Role of Platelets in Rheumatic Chronic Autoimmune Inflammatory Diseases.

Platelets are essential in maintaining blood homeostasis and regulating several inflammatory processes. They constantly interact with immune cells, have immunoregulatory functions, and can affect, through immunologically active substances, endothelium, leukocytes, and other immune response components. In reverse, inflammatory and immune processes can activate platelets, which might be significant in autoimmune disease progression and arising complications. Thus, considering this interplay, targeting platelet activity may represent a new approach to treatment of autoimmune diseases. This review aims to highlight the role of platelets in the pathogenic mechanisms of the most frequent chronic autoimmune inflammatory diseases to identify gaps in current knowledge and to provide potential new targets for medical interventions.

Urinary tract infection in the context of mini-invasive procedures after kidney transplantation.

INTRODUCTION: The use of antibiotic prophylaxis in invasive procedures is generally accepted and highly recommended. The question is the need to apply antibiotic prophylaxis even in the case of mini-invasive procedures in the post-transplantation period. The aim of the study was to dermine the occurrence of infectious complications during mini-invasive procedures (pig-tail extraction, protocol biopsy) withou the use of antibiotic (ATB) prophylaxis. The secondary aim was to identify risk factors for a positive urine culture finding at the time of mini-invasive procedures. MATERIAL: This is a prospective monocentric study in which pacients after kidney transplantation at Transplantation centrum in Martin were included (n = 68). We investigated the incidence of positive urine findings at the time of pig-tail extraction (6 weeks after transplantation) and at the time of protocol biopsy (3 months after transplantation) with comparison within the group with and without ATB prophylaxis. RESULTS: Patients in group without ATB prophylaxis had a significantly higher tacrolimus value at the time of pig-tail extraction (p = 0.0274) and a significantly higher dose of mycophenolic acid at the time of protocol biopsy (p = 0.0429). We did not confirm significant difference in occcurence of positive urine findings at the time of pig-tail extraction or at the time of protocol biopsy. We completed a univariate logistic regression in order to identify a potential risk predictor for positive urine findings at the time of pig-tail extraction and protocol biopsy. None of the monitored parameters, including ATB prophylaxis, was confirmed as risk or protective factor. CONCLUSION: The use of antibiotic prophylaxis during mini-invasive procedures (pig-tail extraction, protocol biopsy) in the posttransplantation period had no effect on positive culture findings at our department. Based on our analysis, we therefore do not use antibiotic prophylaxis in the case of these procedures at our centre (Tab. 3, Fig. 6, Ref. 23).

MiR-126 and miR-146a as markers of type 2 diabetes mellitus: a pilot study.

INTRODUCTION: Despite known risk factors for developing type 2 diabetes mellitus (T2D), the research community still tries to discover new markers that would widen our diagnostic and therapeutic approach to diabetes. Therefore, research on microRNA (miR) in diabetes thrives. This study aimed to assess the utility of miR-126, miR-146a, and miR-375 as novel diagnostic markers for T2D. METHODS: We examined relative quantities of miR-126, miR-146a, and miR-375 in the serum of patients with established type 2 diabetes mellitus (n = 68) and compared these with a control group (n = 29). We also undertook a ROC analysis of significantly changed miR to examine their use as a diagnostic test. RESULTS: MiR-126 (p < 0.0001) and miR-146a (p = 0.0005) showed a statistically significant reduction in patients with type 2 diabetes mellitus. MiR-126 also proved to be an exceptional diagnostic test in our study cohort, with high sensitivity (91 %) and specificity (97 %). We did not find any difference in our study groups' relative quantities of miR-375. CONCLUSION: The study proved a statistically significant reduction of miR-126 and miR-146a in patients with T2D (Tab. 4, Fig. 6, Ref. 51). Text in PDF www.elis.sk Keywords: microRNA, epigenetics, genomics, type 2 diabetes mellitus, miR-126, miR-146a and miR-375.

Plasma levels of direct oral anticoagulants in atrial fibrillation patients at the time of embolic stroke: a pilot prospective multicenter study.

BACKGROUND: Patients with atrial fibrillation (AF) who are on long-term direct oral anticoagulants (DOAC) with low anti-Xa or anti-IIa levels may be at higher risk of recurrent stroke. However, no prospective post-marketing study has investigated these DOAC plasma levels at the time of embolic stroke. The aim of this study was to assess the anti-Xa (rivaroxaban, apixaban) and anti-IIa (dabigatran) plasma levels in DOAC-treated AF patients at the time of acute embolic stroke. PATIENTS AND METHODS: We prospectively identified 43 patients with AF on long-term DOAC who experienced embolic strokes. We compared the DOAC plasma levels of these patients with a control sample of 57 patients who tolerated long-term therapeutic dose DOAC therapy without any adverse event. DOAC levels were assessed with drug-specific anti-Xa chromogenic analysis (rivaroxaban, apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). RESULTS: Dabigatran-treated patients with stroke had significantly lower anti-IIa levels when compared with the trough (40.7 ± 36.9 vs. 85.4 ± 57.2 ng/mL, p < 0.05) and peak samples of the controls (40.7 ± 36.9 vs. 138.8 ± 78.7 ng/mL, p < 0.001). Similarly, there were significantly lower anti-Xa levels in apixaban-treated patients with stroke compared to the trough control samples (72.4 ± 46.7 vs. 119.9 ± 81.7 ng/mL, p < 0.05), and in rivaroxaban- and apixaban-treated patients when compared to peak control samples (rivaroxaban: 42.7 ± 31.9 vs. 177.6 ± 38.6 ng/mL, p < 0.001; apixaban: 72.4 ± 46.7 vs. 210.9 ± 88.7 ng/mL, p < 0.001). CONCLUSION: This observational study showed significantly lower anti-IIa and anti-Xa plasma levels in AF patients with embolic stroke compared to those who tolerated long-term therapeutic dose DOAC therapy.

Pegvisomant in the treatment of acromegaly.

Despite improvements in surgical techniques, current radiotherapy options and development of long-acting somatostatin analogues, biochemical control of acromegaly is not achieved in some patients. The failure to achieve optimal serum growth hormone (RH) and insulin-like growth factor-1 (IGF-1) levels means increased morbidity and mortality of acromegaly patients. The RH receptor antagonist pegvisomant (PEG) is a genetically engineered RH analog that prevents of RH receptor dimerization, i.e. a process that is crucial for the action of RH at the cellular level. The effect of the treatment is suppression of IGF-1 production. In pilot studies, normalization of IGF-1 levels was achieved in up to 90 % of patients receiving PEG. However, PEG efficacy in clinical settings is slightly lower (65 to 97 %) than reported in the key studies. A rare side effect of treatment is elevations of liver transaminases. In addition, pituitary tumor growth progression has been reported in several cases. In this review article, we present long-term data on pegvisomant treatment and discuss its associated risks and benefits.

ROTEM Testing for Direct Oral Anticoagulants.

Direct oral anticoagulants (DOACs) are increasingly used worldwide for the prevention of stroke in patients with atrial fibrillation and to prevent or treat venous thromboembolism. In situations such as serious bleeding, the need for urgent surgery/intervention or the management of a thromboembolic event, the laboratory measurement of DOACs levels or anticoagulant activity may be required. Rotational thromboelastometry (ROTEM) is a viscoelastic hemostatic assay (VHA) which has been used in emergencies (trauma and obstetrics), and surgical procedures (cardiac surgery and liver transplants), but experience with this assay in DOACs-treated patients is still limited. This article reviews the use of ROTEM in the setting of DOACs therapy, focusing on DOACs-associated bleeding and the use of this VHA for the management of reversal strategies for DOACs-associated anticoagulation.

Direct Oral Anticoagulants Plasma Levels in Patients with Atrial Fibrillation at the Time of Bleeding: A Pilot Prospective Study.

ABSTRACT: Patients with atrial fibrillation (AF) on long-term direct oral anticoagulants (DOACs) may be at higher risk of bleeding because of higher anti-Xa or anti-IIa levels. However, there is no postmarketing study investigating these DOAC plasma levels at the time of bleeding. The aim of this study was to evaluate DOAC levels at the time of a bleeding emergency. We analyzed 5440 patients examined at our Emergency Department in from April 1, 2019, to September 30, 2019. During this period, we prospective identified 105 consecutive patients with bleeding while on long-term antithrombotic therapy; 49 patients had AF on DOACs. We compared DOAC levels in patients who bled against a control sample of 55 patients who tolerated long-term high dose DOAC therapy without any emergency. Samples of these patients were tested with drug-specific anti-Xa chromogenic analysis (rivaroxaban and apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). Dabigatran-treated patients who bled had significantly higher anti-IIa levels when compared with trough (261.4 ± 163.7 vs. 85.4 ± 57.2 ng/mL, P < 0.001) and peak samples of controls (261.4 ± 163.7 vs. 138.8 ± 78.7 ng/mL, P < 0.05). Similarly, there were significantly higher anti-Xa levels in rivaroxaban-treated and apixaban-treated patients with bleeding compared with trough control samples (rivaroxaban: 245.9 ± 150.2 vs. 52.5 ± 36.4 ng/mL, P <0.001 and apixaban: 311.8 ± 142.5 vs. 119.9 ± 81.7 ng/mL, P < 0.001), as well as in apixaban-treated patients when compared with peak control samples (311.8 ± 142.5 vs. 210.9 ± 88.7 ng/mL, P < 0.05). Finally, rivaroxaban anti-Xa levels in patients who bled tended to be higher compared with peak control samples (245.9 ± 150.2 vs. 177.6 ± 38.6 ng/mL, P = 0.13). This observational study showed a significant difference in anti-IIa and anti-Xa plasma levels in patients with AF with bleeding complications compared with those who tolerated long-term high-dose DOAC therapy without bleeding complications.

Apixaban: An Optimal Agent for the Treatment of Cancer-Associated Venous Thromboembolism?

BACKGROUND: Apixaban, a direct inhibitor of activated coagulation factor X (FXaI), is being frequently selected for treatment and prevention of venous thromboembolism (VTE). Several reports about possible use of oral FXaI in patients with cancer-associated VTE (CA-VTE) have been published recently. AREAS OF UNCERTAINTY: The efficacy/safety profile of oral FXaI anticoagulation in patients with CA-VTE seems promising; however, several problems remain unanswered. The pharmacologic profile of apixaban could prefer this agent for the treatment of CA-VTE. DATA SOURCES: Currently available medical literature was searched and reviewed to summarize data regarding the use of apixaban for the prevention and treatment of cancer-associated VTE. RESULTS: Apixaban therapy in patients with cancer and VTE is expected to increase as clinicians gain more experience and reassurance with data from real-world studies that are generally promising. Several studies demonstrated that apixaban exhibits noninferiority to warfarin and low molecular weight heparin in preventing recurrent thrombosis in cancer-associated VTE. Nevertheless, there are still concerns regarding the bleeding associated with apixaban therapy, and regarding the optimal management of these bleeding emergencies. THERAPEUTIC OPINION: Although currently available evidence confirms the noninferiority of apixaban for reduction of the risk of recurrent VTE in patients with cancer; there are still concerns regarding the safety, especially in selected subpopulations of these patients.

Rituximab in the treatment of primary glomerulopathies - our experience.

INTRODUCTION: Since 2012, when The Kidney Disease: Improving Global Outcomes (KDIGO) initiative published the first recommendations for the management and treatment of glomerular diseases, there has been enormous progress in understanding pathogenesis, identifying new diagnostic biomarkers and treating these diseases. Rituximab had become a promisisng treatment option in patients with primary glomerular disease, as confirmed by several clinical studies, where it has led to a significant reduction in proteinuria and a reduction in the incidence of relapses of the underlying disease. In this work we present our experiences with rituximab treatment. MATERIALS AND METHODS: We retrospectively analyzed 9 patients with primary glomerulopathy resistant to srandard immunosuppressive therapy who received rituximab as rescue treatment. We evaluated the effect of rituximab induction treatment on the development of quantitative proteinuria. RESULTS: By evaluating the 24-hour proteinuria before and after treatment, we demonstrated a statistically significant decrease in proteinuria in our group of patients immediately after the las dose of rituximab. We did not notice a significant change in renal function. CONCLUSION: Rituximab represents an effective alternative in the treatment of primary glomerulopathies, especially in cases of resistance to standard immunosuppressive therapy, which is shared by the clinical experience presented by us.

Diagnostic hospitalizations before patient inclusion on the waiting list for kidney transplantation.

INTRODUCTION: For kidney transplantation is indicated any patient with chronic kidney disease in the terminal stage, unless it has a contraindication for this operation. The aim of this work is to evaluate the benefit of diagnostic hospitalizations of the patients before inclusion on the waiting list for kidney transplantation and to identify the most common differential diagnostic problems for the indication / contraindication for kidney transplantation. MATERIAL AND METHODS: This is a retrospective analysis, which included all potential recipients who underwent the examination process before inclusion on the waiting list and living donors in the form of diagnostic hospitalization at the Transplant Center at Martin University Hospital in 2016-2019. RESULTS: A total of 49 patients were included in the cohort, the average length of hospitalization was 5.6 days. Kidney trans plantation subsequently underwent 22 of these patients, 3 patients were clearly contraindicated.

The Effect of Proton Pump Inhibitor Withdrawal on Dabigatran Etexilate Plasma Levels in Patients With Atrial Fibrillation: A Washout Study.

BACKGROUND: Several studies demonstrated that proton pump inhibitors (PPIs) co-administrated with dabigatran in patients with atrial fibrillation (AF) decreased dabigatran trough and peak plasma levels. However, it is still unknown whether this interaction is reversible or not, and whether the withdrawal of PPI would lead to normalization of dabigatran plasma levels. AIM OF STUDY: The aim of this study was to determine the effect of PPI withdrawal on dabigatran plasma levels in patients with AF. METHODS: This pilot prospective study enrolled 23 AF patients on long-term dabigatran and PPI therapy (omeprazole 20 mg twice daily or pantoprazole 40 mg once daily). Dabigatran trough and peak levels (ng/mL) were tested on PPI and after a 2-week period of PPI withdrawal with Hemoclot Thrombin Inhibitor Assay. RESULTS: The analysis of dabigatran plasma levels demonstrated significant elevation in trough dabigatran levels after 2 weeks of PPI withdrawal (97.2 ± 79.7 vs. 163.8 ± 105.5 ng/mL; P < 0.05). Moreover, significantly higher peak dabigatran levels were observed after 2 weeks of PPI withdrawal (142.4 ± 102.8 vs. 255 ± 129.5 ng/mL; P ≤ 0.001). CONCLUSIONS: This study showed that a 2-week period of PPI withdrawal lead to a significant increase in dabigatran trough and peak plasma levels in patients with AF.

Effect of Bisoprolol on the Level of Dabigatran.

BACKGROUND: Many patients receiving dabigatran treatment might also require bisoprolol therapy. However, there is a possibility that bisoprolol as significant P-glycoprotein inhibitor might interact with dabigatran. STUDY QUESTION: To investigate the impact of concomitant bisoprolol therapy on dabigatran plasma level in patients with nonvalvular atrial fibrillation. STUDY DESIGN: A pilot drug interaction study in 29 patients with nonvalvular atrial fibrillation on dabigatran therapy. Bisoprolol was administrated in 18 patients. Blood samples were collected at baseline (in the morning, before any medication was administered) and at hour 2 (2 hours after administration of dabigatran and bisoprolol). RESULTS: The dabigatran plasma level was significantly higher at baseline and at hour 2 in patients treated with bisoprolol compared with patients without bisoprolol therapy. In addition, we have shown that this increase is affected by dabigatran dosage and concomitant treatment with proton-pump inhibitor and digoxin. The impact of bisoprolol on dabigatran concentration was still significant despite these confounders. CONCLUSIONS: This study demonstrated the interaction between dabigatran and bisoprolol, which is modulated with dabigatran dosage and concomitant treatment with proton-pump inhibitor and digoxin.

Edoxaban affects TRAP-dependent platelet aggregation.

Edoxaban is an oral anticoagulant drug and a direct factor Xa inhibitor. However, it is still not fully understood if and how edoxaban impacts platelet function. This prospective study aimed to assess in vitro platelet function in patients with atrial fibrillation (AF) receiving edoxaban. It was a single centre study quantifying platelet aggregation in 20 patients treated with edoxaban by light transmission aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly lower 2 h after taking edoxaban compared to baseline value (44.7 ± 32.03% vs. 73.3 ± 25.55%; p < 0.0001). In addition, we did not find any significant difference in results between the patient groups.The TRAP-induced platelet aggregation is reduced in non-valvular AF patients receiving edoxaban.

Dissection of ascending aorta, a diagnosis needs to remember about it.

Acute type A aortic dissection is a life-threating condition, and is associated with significant morbidity and mortality. Patients typically present with the acute onset of chest pain, which occurs in up to 85% of cases. Acute chest pain may lead to the suspicion of acute coronary syndrome, and as the electrocardiogram may indicate ischaemia, patients are given anti-throm botic treatment. Some patients can present without chest pain, but with focal neurological deficits, which can occur with involvement of the great vessel. The authors described three patients with acute type A aortic dissection. Two of them did not present with the acute onset of chest pain, but with focal neurological deficits. Third patient presented with the acute onset of chest pain and the electrocardiogram indicated suspected ischaemia, which led to the suspicion of acute coronary syndrome. The authors presented, that diagnosis of acute type A aortic dissection can be easily overlooked and a high index of suspicion is needed to obtain a timely diagnosis such that appropriate initial therapy can be instituted promptly.

Hemodialysis vascular access dysfunction and its endovascular treatment.

Hemodialysed patients with end stage renal disease are reliant to proper function of vascular access - mostly arterio-venous fistula (AVF). AVF patency is jeopardized by stenosis formation, which needs to be treated before thrombosis. Angioplasty is primarily indicated and prolongs vascular access patency. High pressure balloons and cutting balloons aid to high technical success rate. Angioplasty needs to be repeated in order to maintain long term patency. Drug-eluting balloons prolong long term patency. Stents and stentgrafts are seldom used in inoperable patients and in selected locations. Technical advances allowed endovascular treatment in AVF thrombosis followed by angioplasty of culprit lesion. Vascular access endovascular occlusion is alternative for surgery in inoperable patients. In patients with residual renal function or iodine allergy, intervention could be ultrasound guided or carbon dioxide could be used without the need of iodine contrast.

Glycated haemoglobin as a marker of elevated LDL and TAG: a cohort study.

Patients with less severe glycated haemoglobin (HbA1c) targets may find it difficult to achieve the target values of lipid parameters treatment at high cardiovascular risk. We have been monitoring the correlation between levels of triglycerides (TG), high density lipoprotein (HDL) and low density lipoprotein (LDL) with glycosylated haemoglobin (HbA1c) by IFCC method (method of testing according to the International Federation of Clinical Chemistry and Laboratory Medicine) and by DCCT method (Diabetes Control and Complication Trial) as well as body mass index (BMI) at the time of diagnosis of the disease, that could help identify patients with an increased risk of cardiovascular disease. In the cohort study we were monitoring outpatients with newly diagnosed type 2 diabetes mellitus during a 5 year period. Patients (117 men, 83 women), aged from 30 to 92 years were conducted sampling blood glucose, HbA1c (IFCC/DCCT), HDL, LDL, TG. At baseline, the patients height, weight, waist circumference, calculated BMI and blood pressure were measured. Waist circumference was measured in the horizontal plane in the middle of the distance between the upper edge of the iliac crest and the lower edge of the last rib in the breath. Our study did not exclude patients taking statin or fibrate. The high HbA1c values increased the risk of elevating LDL-cholesterol levels and TAG levels in the whole group (p = 0.012) and (p = 0.017), and the high BMI values increased the risk of lowering HDL-cholesterol levels in the female population (p = 0.010). The results of our study stratify the increased risk of atherogenicity in these groups. HbA1c is a direct marker of elevated LDL and TAG, and indirect marker for coronary artery disease risk assessment.

Proton Pump Inhibitors and Dabigatran Therapy: Impact on Gastric Bleeding and Dabigatran Plasma Levels.

Dabigatran etexilate, a direct thrombin inhibitor, is now frequently used for long-term pharmacological prevention of stroke or systemic embolism in patients with atrial fibrillation. However, such long-term dabigatran therapy (DT) significantly increases the risk of upper gastrointestinal (GI) bleeding. This increased risk of gastric bleeds might be reduced with gastroprotective agents, such as proton pump inhibitors (PPIs). PPIs coadministrated with dabigatran reduce the risk of upper GI bleeding in patients on long-term oral DT. Nevertheless, there is heated discussion regarding interactions between PPI and dabigatran that lead to decreases in dabigatran plasma levels. This article reviews up to date data about the risk of gastric bleeding on dabigatran, the impact of PPI on the reduction of gastric bleeding, and the interaction between PPI and dabigatran leading to decreased dabigatran plasma levels.

The Impact of Proton Pump Inhibition on Dabigatran Levels in Patients With Atrial Fibrillation.

BACKGROUND: Proton pump inhibition (PPI) administrated together with dabigatran reduces the risk of gastrointestinal hemorrhage. However, there is a discussion regarding possible PPI-dabigatran interaction that may reduce the efficacy of this therapy. STUDY QUESTION: To determine the impact of concomitant PPI on dabigatran plasma levels in patients with nonvalvular atrial fibrillation (NV-AF). STUDY DESIGN: A pilot prospective study in patients with NV-AF on dabigatran therapy was performed; 31 patients were enrolled. PPI with either omeprazole or pantoprazole was administrated in 19 patients. MEASURES AND OUTCOMES: Blood samples were taken for the assessment of the dabigatran trough and peak levels. Dabigatran concentration was measured with the Hemoclot Thrombin Inhibitor Assay. RESULTS: There were significant differences in dabigatran trough level comparing patients treated with PPI and patients without PPI (58.86 ± 36.76 ng/mL vs. 110.72 ± 88.47 ng/mL, P < 0.05). Similarly, there were significant differences in dabigatran peak level between compared groups (88.0 ± 20.5 ng/mL vs. 174.4 ± 139.64 ng/mL, P < 0.05). CONCLUSIONS: This pilot study demonstrated the interaction between PPI and dabigatran levels in patients with NV-AF.

Does proton pump inhibition change the on-treatment anti-Xa activity in xabans-treated patients with atrial fibrillation? A pilot study.

Proton pump inhibition (PPI) reduces gastrointestinal bleeding on direct oral anticoagulants. However, PPI may affect dabigatran on-treatment levels; and there is no information regarding the effect of PPI on xabans on-treatment activity. Thus, the aim of this study was to determine the impact of PPI on therapeutic anti-Xa activity in rivaroxaban- and apixaban-treated patients with atrial fibrillation (AF). This single-centre pilot prospective study enrolled 77 consecutive xabans-treated patients (42 rivaroxaban-treated and 35 apixaban-treated patients) with AF. PPI was administrated in 44 patients. Trough and peak anti-Xa activity was assessed with factor Xa-calibrated anti-Xa chromogenic analysis. There were no significant differences in trough anti-Xa activity comparing PPI-treated patients and patients without PPI (80.5 ± 66.5 ng/mL in PPI group vs. 71.6 ± 64.1 ng/mL in non-PPI group, p = 0.57, Table 2). Similarly, there were no significant differences in peak anti-Xa activity between compared groups (175.2 ± 102.5 ng/mL in PPI group vs. 202.9 ± 84.1 ng/mL in non-PPI group, p = 0.21). This pilot study did not reveal significant changes in xabans on-treatment anti-Xa activity according the PPI status.