Therapeutic options for the management of venous thromboembolism (VTE) in patients with cancer remain very limited. Although low-molecular-weight heparin monotherapy has been identified as a simple and efficacious regimen compared with an initial parenteral anticoagulant followed by long-term therapy with a vitamin K antagonist, many clinical questions remain unanswered. These include optimal duration of anticoagulant therapy, treatment of recurrent VTE, and the treatment of patients with concurrent bleeding or those with a high risk of bleeding. Treatment recommendations from consensus clinical guidelines are largely based on retrospective reports or extrapolated data from the noncancer population with VTE, as randomized controlled trials focused on cancer-associated thrombosis are sorely lacking. Furthermore, with improvements in imaging technology and extended survival duration of patients with cancer, we are encountering more unique challenges, such as the management of incidental VTE. Clinicians should be aware of the limitations of the novel oral anticoagulants and avoid the use of these agents because of the paucity of evidence in the treatment of cancer-associated thrombosis.
The serotonin-1A (5-HT 1A ) receptor is the primary somatodendritic autoreceptor that inhibits the activity of serotonergic raphe neurons and is also expressed in nonserotonergic cortical and limbic neurons. Alterations in 5-HT 1A receptor levels are implicated in mood disorders, and a functional C(-1019)G 5-HT 1A promoter polymorphism has been associated with depression, suicide, and panic disorder. We examined the cell-specific activity of identified transcription factors, human nuclear deformed epidermal autoregulatory factor-1 (DEAF-1)-related (
Cell-surface annexin 2 (A2) and its ligand p11 have been implicated in fibrinolysis because of their ability to accelerate tissue plasminogen activator (tPA)-mediated activation of plasminogen to plasmin. Because thrombin is a potent cell modulator obligately produced at the site of clot formation, we hypothesized that the amount of cell-surface A2 and p11 might be altered by thrombin with consequent effects on plasmin generation. In support of this hypothesis, immunofluorescence microscopy and hydrophilic biotinylation experiments showed that both A2 and p11 were significantly increased on the surface of human umbilical vein endothelial cells (HUVECs)treated with thrombin (0.8-8 nM) for 5 minutes followed by 1 hour at 37°C. Intracellular immunofluorescence microscopy and immunoblot analyses of whole cell extracts revealed increased p11 but unchanged A2 in response to thrombin,suggesting that transbilayer trafficking of A2 might be controlled by p11. The thrombin receptor-activating peptide (TRAP) similarly affected cells,demonstrating that cell signaling at least involved the type-1 protease activated receptor (PAR-1). An effect on the fibrinolysis pathway after treatment of HUVECs with thrombin was shown by increased fluorescein-labeled plasminogen binding to cells, which was inhibited by an antibody specific for p11. This was confirmed by observing that thrombin pretreatment of HUVECs increased biotin-modified plasminogen binding. Utilizing a chromogenic assay,pretreatment of HUVECs by thrombin further enhanced activation of the Glu and Lys forms of plasminogen by tPA. These data suggest a novel mechanism that links the coagulation and fibrinolysis pathways by thrombin-mediated feedback.
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