INFUSION OF PHOSPHOLIPID-VESICLES AMPLIFIES THE LOCAL THROMBOTIC RESPONSE TO TNF AND ANTI-PROTEIN-C INTO A CONSUMPTIVE RESPONSE

Inflammation often is considered a contributing factor to both thrombo sis and disseminated intravascular coagulation. The molecular mechanis ms that dictate which of these clinical manifestations will result fro m the inflammatory stimulus remain obscure. Bacterial infection and ce rtain rumors are common initiators of the disseminated intravascular c oagulant response. Complement activation resulting from bacterial infe ction shares with selected tumors the capacity to generate or release membrane particles that lack functional adhesion receptors and hence c ould circulate to amplify a disseminated intravascular coagulant respo nse. We developed a model of venous thrombosis that resulted in locali zed thrombus formation without disseminated intravascular coagulation. The model involves infusion of tumor necrosis factor, blockade of pro tein C and a partial decrease in venous now caused by ligation of the superficial femoral vein without obstruction of the deep femoral vein. Infusion of phospholipid vesicles into this model resulted in amplifi cation of a localized thrombotic response into a consumptive response. Seven different groups of animals were studied. The first three group s established the conditions necessary to produce deep vein thrombosis , The second four groups established the conditions necessary to produ ce disseminated intravascular coagulation. The infusion of phospholipi d vesicles plus tumor necrosis factor and anti-protein C antibody resu lted in consumption of fibrinogen, the production of thrombin/antithro mbin complexes, a fall in platelet count, and venous thrombosis. Witho ut ligation and catheterization phospholipid vesicles failed to produc e the consumptive response. We conclude, therefore, that phospholipid vesicles can amplify a local thrombotic response into a consumptive re sponse, and that vesiculation accompanying inflammation is one means b y which localized coagulant activity may be amplified to produce disse minated intravascular coagulation.