COVID-19 promotes endothelial dysfunction and thrombogenicity: role of proinflammatory cytokines/SGLT2 prooxidant pathway.

BACKGROUND: COVID-19 is associated with an increased risk of cardiovascular complications. Although cytokines have a predominant role in endothelium damage, the precise molecular mechanisms are far from being elucidated. OBJECTIVES: The present study hypothesized that inflammation in patients with COVID-19 contributes to endothelial dysfunction through redox-sensitive SGLT2 overexpression and investigated the protective effect of SGLT2 inhibition by empagliflozin. METHODS: Human plasma samples were collected from patients with acute, subacute, and long COVID-19 (n = 100), patients with non-COVID-19 and cardiovascular risk factors (n = 50), and healthy volunteers (n = 25). Porcine coronary artery endothelial cells (ECs) were incubated with plasma (10%). Protein expression levels were determined using Western blot analyses and immunofluorescence staining, mRNA expression by quantitative reverse transcription-polymerase chain reaction, and the level of oxidative stress by dihydroethidium staining. Platelet adhesion, aggregation, and thrombin generation were determined. RESULTS: Increased plasma levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 were observed in patients with COVID-19. Exposure of ECs to COVID-19 plasma with high cytokines levels induced redox-sensitive upregulation of SGLT2 expression via proinflammatory cytokines IL-1ß, IL-6, and tumor necrosis factor-α which, in turn, fueled endothelial dysfunction, senescence, NF-κB activation, inflammation, platelet adhesion and aggregation, von Willebrand factor secretion, and thrombin generation. The stimulatory effect of COVID-19 plasma was blunted by neutralizing antibodies against proinflammatory cytokines and empagliflozin. CONCLUSION: In patients with COVID-19, proinflammatory cytokines induced a redox-sensitive upregulation of SGLT2 expression in ECs, which in turn promoted endothelial injury, senescence, platelet adhesion, aggregation, and thrombin generation. SGLT2 inhibition with empagliflozin appeared as an attractive strategy to restore vascular homeostasis in COVID-19.

Combination of Primary Hemostatic Disorders and Atrial Fibrillation Increases Bleeding Events Following Transcatheter Aortic Valve Replacement.

Background Patients with atrial fibrillation (AF) are likely to have a poor prognosis including bleedings following transcatheter aortic valve replacement (TAVR). Closure time of adenosine diphosphate (CT-ADP) is a primary hemostasis point-of-care test and is a predictor of bleeding events following TAVR. We aimed to evaluate the impact of ongoing primary hemostatic disorders on bleeding events in TAVR patients with AF. Methods We enrolled 878 patients from our prospective registry. The primary endpoint was VARC-2 major/life-threatening bleeding complications (MLBCs) at 1 year after TAVR and secondary endpoint was major adverse cardiac and cerebrovascular events (MACCEs) at 1 year, defined as a composite of all-cause death, myocardial infarction, stroke, and heart failure hospitalization. Ongoing primary hemostatic disorder was defined by a postprocedural CT-ADP >180 seconds. Results Patients with AF had a higher incidence of MLBCs (20 vs. 12%, p = 0.002), MACCE (29 vs. 20%, p = 0.002), and all-cause mortality (15 vs. 8%, p = 0.002) within 1 year compared to non-AF patients. When the cohort was split into four subgroups according to AF and CT-ADP >180 seconds, patients with AF and CT-ADP >180 seconds had the highest risk of MLBCs and MACCE. Multivariate Cox regression analysis confirmed that the patients with AF and CT-ADP >180 seconds had 3.9-fold higher risk of MLBCs, whereas those patients were no longer associated with MACCE after the adjustment. Conclusion In TAVR patients, AF with postprocedural CT-ADP >180 seconds was strongly associated with MLBCs following TAVR. Our study suggests that persistent primary hemostatic disorders contribute to a higher risk of bleeding events particularly in AF patients.

Management of urgent invasive procedures in patients treated with direct oral anticoagulants: An observational registry analysis.

BACKGROUND: Patients treated with direct oral anticoagulants (DOACs) may require urgent procedures. Managing these patients is challenging due to different bleeding risks and may include laboratory testing, procedural delays, or haemostatic/reversal agent administration. OBJECTIVE: We evaluated management strategies and outcomes of urgent, non-haemostatic invasive procedures in patients treated with DOACs. METHODS AND RESULTS: In a descriptive cohort study, we prospectively evaluated 478 patients in the GIHP-NACO registry, from June 2013 to November 2015. Hospitalised patients receiving dabigatran (n = 160), rivaroxaban (n = 274), or apixaban (n = 44) requiring urgent, procedural interventions were evaluated, of which 384/478 (80 %) were surgical procedures. Orthopaedic surgery included 216/384 patients (56 %), while gastrointestinal surgery included 75/384 (20 %) patients. On admission, the median age was 79 (70-85), and creatinine clearance was <60 mL·min-1 in 316/478 (66 %) patients. DOAC concentration was determined in 277 (58 %) patients and was 85 ng·mL-1 (median; range 0-764), 61 ng·mL-1 (3-541), and 81 ng·mL-1 (26-354) for dabigatran, rivaroxaban, and apixaban, respectively. Procedures were delayed in 194/455 (43 %) of the cases. Excessive bleeding was observed in 62/478 (13 %) procedures, and haemostatic agents were administered in 76/478 (16 %) procedures. By day 30, major cerebral and cardiovascular events were observed in 38/478 (7.9 %) patients, and mortality was 28/478 (5.9 %). CONCLUSIONS: In the GIHP-NACO registry, before specific antidotes were available, DOAC treated patients undergoing urgent invasive procedures were delayed in nearly half of the cases, and showed a low rate of excessive bleeding, suggesting that most urgent procedures can be performed safely without DOAC reversal. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov. Identifier: NCT02185027.

Baseline mean platelet volume is a strong predictor of major and life-threatening bleedings after transcatheter aortic valve replacement.

BACKGROUND: Bleeding following transcatheter aortic valve replacement (TAVR) has important prognostic implications. This study sought to evaluate the impact of baseline mean platelet volume (MPV) on bleeding events after TAVR. METHODS AND RESULTS: Patients undergoing TAVR between February 2010 and May 2019 were included. Low MPV (L-MPV) was defined as MPV ≤10 fL and high MPV (H-MPV) as MPV >10 fL. The primary endpoint was the occurrence of major/life-threatening bleeding complications (MLBCs) at one-year follow-up. Among 1,111 patients, 398 (35.8%) had L-MPV and 713 (64.2%) had H-MPV. The rate of MLBCs at 1 year was higher in L-MPV patients compared with H-MPV patients (22.9% vs. 17.7% respectively, p = 0.034). L-MPV was associated with vascular access-site complications (36.2% vs. 28.9%, p = 0.012), early (<30 days) major bleeding (15.6% vs. 9.4%, p<0.01) and red blood cell transfusion >2 units (23.9% vs. 17.5%, p = 0.01). No impact of baseline MPV on overall death, cardiovascular death and ischemic events (myocardial infarction and stroke) was evidenced. Multivariate analysis using Fine and Gray model identified preprocedural hemoglobin (sHR 0.84, 95%CI [0.75-0.93], p = 0.001), preprocedural L-MPV (sHR 1.64, 95%CI [1.16-2.32], p = 0.005) and closure time adenosine diphosphate post-TAVR (sHR 2.71, 95%CI [1.87-3.95], p<0.001) as predictors of MLBCs. CONCLUSIONS: Preprocedural MPV was identified as an independent predictor of MLBCs one year after TAVR, regardless of the extent of platelet inhibition and primary hemostasis disorders.

Vaccine-induced immune thrombotic thrombocytopenia: current evidence, potential mechanisms, clinical implications, and future directions.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) (also termed thrombosis with thrombocytopenia syndrome or vaccine-induced thrombotic thrombocytopenia or vaccine-induced immune thrombocytopenia) is characterized by (i) venous or arterial thrombosis; (ii) mild-to-severe thrombocytopenia; (iii) positive antiplatelet factor 4 (PF4)-polyanion antibodies or anti-PF4-heparin antibodies detected by the HIT (heparin-induced thrombocytopenia) ELISA; (iv) occurring 5-30 days after ChAdOx1 nCoV-19 (AstraZeneca) or Ad26.COV2.S (Johnson & Johnson/Janssen) vaccination. VITT's incidence is 1 per 100 000 vaccinated people irrespective of age and up to 1 in 50 000 for people <50 years of age with the AstraZeneca COVID-19 vaccine. The exact mechanism by which adenovirus-vectored COVID-19 vaccines trigger this syndrome is still unclear, as for the increased risk for acute cerebral sinus venous thrombosis and splanchnic vein thrombosis as compared to other locations of venous thrombotic events. VITT is associated with the detection of anti-PF4 antibodies, unrelated to previous use of heparin therapy. PF4 antibodies are thought to activate platelets via the platelet FcγRIIA receptors leading to further platelet activation that causes thrombosis and thrombocytopenia.

Bilateral Acute Cardioembolic Limb Ischemia After Coronavirus Disease 2019 Pneumonia in a Lung Transplant Recipient: A Case Report.

Very few cases of lung transplant patients affected by coronavirus disease 2019 (COVID-19) have been reported to date. A 31-year-old patient who underwent bilateral lung transplantation for cystic fibrosis in 2012 was admitted for severe acute lower limb pain. He had a confirmed exposure to COVID-19 and a 3-week history of upper respiratory tract infection. Whole-body computed tomography (CT) angiography revealed an occlusion of the 2 common femoral arteries. CT angiography detected an intracardiac thrombus in the left ventricle. Chest CT angiography showed ground-glass opacities consistent with COVID-19. A bilateral femoral surgical embolectomy using Fogarty catheter was successfully performed. Specific reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 performed on an extracted thrombus was negative, but IgM antibodies specific for COVID-19 were detected. Cardiac magnetic resonance imaging demonstrated a subendocardial and almost transmural late gadolinium enhancement in the mid and distal inferolateral and inferior wall segments, consistent with a nonrecent myocardial infarction and an apical centimetric thrombus adjacent to the lesion. Thrombophilia laboratory tests found the presence of a positive lupus anticoagulant. Treatment with low-molecular-weight heparin and aspirin was prescribed. On day 13, the patient was discharged from the hospital. This case underlines the need to be vigilant with respect to the thrombotic complications of COVID-19 and raises the issue of thrombosis prevention in COVID-19 patients.