesophageal echocardiography or cardiac computed tomography to screen for atrial thrombus. Atrial electrical activity and scar were assessed by electrophysiological study (EPS) and 3-dimensional electroanatomic mapping. Cardiac structure and function were assessed by multimodality cardiac imaging. RESULTS: Twenty-three consecutive patients (8 male; mean age 48.5±14.7 years) with CPWD were included. Only 3 patients demonstrated complete atrial electrical silence with atrial noncapture. Thirteen patients who had invasive atrial endocardial mapping demonstrated extensive scar. Pulse-wave mitral inflow Doppler demonstrated absent and dampened A waves in 18 and 5 patients, respectively. Pulse-wave tricuspid inflow Doppler showed absent and dampened A waves in 19 and 4 patients, respectively. Upon recruitment, 8 patients had previous stroke and 3 patients had atrial thrombus. Warfarin was prescribed to all patients. During median follow-up of 42.0 months, 2 patients developed massive ischemic stroke due to warfarin discontinuation. CONCLUSIONS: Our study suggested that CPWD reflects extensive atrial electrical silence and significantly impaired atrial mechanical function. It was strongly associated with thromboembolism and the clinical triad of CPWD-atrial paralysis-stroke was proposed. Anticoagulation should be recommended in such patients.

Carboxypeptidase U (CPU, TAFIa, CPB2) in Thromboembolic Disease: What Do We Know Three Decades after Its Discovery?

Procarboxypeptidase U (proCPU, TAFI, proCPB2) is a basic carboxypeptidase zymogen that is converted by thrombin(-thrombomodulin) or plasmin into the active carboxypeptidase U (CPU, TAFIa, CPB2), a potent attenuator of fibrinolysis. As CPU forms a molecular link between coagulation and fibrinolysis, the development of CPU inhibitors as profibrinolytic agents constitutes an attractive new concept to improve endogenous fibrinolysis or to increase the efficacy of thrombolytic therapy in thromboembolic diseases. Furthermore, extensive research has been conducted on the in vivo role of CPU in (the acute phase of) thromboembolic disease, as well as on the hypothesis that high proCPU levels and the Thr/Ile325 polymorphism may cause a thrombotic predisposition. In this paper, an overview is given of the methods available for measuring proCPU, CPU, and inactivated CPU (CPUi), together with a summary of the clinical data generated so far, ranging from the current knowledge on proCPU concentrations and polymorphisms as potential thromboembolic risk factors to the positioning of different CPU forms (proCPU, CPU, and CPUi) as diagnostic markers for thromboembolic disease, and the potential benefit of pharmacological inhibition of the CPU pathway.

Angiotensin-converting enzyme 2 (ACE2): COVID 19 gate way to multiple organ failure syndromes.

BACKGROUND: Globally, the current medical emergency for novel coronavirus 2019 (COVID-19) leads to respiratory distress syndrome and death. PURPOSE: This review highlighted the effect of COVID-19 on systemic multiple organ failure syndromes. This review is intended to fill a gap in information about human physiological response to COVID-19 infections. This review may shed some light on other potential mechanisms and approaches in COVID -19 infections towards systemic multiorgan failure syndromes. FINDING: SARS-CoV-2 intervened mainly in the lung with progression to pneumonia and acute respiratory distress syndrome (ARDS) via the angiotensin-converting enzyme 2(ACE2) receptor. Depending on the viral load, infection spread through the ACE2 receptor further to various organs such as heart, liver, kidney, brain, endothelium, GIT, immune cell, and RBC (thromboembolism). This may be aggravated by cytokine storm with the extensive release of proinflammatory cytokines from the deregulating immune system. CONCLUSION: The widespread and vicious combinations of cytokines with organ crosstalk contribute to systemic hyper inflammation and ultimately lead to multiple organ dysfunction (Fig. 1). This comprehensive study comprises various manifestations of different organs in COVID-19 and may assist the clinicians and scientists pertaining to a broad approach to fight COVID 19.

Anticoagulation Strategies in the Management of Lemierre Syndrome: A Systematic Review of the Literature.

OBJECTIVE: To determine the optimal anticoagulation strategy in patients diagnosed with Lemierre Syndrome (LS). DATA SOURCES: A systematic review in accordance with PRISMA guidelines was conducted using PubMed, MEDLINE, Scopus, ProQuest, and CINAHL from January to April 2020. Search terms included "Lemierre Syndrome" AND "anticoagulation" NOT "prophylaxis" OR "atrial fibrillation," in addition to a list of parenteral and oral anticoagulants. Adult patients who developed a clot and required systemic anticoagulation as a result of LS were included in this review. STUDY SELECTION AND DATA EXTRACTION: A total of 4180 records were initially identified, though following the removal of duplicates and nonrelevant entries, 216 full-text articles were reviewed for inclusion; 13 articles were ultimately included. DATA SYNTHESIS: The majority (11/14) of patients developed thromboses of the internal jugular veins, which corresponds to the pathophysiology of LS. Anticoagulation strategies were varied in the included literature, though 12/14 patients initially received a parenteral product. Two patients received a direct-acting oral anticoagulant (DOAC) following either intravenous heparin or subcutaneous enoxaparin and had outcomes similar to patients transitioned to warfarin. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Anticoagulation in LS is a clinical controversy because the thromboembolic events have rarely led to significant complications; thrombi typically resolve independently, and concerns for bleeding risks are well founded; however, this review indicates both the efficacy and safety of anticoagulation. CONCLUSIONS: Anticoagulation is both efficacious and safe in LS, including treatment using a DOAC. Although further studies are needed, clinicians should consider a duration of anticoagulation of 6 to 12 weeks.