No abstract

The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701).

The outcomes of patients developing major bleeding while on oral anticoagulants remain largely unquantified. The objectives of this study were to: (i) describe the burden of major hemorrhage associated with all available oral anticoagulants in terms of proportion of bleeds which are intracranial hemorrhages, in-hospital mortality and duration of hospitalization following major bleeding; (ii) identify risk factors for mortality; and (iii) compare the characteristics of major hemorrhage between cases treated with warfarin and direct oral anticoagulants for the subgroups of patients with atrial fibrillation or venous thromboembolism. This was a multicenter, 3-year prospective cohort study of patients aged ≥18 years on oral anticoagulants who developed major hemorrhage leading to hospitalization. The patients were followed up for 30 days or until discharge or death, whichever occurred first. In total 2,192 patients (47% female, 81% on warfarin, median age 80 years) were reported between October 2013 and August 2016 from 32 hospitals in the UK. Bleeding sites were intracranial (44%), gastrointestinal (33%), and other (24%). The in-hospital mortality was 21% (95% CI: 19%-23%) overall, and 33% (95% CI: 30%-36%) for patients with intracranial hemorrhage. Intracranial hemorrhage, advanced age, spontaneous bleeding, liver failure and cancer were risk factors for death. Compared to warfarin-treated patients, patients treated with direct oral anticoagulants were older and had lower odds of subdural/epidural, subarachnoid and intracerebral bleeding. The mortality rate due to major bleeding was not different between patients being treated with warfarin or direct oral anticoagulants. Major bleeding while on oral anticoagulant therapy leads to considerable hospital stays and short-term mortality.

Gö 6976 is a potent inhibitor of the JAK 2 and FLT3 tyrosine kinases with significant activity in primary acute myeloid leukaemia cellsThe cytokine receptor superfamily, which includes receptors for erythropoietin (EPO), thrombopoietin (TPO) , granulocyte colony-stimulating factor, interferons and interleukins, is characterised by the lack of a catalytic domain in the cytoplasmic portion of the receptor and, as such, lacks intrinsic tyrosine kinase activity. These receptors utilise Janus kinases (JAKs), cytosolic tyrosine kinases, to couple ligand binding with downstream tyrosine phosphorylation. When a ligand binds to a receptor, the receptor dimerises and brings two JAK molecules into close proximity. The JAKs cross/ autophosphorylate and become activated; once activated, they phosphorylate the intracellular domains of the receptor and create docking sites for downstream signalling proteins via their Src homology 2 (SH2) domains (Ihle, 1995). Signal transducers and activators of transcription (STATs) are latent transcription factors residing in the cytoplasm. STATs are phosphorylated by JAKs and homo-or heterodimerise by binding of a phosphorylated tyrosine activation motif on one STAT subunit to the SH2 domain on the other subunit. These dimers then translocate to the nucleus where they bind specific DNA binding motifs to bring about alterations in gene transcription governing cell proliferation and survival. In addition to STATs, other SH2 containing signalling proteins are recruited to the phosphorylated receptor including Src homologous and collagen-like protein, the p85 subunit of PI3-Kinase and other adapter molecules. Once recruited to the receptor, these proteins may become phosphorylated by JAKs, leading to activation of many downstream pathways including SummaryAberrant activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling is implicated in a number of haematological malignancies and effective JAK inhibitors may be therapeutically useful. We found that Gö6976, an indolocarbazole inhibitor of the calcium-dependent isozymes of protein kinase C (PKC), inhibited interleukin 3/granulocyte-macrophage colony-stimulating factor-induced signalling, proliferation and survival whereas Gö6983, a broad spectrum PKC inhibitor, had no such effects. Gö6976 was found to be a direct and potent inhibitor of JAK2 in vitro. Gö6976 also inhibited signalling, survival and proliferation in cells expressing the leukaemia-associated TEL-JAK2 fusion protein and the myeloproliferative disorder (MPD)-associated JAK2 V617F mutant. In primary acute myeloid leukaemia (AML) cells, incubation with Gö6976 reduced constitutive STAT activity in all cases studied. In addition, Akt and mitogen-activated protein kinase phosphorylation were reduced in 4/5 FLT3-internal tandem duplication (ITD) positive AML cases and 7/13 FLT3-wild-type (WT) cases. Expression of FLT3-WT, ITD and D835Y in 32D cells showed that Gö6976 is also a potent inhibitor of WT and mutant FLT3. In AML cells, Gö6976 reduced th...