Oxidative Stress and Vascular Tone
The aberrant biochemistry of SCA promotes premature intravascular hemolysis. This occurs when sickled red cells release free hemoglobin polymers into the blood plasma via the free hemoglobin scavenging mechanism. This consequentially impairs the synthesis and circulation of nitric oxide thus impedes on vascular constriction( Rees, Williams, & Gladwin, 2010). Normal levels of nitric oxide maintain vascular tone by stimulating the vascular endothelium to relax. Accumulation of hemoglobin in the plasma are reported to be avid scavengers of nitric oxide thus reducing its bioavailability(Daves et al., 2019). Moreover, nitric oxide depletion is a precursor to vasospasms even in larger vessels. Inability to maintain a proper vascular tone attributes to SCA-related cerebrovascular disease, priapism and chronic leg ulcers(Kato, Steinberg, & Gladwin, 2017a). Progressive elevation of pulmonary vascular tone and vascular remodeling are also commonly manifested in individuals with SCA. In one study, 20 autopsies were performed on individuals with Hemoglobin S. It was reported that 75% of these individuals demonstrated signs of pulmonary hypertension (Haque et al., 2002).
Pharmaceutical prevention of intravascular hemolysis directly correlates with ameliorating clinically related outcomes. The sickle red cell release of oxygenated hemoglobin into the endothelium increases the risk of oxidative stress and induces intravascular hemolysis. Furthermore, the production and release of highly reactive ferric heme and iron in the blood plasma promotes the generation of hydroxyl radicals and ultimately oxidative damage((Fanis, Phylactides, Voskou, Kleanthous, & Aslan, 2015). In a 2019 study of 147 individuals, blood analysis via biochemical testing revealed an increased level of hydroxyl radicals and nitric oxide production prevalent in the SCD group. Aberrant blood element interactions not directly affected by the HbS mutation paves the way for ischemic reperfusion injury and supports elevated inflammatory tone(Kato et al., 2017a).
Evidence supports that alteration of hemoglobin capacity is a precursor to chronic inflammatory disease (Biswal et al., 2019). Studies that effectively target the reduction of oxidative and nitrosative stress in SCD remain in progression. Although proving the efficacy of nitric oxide inhalation therapy was unsuccessful(Ehman et al., 2017), a new therapeutic agent that deters oxidative stress has recently been the 1st FDA approved SCA-pathology targeting therapy since Hydroxyurea 30 years prior.
L-Glutamine is known for its increased uptake by sickled red cells in comparison to normal erythrocytes(Niihara, Zerez, Akiyama, & Tanaka, 1998). NAD+ uptake by cells slow oxidative damage hereby discouraging various clinical expressions. Although the pathologic mechanism is not fully understood, the efficacy of L-glutamine in reduction of VOC occurrences is an evidence-based phenomenon. In 2018, a double- blind phase 3 trial demonstrated a significant reduction in sickle cell related pain crises after receiving L-glutamine orally over the course of 48 weeks. A large portion of these participants were also noted as intolerable to hydroxyurea(New et al., 2018).
Targeting SCA Pathophysiology
Atypical Endothelial Interactions
Heterocellular aggregates are understood to propagate the phenomenon of vascular occlusion(Kau, Finnegan, & Barabino, 2009). The lifespan of an erythrocyte in a healthy individual is 120 days and is drastically shortened to 12 days in a person with sickle cell anemia; stimulating the increased production of reticulocytes rich in adhesion molecules. Both sickled erythrocytes and reticulocytes express more endothelial adhesion relative to normal erythrocytes (de Montalembert et al., 2014; Morikis et al., 2017). This phenomenon is attributed to the mechanistic role of extracellular matrix proteins and molecular interactions amongst blood formed elements and the vascular endothelium.
When Leukocyte concentrations rise, so does its tendency to adhere to the endothelium, platelets and each other. Modifying the expression of adhesion on cell endothelium is currently being investigated. Clinicians have studied ways to chemically block leukocytes and other adhesion mediated molecules in order to reduce blood viscosity and impede vasoocclusive pain episodes(VOC)(El Nemer et al., 2016; Molokie et al., 2017). Of note is the inhibition of the adhesion mediated molecule P-selectin, a molecule known for upregulation in endothelial cells. A placebo controlled, phase II experiment tested Crizanlizumab and its effectiveness; a
humanized antibody proven to bind to P-selectin and inhibit cell to cell related adhesion. A total of 198 adult patients were involved and those who received high dose Crizanlizumab resulted in a significant decline (62.9%) in sickle cell pain crisis(Friedrisch et al., 2016). Studies also support the benefit of an antiplatelet agent in treatment of sickle cell related complications.
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Prasugrel functions to inhibit platelet activation and adenosine diphosphate mediated agglutination. The drug was studied in multiple phase 1 placebo controlled settings and demonstrated a reduction in platelet surface P-selectin in adults with SCA(Jakubowski et al., 2013; Wun et al., 2013)
Prevention of Erythrocyte Dehydration
Sickled erythrocyte dehydration plays an important role in diminished organ perfusion (Ballas et al., 2016). Maintenance of intracellular volume and proper ion concentrations is imminent in avoidance of erythrocyte dehydration. Yet it is a fate in repeated sickling. Several channels are critically involved but emphasis has been placed on the irregular functioning of the kalium-chloride cotransport system (KCC) and Gardos channel in SCA. KCC activity increases in proportion to repeated sickling; functioning pathologically in sickle cells to overshoot its target hemoglobin concentration and priming the reticulocyte to sickle(Lew et al., 2002). HbS polymerization activates a nonselective cation leaky pathway in a fraction of sickle cells upon deoxygenation. Calcium permeabilization promotes membrane protein digestion via activation of proteolytic enzymes like phospholipase and protease. One clinical investigation demonstrated a notable decline in erythrocyte KCC activity and permeabilization in the presence of magnesium intercellularly. Magnesium as an oral supplement for patients with sickle cell anemia demonstrated a notable improvement in erythrocyte dehydration (Fransechi et al., 1997).
Nevertheless, red blood cell magnesium levels, not serum magnesium is encouraged to be used as a determinant of SCA-related hospitalizations. Evidence shows that a patient with a lower concentration of erythrocyte magnesium strongly correlates with the increased risk of more frequent VOC episodes(Yousif, Hassan, & Al-Naama, 2018).
Although pharmacologically targeting the gardos channel in vitro has not been as successful as KCC modifications, a deepened understanding of its biochemistry has encouraged researchers to find efficient ways to upregulate potassium in SCA. Nevertheless, binding of upregulated vasoactive substance ET1, a potent vasoconstrictor, alters the mechanism of the gardos channel in an anoxic environment(Brugnara, 2018); Senicapoc is a gardos channel blocker that has been tested to increase intracellular potassium levels and counteract dehydration. In a phase II study, 145 patients received oral Senicapoc over the course of 52 weeks. Data showed a notable increase in hemoglobin levels and a reduction in dense erythrocytes (Ataga et al., 2011). Although the rate in which hemolysis improved relative to the placebo group was deemed insignificant, research is still in progress for pharmaceutically targeting erythrocyte dehydration for SCA.
Stem Cell Transplantation
Allogenic hematopoietic stem cell transplantation (HSCT) is the sole curative possibility for sickle cell patients who present with a severe clinical presentation. To date, human leukocyte antigen matched sibling donor (MSD) HSCT has the highest event free survival rates of 93- 97%(Gluckman, 2013). Reports show that transplant recipients have absolute resolution of their sickle cell related complications; including no further organ reperfusion damage or episodes of vasoocclusion (Roth, Krystal, Manwani, Driscoll, & Ricafort, 2012). Studies even report reduced levels in toxicities from 22.6% to 3% with the use of reduced-intensity conditioning regimens such as antithymocyte globulin (ATG) which limit the likelihood of organ transplant rejection (Margueritte et al., 2007).
Notwithstanding the success of allogenic MSD-HSCT, the donor pool for engraftment recipients remain low since only 20% of minorities have a matched sibling donor(Horan, Liesveld, Fenton, Blumberg, & Walters, 2005). The World Marrow Donor Association reports only 33% of African Americans having a match; attributed to having a less common more diverse haplotype. The battle continues in HSCT donor pool expansion although recent efforts in using alternative donor sources has demonstrated an encouraging outcome. Of note is matched unrelated donor (MUD) HSCT although mitigating occurrences of graft versus host disease remains limited with varied results. Walters et al reported a 1 to 2 year event free survival rates of 76% and 69% respectively and overall survival of 96% and 79% in recipients of Haploidentical HSCT. Moreover, rates of graft versus host disease (GVHD) were reported to be higher (62%) compared to having a related donor(Guilcher et al., 2018). The use of post- transplant cyclophosphamide which functions to impede alloreactive T cells in MUD HSCT has been recently used in a series of pilot studies to impede high levels of GVHD (Adamkiewicz et al., 2004). Bolanos et al was a study that used a haploidentical sibling, parent or child donor and cyclophosphamide as a non-myeloablative conditioning regimen which resulted in a 43% graft failure rate(Jones et al., 2012). Nevertheless, lack of larger studies on HSCT donor expansion and a standard criteria for donor recipients remain barriers treatment efficacy.
Conclusion
Although the genetic basis of sickle cell anemia is well reported, the quest for a deepened understanding of its complex pathogenesis continues. This has encouraged scientist globally to find ways in which therapeutic agents can target elements that exacerbate vasoocclusion and hemolysis. Understanding the roles of increasing HbF production, prevention of cellular and sickle red cell adhesion, inflammation, NO depletion and hemolysis have paved the for oral therapeutic advancements for SCD. Although there is a demand for more clinical trials and analysis, efforts toward producing effective treatment options that are available globally are at its all-time high.
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