MORE EARLY BLEEDS ASSOCIATED WITH HIGH BASELINE DIRECT ORAL ANTICOAGULANT LEVELS IN ATRIAL FIBRILLATION: THE MAS STUDY.

Treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) patients is effective and safe. However, bleeding complications still occur. Whether the measurement of DOAC levels may further improve treatment efficacy and safety is still an open issue. In the "Measure and See" (MAS) Study (#NCT03803579) venous blood was collected 15-30 days after DOAC initiation in AF patients who were then followed for one year to record the occurrence of major and clinically relevant non-major bleeding. DOAC plasma levels were measured in one laboratory, and results were kept blind to patients and treating doctors. Trough DOAC levels were assessed in 1657 patients [957 (57.7%) and 700 treated with standard and low-dose, respectively]. Fifty bleeding events were recorded during 1606 years of follow-up (3.11% pt/yrs). Fifteen bleeding events (4.97% pt/yrs) occurred in patients with C-trough standardized values in the highest activity class (> 0.50); whereas 35 events (2.69% pt/yrs) occurred in those with values in the two lower classes ( 0.50, p= 0.0401). Increasing DOAC levels and low-dose DOAC use were associated with increased bleeding risk in the first three months of treatment. 19% of patients receiving low doses had standardized activity values in the highest class. More bleeding occurred in patients treated with low (4.3% pt/yrs) than standard (2.2% pt/yrs; p= 0.0160) dose DOAC. Early measurement of DOAC levels in AF patients identified many subjects with high activity levels despite the low doses use and had more bleeding risk during the first 3 months of treatment.

Thrombotic events associated with low baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study.

ABSTRACT: Although effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve treatment efficacy is an open issue. We carried out the observational, prospective, multicenter Measure and See (MAS) study. Blood was collected 15 to 30 days after starting DOAC treatment in patients with AF who were followed-up for 1 year. Plasma samples were centralized for DOAC level measurement. Patients' DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values (representing the distance of each value from the overall mean) by subtracting the DOAC-specific mean value from the original values and dividing by the standard deviation. Trough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. In total, 21 thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% of patients per year). Of 21 thrombotic events, 17 occurred in patients whose standardized activity levels were below the mean of each DOAC (0); the incidence was the highest (4.82% of patients per year) in patients whose standardized values were in the lowest class (-1.00 or less). Early measurement of DOAC levels in patients with AF allowed us to identify most of the patients who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.

Leukocyte cell population data as potential markers of COVID-19 disease characterization.

Background: The usefulness of leukocyte cell population data (CPD) is currently being investigated. In COVID-19 pandemic several reports showed the clinical importance of hematological parameters. Our study aimed to assess CPDs in Sars CoV-2 patients as new disease markers. Methods: From February to April 2020 (1st wave) 540 and from September to December 2020 (2nd wave) 2821 patients respectively were enrolled. SARS CoV-2 infection diagnosis was carried out by Multiplex rRT-PCR from nasopharyngeal swabs. CPDs were detected by XN 2000 hematology analyzer (Sysmex Corporation). A comparison between two disease waves was performed. Additionally, C-reactive protein (CRP) and lactate dehydrogenase (LDH) were assayed. Results: CPDs were classified into: cell complextity, DNA/RNA content and abnormal sized cells. We detected parameters increased from the reference population for all cell types for both 1st and 2nd wave (p<0.05). However, in the 2nd vs 1st wave 5 CPDs vs 9 CPDs were found. In addition we observed higher CPD values of the 1st compared to 2nd wave: (NE-SFL) (p<0.001), (LY-Y) (p<0.0001), (LY-Z) (p<0.0001), (MO-X) (p<0.0001), (MO-Y) (p<0.0001). These findings were confirmed by the higher concentrations of CRP and LDH in the 1st vs 2nd wave: 17.3 mg/L (8.5-59.3) vs 6.3 mg/L (2.3-17.6) (p<0.001) and 241.5 IU/L (201-345) vs 195 IU/L (174-228) (p< 0.001) (median, interquartile range) respectively. Conclusions: CPDs showed increased cell activation in 1st wave patients confirmed by clinical and biochemical data, associated with worse clinical conditions. Results highlighted the CPDs as disease characterization markers or useful for a risk model.

Safety and effectiveness of biosimilar enoxaparin (Inhixa) for the prevention of thromboembolism in medical and surgical inpatients.

In 2016, biosimilar enoxaparin (Inhixa®, Techdow) was introduced in European markets with the same indications as branded enoxaparin (Clexane®, Sanofi). Its use is constantly increasing in clinical practice, however, little information from post-marketing clinical trials is available on its safety and effectiveness. We conducted an observational, retrospective study to assess the safety and effectiveness of Inhixa in preventing venous thromboembolism (VTE) in medically ill patients and in patients undergoing major abdominal surgery. We then compared our results with the incidence of symptomatic VTE and bleeding events during treatment with Clexane by pooling the results of clinical studies carried out in the same settings. We enrolled 381 patients, 189 admitted to a Medical Department and 192 to a Surgical Department from two single institutions. The incidence of major bleeding events was 1.8% globally (95% IC 0.7-3.8), 1.6% in medical patients (95% IC 0.3-4.6) and 2.1% in surgical patients (95% IC 0.6-5.3). VTE rate was 0.5% in the whole population (95% IC 0.1-1.9) and 0.5% (95% IC 0.01-2.9) in each group, respectively. The pooled estimate of the incidence of major bleeding with Clexane was 0.5% (IC 95%: 0.2-1.1) in medical patients and 2.6% (IC 95% 1.3-5.1) in surgical patients. The incidence of thrombotic events was 0.6% (IC 95%: 0.2-1.8) and 0.7% (CI95% 0.3-1.6), respectively. The incidence of bleeding and thrombosis in medical and surgical patients receiving Inhixa was low suggesting biosimilar enoxaparin is a valid alternative to branded enoxaparin.

Determination of vitamin K1 in plasma by solid phase extraction and HPLC with fluorescence detection.

We describe a procedure for quantification of vitamin K(1) in human plasma by HPLC. Samples, enriched with a vitamin K derivative as internal standard, were deproteinized, purified on polymeric RP-SPE cartridges and injected into HPLC equipped with a post-column on-line zinc metal reactor and a fluorometric detector. Median level in blood donors (n=87) was 1.967 nmol/L (0.93-4.01, 5th-95th percentiles), with a significant correlation between plasma levels and age (r=0.276, p=0.00958) and a lower (not significant) value in women than in men. This method, easy-to-handle and with a high throughput, can be used to identify covert states of vitamin K intake deficiency in patients thus at risk of alterations in blood clotting or bone mineralization.

Atrial fibrillation and psychological factors: a systematic review.

BACKGROUND: Psychological factors have been suggested to have an influence in Atrial Fibrillation (AF) onset, progression, severity and outcomes, but their role is unclear and mainly focused on anxiety and depression. METHODS: A systematic electronic search had been conducted to identify studies exploring different psychological factors in AF. The search retrieved 832 articles that were reviewed according to inclusion criteria: observational study with a control/comparison group; use of standardized and validated instruments for psychological assessment. Results were summarized qualitatively and quantitatively by effect size measure (Cohen's d and its 95% confidence interval). Cochrane Collaboration guidelines and the PRISMA Statement were adopted. RESULTS: Eight studies were included in the systematic review. Depression was the most studied construct/ but only one study showed a clear link with AF. The remaining studies showed small and non-significant (95% CI [-0.25-1.00]) differences between AF and controls, no differences in frequency of depression history (95% CI [-0.14-0.22]) or in case frequency (95% CI [-0.50-0.04]). Miscellaneous results were found as far as anxiety: AF patients showed higher levels when compared to healthy subjects (95% CI [2.05-2.95]), but findings were inconsistent when compared to other heart diseases. Considering personality and life-events preceding AF, we respectively found a large (95% CI [1.87-2.49]) and a moderate to large effect (95% CI [0.48-0.98]). DISCUSSION: The small number of studies does not allow to draw clear-cut conclusions on the involvement of psychological factors in AF. Promising lines of research are related to personality and adverse life-events, and to the increase of longitudinal design studies. Some methodological problems could be overcome by including clinical psychologists in the implementation of research protocols.

Levels of soluble endothelial protein C receptor are associated with CD4+ changes in Maraviroc-treated HIV-infected patients.

BACKGROUND: Inflammation is a key feature of HIV infection and is correlated with long-term negative cardiovascular outcomes. Therapy-induced increases in CD4(+) cell counts can control inflammation, as shown by decreases of coagulation and inflammation markers during efficacious therapy. Maraviroc, a CCR5-antagonist, has resulted in larger increases in CD4(+) counts both in naïve and experienced subjects compared to traditional antiretroviral therapy. OBJECTIVES AND METHODS: To examine if a member of the protein C anticoagulant and anti-inflammatory pathway, and marker of coagulation and inflammation, the soluble endothelial protein C receptor, is modified by infection and therapy-related variables in patients treated with Maraviroc. Endothelial protein C receptor, together with other established markers of inflammation and coagulation (CRP, IL-6, D-dimer and soluble thrombomodulin) was studied in 43 patients on traditional antiretroviral therapy and in 45 on Maraviroc during 48 weeks of follow-up. RESULTS: Soluble endothelial protein C receptor was the only marker that could discriminate at least partially between patients with a good response to Maraviroc and patients who did not respond with an adequate increase in CD4(+) cell counts (more than 500 cells/µL by week 48). CONCLUSIONS: Elevated levels of soluble endothelial protein C receptor, a sensitive marker of endothelial damage, indicated a low level of inflammation and coagulation activation in Maraviroc treated patients not picked up by other widely used markers. Persistent elevated levels of this marker at 48 weeks from beginning of treatment with Maraviroc were related to a poor increase in CD4(+) cells.

A proteomic analysis of changes in prothrombin and plasma proteins associated with the G20210A mutation.

The G-->A mutation at position 20210 of the prothrombin gene, localized in the 3'-polyadenylation untranslated region of the mRNA, is a recognized genetic risk factor for venous thromboembolism. The mechanism by which this base change confers an increased risk of thrombosis compared to noncarriers is undefined. Studies on the mRNA suggest enhanced cleavage site recognition and a change in the location of the 3'-cleavage/polyadenylation reaction, but no defined model has been proposed. The present study, based on proteomic investigation by two-dimensional gel electrophoresis and electrospray ionization (ESI) tandem mass spectrometry (MS/MS) protein identification, suggests that the G20210A mutation is associated with increased glycosylation of prothrombin, which confers greater stability to the protein. Additionally, proteomic investigation of pooled plasma showed that expression levels of six spots, three of them identified by ESI MS/MS, were altered in subjects carrying the mutation, suggesting a possible cooperative effect in the thrombotic risk increment induced by the mutation.