The presence of a central venous catheter (CVC) is the single most important risk factor for venous thromboembolism (VTE) is children. These catheters are often necessary for the care of premature neonates and children with acute and chronic diseases, and are used for intravenous nutrition, chemotherapy, dialysis, prolonged antibiotics, or supportive therapy. The use of CVCs to provided supportive care for ill children continues to rise, as does the incidence of complicating thrombosis. CVC-related VTE (CVC-VTE) can result in significant morbidity and mortality. Therefore, it is necessary to identify patients who are "high risk", in whom prevention strategies may be developed. This proposal will examine risk factors for the development of CVC-VTE in pediatric patients with cystic fibrosis (CF), a fairly uniform population that has repeated requirements for CVCs. Based on preliminary data by the principal investigator showing that infection by a specific pathogen correlates with risk of thrombosis, we hypothesize that systemic inflammation with consequent platelet activation in patients with CF is exacerbated by specific pathogens, resulting in a prothrombotic state that leads to the development of CVC-VTE. This proposal aims to test this hypothesis in a prospective clinical study and to define the incidence of both CVC-VTE in patients with CF, to understand the pathophysiology of these iatrogenic thrombi, and to identify laboratory markers that may help predict which CF patients are at high risk for VTE. We propose a single institution cohort study utilizing venography and ultrasound at the time of CVC placement followed by repeat imaging studies at 30 days or at the time of catheter removal in patients with CF.
Specific Aim 1 will determine the incidence and prevalence of VTE in patients with CF who require a CVC.
Specific Aim 2 will examine whether VTE in CF patients is associated with specific respiratory pathogens, as determined by a sputum sample.
Specific Aim 3 will define the mechanisms that lead to CVC-VTE in patients with CF, focusing on a novel model on the etiologic importance of defensins in this process. These studies should provide insight into the basis of such thrombosis in a pediatric population, and lead to future studies directed at prevention strategies for high-risk patients, with and without CF. Decreasing the risk of CVC-VTE should have tremendous positive impact on the care of children with chronic diseases. The applicant is interested in establishing a career as a clinician-scientist with expertise in the care of pediatric patients with thrombosis. The above proposed studies, set within an organized effort that includes formal clinical research education and additional laboratory training, and guided by experienced and dedicated mentors, should enable the applicant to begin to successfully establish such a career.