Cytokines play a key role in the host response to microbial infection. These mediators are induced following contact with Gram (-) bacteria, and have a wide range of effects including influencing hemostatic factors, which are risk indicators for thrombotic events. Experimental evidence has conclusively established that a low-dose endotoxin bolus in healthy human volunteers alters rheologic parameters via a cytokine cascade resulting in a transient procoagulant state. Further, recent case-control studies have shown severe periodontal disease to be a strong independent risk factor for myocardial infarct and stroke. While causation has not been established, the initiating step is likely the transient bacteremia that result when the highly vascular, chronically inflamed periodontium is mechanically irritated by chewing, toothbrushing, and dental procedures. We hypothesize that chronic Gram(-) infection of the periodontium represents a potential source of circulating endotoxin which may adversely effect the coagulation system via a transient bacteremia-induced cytokine cascade, resulting in a net procoagulant state. The goal of this study is to explore the association of severe periodontitis and hemostatic variables. We suggest that patients with severe chronic adult periodontitis are at risk for altered rheologic and hemostatic variables as has been shown in experimental endotoxemia studies. Specifically, we will monitor the sera of 20 adults with severe periodontitis during common dental manipulations and periodontal treatment to determine the temporal appearance of endotoxin, inflammatory cytokines, and coagulation products, and to test whether conservative therapy can reduce serum levels of acute phase proteins. This study will help to define the pathophysiology of the thrombotic disorder-periodontitis relationship, and identify future thrombotic disorder prevention strategies. This study will be the first to experimentally demonstrate whether periodontal disease is a systemic modifier of clinically relevant hemostatic variables, and is designed to establish a molecular mechanism to explain this relationship. A positive finding in this regard should have broad ramifications for both dentistry and medicine. Dr. Engebretson will receive training in research methodology and molecular biology in order to explore the mechanisms of periodontal medicine through the conduct of human clinical studies as a career goal.