Program Director/Principal Investigator (Last, First, Middle) Pawlinski, Rafal and Key, Nigel Abstract Venous thromboembolism (VTE) is the third most common form of cardiovascular disease after myocardial infarction and ischemic stroke, with approximately 900,000 cases annually in the United States. VTE may present clinically as deep vein thrombosis (DVT) and/or pulmonary embolism (PE). However, it is unknown why some patients present with symptomatic DVT, while others present with PE. In recent years, it has been established that individuals with sickle cell disease (SCD), as well as carriers for SCD -- who are said to have sickle cell trait -- are at increased risk of VTE. Interestingly and unusually, in both sickle cell disease and trait, a skewed distribution in the proportions of patients with DVT and PE (in favor of PE) is observed. We have termed this phenomenon “the sickle cell paradox”. SCD is due to an inherited mutation in hemoglobin that is expressed exclusively in red blood cells (RBCs). Therefore, in this proposal, we postulate that a greater understanding of the mechanism of VTE in SCD, as well as an explanation for the sickle cell paradox, will be explained by a detailed study of the role of sickle RBCs in VTE. To address this question, we will utilize animal models of SCD with experimentally induced venous thrombi, while concurrently studying the qualitative aspects of blood clots formed from the blood of patients with SCD ex vivo. Towards this goal, we will address the following specific aims: in Aim 1, we will determine the effect of RBCs on venous thromboembolism in a mouse model of SCD. We expect that partial RBC exchange will result in smaller, more stable DVTs and a reduced incidence of PE. In Aim 2, we will investigate how sickle RBCs enhance thrombin generation in SCD. In the third Aim, we will determine the cellular and molecular mechanisms that attenuate sensitivity of sickle clots to fibrinolysis. We anticipate this effect is mediated both by the inherited defect in SCD RBCs, but also the fact that platelets in patients with SCD are over-activated. Finally, in Aim 4, we will determine whether reduction of platelet numbers reduces VTE and restores normal susceptibility to fibrinolysis in sickle mice and SCD patients undergoing chronic RBC exchange. With an annual worldwide SCD birth rate of more than 300,000 (and an estimated 250 million individuals with sickle trait), a greater mechanistic understanding of VTE in sickle cell disorders is a high priority. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page