Pathophysiological insights in sickle cell disease

Abstract

The first coherent pathophysiological scheme for sickle cell disease (SCD) emerged in the sixties-seventies based on an extremely detailed description of the molecular mechanism by which HbS in its deoxy-form polymerises and forms long fibres within the red blood cell that deform it and make it fragile. This scheme explains the haemolytic anaemia, and the mechanistic aspects of the vaso-occlusive crises (VOCs), but, even though it constitutes the basic mechanism of the disease, it does not account for the processes that actually trigger VOCs. This paper reviews recent data which imply: red blood cell dehydration, its abnormal adhesion properties to the endothelium, the participation of inflammatory phenomenon and of a global activation of all the cells present in the vessel, and finally, abnormalities of the vascular tone and of nitric oxide metabolism. These data altogether have shed a new light on the pathophysiology of the first molecular disease i.e. sickle cell disease.

Fig. 1

Basic pathophysiological mechanism of sickle cell disease: the polymerization of deoxy-HbS. The replacement of a glutamic acid by a valine residue at position 6 in the β-globin polypeptide chain characterizes the abnormal haemoglobin of SCD: HbS. At low oxygen pressure, deoxy-HbS polymerises and gets organised in long polymer fibres that deform, stiffen, and weaken the red blood cell (not shown). This process represents the basic mechanisms leading to haemolytic anaemia and to vaso-occlusive events in the microcirculation. [Source: Modified from Labie and Elion32].

Fig. 2

Membrane alterations in the sickle red blood cell. Formation of the deoxy-HbS polymer fibres triggers a whole series of changes of the red blood cell membrane. Ion channels are affected and their dysfunction is responsible for a cellular dehydration which, in a vicious circle, favours deoxy-HbS polymerization. Hemichromes are released and lead, in particular, to the formation of protein band 3 aggregates on which anti-band 3 IgGs accumulate. The liberation of heme and Fe³⁺ favours an oxidizing microenvironment. Exposure of anionic phosphatidylserines at the external side of the membrane creates a procoagulant surface. Finally, microparticles are released. [Source: Modified and completed from Elion and Labie33].

Fig. 3

Adhesion of sickle red blood cells to the endothelium and cell activation. Simplified scheme of the main interactions involved in the abnormal adhesion of the sickle red blood cells to the endothelium. Locally, endothelial damage exposes sub-endothelial structures that also participate to the adhesion process. Some adhesion proteins are activated by extracellular stimuli. It is the case of the basal cell adhesion molecule (Lutheran blood group) (Lu/BCAM) that expresses its adhesion properties only when phosphorylated via the protein kinase A-dependent (PKA) pathway when the red blood cell is activated by epinephrine. 2-AR, type 2 adrenergic receptor; Fn, fibronectin; TSP, thrombospondin; Ln, laminin; α4β1, α4β1 integrin (or VLA-4). [Source: Modified from Elion et al34].