Arteriosclerosis, thrombosis, and vascular biology
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Arterioscler. Thromb. Vasc. Biol. · Aug 2009
Historical ArticleThe tissue-type plasminogen activator story.
Milestones in the development of tissue-type plasminogen activator (t-PA) as a fibrin-specific thrombolytic agent include: purification of human t-PA from the culture fluid of the Bowes melanoma cell line, elucidation of the molecular basis of fibrin-specific plasminogen activation, first experimental animal models of thrombosis, first patient (renal allograft) treated with melanoma t-PA, pilot studies in patients with acute myocardial infarction, cloning and expression of recombinant t-PA providing sufficient amounts for large scale clinical use, and demonstration of its therapeutic benefit in large multicenter clinical trials.
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Arterioscler. Thromb. Vasc. Biol. · Mar 2009
ReviewVenous thromboembolism: risk factors for recurrence.
Patients who have a first episode of venous thromboembolism (VTE) have an elevated risk of a recurrent episode, and this necessitates secondary prophylaxis. Anticoagulant therapy is a double-edged sword, however, as it reduces the risk of recurrent VTE but increases the risk of hemorrhage. This balance must be taken into account when assessing the risk-benefit ratio of long-term anticoagulation. ⋯ Intrinsic features of patients with VTE (gender, age, hereditary thrombophilia) have also been linked to the risk of recurrent VTE. There is increasing evidence that a normal D-dimer level and the absence of residual venous thrombosis after discontinuation of oral anticoagulation are associated with a lower risk of recurrent VTE events. Future studies are needed to refine the predictive value of known risk factors for VTE recurrence and to discover better markers.
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The purpose of this review is to summarize the epidemiology of venous thromboembolism (VTE) in pregnancy and describe strategies used to prevent and treat it. The main reason for the increased risk of VTE in pregnancy is hypercoagulability. The hypercoagulability of pregnancy, which has likely evolved to protect women from the bleeding challenges of miscarriage and childbirth, is present as early as the first trimester and so is the increased risk of VTE. ⋯ For fetal reasons, the preferred agents for anticoagulation in pregnancy are heparins. There are no large trials of anticoagulants in pregnancy and recommendations are based on case series and the opinion of experts. Nonetheless, anticoagulants are believed to improve the outcome of pregnancy for women who have or have had VTE.
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Arterioscler. Thromb. Vasc. Biol. · Feb 2009
Altered shear stress stimulates upregulation of endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-beta1-dependent pathway.
Hemodynamics has been associated with aortic valve (AV) inflammation, but the underlying mechanisms are not well understood. Here we tested the hypothesis that altered shear stress conditions stimulate the expression of cytokines and adhesion molecules in AV leaflets via a bone morphogenic protein (BMP)- and transforming growth fact (TGF)-beta1-dependent pathway. ⋯ The results demonstrate that altered hemodynamics stimulates the expression of AV leaflet endothelial adhesion molecules in a TGF-beta1- and BMP-4-dependent manner, providing some potential directions for future drug-based therapies for AV diseases.
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Arterioscler. Thromb. Vasc. Biol. · Nov 2008
Hepatocyte growth factor inhibits VEGF-forkhead-dependent gene expression in endothelial cells.
Recently, we reported that the forkhead transcription factor, FKHR/FOXO1, is required for vascular endothelial growth factor (VEGF)-mediated upregulation of a number of genes in endothelial cells. Here, we tested the hypothesis that hepatocyte growth factor (HGF), a potent activator of PI3K-Akt in endothelial cells, is capable of depleting the nucleus of FKHR/FOXO1 and thus inhibiting VEGF induction of this class of genes. ⋯ These findings suggest that physiological agonists of PI3K-Akt signaling pathway may modulate VEGF-FKHR/FOXO1-dependent gene expression in endothelial cells. The data underscore the importance of the "set point" of the endothelial cell when considering mechanisms of signal transduction.