Complications of Hemolysis and Transfusion Therapy

New York Blood Center, New York NY

Investigators

Linked publications & trials

Abstract

Our Program Project focuses on mechanistic understanding of the beneficial and harmful effects of red blood cell (RBC) transfusions in patients with hemoglobinopathies, in particular sickle cell disease (SCD). Focusing on key humoral immune cells and hematopoietic niche cells, we have identified altered heme- and EPO-sensing mechanisms as pathologic drivers in SCD and key to the response to transfusions. The overall working hypothesis of this PPG is that excessive heme and high EPO levels in SCD leads to altered immune system response and a dysregulated bone marrow niche. We further posit that effectiveness of transfusions in SCD depends on their ability to switch the proinflammatory to an anti-inflammatory environment. Building on highly inter-related and synergistic research projects led by a group of multidisciplinary local experts, including a highly promising ESI, we will interrogate the impact of hemolysis and outcome of transfusions on complications associated with SCD, ranging from alloimmunization (Project 1) and infections of hemoparasites (Project 2) and hematopoietic transplant outcomes (Projects 3 and 4). Specifically, we will probe how heme and EPO sensing pathways in B and T cells during transfusions directly affect humoral immune responses, including allo- and autoimmunization and delayed hemolytic transfusion reactions (DHTR) risk (Project 1). We will examine molecular drivers of heme overload in SCD, focusing on RBC membrane lipid changes and metabolic pathways with the hypothesis that they impact the degree of RBC sickling and hemolysis and ultimately the severity of SCD complications, including DHTRs and in transfusion-transmitted infections with hemoparasites (Project 2). Our data support an anti-inflammatory metabolic switch of heme-induced inflammatory macrophages in SCD by transfusions. Focusing on bone marrow erythroblastic island macrophages (BM EBI) which we have identified as expressing EPO receptor, we will examine how hemolysis alters EPOR signaling in BM EBI macrophages in SCD and its impact on erythropoiesis and chronic inflammation in the bone marrow niche (Project 3). We will also probe heme driven SCD bone marrow hematopoietic niche dysfunction in promoting heightened platelet production, increased platelet activation and dysregulated erythropoiesis, which can be reversed by transfusions (Project 4 ESI). An Administrative Core will facilitate communication and integrate scientific goals and assure that high scientific productivity standards are maintained. The Human Subject Core will provide clinically annotated biological samples as well as clinically based insights to facilitate and enhance the clinical applicability of the findings emerging from this Program Project. We believe that the proposed Projects are highly interactive and that advances developed within each will have great value to other Projects. We further believe that through a PPG mechanism our Program will achieve a comprehensive mechanistic understanding how transfusions impact key heme and EPO pathways in hemoglobinopathies will provide the necessary framework for optimization of transfusion management and support for these highly vulnerable patient population.