Dietary and Protective Factors to Halt or Mitigate Progression of Autoimmunity, COVID-19 and Its Associated Metabolic Diseases.

COVID-19 is without any doubt the worst pandemic we have faced since the H1N1 virus outbreak. Even if vaccination against SARS-CoV-2 infection is becoming increasingly available, a more feasible approach for COVID-19 prevention and therapy is still needed. Evidence of a pathological link between metabolic diseases and severe forms of COVID-19 has stimulated critical reflection and new considerations. In particular, an abnormal immune response observed in certain patients with SARS-CoV-2 infection suggested possible common predisposing risk factors with autoimmune diseases such as Type 1 Diabetes (T1D). Correct supplementation with dietary factors may be key to preventing and counteracting both the underlying metabolic impairment and the complications of COVID-19. A set of agents may inhibit the cytokine storm and hypercoagulability that characterize severe COVID-19 infection: vitamin D3, omega-3 polyunsaturated fatty acids, polyphenols like pterostilbene, polydatin and honokiol, which can activate anti-inflammatory and antioxidant sirtuins pathways, quercetin, vitamin C, zinc, melatonin, lactoferrin and glutathione. These agents could be highly beneficial for subjects who have altered immune responses. In this review, we discuss the antiviral and metabolic effects of these dietary factors and propose their combination for potential applications in the prevention and treatment of COVID-19. Rigorous studies will be fundamental for validating preventive and therapeutic protocols that could be of assistance to mitigate disease progression following SARS-CoV-2 infection.

Physiologic and biochemical rationale for treating COVID-19 patients with hyperbaric oxygen.

The SARS-Cov-2 (COVID-19) pandemic remains a major worldwide public health issue. Initially, improved supportive and anti-inflammatory intervention, often employing known drugs or technologies, provided measurable improvement in management. We have recently seen advances in specific therapeutic interventions and in vaccines. Nevertheless, it will be months before most of the world's population can be vaccinated to achieve herd immunity. In the interim, hyperbaric oxygen (HBO2) treatment offers several potentially beneficial therapeutic effects. Three small published series, one with a propensity-score-matched control group, have demonstrated safety and initial efficacy. Additional anecdotal reports are consistent with these publications. HBO2 delivers oxygen in extreme conditions of hypoxemia and tissue hypoxia, even in the presence of lung pathology. It provides anti-inflammatory and anti-proinflammatory effects likely to ameliorate the overexuberant immune response common to COVID-19. Unlike steroids, it exerts these effects without immune suppression. One study suggests HBO2 may reduce the hypercoagulability seen in COVID patients. Also, hyperbaric oxygen offers a likely successful intervention to address the oxygen debt expected to arise from a prolonged period of hypoxemia and tissue hypoxia. To date, 11 studies designed to investigate the impact of HBO2 on patients infected with SARS-Cov-2 have been posted on clinicaltrials.gov. This paper describes the promising physiologic and biochemical effects of hyperbaric oxygen in COVID-19 and potentially in other disorders with similar pathologic mechanisms.

Curcuminoids supplementation ameliorates iron overload, oxidative stress, hypercoagulability, and inflammation in non-transfusion-dependent ß-thalassemia/Hb E patients.

Curcuminoids, polyphenol compounds in turmeric, possess several pharmacological properties including antioxidant, iron-chelating, and anti-inflammatory activities. Effects of curcuminoids in thalassemia patients have been explored in a limited number of studies using different doses of curcuminoids. The present study aims to evaluate the effects of 24-week curcuminoids supplementation at the dosage of 500 and 1000 mg/day on iron overload, oxidative stress, hypercoagulability, and inflammation in non-transfused ß-thalassemia/Hb E patients. In general, both curcuminoids dosages significantly lowered the levels of oxidative stress, hypercoagulability, and inflammatory markers in the patients. In contrast, reductions in iron parameter levels were more remarkable in the 1000 mg/day group. Subgroup analysis revealed that a marker of hypercoagulability was significantly decreased only in patients with baseline ferritin ≤ 1000 ng/ml independently of curcuminoids dosage. Moreover, the alleviation of iron loading parameters was more remarkable in patients with baseline ferritin > 1000 ng/ml who receive 1000 mg/day curcuminoids. On the other hand, the responses of oxidative stress markers were higher with 500 mg/day curcuminoids regardless of baseline ferritin levels. Our study suggests that baseline ferritin levels should be considered in the supplementation of curcuminoids and the appropriate curcuminoids dosage might differ according to the required therapeutic effect. Thai Clinical Trials Registry (TCTR): TCTR20200731003; July 31, 2020 "retrospectively registered".

Ankaferd hemostat (ABS) as a potential mucosal topical agent for the management of COVID-19 syndrome based on its PAR-1 inhibitory effect and oestrogen content.

COVID-19 due to the SARS-CoV-2 infection is a multi-systemic immune syndrome affecting mainly the lungs, oropharyngeal region, and other vascular endothelial beds. There are tremendous ongoing efforts for the aim of developing drugs against the COVID-19 syndrome-associated inflammation. However, currently no specific medicine is present for the absolute pharmacological cure of COVID-19 mucositis. The re-purposing/re-positioning of already existing drugs is a very important strategy for the management of ongoing pandemy since the development of a new drug needs decades. Apart from altering angiotensin signaling pathways, novel drug candidates for re-purposing comprise medications shall target COVID-19 pathobiology, including pharmaceutical formulations that antagonize proteinase-activated receptors (PARs), mainly PAR-1. Activation of the PAR-1, mediators and hormones impact on the hemostasis, endothelial activation, alveolar epithelial cells and mucosal inflammatory responses which are the essentials of the COVID-19 pathophysiology. In this context, Ankaferd hemostat (Ankaferd Blood Stopper, ABS) which is an already approved hemostatic agent affecting via vital erythroid aggregation and fibrinogen gamma could be a potential topical remedy for the mucosal management of COVID-19. ABS is a clinically safe and effective topical hemostatic agent of plant origin capable of exerting pleiotropic effects on the endothelial cells, angiogenesis, cell proliferation and vascular dynamics. ABS had been approved as a topically applied hemostatic agent for the management of post-surgical/dental bleedings and healing of infected inflammatory mucosal wounds. The anti-inflammatory and proteinase-activated receptor axis properties of ABS with a considerable amount of oestrogenic hormone presence highlight this unique topical hemostatic drug regarding the clinical re-positioning for COVID-19-associated mucositis. Topical ABS as a biological response modifier may lessen SARS-CoV-2 associated microthrombosis, endothelial dysfunction, oropharyngeal inflammation and mucosal lung damage. Moreover, PAR-1 inhibition ability of ABS might be helpful for reducing the initial virus propagation and mocasal spread of COVID-19.

Viral Coagulopathy in Patients With COVID-19: Treatment and Care.

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.

Prothrombin Complex Concentrate before Urgent Surgery in Patients Treated with Rivaroxaban and Apixaban.

INTRODUCTION: Patients treated with direct Xa inhibitors may require urgent surgery. Administration of prothrombin complex concentrate (PCC) in this setting is common; however, it is based on limited experience in healthy volunteers. OBJECTIVE: To characterize the population receiving PCC for apixaban/rivaroxaban reversal prior to an urgent surgery and evaluate its efficacy and safety. METHODS: This was a retrospective study in 2 tertiary hospitals. Bleeding was evaluated based on surgical reports, hemoglobin drop, and the use of blood products or additional PCC during 48 h. Safety measures were thrombotic complications and 30-day mortality. RESULTS: Sixty-two patients aged 80.7 ± 9 years, treated with apixaban (39.63%) or rivaroxaban (23.37%), received PCC before an urgent surgery/procedure. Most underwent abdominal operation (61%), orthopedic surgery (13%), or transhepatic cholecystostomy insertion (10%). Bleeding during surgery was reported in 3 patients (5%), no patient required additional PCC, and 16 patients (26%) received packed cells (median: 1 unit, range: 1-5). The 30-day mortality and thrombosis rates were 21% (n = 13) and 3% (n = 2), respectively. The cause of death was related to the primary disease, most commonly sepsis. No patient died due to bleeding/thrombosis. CONCLUSIONS: Our results support the use of PCC to achieve hemostasis in patients treated with Xa inhibitors prior to an urgent surgery.

Poor response to rivaroxaban in nephrotic syndrome with acute deep vein thrombosis: A case report.

RATIONALE: Hypercoagulability can lead to thromboembolic events that are a life-threatening complication of nephrotic syndrome (NS). Conventional anticoagulants are first-line treatment in the presence of demonstrated thrombosis in NS. Direct-acting oral anticoagulants (DOACs) have provided useful alternatives for the prevention and treatment of thromboembolic events. PATIENT CONCERNS: A 59-year-old male developed lower limbs deep vein thrombosis (DVT) during the early course of NS but presented poor response to oral therapeutic doses of rivaroxaban. The decision was made to switch from rivaroxaban to heparin and subsequently bridged to warfarin. The patient presented significant clinical symptom improvement. DIAGNOSIS: NS with Lower limbs DVT. INTERVENTIONS: Rivaroxaban was discontinued and switch to heparin and subsequently bridged to warfarin. OUTCOMES: Venography result of both lower limb vein showed the venous wall was smooth without obvious stenosis or obstruction. Edema of the patient's lower limbs gradually improved and disappeared. LESSONS: The existing published data on the application of DOACs in NS are limited. DOACs have an immediate anticoagulant effect and have demonstrated safety and efficacy and required no routine monitoring, however, application of these agents in NS likely requires further investigation before widespread adoption.

[ST elevation myocardial infarction in young adults: Is there an interest for thrombophilia screening?] / Syndrome coronarien aigu avec sus-décalage du segment ST chez les jeunes adultes : le bilan de thrombophilie a-t-il un intérêt ?

BACKGROUND: Coronary lesions characteristics as well as patient thrombogenicity can explain coronary events manifestation. In young patient, local conditions are usually less important and thrombogenicity could play a significant role. Assessing thrombophilia could be justified in young patients and may induce an adapted therapeutic management. PURPOSE: We aimed to assess the prevalence of thrombophilia and therapeutic modification in young adults aged≤55 years admitted in our department for ST elevation myocardial infarction (STEMI). METHODS: From January 2013 to January 2017, data on all patients aged≤55 years with STEMI admitted in emergency were retrospectively retrieved from our database. Thrombophilia investigation was made regarding clinical (with or without cardiovascular risk factors [CVRF]), biological and/or angiographic evaluation. RESULTS: A total of 133 patients aged≤55 years with STEMI were included. Cardiac arrest occurred in 15 patients (11%). One or less CVRF were found in 47 patients (35%). Smoking was reported in 93 patients (70%) and drug addiction (cannabis, cocaine) in 19 patients (14%). A subset of 51 patients (38%) were screened for thrombophilia. Patients with thrombophilia assessment were younger, less active smokers and presented less CVRF than patients without investigation (P<0.001). Single vessel diseased was found in 88 patients (66%). No differences regarding coronary procedural characteristic were found between the two groups. The most frequently encountered aetiology, found in 122 patients (92%), was de novo intra-arterial thrombosis related to atherosclerosis. In patients with thrombophilia assessment (n=51), one or more abnormal biological results was found in 22 patients (43%) and a therapeutic adjustment was made in 6 patients (12%). CONCLUSION: Thrombophilia screening in young STEMI adults showed an abnormality in 43% of cases. Antithrombotic treatment can be modified after its demonstration.

On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin: Insights From ROCKET AF.

BACKGROUND: Despite rapid clinical adoption of novel anticoagulants, it is unknown whether outcomes differ among patients with worsening renal function (WRF) taking these new drugs compared with warfarin. We aimed to determine whether the primary efficacy (stroke or systemic embolism) and safety (major bleeding and nonmajor clinically relevant bleeding) end points from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial) differed among participants with WRF taking rivaroxaban and those taking warfarin. METHODS: After excluding patients without at least 1 follow-up creatinine measurement (n=1624), we included all remaining patients (n=12 612) randomly assigned to either rivaroxaban or dose-adjusted warfarin. On-treatment WRF (a decrease of >20% from screening creatinine clearance measurement at any time point during the study) was evaluated as a time-dependent covariate in Cox proportional hazards models. RESULTS: Baseline characteristics were generally similar between patients with stable renal function (n=9292) and WRF (n=3320). Rates of stroke or systemic embolism, myocardial infarction, and bleeding were also similar, but WRF patients experienced a higher incidence of vascular death versus stable renal function (2.21 versus 1.41 events per 100 patient-years; P=0.026). WRF patients who were randomized to receive rivaroxaban had a reduction in stroke or systemic embolism compared with those taking warfarin (1.54 versus 3.25 events per 100 patient-years) that was not seen in patients with stable renal function who were randomized to receive rivaroxaban (P=0.050 for interaction). There was no difference in major or nonmajor clinically relevant bleeding among WRF patients randomized to warfarin versus rivaroxaban. CONCLUSIONS: Among patients with on-treatment WRF, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin, without an increase in the composite bleeding end point. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

Elevated Serum Levels of SCUBE1, a Marker for Coagulation, in Patients with Breast Cancer.

Breast cancer (BC) is the most common cancer among women and a major cause of death. Signal Peptide-Cub-Epidermal growth factor domain-containing protein-1 (SCUBE1) is secreted under hypoxia and inflammatory conditions from platelet alpha granules. Its biological function is uncertain, although it may be a procoagulant substance in cancer patients. SCUBE1 is useful for identifying thrombotic diseases, including cancers and acute coronary syndromes. D-dimer reflects the relationship between coagulation activation and fibrinolysis; namely, thrombosis and D-dimer levels are closely linked. This is the first investigation of the potential diagnostic and prognostic value of SCUBE1 levels in patients with BC. Fifty patients and 33 age-matched and body mass index-matched healthy controls were enrolled. Blood samples were collected before chemotherapy regimens commenced. Serum SCUBE1 and D-dimer levels were measured before adjuvant chemotherapy and were compared to the healthy controls. SCUBE1 levels were determined using an enzyme-linked immunosorbent assay (ELISA) method. SCUBE1 and D-dimer levels were significantly higher in patients than in the controls (p = 0.03 and p < 0.001, respectively). A cut-off value of 1.55 ng/mL for SCUBE1 was associated with 62% sensitivity and 72.7% specificity and with positive predictive value of 77.5% and negative predictive value of 55.8%. Two patients with high SCUBE1 and D-dimer levels also developed pulmonary embolism. SCUBE1 may indicate hypercoagulability in patients with BC and thus help identify patients at greater risk of thrombosis and requiring anti-thrombosis treatment. SCUBE1 may also be used as an assistant test for identifying patients at risk of BC.

[Factors Associated with Direct Oral Anticoagulants versus Vitamin K Antagonists in Patients with Non-valvular Atrial Fibrillation]. / Facteurs associés à la prescription d'anticoagulants oraux directs versus anti-vitamines K dans la fibrillation atriale non valvulaire.

OBJECTIVE: Describing the factors associated with direct oral anticoagulants (DOA) prescription in patients with atrial fibrillation (AF). METHOD: This study was performed in Toulouse on a cohort of patients received in rhythmology consultation, treated with vitamin K antagonists (VKA) or DOA for AF. A multivariate model was performed using logistic regression to describe the factors associated with DOA prescription and secondly, those associated with discontinuation of the anticoagulant. RESULTS: Among the 140 patients included, 96 (66%) were treated with VKA and 48 (34%) with DOA. Recent AF diagnosis (OR 7.52, 95% CI [2.41;23.29], p = 0.001), previous exposure to VKA (OR 17.11, 95% CI [4.48;60.91], p<0.001), and no current exposure to anti-platelet agents (APA) (OR 7.69, 95% CI [1.22; 50.00], p = 0.030) were associated to DOA prescription. Discontinuation of the anticoagulant (n=24) was associated to DOA intake (OR 2.71, 95% CI [1.21; 6.08], p = 0.016). DISCUSSION: DOA are less prescribed than VKA in patients treated with APA. DOA switch to VKA was not systematic in patients diagnosed for a long time. However, international normalized ratio (INR) values were stable in most of patients treated with VKA at the switching to DOA. A more powerful study would confirm the factors associated with DOA prescription.

Comparison of the short-term risk of bleeding and arterial thromboembolic events in nonvalvular atrial fibrillation patients newly treated with dabigatran or rivaroxaban versus vitamin K antagonists: a French nationwide propensity-matched cohort study.

BACKGROUND: The safety and effectiveness of non-vitamin K antagonist (VKA) oral anticoagulants, dabigatran or rivaroxaban, were compared with VKA in anticoagulant-naive patients with nonvalvular atrial fibrillation during the early phase of anticoagulant therapy. METHODS AND RESULTS: With the use of the French medico-administrative databases (SNIIRAM and PMSI), this nationwide cohort study included patients with nonvalvular atrial fibrillation who initiated dabigatran or rivaroxaban between July and November 2012 or VKA between July and November 2011. Patients presenting a contraindication to oral anticoagulants were excluded. Dabigatran and rivaroxaban new users were matched to VKA new users by the use of 1:2 matching on the propensity score. Patients were followed for up to 90 days until outcome, death, loss to follow-up, or December 31 of the inclusion year. Hazard ratios of hospitalizations for bleeding and arterial thromboembolic events were estimated in an intent-to-treat analysis using Cox regression models. The population was composed of 19 713 VKA, 8443 dabigatran, and 4651 rivaroxaban new users. All dabigatran- and rivaroxaban-treated patients were matched to 16 014 and 9301 VKA-treated patients, respectively. Among dabigatran-, rivaroxaban-, and their VKA-matched-treated patients, 55 and 122 and 31 and 68 bleeding events and 33 and 58 and 12 and 28 arterial thromboembolic events were observed during follow-up, respectively. After matching, no statistically significant difference in bleeding (hazard ratio, 0.88; 95% confidence interval, 0.64-1.21) or thromboembolic (hazard ratio, 1.10; 95% confidence interval, 0.72-1.69) risk was observed between dabigatran and VKA new users. Bleeding (hazard ratio, 0.98; 95% confidence interval, 0.64-1.51) and ischemic (hazard ratio, 0.93; 95% confidence interval, 0.47-1.85) risks were comparable between rivaroxaban and VKA new users. CONCLUSIONS: In this propensity-matched cohort study, our findings suggest that physicians should exercise caution when initiating either non-VKA oral anticoagulants or VKA in patients with nonvalvular atrial fibrillation.

Safety of early initiation of rivaroxaban or dabigatran after thrombolysis in acute ischemic stroke.

The introduction of direct oral anticoagulants (DOA) in the early stage of cerebral infarction after thrombolysis may reduce the recurrence rate but raises safety concern. We sought to study the feasibility and safety of the introduction of rivaroxaban or dabigatran in this context. Thirty-four consecutive patients admitted for ischemic stroke related to non-valvular atrial fibrillation in whom DOA were given within the first two weeks following intravenous rt-PA were studied. A clinical and radiological monitoring protocol was established to ensure the safety of the prescription. None of the patients experienced symptomatic hemorrhagic transformation or a symptomatic recurrent ischemic event after early rivaroxaban or dabigatran introduction.

Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome.

Hemolytic uremic syndrome is a rare disease, frequently responsible for renal insufficiency in children. Recent findings have led to renewed interest in this pathology. The discovery of new gene mutations in the atypical form of HUS and the experimental data suggesting the involvement of the complement pathway in the typical form, open new perspectives for treatment. This review summarizes the current state of knowledge on both typical and atypical hemolytic uremic syndrome pathophysiology and examines new perspectives for treatment.

[Current management of thalassemia intermedia]. / Prise en charge actuelle des thalassémies intermédiaires.

Thalassemia intermedia is a clinical entity where anemia is mild or moderate, requiring no or occasional transfusion. Non-transfusion-dependent thalassemia encompasses 3 main clinical forms: beta-thalassemia intermedia, hemoglobin E/beta-thalassemia and alpha-thalassemia intermedia (HbH disease). Clinical severity of thalassemia intermedia increases with age, with more severe anemia and more frequent complications such as extramedullary hematopoiesis and iron overload mainly related to increased intestinal absorption. Numerous adverse events including pulmonary hypertension and hypercoagulability have been associated with splenectomy, often performed in thalassemia intermedia patients. The potential preventive benefit of transfusion and chelation therapies on the occurrence of numerous complications supports the strategy of an earlier therapeutic intervention. Increasing knowledge about pathophysiological mechanisms involved in thalassemia erythropoiesis and related iron overload is currently translating in novel therapeutic approaches.