Blood rheology biomarkers in sickle cell disease.
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ABSTRACT:
SUBMITTER: Lu M
PROVIDER: S-EPMC7016416 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Blood rheology biomarkers in sickle cell disease.
Lu Madeleine M Rab Minke Ae MA Shevkoplyas Sergey S SS Sheehan Vivien A VA
Experimental biology and medicine (Maywood, N.J.) 20200116 2
Similar Datasets
Project description:In sickle cell disease, aberrant blood flow due to oxygen-dependent changes in red cell biomechanics is a key driver of pathology. Most studies to date have focused on the potential role of altered red cell deformability and blood rheology in precipitating vaso-occlusive crises. Numerous studies, however, have shown that sickle blood flow is affected even at high oxygen tensions, suggesting a potentially systemic role for altered blood flow in driving pathologies, including endothelial dysfunction, ischemia, and stroke. In this study, we applied a combined experimental-computation approach that leveraged an experimental platform that quantifies sickle blood velocity fields under a range of oxygen tensions and shear rates. We computationally fitted a continuum model to our experimental data to generate physics-based parameters that capture patient-specific rheological alterations. Our results suggest that sickle blood flow is altered systemically, from the arterial to the venous circulation. We also demonstrated the application of this approach as a tool to design patient-specific transfusion regimens. Finally, we demonstrated that patient-specific rheological parameters can be combined with patient-derived vascular models to identify patients who are at higher risk for cerebrovascular complications such as aneurysm and stroke. Overall, this study highlights that sickle blood flow is altered systemically, which can drive numerous pathologies, and this study demonstrates the potential utility of an experimentally parameterized continuum model as a predictive tool for patient-specific care.
| S-EPMC7732763 | biostudies-literature
Project description:Sickle cell blood demonstrates oxygen-dependent flow behavior as a result of HbS polymerization during hypoxia, and these rheological changes provide a biophysical metric that can be used to quantify the pathological behavior of the blood. Relating these rheological changes directly to hemoglobin oxygen saturation would improve our understanding of SCD pathogenesis and the potential effects of therapeutic drugs. Towards this end, we have developed a microfluidic platform capable of spectrophotometric quantification of Hb-O2 saturation and simultaneous evaluation of the accompanying rheological changes in SCD blood flow. We demonstrated the ability to measure changes in Hb-O2 affinity and a restoration of oxygen-independent blood flow behavior after incubation with voxelotor, an oxygen affinity modifying drug approved for use in SCD. We also identified regimes in Hb-O2 saturation where the effects of HbS polymerization begin to take effect in contributing to pathological flow behavior, independent of voxelotor treatment. In contrast, incubation with voxelotor recovered oxygen-dependent blood flow over a range of PO2, providing a framework for understanding voxelotor's therapeutic effect in lowering the PO2 at which the requisite Hb-O2 saturation is reached to observe pathological blood flow. These results help explain the mechanistic effects of voxelotor and show the potential of this platform to identify affinity-modifying compounds and evaluate their therapeutic effect on blood flow.
| S-EPMC10165883 | biostudies-literature
Project description:Sickle cell anemia (SCA) is a disease that affects red blood cells (RBCs). Healthy RBCs are highly deformable objects that under flow can penetrate blood capillaries smaller than their typical size. In SCA there is an impaired deformability of some cells, which are much stiffer and with a different shape than healthy cells, and thereby affect regular blood flow. It is known that blood from patients with SCA has a higher viscosity than normal blood. However, it is unclear how the rigidity of cells is related to the viscosity of blood, in part because SCA patients are often treated with transfusions of variable amounts of normal RBCs and only a fraction of cells will be stiff. Here, we report systematic experimental measurements of the viscosity of a suspension varying the fraction of rigid particles within a suspension of healthy cells. We also perform systematic numerical simulations of a similar mixed suspension of soft RBCs, rigid particles, and their hydrodynamic interactions. Our results show that there is a rheological signature within blood viscosity to clearly identify the fraction of rigidified cells among healthy deformable cells down to a 5% volume fraction of rigidified cells. Although aggregation of RBCs is known to affect blood rheology at low shear rates, and our simulations mimic this effect via an adhesion potential, we show that such adhesion, or aggregation, is unlikely to provide a physical rationalization for the viscosity increase observed in the experiments at moderate shear rates due to rigidified cells. Through numerical simulations, we also highlight that most of the viscosity increase of the suspension is due to the rigidity of the particles rather than their sickled or spherical shape. Our results are relevant to better characterize SCA, provide useful insights relevant to rheological consequences of blood transfusions, and, more generally, extend to the rheology of mixed suspensions having particles with different rigidities, as well as offering possibilities for developments in the field of soft material composites.
| S-EPMC8925304 | biostudies-literature
Project description:Sickle cell disease (SCD) is a recessive genetic blood disorder exhibiting abnormal blood rheology. Polymerization of sickle hemoglobin, due to a point mutation in the β-globin gene of hemoglobin, results in aberrantly adhesive and stiff red blood cells (RBCs). Hemolysis, abnormal RBC adhesion, and abnormal blood rheology together impair endothelial health in people with SCD, which leads to cumulative systemic complications. Here, we describe a microfluidic assay combined with a micro particle image velocimetry technique for the integrated in vitro assessment of whole blood viscosity (WBV) and RBC adhesion. We examined WBV and RBC adhesion to laminin (LN) in microscale flow in whole blood samples from 53 individuals with no hemoglobinopathies (HbAA, N = 10), hemoglobin SC disease (HbSC, N = 14), or homozygous SCD (HbSS, N = 29) with mean WBV of 4.50 cP, 4.08 cP, and 3.73 cP, respectively. We found that WBV correlated with RBC count and hematocrit in subjects with HbSC or HbSS. There was a significant inverse association between WBV and RBC adhesion under both normoxic and physiologically hypoxic (SpO2 of 83%) tests, in which lower WBV associated with higher RBC adhesion to LN in subjects with HbSS. Low WBV has been found by others to associate with endothelial activation. Altered WBV and abnormal RBC adhesion may synergistically contribute to the endothelial damage and cumulative pathophysiology of SCD. These findings suggest that WBV and RBC adhesion may serve as clinically relevant biomarkers and endpoints in assessing emerging targeted and curative therapies in SCD.
| S-EPMC7689825 | biostudies-literature
Project description:Sickle cell disease (SCD) afflicts millions of people worldwide and is associated with considerable morbidity and mortality. Chronic and acute vaso-occlusion are the clinical hallmarks of SCD and can result in pain crisis, widespread organ damage, and early movtality. Even though the molecular underpinnings of SCD were identified more than 60 years ago, there are no molecular or biophysical markers of disease severity that are feasibly measured in the clinic. Abnormal cellular adhesion to vascular endothelium is at the root of vaso-occlusion. However, cellular adhesion is not currently evaluated clinically. Here, we present a clinically applicable microfluidic device (SCD biochip) that allows serial quantitative evaluation of red blood cell (RBC) adhesion to endothelium-associated protein-immobilized microchannels, in a closed and preprocessing-free system. With the SCD biochip, we have analyzed blood samples from more than 100 subjects and have shown associations between the measured RBC adhesion to endothelium-associated proteins (fibronectin and laminin) and individual RBC characteristics, including hemoglobin content, fetal hemoglobin concentration, plasma lactate dehydrogenase level, and reticulocyte count. The SCD biochip is a functional adhesion assay, reflecting quantitative evaluation of RBC adhesion, which could be used at baseline, during crises, relative to various long-term complications, and before and after therapeutic interventions.
| S-EPMC4959913 | biostudies-literature
Project description:Patients with sickle cell disease (SCD) have poorly deformable red blood cells (RBC) that may impede blood flow into microcirculation. Very few studies have been able to directly visualize microcirculation in humans with SCD. Sublingual video microscopy was performed in eight healthy (HbAA genotype) and four sickle cell individuals (HbSS genotype). Their hematocrit, blood viscosity, red blood cell deformability, and aggregation were individually determined through blood sample collections. Their microcirculation morphology (vessel density and diameter) and microcirculation hemodynamics (local velocity, local viscosity, and local red blood cell deformability) were investigated. The De Backer score was higher (15.9 mm-1) in HbSS individuals compared to HbAA individuals (11.1 mm-1). RBC deformability, derived from their local hemodynamic condition, was lower in HbSS individuals compared to HbAA individuals for vessels < 20 μm. Despite the presence of more rigid RBCs in HbSS individuals, their lower hematocrit caused their viscosity to be lower in microcirculation compared to that of HbAA individuals. The shear stress for all the vessel diameters was not different between HbSS and HbAA individuals. The local velocity and shear rates tended to be higher in HbSS individuals than in HbAA individuals, notably so in the smallest vessels, which could limit RBC entrapment into microcirculation. Our study offered a novel approach to studying the pathophysiological mechanisms of SCD with new biological/physiological markers that could be useful for characterizing the disease activity.
| S-EPMC9967909 | biostudies-literature
Project description:IntroductionSickle cell disease (SCD) is a genetic blood disorder caused by a mutation in the HBB gene, which encodes the beta-globin subunit of hemoglobin. This mutation leads to the production of abnormal hemoglobin S (HbS), causing red blood cells to deform into a sickle shape. These deformed cells can block blood flow, leading to complications like chronic hemolysis, anemia, severe pain episodes, and organ damage. SCD genotypes include HbSS, HbSC (HbC is an abnormal variant of hemoglobin), and HbS/β-thalassemia. Sickle cell trait (SCT), HbAS, represents the carrier state, while other hemoglobin variants include HbCC, HbAC, and the normal HbAA. Over 7.5 million people worldwide live with SCD, with a high mortality rate in sub-Saharan Africa, including Ghana. Despite its prevalence, SCD is underdiagnosed and poorly managed, especially in children. Characterized by intravascular hemolysis, SCD leads to oxidative stress, endothelial activation, and systemic inflammation. Identifying circulating blood biomarkers indicative of organ damage and systemic processes is vital for understanding SCD and improving patient management. However, research on biomarkers in pediatric SCD is limited and few have been identified and validated. This study explores specific circulating biomarkers in pediatric SCD in Ghana (West Africa), hypothesizing that inflammatory and neuronal injury markers in children with SCD could predict disease outcomes.MethodsClinical data were collected from 377 children aged 3-8 years with various Hb genotypes, including SCD and SCT, at Korle-Bu Teaching Hospital in Accra, Ghana (2021-2022). A total of 80 age- and sex-matched subjects were identified. A cross-sectional study utilized a multiplexed immunoassay procedure to evaluate serum biomarkers, including cytokines, chemokines, vascular injury markers, systemic inflammation markers, cell-free heme scavengers, brain-derived neurotrophic factor (BDNF), and angiogenic factors.ResultsElevated levels of BDNF, Ang-2, CXCL10, CCL11, TNF-α, IL-6, IL-10, IL12p40, ICAM-1, VCAM-1, Tie-2, and VEGFA were observed in HbSS subjects, correlating with hemoglobin level, leukocyte, and erythrocyte counts. Heme scavengers like HO-1, hemopexin, and haptoglobin also correlated with these parameters. ROC and AUC analyses demonstrated the potential of these biomarkers in predicting SCD outcomes.ConclusionThese findings suggest that there are significant differences between biomarker expression among the different genotypes examined. We conclude that a predictive algorithm based on these biomarkers could be developed and validated through longitudinal assessment of within-genotype differences and correlation of the data with disease severity or outcomes. With such a tool one can enhance SCD management and improve patient outcomes. This approach may pave the way for personalized interventions and better clinical care for pediatric SCD patients.
| S-EPMC11694143 | biostudies-literature
Project description:Sickle cell trait (SCT) is the benign heterozygous carrier state for the sickle variant of the HBB gene. Most of the ~300 million people with SCT worldwide will not experience any significant complications. However, accumulating evidence finds SCT associated with increased risk for the common conditions of chronic kidney disease and venous thromboembolism, and severe but rare renal medullary carcinoma and exercise-induced rhabdomyolysis. The mechanism is uncertain, but probably involves pathological rheology of SCT blood in regions of low oxygen tension, resulting from sickle haemoglobin polymerization in SCT red cells and leading to reduced blood flow and further tissue hypoxia and damage. Here, we used an in vitro microfluidic flow system to study the oxygen-dependent rheology of SCT blood and show that 5-(hydroxymethyl)furfural, a natural breakdown product of glucose and fructose-containing foods, such as fruit juices, can reduce the effects of hypoxia on SCT blood rheology in vitro, restoring near-normal flow velocities at very low oxygen. While opinions regarding the clinical significance of the risks associated with SCT are still evolving, these results suggest that a compound present in some food may provide a potential approach for managing risks that may be associated with SCT.
| S-EPMC7150585 | biostudies-literature
Project description:Sickle cell disease (SCD) is a genetic disease caused by a single mutation in the ?-globin gene, leading to the production of an abnormal hemoglobin called hemoglobin S (HbS), which polymerizes under deoxygenation, and induces the sickling of red blood cells (RBCs). Sickled RBCs are very fragile and rigid, and patients consequently become anemic and develop frequent and recurrent vaso-occlusive crises. However, it is now evident that SCD is not only a RBC rheological disease. Accumulating evidence shows that SCD is also characterized by the presence of chronic inflammation and oxidative stress, participating in the development of chronic vasculopathy and several chronic complications. The accumulation of hemoglobin and heme in the plasma, as a consequence of enhanced intravascular hemolysis, decreases nitric oxide bioavailability and enhances the production of reactive oxygen species (ROS). Heme and hemoglobin also represent erythrocytic danger-associated molecular pattern molecules (eDAMPs), which may activate endothelial inflammation through TLR-4 signaling and promote the development of complications, such as acute chest syndrome. It is also suspected that heme may activate the innate immune complement system and stimulate neutrophils to release neutrophil extracellular traps. A large amount of microparticles (MPs) from various cellular origins (platelets, RBCs, white blood cells, endothelial cells) is also released into the plasma of SCD patients and participate in the inflammation and oxidative stress in SCD. In turn, this pro-inflammatory and oxidative stress environment further alters the RBC properties. Increased pro-inflammatory cytokine concentrations promote the activation of RBC NADPH oxidase and, thus, raise the production of intra-erythrocyte ROS. Such enhanced oxidative stress causes deleterious damage to the RBC membrane and further alters the deformability of the cells, modifying their aggregation properties. These RBC rheological alterations have been shown to be associated to specific SCD complications, such as leg ulcers, priapism, and glomerulopathy. Moreover, RBCs positive for the Duffy antigen receptor for chemokines may be very sensitive to various inflammatory molecules that promote RBC dehydration and increase RBC adhesiveness to the vascular wall. In summary, SCD is characterized by a vicious circle between abnormal RBC rheology and inflammation, which modulates the clinical severity of patients.
| S-EPMC7082402 | biostudies-literature
Project description:We present a microfluidic approach that allows simultaneous interrogation of RBC properties in physiological flow conditions at a single cell level. With this method, we studied healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS) containing RBCs using whole blood samples from twelve subjects. We report that HbS-containing RBCs are heterogeneous in terms of adhesion and deformability in flow.
| S-EPMC4241514 | biostudies-literature