Session: 301. Vascular Wall Biology, Endothelial Progenitor Cells, and Platelet Adhesion, Activation, and Biochemistry: Poster I
Hematology Disease Topics & Pathways:
Diseases, Bleeding and Clotting, platelets, Thrombosis, Biological Processes, Cell Lineage, Clinically relevant, Thrombotic Disorders
Collagen and thromboplastin (TF) were administered intravascularly (IV) to C57BL/6 (WT) mice and the pulmonary microcirculation was visualized using quantitative fluorescence intravital fluorescence lung microscopy (qFILM). Fluorochrome-conjugated anti-mouse CD49b Ab and dextran was administered IV for in vivo staining of circulating platelets and visualization of blood vessels, respectively. Pulmonary thrombosis was defined as occlusion of blood vessels with platelet aggregates leading to pulmonary ischemia. Additionally, quantitative microfluidic fluorescence microscopy (qMFM) was used to study the effect of platelet αIIbβ3 inhibition on platelet procoagulant activity in human blood under vascular mimetic flow conditions.
Collagen and TF triggered dose-dependent pulmonary thrombosis in mice in vivo, which involved development of platelet-rich thrombi in the pulmonary arteriolar bottlenecks (junction of pulmonary arteriole and capillaries), resulting in a transient ischemia in the arteriole and the down-stream capillary tree. The pulmonary arteriole thrombosis triggered by IV collagen or TF was protracted, lethal and completely abrogated following IV administration of αIIbβ3 receptor inhibitor (eptifibatide). Inhibition of platelet αIIbβ3 also significantly reduced platelet procoagulant activity, fibrin formation and thrombus formation in human blood flowing through microfluidic channels ex vivo.
Our current findings suggest that αIIbβ3-dependent platelet procoagulant activity promotes pulmonary thrombosis. Both our models have potential application in investigating the molecular determinants of pulmonary thrombosis in diverse pulmonary disorders as well as evaluating efficacy of new antithrombotic drugs.
Disclosures: Gladwin: Globin Solutions: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Not relevant to SCD; Bayer: Consultancy, Research Funding; Actelion: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.
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