Pleiotropic effects of intravascular haemolysis on vascular homeostasis

Abstract

Summary The breakdown of senescent or defective red blood cells releases red cell contents, especially hemoglobin, which scavenges nitric oxide (NO) and decomposes to heme and free iron. These are potent oxidants, all of which have promoted the evolution of inducible and vasculoprotective compensatory pathways to rapidly clear and detoxify hemoglobin, heme and iron. Chronic hemolytic red cell disorders as diverse as sickle cell disease, thalassemia, unstable hemoglobinopathy, cytoskeletal defects and enzymopathies have been linked to a clinical constellation of pulmonary hypertension, priapism, leg ulceration and possibly cerebrovascular disease and thrombosis. Besides free hemoglobin, hemolysis has been associated with extracellular arginase that limits substrate availability to NO synthase, endogenous inhibitors of NO synthase activity, and inappropriate activation of hemostatic pathways. This article reviews the hemolytic disorders that have been reported to manifest vascular complications, and explores the speculative possibility that hemolysis mediates some of the vascular complications of inflammation and diabetes.

Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHLR200W mutation (Chuvash polycythemia)

“…Elevation of tricuspid regurgitation velocity by echocardiography is common in hemolytic hematologic disorders such as sickle cell anemia, thalassemia and paroxysmal nocturnal hemoglobinuria, [29][30][31][32][33] and potential contributing mechanisms include a hemolysis-induced vasculopathy, 34 volume overload, and diastolic dysfunction. 29,35 In contrast to sickle cell disease, we found no evidence that subjects with Chuvash polycythemia had significant hemolysis or diastolic dysfunction.…”

Association of circulating transcriptomic profiles with mortality in sickle cell disease

“…Contributing pathways to the development of these complications including the role of hemolysis and heme-based injury, the vascular endothelium, the effects of hypoxia and inflammation-and immune-mediated cell activation have been extensively studied. [1][2][3][4][5][6][7] Despite its Mendelian inheritance, the course of patients with SCD is highly variable. There is significant heterogeneity in the rate of development of acute and chronic pain, cerebrovascular disease, acute chest syndrome, 8,9 pulmonary hypertension (PH), diastolic dysfunction, renal failure, hemolytic anemia, and premature or sudden death.…”

Development of Recombinant Hemoglobin-Based Oxygen Carriers

“…Outside the red cells, however, all levels of acellular Hb are associated with some degree of enhanced morbidity and mortality rates (122,138). Small-to-moderate levels of hemolysis (10-100 lM free Hb) can occur after red blood cell transfusions, chronic inflammatory disorders, myocardial infarction, septic shock, sickle cell crises, and physical injury (19,67). Ten-fold higher levels of free Hb (200-1000 lM) can occur due to acute hemolytic disorders, hemorrhaging, or trauma (122), and even higher levels of acellular Hb (2000-6000 lM) are generated after HBOC infusion (19,67).…”

“…Small-to-moderate levels of hemolysis (10-100 lM free Hb) can occur after red blood cell transfusions, chronic inflammatory disorders, myocardial infarction, septic shock, sickle cell crises, and physical injury (19,67). Ten-fold higher levels of free Hb (200-1000 lM) can occur due to acute hemolytic disorders, hemorrhaging, or trauma (122), and even higher levels of acellular Hb (2000-6000 lM) are generated after HBOC infusion (19,67). Regardless of dosage, there is a general consensus that toxic reactions associated with acellular Hb are either the direct cause of the pathology or an enhancer of pre-existing clinical conditions.…”