scholarly journals Mn Porphyrin-Based Redox Active Drugs Improve Anemia and Reduce Organ Damage in a Murine Model of Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2255-2255
Author(s):  
Madhan Thamilarasan ◽  
Rodolfo Estupinan ◽  
Rahima Zennadi
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Oxidative Damage ◽  
Annexin V ◽  
Endothelial Activation ◽  
Organ Damage ◽  
Vehicle Group ◽  
Cell Disease ◽  
Redox Active ◽  
Mn Porphyrins

Sickle cell disease (SCD) is caused by a point mutation in the β-globin gene that leads to devastating downstream consequences including chronic hemolytic anemia, episodic vascular occlusion, and cumulative oxidative organ damage resulting in death. Targeting the mechanisms leading to organ injury could bring out therapeutic approaches. Sickle red blood cell (RBC) oxidative damage, which leads to hemolysis, could participate in endothelial activation and organ damage. Recently, we show that NADPH oxidases (NOXs) are a major player in generating reactive oxygen species (ROS) within sickle RBCs to mediate adhesion and vaso-occlusion. We have now evaluated the effects of reducing ROS in sickle RBCs on hemolysis, and its consequences on endothelial activation and organ damage in sickle mice in vivo. To inactive RBC NOXs, thus reduce ROS levels, we used the redox-active manganese (Mn) porphyrins, MnTnBuOE-2-PyP5+ (MnBuOE) and MnTE-2-PyP5+ (MnE), commonly known as superoxide dismutase (SOD) mimics. Treatments of sickle mice for 4 weeks with 0.1 mg/kg MnBuOE and 1 mg/kg MnE significantly reduced sickle RBC ROS production profile compared to sickle RBC ROS levels in the control vehicle group (p<0.05), suggesting that Mn porphyrins protects sickle RBCs especially against NOX activation. Mn porphyrins also significantly affected apoptosis-like RBC death called eryptosis characterized by accelerated membrane senescence and PS externalization. Sickle mice-treated with vehicle showed 4.98±0.6% annexin V-positive sickle RBCs. However, 0.1 mg/kg MnBuOE and 1 mg/kg MnE markedly decreased the percentage of annexin V-binding sickle RBCs by 54% (p=0.0009) and 56% (p=0.0007), respectively. As a result of improved eryptosis, RBC counts rose from 5.23 x 106/mL in vehicle-treated sickle mice to 5.99 x 106/mL in MnE-treated mice. Hemoglobin (Hb) levels also rose from 7 g/dL in the vehicle group to 8.55 g/dL in MnE-treated mice. Accordingly, hematocrits rose from 26.1% in vehicle-treated mice to 28.59% in MnE-treated mice. Yet, reticulocyte counts were not significantly different between vehicle and MnE-treated sickle mice, implying less hemolysis and not an increase in RBC production. The effect of reduced hemolysis by Mn porphyrins on oxidative stress in different organs was next assessed. MnBuOE and MnE decreased ROS levels in the kidneys (p<0.03 for MnBuOE and MnE), liver (p<0.05 for MnBuOE and MnE), and spleen (p<0.004 for MnBuOE and MnE) compared to the vehicle-treated group. Since organ ROS levels were lowered, this outcome may be accompanied by down-regulation of activation of endothelial adhesion molecules VCAM-1, ICAM-1, and P-selectin, markers of endothelial dysfunction and disease severity and/or RBC and leukocyte adhesion in SCD. Indeed, adhesion molecule expression assays by qRT-PCR showed that MnBuOE suppressed ICAM-1 and VCAM-1 expression in the lungs (p<0.0001 and p=0.0054, respectively) and kidneys (p=0.0072 and p=0.0004, respectively), and P-selectin expression (p=0.0058) in the kidneys. MnE also down-regulated the expression of ICAM-1 in the lungs (p<0.0001) and kidneys (p=0.0125), and VCAM-1 (p=0.0038) in the kidneys. These drugs had no effect on ICAM-1, VCAM-1, and P-selectin expression in the liver and spleen. Based on these data, we assumed that Mn porphyrins might rescue damage of organs typically affected and impaired in SCD. Apoptosis and necrosis of the kidneys, liver, and spleen were assessed using annexin V apoptosis detection kit and H&E staining. Sickle mice treated with vehicle showed marked apoptosis in the kidney, liver, and spleen (p=0.0314) tissues, and necrosis. However, 0.1 mg/kg MnBuOE and 1 mg/kg MnE significantly decreased apoptosis (p<0.0001) and necrosis in the kidneys, and liver (p=0.0355). MnBuOE also reduced apoptosis (p=0.0314) and necrosis in the spleen. These data suggest that Mn porphyrins can alleviate organ impairment and damage via at least RBC and endothelial oxidative stress reduction. As a result of these beneficial outcomes of reduced hemolysis, endothelial oxidative damage and dysfunction, Kaplan-Meier survival curves showed a dramatic prolonged survival of sickle mice challenged with TNFα (p = .0009, log-rank test). Our data suggest that Mn porphyrins, by repressing NOX-mediated hemolysis could represent a novel therapeutic intervention to especially alleviate hemolysis-mediated endothelial activation and organ damage in SCD. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 296
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Organ Damage ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents ◽  
Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

Oxidative Stress and Vaso-Occlusion in Sickle Cell Disease: Role of Activated Leukocytes and Redox Active Iron.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3165-3165 ◽  
Author(s):  
John D. Belcher ◽  
Hemachandra Mahaseth ◽  
Thomas E. Welch ◽  
Felix Boakye-Agyeman ◽  
Robert P. Hebbel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Blood Cell ◽  
Sickle Cell ◽  
Ambient Air ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Active Iron ◽  
Redox Active ◽  
Hypoxia Reoxygenation

Abstract Sickle cell disease (SCD) is a disease of oxidative stress. We and others have demonstrated increased oxidative stress, inflammation, endothelial cell activation and white blood cell counts in human patients and transgenic murine models of SCD. Leukocytosis in SCD is associated with increases in the incidence of pain crisis, acute chest syndrome, stroke and mortality. We hypothesize that reactive oxygen species (ROS) derived from leukocytes and excess redox active iron promote vascular inflammation and vaso-occlusion. Leukocytes were activated in S+S-Antilles sickle mice compared to normal C57BL/6 control mice as measured by the percentage of leukocytes expressing CD11b on their surface in ambient air (25.4% vs. 19.3%, p&lt;0.05) and after exposure of mice to hypoxia-reoxygenation (31.7% vs. 23.0%, p&lt;0.05). In addition, resting leukocytes from S+S-Antilles mice produce 1.8-fold more H2O2 than normal mice (p&lt;0.05) as measured by Amplex Red (10-acetyl-3,7-dihydroxyphenoxazine) fluorescence. These leukocyte oxidants are especially toxic in the presence of excess redox active iron. Histopathology of the lungs and livers of 10 week old S+S-Antilles and BERK sickle mice showed red blood cell (RBC) congestion compared to normal. In addition, the sickle livers had multiple areas of infarction and inflammatory leukocyte infiltration. The heme contents of S+S-Antilles sickle lungs and livers were increased by 37- and 4.9-fold, respectively, compared to normals (p&lt;0.05 for both organs). Furthermore, there was significantly more chelatable iron that is potentially redox active as measured by Ferene-S in sickle lungs (21.0-fold, p&lt;0.05) and livers (2.4-fold, p&lt;0.05) compared to normals. Thus, these data demonstrate there is an explosive pro-oxidative environment in sickle mice. These excess oxidants lead to NF-kB activation, VCAM-1 and ICAM-1 expression, and increased oxidative injury, as seen histopathologically by nitro-tyrosine and dihydroethidium staining in organs. Hypoxia-reoxygenation, which induces RBC sickling and enhances ROS production in sickle mice, causes an increase in leukocyte rolling (4.4-fold, S+S-Antilles vs. normal, p&lt;0.05) and adhesion (6.5-fold, p&lt;0.05). Hypoxia-reoxygenation induces transient vaso-occlusion in 12% and 24% of the subcutaneous venules of S+S-Antilles and BERK mice respectively. No vessels become static in normal mice (p&lt;0.05 sickle vs. normal). Hypoxia-reoxygenation-induced vaso-occlusion can be inhibited by antibodies to P-selectin, VCAM-1 or ICAM-1. Furthermore, scavenging ROS with the SOD and catalase mimetic, polynitroxyl albumin or the iron chelator Trimidox, inhibited hypoxia-reoxygenation-induced vaso-occlusion (p&lt;0.05). We conclude that oxidative stress derived from activated leukocytes and excess redox active iron plays a critical role in promoting vaso-occlusion and organ injury in SCD. We speculate that iron chelators, leukocyte adhesion molecule blockade and anti-oxidants will modulate vaso-occlusion in patients with SCD.

Reduced Oxidative Stress and Enhanced Nitric Oxide (NO) Bioavailability in Transgenic-Knockout Sickle Mice Expressing Fetal Hemoglobin (HbF) Is Mediated by Decreased Sickling and Hemolysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 842-842
Author(s):  
Trisha Dasgupta ◽  
Mary E. Fabry ◽  
Dhananjay K. Kaul
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Manipulation ◽  
Fetal Hemoglobin ◽  
Organ Damage ◽  
Multiple Organ ◽  
Protective Effects ◽  
Cell Disease ◽  
No Bioavailability

Abstract The primary event in the vaso-occlusive pathophysiology of sickle cell disease (SCD) is polymerization of hemoglobin S under deoxygenated conditions. In SCD, sub-clinical transient vaso-occlusive events caused by red cell sickling are likely to be more frequent resulting in “reperfusion injury” that generates reactive oxygen species and results in chronic oxidative stress that will contribute to multiple organ damage. In fact, previous studies have suggested that sickling is etiologic to repefusion injury and oxidative stress (Kaul and Hebbel, JCI, 2000), although the effect of antisickling therapy on oxidative stress has not been evaluated. Increasing the levels of antisickling fetal hemoglobin (HbF) by hydroxyurea therapy markedly reduces polymer formation. HbF exerts an ameliorating effect in sickle cell disease patients both on red cells and in the prevention of multiple organ damage. Here, we hypothesize that induction of HbF by genetic manipulation (in the absence of pharmacological manipulation) will reduce organ oxidative stress by reducing sickling and hemolysis, and thereby increase NO bioavailability. To test our hypothesis, we measured activity of selected antioxidants and lipid peroxidation (LPO) in BERK mice expressing exclusively human α- and βS-globins and varying levels of HbF, i.e., BERK (<1% HbF), BERKγM (20% HbF) and BERKγH (40% HbF). Percent sickled cells in venous samples (drawn in 2.5% glutaraldehyde solution in 0.1M cacodylate buffer) showed a distinct decrease with increased %HbF (P<0.05, multiple comparisons). Consistent with maximal sickling, BERK mice showed 5.4–6.9-fold increase in LPO in various tissues (muscle, kidney and liver) compared with C57BL controls (P<0.001). In contrast, BERKγM and BERKγH mice showed a marked decrease (73% and 80%, respectively) in LPO compared with BERK mice (P<0.001). Also, activity/levels of antioxidants (superoxide dismutase [SOD], catalase, glutathione peroxidase [GPx] and reduced glutathione [GSH]) showed significant decreases in BERK mice (P<0.001–0.00001). On the other hand, BERKγM and BERKγH mice showed significant increases in antioxidant activity (P<0.05–0.0001). Induction of HbF was associated with increased levels of NO metabolites (NOx) and reduced hemolysis; the latter is in agreement with our previous observations in BERKγM mice (Kaul et al. JCI, 2004). These results strongly suggest that reduced sickling and hemolysis in the presence of HbF cause increased NO bioavailability. NO is well known to exert antioxidative effects. Thus, we show for the first time that the induction of antisickling HbF leads to an increase in NO bioavailability and a decrease in oxidative stress, and that these protective effects are mediated primarily by reduced intravascular sickling.

scholarly journals Protection of Microvascular Liver Perfusion with 5-Hydroxymethylfurfural in Sickle Cell Disease Mice Following Hypoxia-Induced Vasoocclusion

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3382-3382 ◽  
Author(s):  
Michael Wright ◽  
Derek Sim ◽  
Magdalena Alonso-Galicia ◽  
Katalin Kauser ◽  
Keith Abe
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Liver Perfusion ◽  
Organ Damage ◽  
Extramedullary Hematopoiesis ◽  
T Test ◽  
Vehicle Group ◽  
Cell Disease ◽  
And Control

Abstract Introduction: Sickle cell disease (SCD) is a debilitating genetic disorder, and the resultant "sickling" deformity of red blood cells leads to acute vasoocclusive (VOC) events and chronic disease in multiple organs. Sickle cell hepatopathy, arising from VOC events in the hepatic sinusoids, which can lead to fatal sickle cell intrahepatic cholestasis, is estimated to occur in approximately 10% of the SCD population. Using contrast-enhanced ultrasound (CEUS), we measured microvascular liver perfusion (MVLP) in SCD and control mice at basal levels to determine if noninvasive CEUS can be utilized to assess the underlying extent of disease and also investigated the effect of hypoxia-induced VOC with and without treatment with an antisickling agent, 5-hyroxymethylfurfural (5-HMF). Methods: Townes sickle cell mice (SCD), homozygous for hα:βs -globulin, approximately 7−9 weeks of age (n=28), and control mice, homozygous for hα:β-globulin (n=11), were used in these studies. CEUS perfusion imaging (Vevo® 2100) was performed on a central cross-section of the liver at the renal artery. Contrast agent was administered as an intravenous bolus via tail vein to anesthetized mice (isoflurane with ~21% O2); peak enhancement (PE) was analyzed with VisualSonics software. CEUS measurements were obtained at baseline and following either (1) hypoxia, 60 minutes with 5.5.% O2 followed by ~60 minutes of reoxygenation at room oxygen (~21% O2) or (2) normoxia, ~120 minutes at room oxygen. 5-HMF at 20 and 200 mg/kg PO or vehicle was administered following baseline PE measurement and approximately 30 minutes before start of hypoxia. Results: MVLP in SCD (n=28) was significantly reduced by approximately 40% compared with controls (n=11) at baseline (PE of 14.0±0.7 linear arbitrary units [l.a.u.] vs. 23.6±2.1 l.a.u.), respectively, P<0.001 [Student t test]). Normoxic SCD maintained similar PE to baseline levels (Table 1); however, hypoxia significantly reduced MVLP by 49% in SCD mice. In contrast, hypoxia had no significant effect in control mice. 5-HMF at 20 and 200 mg/kg resulted in a dose-dependent increase in posthypoxia MVLP. 5-HMF at 200 mg/kg was not significantly different from baseline PE, and 5-HMF at 20 mg/kg increased MVLP by approximately 50% compared with the vehicle group posthypoxia (26% vs 49% reduction in MVLP, respectively). Pathologic evaluation of naive SCD formalin-fixed liver tissues (n=10) showed congestion, necrosis, hepatocellular hypertrophy, and extramedullary hematopoiesis. Table 1. CEUS-Acquired Microvascular Liver Perfusion in SCD and Control Mice (mean ± SEM) Strain Dose Oxygen Status Mice, n Baseline PE, l.a.u. Posthypoxia/Normoxia PE, l.a.u. Change From Baseline, % Control Vehicle Hypoxic 11 23.6±2.1 22.1±2.1 -7 SCD Vehicle Normoxic 4 14.0±2.1 13.3±1.6 -3 SCD Vehicle Hypoxic 8 15.4 ±1.6 7.0±0.9* -49 SCD HMF, 20 mg/kg Hypoxic 8 12.8±0.9 9.2±0.7* -26 SCD HMF, 200 mg/kg Hypoxic 8 13.8±1.5 11.9±1.2 -12 *Statistically significant reduction compared with baseline PE (P <0.01, Student t test). Summary: CEUS measured lower basal levels of MVLP in SCD compared with control mice, which correlated with pathologic findings of congestion and necrosis in the livers of SCD mice. The hypoxia-induced VOC decrease in MVLP was present only in the SCD mice; no effect was observed in control mice. Treatment with the antisickling agent, 5-HMF, dose-dependently ameliorated the hypoxia-induced VOC decrease in MVLP in SCD mice. Based on these results, CEUS may be considered as a noninvasive method to measure acute and chronic organ perfusion changes for evaluating new therapeutics for sickle cell-mediated VOC events and end-organ damage. Disclosures Wright: Bayer HealthCare LLC: Employment. Sim:Bayer HealthCare LLC: Employment. Alonso-Galicia:Bayer HealthCare LLC: Employment. Kauser:Bayer HealthCare LLC: Employment. Abe:Bayer HealthCare LLC: Employment.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

2020 ◽  
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Metabolism ◽  
Globin Gene ◽  
Organ Damage ◽  
Beta Globin ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb) that affects approximately a millions people worldwide. It is characterized by a single nucleotide substitution on the &beta;-globin gene, leading to the production of abnormal sickle hemoglobin with multi-system consequences. Mutated Hb leads to profound changes in: i) red blood cell metabolism and physiology; ii) endothelial signaling; and iii) immune response. Oxidative stress is an important hallmark of SCD. It plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e. by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

Increased Procoagulant Activity of Red Blood Cells from Patients with Homozygous Sickle Cell Disease and β-Thalassemia

1996 ◽  
Vol 76 (03) ◽  
pp. 322-327 ◽  
Author(s):  
Dominique Helley ◽  
Amiram Eldor ◽  
Robert Girot ◽  
Rolande Ducrocq ◽  
Marie-Claude Guillin ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Annexin V ◽  
Mean Value ◽  
Procoagulant Activity ◽  
Dependent Manner ◽  
Cell Disease ◽  
Homozygous Sickle Cell Disease

SummaryIt has recently been proved that, in vitro, red blood cells (RBCs) from patients with homozygous β-thalassemia behave as procoagulant cells. The procoagulant activity of β-thalassemia RBCs might be the result of an increased exposure of procoagulant phospholipids (i. e. phosphatidylserine) in the outer leaflet of the membrane. In order to test this hypothesis, we compared the catalytic properties of RBCs of patients with β-thalassemia and homozygous sickle cell disease (SS-RBCs) with that of controls. The catalytic parameters (Km, kcat) of prothrombin activation by factor Xa were determined both in the absence and in the presence of RBCs. The turn-over number (kcat) of the reaction was not modified by normal, SS- or (3-thalassemia RBCs. The Km was lower in the presence of normal RBCs (mean value: 9.1 µM) than in the absence of cells (26 µM). The Km measured in the presence of either SS-RBCs (mean value: 1.6 µM) or β-thalassemia RBCs (mean value: 1.5 pM) was significantly lower compared to normal RBCs (p <0.001). No significant difference was observed between SS-RBCs and p-thalassemia RBCs. Annexin V, a protein with high affinity and specificity for anionic phospholipids, inhibited the procoagulant activity of both SS-RBCs and (3-thalassemia RBCs, in a dose-dependent manner. More than 95% inhibition was achieved at nanomolar concentrations of annexin V. These results indicate that the procoagulant activity of both β-thalassemia RBCs and SS-RBCs may be fully ascribed to an abnormal exposure of phosphatidylserine at the outer surface of the red cells.

scholarly journals Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management

2011 ◽  
Vol 86 (6) ◽  
pp. 484-489 ◽  
Author(s):  
Erfan Nur ◽  
Bart J. Biemond ◽  
Hans-Martin Otten ◽  
Dees P. Brandjes ◽  
John-John B. Schnog ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Disease Management ◽  
Sickle Cell ◽  
Cell Disease

scholarly journals Targeting pain at its source in sickle cell disease

2018 ◽  
Vol 315 (1) ◽  
pp. R104-R112 ◽  
Author(s):  
Kanika Gupta ◽  
Om Jahagirdar ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Somatosensory System ◽  
Organ Damage ◽  
Mast Cell Activation ◽  
Cell Disease ◽  
Central Nervous Systems

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

scholarly journals Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 144
Author(s):  
Olivia Edwards ◽  
Alicia Burris ◽  
Josh Lua ◽  
Diana J. Wilkie ◽  
Miriam O. Ezenwa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Cells ◽  
Cell Disease ◽  
Free Hemoglobin ◽  
Cerebral Tissue ◽  
Sickle Hemoglobin ◽  
Haptoglobin Polymorphism

This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology. Hp is a blood serum glycoprotein responsible for binding and removing toxic free hemoglobin from the vasculature. The role of Hp in patients with SCD is critical in combating blood toxicity, inflammation, oxidative stress, and even stroke. Ischemic stroke occurs when a blocked vessel decreases oxygen delivery in the blood to cerebral tissue and is commonly associated with SCD. Due to the malformed red blood cells of sickle hemoglobin S, blockage of blood flow is much more prevalent in patients with SCD. This review is the first to evaluate the role of the Hp polymorphism in the incidence of stroke in patients with SCD. Overall, the data compiled in this review suggest that further studies should be conducted to reveal and evaluate potential clinical advancements for gene therapy and Hp infusions.

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