Mechanisms for Deep Vein Thrombosis following Stroke

Project Summary/Abstract Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) have an immense impact on morbidity and mortality. Acute ischemic stroke and aging are considered significant risk for developing life-threatening VTE events. While prophylactic anticoagulation reduces the rates of VTE in such high-risk patients, they only prevent approximately half of the expected VTE events and are associated with significant risk of bleeding, suggesting the critical need for novel and safe adjuvant treatments to reduce VTE burden. In recent years, compelling evidence has emerged that implicates neutrophils in the initiation and pathogenesis of deep vein thrombosis (DVT). In pilot studies, we found that stroke increases the risk of DVT, both in mice and humans and integrin α9 is upregulated on neutrophils following stroke in humans and in mice and it contributes to adhesion of neutrophils to the endothelium. We also observe that neutrophil specific α9-/- mice were less susceptible to DVT. Our central hypothesis is that neutrophil integrin α9 promotes DVT in the context of aging and stroke. The overall objective of the proposal is to evaluate the mechanisms by which neutrophil integrin α9 promotes DVT while exploring its relevance and therapeutic potential in reducing poststroke DVT. In aim 1, we will determine the mechanistic role of neutrophil integrin α9 in promoting DVT in the context of stroke and aging. We will evaluate underlying molecular mechanisms that contributes to poststroke neutrophil adhesion and DVT. For optimal scientific rigor and to ensure reproducibility of the results, we will test this hypothesis considering age, sex and the presence and absence of ischemic stroke. We will use clinically relevant models (filament/embolic stroke models and IVC stenosis models for DVT). In aim 2, we will determine the translational impact of inhibiting integrin α9 on venous thrombosis. We will use well characterized anti-integrin α9 antibody in mouse models. By utilizing whole blood samples from controls and patients with ischemic stroke, we will determine in vitro effect of integrin α9 inhibition on magnitude of venous thrombosis. This project will provide robust evidence that neutrophil integrin α9 promotes DVT in the context of stroke and aging. A longer-term impact of the project will be facilitation of the development of anti-integrin α9 therapeutics that can be used in combination with current thromboprophylaxis regimens to reduce VTE burden in such high-risk population.