Slide 1: Overview of Ineffective Erythropoiesis and Hemolysis in Thalassemia
Overview of Ineffective Erythropoiesis and Hemolysis in Thalassemia THA-ALL-0092 / September 2024
Slide 2: Contents
Contents Overview of Anemia 4 Overview of Ineffective Erythropoiesis and Hemolysis in Thalassemia 8 Complications of Ineffective Erythropoiesis and Hemolysis in Thalassemia 13 Summary 19 THA-ALL-0092 / September 2024
Slide 3: Overview of Anemia
Overview of Anemia THA-ALL-0092 / September 2024
Slide 4: Erythropoietin Plays a Central Role in Erythropoiesis
Erythropoietin Plays a Central Role in Erythropoiesis EPO binds to EpoR on ErP cells to initiate JAK2 activation1,2,4,5 ▪ Production of EPO is regulated by an oxygen-sensitive feedback loop1–3 EPO ErP ▪ Low levels of oxygen tension stimulate secretion of EPO by the kidneys ▪ Circulating EPO binds to
Slide 5: The Production of Healthy RBCs Depends on Iron Homeostasis and is Regulated by Erythropoietin and Hepcidin
The Production of Healthy RBCs Depends on Iron Homeostasis and is Regulated by Erythropoietin and Hepcidin Mechanism of RBC production9 ▪ Produced by the liver, hepcidin Liver regulates iron homeostasis by inhibiting enteral iron absorption and the release of iron into the Hepcidin EPO circulation1–
Slide 6: Processes Implicated in the Pathogenesis of Anemia
Processes Implicated in the Pathogenesis of Anemia ▪ Anemia is characterized by low concentrations of hemoglobin or hematocrit, resulting in decreased oxygen-carrying capacity of RBCs and low oxygen conditions that can impact any organ1 Ineffective Hemolysis4,7–9 erythropoiesis (IE)2–6 ▪ Inability t
Slide 7: Overview of Ineffective Erythropoiesis and Hemolysis in Thalassemia
Overview of Ineffective Erythropoiesis and Hemolysis in Thalassemia THA-ALL-0092 / September 2024
Slide 8: Overview: Pathophysiology of Thalassemia
Overview: Pathophysiology of Thalassemia RBC, red blood cell Taher A, et al. N Engl J Med 2021;384;(8)727–43. THA-ALL-0092 / September 2024
Slide 9: IE and Chronic Hemolysis are Pathologic Drivers of Anemia in Thalassemia
IE and Chronic Hemolysis are Pathologic Drivers of Anemia in Thalassemia Mechanism of IE and hemolysis in thalassemia1–3 β-thalassemia1–5 α-thalassemia6–9* Bone marrow ▪ Decrease or loss of α-globin chain production or ▪ Decrease or loss of β-globin chain production impaired function ▪ Excess unboun
Slide 10: Chronic Anemia from IE and Hemolysis Drives Dysregulation of EPO and Hepcidin
Chronic Anemia from IE and Hemolysis Drives Dysregulation of EPO and Hepcidin Normal erythropoiesis5 ▪ In thalassemia, IE and hemolysis cause a chronic shortage of RBCs, leading to Erythropoiesis EPO Hepcidin chronic anemia; the resultant hypoxia drives compensatory erythropoietic Erythrocyte activi
Slide 11: Iron Loading Anemia is Triggered by IE
Iron Loading Anemia is Triggered by IE Iron loading and erythropoiesis2,5,7,8 ▪ In response to hypoxia and HIF2-α, Kidney increased EPO released from the Anemia/hypoxia2,7,8 kidney suppresses hepcidin via ↑ HIF2-α ERFE secretion from erythroblasts in the marrow1–4 ▪ GDF15 is another stress ↑ ROS8 EP
Slide 12: Biomarkers of IE, Hemolysis, and Iron Homeostasis
Biomarkers of IE, Hemolysis, and Iron Homeostasis Biomarker Healthy reference range Patients with thalassemia Hemoglobin concentration (g/dL)1,2 11.6–16.6 Decreased Hemolytic biomarkers3-9 Lactate dehydrogenase (U/L) 122–222 Increased Haptoglobin (mg/dL) 30–200 Decreased Reticulocyte count (x109/L)
Slide 13: Complications of Ineffective Erythropoiesis and Hemolysis in Thalassemia
Complications of Ineffective Erythropoiesis and Hemolysis in Thalassemia THA-ALL-0092 / September 2024
Slide 14: Overview: Complications in Thalassemia
Overview: Complications in Thalassemia RBC, red blood cell. Taher A, et al. N Engl J Med 2021;384;(8)727–43. THA-ALL-0092 / September 2024
Slide 15: IE Contributes to Iron Overload, Which Drives Multiple Downstream Complications in Thalassemia
IE Contributes to Iron Overload, Which Drives Multiple Downstream Complications in Thalassemia IE and iron overload in thalassemia1 IE ▪ Iron overload can lead to Liver dysfunction Iron overload in liver dysfunction, including organs and iron toxicity Iron homeostasis dysregulated fibrosis, cirrhosi
Slide 16: IE and Hemolysis Contribute to Hypercoagulation in Patients with Thalassemia via Several Mechanisms
IE and Hemolysis Contribute to Hypercoagulation in Patients with Thalassemia via Several Mechanisms Several mechanisms have been implicated in the pathogenesis of hypercoagulation in thalassemia1–9 Hemolysis Release of Hb and heme IE ▪ An elevated (>4-fold) risk of Heme disintegration results stimul
Slide 17: Hypercoagulability in NTDT may Lead to Downstream Vascular Anomalies and Mortality
Hypercoagulability in NTDT may Lead to Downstream Vascular Anomalies and Mortality Impact of hypercoagulability in NTDT1,2,3 Silent strokes ▪ In a retrospective study of patients with NTDT (N=2,033), thrombosis was among the most common causes of death in this patient population3 Pulmonary hypertens
Slide 18: Extramedullary Hematopoiesis is a Complication of IE
Extramedullary Hematopoiesis is a Complication of IE ▪ Erythroid expansion caused by IE is associated with ▪ In thalassemia, anemia and hypoxia increase levels extramedullary hematopoiesis (EMH), the homing and of EPO, thus activating JAK2, which acts on erythroid proliferation of erythroid precurso
Slide 19: Erythroid Expansion Caused by IE Drives Pathological Changes in Bone Composition, Structure, and Morphology
Erythroid Expansion Caused by IE Drives Pathological Changes in Bone Composition, Structure, and Morphology Pathogenesis of bone remodeling6 Bone disease in thalassemia [OPG] < [RANKL] ▪ Erythroid expansion and IE are directly implicated as pathogenic drivers of osteoporosis1 ▪ Although the exact ca
Slide 20: Summary
Summary THA-ALL-0092 / September 2024
Slide 21: Summary
Summary IE and hemolysis are key drivers of anemia and thalassemia1–4 Erythroid expansion is a compensatory feature of thalassemia and is driven by upregulation of EPO, which inhibits hepcidin and increases the availability of iron for erythropoiesis5,6 Chronic anemia caused by IE and hemolysis driv