Newer Aspects of the Pathophysiology of Sickle Cell Disease Vaso-Occlusion

Abstract

Sickle cell disease is an inherited disorder of hemoglobin (Hb) synthesis, caused by a single nucleotide substitution (GTG>GAG) at the sixth codon of the beta-globin gene, leading to the production of a defective form of Hb, Hb S. When deoxygenated, Hb S polymerizes, damaging the sickle erythrocyte and it is this polymerization that is the primary indispensable event in the molecular pathogenesis of sickle cell disease. Hb S polymerization results in a series of cellular alterations in red cell morphology and function that shorten the red cell life span and leads to vascular occlusion. Sickle cell disease vaso-occlusion is now known to constitute a complex multifactorial process characterized by recurrent vaso-occlusion, ischemia-reperfusion injury, and oxidative stress with consequent vascular endothelial cell activation that induces a chronic inflammatory state in sickle cell disease individual and is propagated by elevated levels of circulating inflammatory cytokines. Activation of the endothelium results in the induction of endothelial adhesion molecule expression that mediates red and white cell adhesion to the vessel wall and the formation of heterocellular aggregates, followed by secondary red cell trapping, all of which contribute to reduced blood flow and eventually obstruction of the micro-circulation. Reduced nitric oxide bioavailability, caused principally by its consumption by cell-free Hb, liberated during intravascular hemolysis, contributes to this process by facilitating vasoconstriction and adhesion molecule activity.

Sickle-Cell Pain: Advances in Epidemiology and Etiology

“…Vasculopathy contributes to tissue ischemia and necrosis in these and other complications of SCD, potentially ending in organ failure of the spleen, kidneys, heart, lungs, brain, liver, and bone, and in early death. 30 Reliable biomarkers of chronic vasculopathy in SCD are being researched 31 ; however, biomarkers able to distinguish the severity and temporal changes in stimuli underlying pain exacerbations have still not been identified. Dampier et al's longitudinal studies of SCD children demonstrate similar clinical features and similar predictive hematologic parameters of home-managed versus acute caremanaged pain, implying a single underlying pain stimulus of variable intensity.…”

Cytotoxicity and DNA damage in the neutrophils of patients with sickle cell anaemia treated with hydroxyurea

“…The endothelial activation results in increased expression of adhesion molecules on neutrophils, such as E-selectin, P-selectin and ICAM-1 (Intercellular Adhesion Molecule-1), inducing the chemotaxis of neutrophils and its interaction with adhesion molecules on sickle red blood cells, other leukocytes and platelets, leading to pancellular activation resulting in the release of most proinflammatory cytokines. Thus, there is a vicious circle between production of inflammatory mediators and cellular adhesion to the endothelium, leading to a state of chronic inflammation, fundamental to the process of vaso-occlusion (Okpala, 2006;Canalli et al, 2008;Conran, Franco-Penteado, Costa, 2009;Segel, Halterman, Lichtman, 2011).…”

“…HU inhibits the enzyme ribonucleotide reductase (RNR), causes cell-cycle arrest, and allows globin genes to be more actively expressed. By killing cycling cells, HU changes the kinetics of erythroid proliferation, forcing more F cells to be produced from primitive progenitors and directly stimulating HbF production (Franco et al, 2006).Furthermore, HU therapy increases haemoglobin concentration, reduces the expression of adhesion molecules on erythrocytes, platelets and neutrophils, decreases the production of granulocytes and contributes to the improvement of clinical events, reducing the number of hospital admissions, the frequency of painful episodes, the need for transfusion and the occurrence of CVA and ACS (Platt et al, 1984;Steinberg et al, 2003;Zago, Pinto, 2007;Cartron, Elion, 2008;Orah, Platt, 2008;Conran, Franco-Penteado, Costa, 2009;Lou et al, 2009).…”

Apolipoprotein A-I and serum amyloid A plasma levels are biomarkers of acute painful episodes in patients with sickle cell disease

“…1 Infection and inflammation may promote coagulation cascades, leukocyte activation, and endothelial activation, which may further contribute to vascular obstruction. 2,3 These painful crises are unpredictable, but may follow exposure to cold or, less commonly, emotional stress, exercise, or alcohol. 1,4 Hematologic risk factors include elevated hematocrit, known to be increased in the presence of concomitant alpha thalassemia, and low fetal hemoglobin levels.…”