The multifaceted role of ischemia/reperfusion in sickle cell anemia

Abstract

The sickle mutation in the HBB gene encoding β globin results in formation of sickle hemoglobin (HbS) rather than normal HbA. When homozygous, this causes sickle cell anemia (SCA), a unique disease characterized by hemolytic anemia, recurrent vascular occlusions, a systemic inflammatory state, substantial multiorgan disease, foreshortened lifespan, and much suffering. All this stems from the abnormal behaviors of HbS: deoxygenated HbS assembles reversibly into rigid polymers (1), and oxygenated HbS is modestly unstable (2). While the former dominates the disease, the latter does foster development of pathogenic red blood cell (RBC) membrane abnormalities, as reviewed elsewhere (3, 4). Vaso-occlusions punctuate the clinical course with severe acute painful episodes that are unpredictable in occurrence and variable in frequency. Despite its prominence, sickle vaso-occlusion still presents abundant mysteries that have prompted counterpoised queries (5): "Why don't vaso-occlusions occur all the time?" versus "Why do vaso-occlusions occur at all?" The answer to both questions, we believe, is that SCA is a disease powered by ischemia/reperfusion (I/R) injury pathobiology, a conclusion grounded in data from sickle transgenic mice, SCA patients, and the general I/R literature. In particular, I/R pathophysiology underlies the unique inflammatory context of SCA, a state that is cyclic, systemic, intense, complex, unstable, and perpetual. Thus, we regard I/R as the modern formulation of the "vicious cycle" between erythrostasis and occlusion presciently posited by Ham and Castle in 1942 (Figure 1). In this Review, we briefly describe the concept of I/R injury and then emphasize the I/R features of the sickle context that match classical I/R models and diseases. We then link these features to the vascular wall pathobiology of SCA and thence to specific clinical features. We conclude by commenting on therapeutic implications and opportunities.

Targeting AnxA1/Formyl Peptide Receptor 2 Pathway Affords Protection against Pathological Thrombo-Inflammation

“…Having characterised the effects of AnxA1 Ac2-26 on inflammation-induced thrombosis instigated by LPS, we next wanted to ascertain whether the protective effects elicited by the AnxA1 peptide were specific to the LPS experimental model of thrombo-inflammation. As such, we focused on SCD, an inherited autosomal recessive disorder (resulting from a single amino acid substitution in the haemoglobin β chain) whose pathophysiology is characterized by relentless thrombo-inflammation, enabling heightened propensity for I/RI events such as stroke [ 7 , 8 ].…”

“…Although the exact mechanisms responsible for post-ischaemic cerebral damage in stroke remain undefined, the intertwined processes of thrombosis and inflammation play crucial roles in the pathophysiology [ 4 , 5 , 6 ]. Unregulated thrombo-inflammation, which involves a complex relationship between inflammatory leukocytes (e.g., neutrophils), platelets, and the vascular endothelium, is also associated with a number of comorbidities such as sickle cell disease (“SCD” [ 7 , 8 ]) and infections (e.g., sepsis [ 9 , 10 ]), which predispose individuals to ischaemic stroke. In the case of SCD, ~11% of SCD patients have a stroke before the age of 20, increasing to 24% by the age of 45 [ 11 ].…”

Thromboinflammatory mechanisms in sickle cell disease - challenging the hemostatic balance

“… 5 Similarly, the ischemia-reperfusion events that result from vaso-occlusive processes in the microcirculation also activate inflammatory cells and initiate sterile inflammatory processes and oxidant generation. 6 …”

“…Endothelial activation, a hallmark of SCD pathophysiology, augments pro-inflammatory molecule generation, and in vitro and in vivo studies suggest that it is the adhesion and capture of activated and more adhesive red cells, leukocytes and platelets to the endothelium of the blood vessel wall that trigger vaso-occlusion. 6-8 Endothelial cells and leukocytes also play major roles in generating the plethora of pro-inflammatory molecules that are upregulated in SCD, including cytokines (such as tumor necrosis factor and interleukin-1β), chemokines, growth factors, eicosanoids and peptides, all of which can further stimulate cells, and induce expression of surface adhesion mo - lecules. 9 Activation of platelets is another characteristic of SCD, in which these cells participate in the generation of inflammatory molecules and heterocellular interactions that propagate vaso-occlusive processes, as will be discussed later.…”

Sickle Cell Disease: A Paradigm for Venous Thrombosis Pathophysiology

“…FXI deficiency and inhibition of FXII-dependent FXI activation does not impact thrombin generation in sickle cell mice, but FXII deficiency attenuates thrombin generation in sickle mice [ 60 ]. Cell death during I/R injury [ 61 ] and release of histone-DNA complexes (nucleosomes) initiate inflammation, and can propagate thrombosis and lead to fibrin deposition [ 62 , 63 ]. In SCD patients, the presence of the following substances in blood, e.g., negatively charged cell surface membranes phosphatidylserine (PS) exposure on red and other cell-derived EVs, nucleic acids [ 64 ], and platelet derived polyphosphates, explain contact pathway activation [ 18 , 21 , 65 , 66 ].…”