Venous Thrombosis–Associated Inflammation and Attenuation With Neutralizing Antibodies to Cytokines and Adhesion Molecules

Abstract

Thrombosis and inflammation are closely related. However, the response of the vein wall to venous thrombosis has been poorly documented. This study examines the hypothesis that venous thrombosis is associated with an inflammatory response in the vein wall. In a rat model of inferior vena caval thrombosis, vein wall was temporally examined for inflammation by assessment of histopathology, leukocyte morphometrics, and cytokine levels. Animals were killed 1 hour and 1, 3, and 6 days after thrombus induction. Our findings demonstrated an early (day 1) neutrophil infiltration into the vein wall followed by a later (days 3 and 6) monocyte/macrophage and lymphocyte response. Cytokines were elevated only under conditions of venous thrombosis. Levels of epithelial neutrophil activating protein–78 (ENA-78), tumor necrosis factor–α (TNF), interleukin-6, and JE/monocyte chemoattractant protein–1 (JE/MCP-1) increased over the 6-day period, while macrophage inflammatory protein-1α (MIP-1α) peaked at day 3 after thrombus induction. Additionally, rats were passively immunized with neutralizing antibodies to TNF, ENA-78, MIP-1α, JE/MCP-1, intercellular adhesion molecule–1 (ICAM-1), and CD18 compared with control antibodies. The most effective antibody early after thrombus induction for attenuating vein wall neutrophil extravasation was anti-TNF (P<.01). The monocyte/macrophage extravasation was inhibited most by anti–ICAM-1 followed by anti-TNF (P<.01). These findings demonstrate that venous thrombosis is associated with significant vein wall inflammation that is partially inhibited by neutralizing antibodies to cytokines and adhesion molecules.