The effect of direct oral anticoagulants (DOACs) on laboratory tests dependent on the production of their targets, factor IIa and factor Xa (FXa), is a well-known problem and can cause both false ...positive and negative results. Therefore, the correct interpretation of tests performed in patients receiving DOACs is necessary to avoid misclassification and subsequent clinical consequences. However, even with significant experience, there are situations where it is not possible to assess the influence of some methods. Particularly important is the situation in the diagnosis of lupus anticoagulants using the dilute Russell viper venom timetest, which is based on direct FXa activation. A very promising solution to this situation is offered by the DOAC laboratory balancing procedure DOAC-Stop. For evaluating the effectiveness of this procedure, 60 (20 apixaban, 20 dabigatran, and 20 rivaroxaban) patients treated with DOACs were enrolled. All patient samples were analyzed for the presence of individual DOAC types and subsequently subjected to the DOAC-Stop procedure.We evaluated its effectiveness by our own high-performance liquid chromatography-coupled tandem mass spectrometrymethod, which simultaneously sets all high-sensitivity DOACs. Unlike coagulation tests based on the determination of the residual effects of DOACs on target enzymes, which is complicated by extensive interindividual variation, this methodology is highly specific and sensitive.The DOAC-Stop procedure eliminated dabigatran from 99.5%, rivaroxaban from 97.9%, and apixaban from 97.1% of participants in our group. Residual amounts did not exceed 2.7 ng/mL for dabigatran, 10.9 ng/mL for rivaroxaban, or 13.03 ng/mL for apixaban, which are safe values that do not affect either screening or special coagulation tests.
The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To ...tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.
We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis ...(SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.
Primary myelofibrosis (PMF) is a chronic clonal myeloid disorder. Together with essential thrombocythemia (ET) and polycythemia vera (PV), it belongs to a group of Philadelphia chromosome-negative ...myeloproliferative neoplasms. An integral part of laboratory tests carried out in this disease group is detecting the presence of mutations in the Janus kinase 2 gene at position 617 (JAK2 V617F) and in the gene encoding for the receptor for thrombopoietin (myeloproliferative leukemia virus oncogene, MPL) found in approximately 60% of PMF patients. The discovery of mutations affecting exon 9 of the calreticulin (CALR) gene was of great benefit to the diagnosis of the diseases in JAK2 V617F and MPL unmutated cases. This is a study of the effect of a mutation in the CALR gene on the clinical course in patients with primary, post-ET and post-PV myelofibrosis. Analysis of 66 patients (54.5% JAK2 V617F; 34.8% CALR; 6.1% MPL; 3.0% triple negative; 1.5% coincidence of CALR and JAK2 V617F) confirmed a different phenotype of the disease in CALR-mutated patients as compared with CALR-unmutated individuals. Those with CALR mutation were significantly younger and had borderline higher platelet counts, less pronounced splenomegaly and less frequent B symptoms at diagnosis. The study suggests that the driver mutation types define variations in the biological basis, clinical manifestations and course of the disease. The presence of CALR mutation has been shown to be an independent prognostic favorable factor. Careful risk stratification of these patients is of great importance to adequate therapeutic decision-making and aids in selecting high-risk patients eligible for allogeneic hematopoietic stem cell transplantation which continues to be the only treatment modality for myelofibrosis having curative potential.
Primary myelofibrosis (PMF) is a chronic clonal myeloid disorder. Together with essential thrombocythemia (ET) and polycythemia vera (PV), it belongs to a group of Philadelphia chromosome-negative ...myeloproliferative neoplasms. Thrombotic events are serious complications negatively influencing the quality and length of these patients' lives. The confirmed risk factors for venous thromboembolism are age over 60 years, a positive history of thromboembolism, presence of common cardiovascular risks, JAK2 V617F mutation and, according to some authors, leukocytosis. Various opinions on the role of thrombocythemia have been published. The present study was undertaken to evaluate the benefit of thrombin generation test and its potential use in predicting the risk of thrombosis in MF patients.
The analysis included plasma samples obtained from 36 patients diagnosed with MF in our center from 2004 to 2016 (JAK2 V617-positive 53%; CALR-positive 31%; MPL-positive 14%; triple negative 2%) and a control group comprising 20 healthy volunteer blood donors. Thrombin generation was measured in platelet-rich plasma using the TECHNOTHROMBIN® TGA kit (Technoclone, Austria) and the fully automated system Ceveron® Alpha (Technoclone). The results were correlated with clinical and laboratory parameters of the patients.
There were differences in thrombin generation as expressed by endogenous thrombin potential (ETP) between patients and healthy controls, with ETP being lower in the patient group (p = 0.0003). Analysis confirmed a significant correlation between thrombin generation and platelet counts, with higher thrombin generation in patients with thrombocythemia > 400 x 109/L (p = 0.04). ETP values were consistently higher in earlier disease stages and lower in CALR-mutated myelofibrosis.
In MF patients, thrombin generation is mainly influenced by platelet counts and, to a lesser extent, by mutation status, activity, and progression of the disease. Thrombin generation test results have confirmed that thrombocythemia is a potential risk factor for thrombotic complications.
We use scanning tunneling microscopy and X-ray spectroscopy to characterize the atomic and electronic structure of boron-doped and nitrogen-doped graphene created by chemical vapor deposition on ...copper substrates. Microscopic measurements show that boron, like nitrogen, incorporates into the carbon lattice primarily in the graphitic form and contributes ~0.5 carriers into the graphene sheet per dopant. Density functional theory calculations indicate that boron dopants interact strongly with the underlying copper substrate while nitrogen dopants do not. The local bonding differences between graphitic boron and nitrogen dopants lead to large scale differences in dopant distribution. The distribution of dopants is observed to be completely random in the case of boron, while nitrogen displays strong sublattice clustering. Structurally, nitrogen-doped graphene is relatively defect-free while boron-doped graphene films show a large number of Stone-Wales defects. These defects create local electronic resonances and cause electronic scattering, but do not electronically dope the graphene film.
The discovery of a universal behavior in rare‐earth (RE)‐substituted perovskite BiFeO3 is reported. The structural transition from the ferroelectric rhombohedral phase to an orthorhombic phase ...exhibiting a double‐polarization hysteresis loop and substantially enhanced electromechanical properties is found to occur independent of the RE dopant species. The structural transition can be universally achieved by controlling the average ionic radius of the A‐site cation. Using calculations based on first principles, the energy landscape of BiFeO3 is explored, and it is proposed that the origin of the double hysteresis loop and the concomitant enhancement in the piezoelectric coefficient is an electric‐field‐induced transformation from a paraelectric orthorhombic phase to the polar rhombohedral phase.
A universal behavior in rare‐earth‐substituted BiFeO3 has been discovered. The property‐enhancing morphotropic phase boundary can be achieved by controlling the average A‐site ionic radius. An electric‐field‐induced transformation from a paraelectric orthorhombic phase to the polar rhombohedral phase is proposed as the origin of the observed double hysteresis loop and the concomitant enhancement in the piezoelectric coefficient at the boundary.
Summary
East Balkan Swine (EBS) Sus scrofa is the only aboriginal domesticated pig breed in Bulgaria and is distributed on the western coast of the Black Sea in Bulgaria. To reveal the breed's ...genetic characteristics, we analysed mitochondrial DNA (mtDNA) and Y chromosomal DNA sequences of EBS in Bulgaria. Nucleotide diversity (πn) of the mtDNA control region, including two newly found haplotypes, in 54 EBS was higher (0.014 ± 0.007) compared with that of European (0.005 ± 0.003) and Asian (0.006 ± 0.003) domestic pigs and wild boar. The median‐joining network based on the mtDNA control region showed that the EBS and wild boar in Bulgaria comprised mainly two major mtDNA clades, European clade E1 (61.3%) and Asian clade A (38.7%). The coexistence of two mtDNA clades in EBS in Bulgaria may be the relict of historical pig translocation. Among the Bulgarian EBS colonies, the geographical differences in distribution of two mtDNA clades (E1 and A) could be attributed to the source pig populations and/or historical crossbreeding with imported pigs. In addition, analysis of the Y chromosomal DNA sequences for the EBS revealed that all of the EBS had haplotype HY1, which is dominant in European domestic pigs.
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