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Ruolo dell'inibitore della trombina dabigatran nella crescita neoplastica
Full text linkBackground: venous thromboembolism, a common complication of several malignant diseases, is a cause of poorest prognosis for the patients with respect to patients suffering for thrombus manifestation only. This occurs in the presence of a hypercoagulability state caused by coagulation factor that activate a number of pathways involved in tumor progressions. Among this factors, thrombin, a serine-protease implicated in the coagulation of fibrin, showed several physiologic and pathologic features and controls several cellular functions, including mitogenesis, cell adhesion, and angiogenesis. All this cellular responses are mediated by the thrombin-induced activation of PAR-1, a protease activated receptor expressed on the membrane of different cell types. Dabigatran is a new oral anticoagulant used in clinics for venous thromboembolism that inhibits effects of thrombin in a reversible manner by directly binding thrombin and altering its conformation.
Aim: This study aims to evaluate the modulatory effects of dabigatran on tumor progression induced by thrombin. Moreover, we aim to study the effects of dabigatran in the regulation of cell cycle and proliferation in different tumor cell lines and of the neoangiogenesis induced by thrombin, with particular emphasis on the expression of Twist and Gro-α.
Materials and methods:the tumor cell lines MCF-7 and U87-MG, from breast cancer and glioblastoma, respectively, and the endothelial cell line HUVEC, were used to evaluatethe effects of dabigatran on thrombin-induced proliferation (MTS assay), cell cycle (propidium iodide, PI, and BrdU assay) and expression of p27 and cyclin D1 by western blot, both proteins involved in regulation of cell cycle. Cell death of cells under treatment with thrombin and thrombin + dabigatran was evaluated by flow cytometry with PI and anexinV. We also evaluated the expression of Twist and Gro-α on tumoral cell lines, treated as above described,by real time PCR and western blot. Furthermore, we evaluated the effect of dabigatran on chemiotaxis (boyden chamber) and cord formation on matrigel.
Results: This study demonstrated that thrombin induced an increased proliferation, the upregulation of cyclin D1 expression and the downregulation of p27, a protein regulating the cell cycle by increasing the amount of cells in S phase, on MCF-7 cells, effects reversed by treatment with dabigratran. On the contrary, U87-MG cells showed a reduced proliferation and an increased escape from cell death, following thrombin treatment. With regards to the vessel formation, thrombin upregulates the mRNA and protein expression of Twist and Gro-α and enhanced chemiotaxis of MCF-7, U87-MG, and HUVEC cells and stimulated tube formations in HUVEC cells, all effects hampered by the treatment with dabigatrans.
Discussion: Thrombin stimulates cell proliferation, migration of tumor cell and tube formation in HUVEC endothelial cell line. dabigatran reduced cell proliferation, by modulating the expression of cyclin D1 and p27, both proteins involved in cell cycle regulation. Furthermore dabigatran inhibited neoangiogenesis and migration by reducing the expression of Twist and Gro-α on tumor and endothelial cell lines, and significantly decreased tube formation and chemiotaxis. Our data indicated that dabigatran could be used not only as an anticoagulant, but also as an anti-proliferative and anti-angiogenetic drug to prevent tumor progression in patients suffering for different tumors
Pathogenetic Role of Factor VII Deficiency and Thrombosis in Cross-Reactive Material Positive Patients
No full textMyocardial Infarctions and Other Acute Coronary Syndromes in Rare Congenital Bleeding Disorders: A Critical Analysis of All Reported Cases.
No full textPrevalence of hypertension and its complications in congenital Prekallikrein deficiency: analysis of all reported cases and clinical significance.
No full textVenous thrombosis in von Willebrand disease as observed in one centre and as reported in the literature.
No full textThe aim of this article was to investigate the prevalence of venous thrombosis in patients with von Willebrand disease. Personal records on 486 patients were reevaluated together with a time unlimited PubMed search. The venous thrombotic event had to be proven by objective means. Only cases of congenital von Willebrand disease were taken into consideration and all types of the diseases were included. No case of venous thrombosis was reported in our cohort of patients. On the contrary, 33 patients with proven venous thrombosis were gathered from the literature (17 cases of deep venous thrombosis with or without pulmonary embolism; isolated pulmonary embolism was seen in seven instances, superficial veins or portal system thrombosis was present in the remaining cases). Associated risk factors, mainly replacement therapy, were present in 26 cases. Therapeutic approach was usually based on heparin and Coumadin. Overall results were fair or good, as no fatalities occurred
Associated risk factors and arterial occlusions in patients with von Willebrand disease: Analysis of the literature and report of two cases
No full textDabigatran antagonizes growth, cell-cycle progression, migration, and endothelial tube formation induced by thrombin in breast and glioblastoma cell lines
Full text linkThrombin activates its G-coupled seven transmembrane protease-activated recep- tor (PAR-1) by cleaving the receptor’s N-terminal end. In several human cancers, PAR-1 expression and activation correlates with tumor progression and metasta- tization. This provides compelling evidence for the effectiveness of an appropriate antithrombin agent for the adjuvant treatment of patients with cancer. Dabigatran is a selective direct thrombin inhibitor that reversibly binds to thrombin. In this study, we aimed to explore if dabigatran may affect mechanisms favoring tumor growth by interfering with thrombin-induced PAR-1 activation.
We con rmed that exposure of tumor cells to thrombin signi cantly increased cell proliferation and this was coupled with downregulation of p27 and con- comitant induction of cyclin D1. Dabigatran was consistently effective in an- tagonizing thrombin-induced proliferation as well as it restored the baseline pattern of cell cycle protein expression. Thrombin signi cantly upregulated the expression of proangiogenetic proteins like Twist and GRO-α in human umbili- cal vascular endothelial cells (HUVEC) cells and their expression was signi cantly brought down to control levels when dabigatran was added to culture. We also found that the chemoattractant effect of thrombin on tumor cells was lost in the presence of dabigatran, and that the thrombin antagonist was effective in dampening vascular tube formation induced by thrombin. Our data support a role of thrombin in inducing the proliferation, migration, and proangiogenetic effects of tumor cells in vitro. Dabigatran has activity in antagonizing all these effects, thereby impairing tumor growth and progression. In vivo models may help to understand the relevance of this pathwa
Bleeding manifestations apparently unrelated to coagulation or other organic disorders: A tentative classification and diagnostic clues
Full text linkObjective: To study the features of bleeding conditions apparently not associated with vascular, platelet, or clotting dysfunctions. Method:Conditionsthatmaymeetthesecriteriaare:Münchausensyndromefactitiousorfictitious,suicidalor homicidal bleeding, bleeding due to self-punishment, stigmatization, the battered child syndrome, and psychogenic bleeding. Results: The importance of these variegate conditions is not trivial in clinical practice. Differential diagnosis may be difficult and involve other specialists besides hematologists. Occasionally, invasive procedures are involved. Discussion: The occurrence of bleeding in patients, without a clotting defect or a systemic disorder and a negative family history for bleeding represents a diagnostic challenge. A careful examination of the physical and psychological status of the patient and an appropriate evaluation of the environment in which bleeding occurs, is always neede
Complex History of the Discovery and Characterization of Congenital Factor X Deficiency.
Full text linkFactor X (FX) plays a pivotal role in blood coagulation. FX represents the point where all coagulation systems converge and, once activated, it converts prothrombin into thrombin. The discovery and definition of FX are based on the description between 1956 and 1957 about three patients and their families with a peculiar defect later demonstrated to be almost identical. These patients were an American (Mr. Stuart), a British (Ms. Prower), and a Swiss with Italian background (infant Delia B). We stated "almost identical" because immunological and molecular biology studies subsequently revealed that even though the basic clotting defect was identical, the FX protein level and the mutation were different in each case. Mr. Stuart had no FX protein in his plasma and the mutation was Val298Met (homozygote). Ms. Prower instead had a normal level of FX protein and the mutation was Arg287Trp + Asp282Asn (compound heterozygote). Unfortunately, the status of the Swiss patient in this regard is not known. Subsequent studies described a few major variants (FX Friuli, FX Melbourne, FX Padua, and other similar patients), which showed peculiar activation patterns (FX Friuli had a normal Russell viper venom clotting time; FX Melbourne was defective only in the intrinsic coagulation system; FX Padua, on the contrary, was defective only in the extrinsic coagulation system). All these studies have informed on the great heterogeneity and complexity of the FX defect. The story of the discovery and classification of FX deficiency has contributed considerably to our understanding of blood coagulation. The three original families and the families of the major variants, together with the researchers that discovered them, should be remembered with deep respect and gratitude
A family with factor x deficiency from Argentina: a compound heterozygosis due to the combination of a new mutation (Gln138Arg) with an already known one (Glu350Lys)
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