Recurrent venous thromboembolism.

A previous venous thromboembolism is the most important risk factor for predicting recurrence of the condition. Several studies have shown that routine testing for inherited thrombophilias is not helpful in predicting the risk of recurrence or altering treatment decisions, and therefore is not cost-effective. Updated practice guidelines from the American College of Chest Physicians shift the focus away from laboratory testing and place stronger emphasis on identifying clinical factors when making treatment decisions. The major determinants for treatment duration are whether the deep venous thrombosis was located in a distal or proximal vein, whether the thrombotic episode was an initial or recurrent event, and whether transient risk factors were present. Persistent elevations on the D-dimer test or the presence of residual thrombosis may provide further information to predict recurrence risk and determine treatment duration. Screening for antiphospholipid syndrome and/or malignancy should be considered in patients presenting with arterial thrombosis, thrombosis at an unusual site, or recurrent pregnancy loss. Patients with venous thromboembolism and a known malignancy should be treated with low-molecular-weight heparin rather than oral anticoagulation as long as the cancer is active. All patients with recurrent, unprovoked venous thromboembolism should be considered for long-term treatment.

Murine macrophages produce endothelin-1 after microbial stimulation.

Endothelin-1 (ET-1) was originally characterized as a potent vasoconstrictor secreted by the endothelium and participating in the regulation of vascular tone. Subsequent analysis has revealed ET-1 to be a multifunctional peptide produced by a wide variety of cells and tissues under normal and pathologic conditions. The importance of macrophages as a source of ET-1 during infection and inflammation is supported by clinical observations in humans and in animal models of inflammation. We hypothesize that the production of ET-1 is part of the characteristic macrophage response to infection, and have begun to investigate the ability of various classes of microbes or microbial products to induce macrophage ET-1 production. We report the production of ET-1 by murine macrophages in response to stimulation with both gram-positive and gram-negative bacteria. Stimulation of macrophages with yeast (Candida albicans or Saccharomyces cerevisiae) or the protozoan parasite Leishmania major, elicited no significant release of ET-1. The production of ET-1 in response to lipopolysaccharide (LPS) was dose and time dependent, and required the expression of a functional toll-like receptor 4 (TLR4). Pharmacologic inhibition of the transcription factor, nuclear factor-kappaB (NF-kappaB) suppressed LPS-induced ET-1 production. Our findings complement the growing body of literature implicating a role for macrophage-derived ET-1 in inflammatory pathologies. The production of ET-1 by macrophages during infection and inflammation has the potential to affect tissue perfusion, leukocyte extravasation, and immune cell function.