Hemolysis Derived Products Toxicity and Endothelium: Model of the Second Hit

Abstract

Vascular diseases are multifactorial, often requiring multiple challenges, or ‘hits’, for their initiation. Intra-vascular hemolysis illustrates well the multiple-hit theory where a first event lyses red blood cells, releasing hemolysis-derived products, in particular cell-free heme which is highly toxic for the endothelium. Physiologically, hemolysis derived-products are rapidly neutralized by numerous defense systems, including haptoglobin and hemopexin which scavenge hemoglobin and heme, respectively. Likewise, cellular defense mechanisms are involved, including heme-oxygenase 1 upregulation which metabolizes heme. However, in cases of intra-vascular hemolysis, those systems are overwhelmed. Heme exerts toxic effects by acting as a damage-associated molecular pattern and promoting, together with hemoglobin, nitric oxide scavenging and ROS production. In addition, it activates the complement and the coagulation systems. Together, these processes lead to endothelial cell injury which triggers pro-thrombotic and pro-inflammatory phenotypes. Moreover, among endothelial cells, glomerular ones display a particular susceptibility explained by a weaker capacity to counteract hemolysis injury. In this review, we illustrate the ‘multiple-hit’ theory through the example of intra-vascular hemolysis, with a particular focus on cell-free heme, and we advance hypotheses explaining the glomerular susceptibility observed in hemolytic diseases. Finally, we describe therapeutic options for reducing endothelial injury in hemolytic diseases.

Complement activation in sickle cell disease: Dependence on cell density, hemolysis and modulation by hydroxyurea therapy

“…This over activation is indeed at least in part heme‐dependent since it was inhibited by the heme scavenger hemopexin. In similar experimental settings, complement over activation on ECs was detected in the sera of patients with atypical hemolytic uremic syndrome, as well as from other diseases with intravascular hemolysis, such as HELLP syndrome (hemolysis, elevated liver enzymes, and a low platelet count) and preeclampsia . It is tempting to speculate that in these diseases, heme could be the trigger of EC activation, rendering them susceptible to complement activation .…”

Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases

“…In parallel, free Hb is highly toxic for endothelial cells [22]. Important frictional forces, involving RBCs colliding with endothelial cells are also, with time, the main determinant of endothelial abrasion in conductance arteries [23].…”

TLR4 Signaling by Heme and the Role of Heme-Binding Blood Proteins

“…Finally, free heme may contribute to the inflammatory activation of the endothelium via complement activation as demonstrated in various experimental models of intravascular hemolysis ( 51 , 73 ). These studies have also provided experimental evidence that free heme may be an important second signal for pre-existing conditions of pro-inflammatory endothelial activation to further escalate the inflammatory vascular damage in disorders such as SCD and atypical hemolytic uremic syndrome ( 74 ).…”