scholarly journals Vaso-Occlusion in Sickle Cell Disease: Is Autonomic Dysregulation of the Microvasculature the Trigger?

2019 ◽  
Vol 8 (10) ◽  
pp. 1690 ◽  
Author(s):  
Saranya Veluswamy ◽  
Payal Shah ◽  
Christopher Denton ◽  
Patjanaporn Chalacheva ◽  
Michael Khoo ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Critical Role ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Hemoglobin S

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.

Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 84-90 ◽  
Author(s):  
Marilyn J. Telen
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Adhesion Molecules ◽  
Sickle Cell ◽  
Vascular Endothelium ◽  
Blood Cells ◽  
Cell Disease ◽  
Adhesive Interactions ◽  
Lines Of Evidence

AbstractA number of lines of evidence now support the hypothesis that vaso-occlusion and several of the sequelae of sickle cell disease (SCD) arise, at least in part, from adhesive interactions of sickle red blood cells, leukocytes, and the endothelium. Both experimental and genetic evidence provide support for the importance of these interactions. It is likely that future therapies for SCD might target one or more of these interactions.

scholarly journals Persistence of Chronic Inflammation Despite Years of Transfusion Program in SCD Patients: Changing Red Blood Cells Is Not Sufficient to Treat Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 764-764
Author(s):  
Abdoul Karim Dembele ◽  
Patricia Hermand-Tournamille ◽  
Florence Missud ◽  
Emmanuelle Lesprit ◽  
Malika Benkerrou ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Chronic Inflammation ◽  
Sickle Cell ◽  
Blood Cells ◽  
Healthy Controls ◽  
Cell Disease ◽  
The Impact

Abstract Sickle cell disease (SCD) is a severe hemoglobinopathy due to abnormal hemoglobin S (HbS). Although red blood cell dysfunction is at the core of the SCD pathophysiology, several studies have highlighted the important role of inflammatory cells like neutrophils. One of the most serious complications of SCD is cerebral vasculopathy (CV), due to the occlusion of one or more intracranial or cervical arteries. In 1998, the STOP study demonstrated that monthly blood transfusions could reduce the risk of stroke by 90% in children with CV. However, there is large heterogeneity in the evolution of CV under chronic transfusion, sometimes requiring exchange transfusion (ET) program for years without succeeding in healing the CV. The aim of the study is to investigate the impact of long-term transfusion program on neutrophil dysfunction, in order to understand if persistent inflammation could contribute to the non-healing of CV despite HbS permanently below 40%. In SCD children undergoing ET program for at least 1 year, we analysed i)the phenotype of neutrophils with 8 markers of activation/adhesion/ageing, ii)the plasmatic levels of elastase, witnessing the NETose activity of neutrophils, and iii)the ex-vivo adhesion of neutrophils on activated endothelial cells. One hundred and two SCD children with an ET transfusion program for at least 6 months because of CV were included in the study. ET session, carried out every 5 weeks and most of the time by erythrapheresis, reached their biological objectives with a mean HbS rate after ET session of 14.1%, and 35.4% before the next ET session, which means that these patients globally live at an average HbS level of 24% for at least 1 year. We managed to limit iron overload with a mean ferritinemia of 207 µg/L in the whole cohort. Despite these satisfactory results in terms of HbS reduction, the efficiency in curing the CV was modest in accordance with the previously described efficiency of ET program in SCD children: after a mean ET program duration of 4.4 years only 22% of them had an improvement of their CV since the beginning of the ET program, while 60% of them had a stagnation of their CV, and 18% of them worsened their vascular lesions. Considering inflammatory parameters, the patients had persistence of high leukocytosis and high neutrophils count (respective mean of 9810 G/L and 5742 G/L), significantly not different of neutrophils count before inclusion in the ET program. In a random subgroup of 20 patients, we analysed neutrophils phenotype, NETose and endothelial adhesion and compared them to healthy controls and SCD children without ET, treated or not with Hydroxyurea (HU). Overall, we observed as expected an activated, aged and adherent profile of neutrophils from untreated SCD children compared to healthy controls, characterized by an overexpression of CD18/CD11b (p=0,03), CD18/CD11a (p=0,02), CD162 (p=0,01), CD66a (p=0,01) and the ageing markers CD184 high/CD62Llow (p=0,04) as well as a higher plasmatic level of elastase (p=0. 01) and higher adhesion of neutrophils to endothelial cells. All these parameters were alleviated in SCD patients treated with HU. In SCD patient undergoing ET program, we found a similar profile of activated neutrophils to that of untreated SCD patients with a similar expression of activation molecules, high level of elastase and the same increase of neutrophils adhesion to endothelial cells compared to controls, witnessing a persistence of chronic inflammation despites years of ET. Overall, our study highlights that the replacement of sickle red blood cells, even for years, is not sufficient to reverse the deleterious inflammatory phenotype of neutrophils. Given the major role of inflammation in endothelial dysfunction, these could contribute to the persistence of CV in a majority of patients despite efficient ET programs. This raises the question of systematically combining ET program with anti-inflammatory treatment such as HU or P-selectin inhibitors in children with CV. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evolving treatment paradigms in sickle cell disease

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 440-446 ◽  
Author(s):  
Ramasamy Jagadeeswaran ◽  
Angela Rivers
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Cellular Adhesion ◽  
Ros Generation ◽  
Cell Disease ◽  
Therapeutic Approaches ◽  
Chronic Hemolytic Anemia

AbstractSickle cell disease (SCD) is an inheritable hemoglobinopathy characterized by polymerization of hemoglobin S in red blood cells resulting in chronic hemolytic anemia, vaso-occlusive painful crisis, and multiorgan damage. In SCD, an increased reactive oxygen species (ROS) generation occurs both inside the red blood cells and inside the vascular lumen, which augment hemolysis and cellular adhesion. This review discusses the evolving body of literature on the role of ROS in the pathophysiology of SCD as well as some emerging therapeutic approaches to SCD with a focus on the reduction of ROS.

More Efficient Exchange of Sickle Red Blood Cells Can be Achieved By Exchanging the Densest Red Blood Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3856-3856
Author(s):  
Suzanne Thibodeaux ◽  
Leah Irwin ◽  
Lita Jamensky ◽  
Kevin Schell ◽  
Una O'Doherty
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Blood Cells ◽  
Wild Type ◽  
Cell Disease ◽  
Hemoglobin S ◽  
And Control ◽  
Exchange Parameters

Abstract Background: In sickle cell disease, it is well established that cells containing two mutated hemoglobins (SS) are denser than cells containing wild-type hemoglobin. We asked whether we could more efficiently exchange red blood cells (RBCs) in sickle cell anemia patients by exploiting the denser property of RBCs containing hemoglobin SS compared to wild-type RBCs. Methods: To probe this question, we performed a series of experiments using the waste bags from sickle cell patients as simulated patients. We exchanged the simulated patient with one RBC volume using recently expired ABO compatible RBC units on a COBE Spectra apheresis instrument. We measured hematocrit and hemoglobin S levels in the simulated and control patient bag before and after the exchange. In the experimental scenario, we programmed the COBE Spectra to exchange the bottom half of the RBCs by indicating that the hematocrit was half of the true hematocrit (e.g. 21% when the hematocrit of the bag was 42%). For control exchanges we programmed the COBE Spectra to exchange the entire RBC volume by programing the hematocrit to be the true one (for this example 42%). Results: The percentage of hemoglobin S was more effectively diminished in our modified exchanges that targeted dense RBCs than in control exchanges. Our experimental exchanges were also more effective than expected for a 1 red blood cell volume exchange by Poisson calculation (n=5). In an optimized experiment, hemoglobin S was reduced from 23.7% to 1.3 % after exchanging 1 RBC volume using our modified approach while it was reduced from 23.2 to 5.4% using the control or routine exchange parameters. The same volume of donor RBCs (1 RBC volume) was used to exchange our experimental and control simulations. We obtained a 95% reduction of hemoglobin S in our experimental conditions and a 77% reduction in our control conditions. The instrument was programmed to compensate for RBC depletion with the modified RBC exchange. The compensation is necessary to maintain a constant hematocrit since more RBCs are present in the bottom half than top half of the centrifuged RBCs. Conclusions: It is possible to exchange sickle cell anemia patients more effectively by taking advantage of the fact that RBCs containing hemoglobin SS are denser than normal RBCs. Using waste products from sickle cell anemia exchanges provides an opportunity to safely optimize exchange parameters. This approach should allow us to: 1) achieve a higher reduction in hemoglobin S in patients, 2) achieve the previous levels of reduction using fewer donor units and/or 3) combine red cell exchange with other therapies for sickle cell disease, such as hydroxyurea, by taking advantage of the differential densities and selective depletion of red blood cells containing different levels of hemoglobin F. Disclosures No relevant conflicts of interest to declare.

scholarly journals Single Needle Option: An Alternative to Dual-Needle Access in Erythrocytapheresis in Patients with Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4284-4284
Author(s):  
Teresa Munson ◽  
Jun Zhao ◽  
Esther Elise Knapp ◽  
Charmaine Du Toit ◽  
Ashok Raj ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Vascular Access ◽  
Blood Cells ◽  
Red Cells ◽  
Cell Disease ◽  
Inlet Flow ◽  
Flow Rates ◽  
Hemoglobin S

Abstract Background: Erythrocytapheresis or red cell exchange (RCE) is an invaluable treatment option for patients with complications related sickle cell disease, including acute stroke, stroke prevention, acute chest syndrome, and recurrent pain crisis. The procedure entails the removal of each patient's red blood cells containing the abnormal sickle hemoglobin and replacing them with normal red blood cells carrying non-sickled hemoglobin. Adequate vascular access is essential for erythrocytapheresis to allow for high flow rates and various forms of access are used including peripheral veins and central venous access devices. Our center typically uses a single vortex port (Angiodynamics, Walnut Creek, CA) with placement of a peripheral IV at time of procedure in order to maintain a circuit for exchange. Using peripheral access reliably becomes particularly difficult in young patients and those that require multiple access over time due to scaring. To ensure a successful procedure in patients with poor peripheral access, a single-needle (SN) option for TPE (SN-TPE) that is available on Spectra Optia (Terumo BCT, Lakewood, CO) was used. The single-needle procedure utilizes intermittent, rather than continuous, flow, and thus requires extra procedure run time. One discontinuous cycle consists of "exchanging red cells," which is the drawing of blood and removal of the red cells, and "adjusting the volume in the reservoir," which is the returning of blood. These cycles continue until the procedure is complete. This procedure allows us to continue RCE in a select number of patients with poor vascular access. Methods: We evaluated our institutional experience on patients treated using single-needle RCE. In addition, information regarding each RCE session was collected including duration of procedure and inlet flow rate. Results: An average of 45 RCE procedures are performed each month. Patients are scheduled every 3 to 8 weeks, with an average of every 4-5 week frequency. We started the Single Needle option in July of 2019 on 3 patients: one adult aged patient and 2 pediatric patients. By the end of 2019 we had perform a total of 27 SN procedures. In 2020, we performed a total of 112 SN procedures, average of 9 procedures each month. As of the first 6 months of 2021, we have completed 35 SN procedures, averages 6 a month. In patients undergoing single needle exchange we were able to increase inlet flow rates from an average of 30-50ml/min to 60-80ml/min. This decreased the duration of run times from 120-198 min to 77- 119 min. Pre and post hemoglobin S% was comparable between dual and single exchange patients and there was no change in the interval between RCE sessions. Conclusion: With our increasing experience with single-needle RCE, our findings suggest that RCE can be successfully completed using the single-needle option with no impact on pre- and post-exchange hemoglobin S% levels. There was a reduction in the total length of procedure due to ability to maintain higher inlet rates and decreased time to obtain access for RCE. The single needle option also improved patient satisfaction due to more reliable access and negating need for peripheral IV access. Disclosures Munson: Terumo Medical Corporation: Consultancy, Honoraria, Speakers Bureau. Raj: Forma therapeutics: Consultancy; Terumo Medical Corporation: Honoraria, Speakers Bureau; Global biotherapeutics: Speakers Bureau.

scholarly journals GBT440 reverses sickling of sickled red blood cells under hypoxic conditions in vitro

2018 ◽  
Vol 10 (2) ◽  
Author(s):  
Kobina Dufu ◽  
Donna Oksenberg
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Oxygen Affinity ◽  
Microvascular Blood Flow ◽  
Cell Disease ◽  
Hypoxic Conditions

Sickle cell disease is characterized by hemolytic anemia, vasoocclusion and early mortality. Polymerization of hemoglobin S followed by red blood cell sickling and subsequent vascular injury are key events in the pathogenesis of sickle cell disease. Sickled red blood cells are major contributors to the abnormal blood rheology, poor microvascular blood flow and endothelial injury in sickle cell disease. Therefore, an agent that can prevent and or reverse sickling of red blood cells, may provide therapeutic benefit for the treatment of sickle cell disease. We report here that GBT440, an anti-polymerization agent being developed for the chronic treatment of sickle cell disease, increases hemoglobin oxygen affinity and reverses in vitro sickling of previously sickled red blood cells under hypoxic conditions. Our results suggest that besides preventing sickling of red blood cells, GBT440 may mitigate vasoocclusion and microvascular dysfunction by reversing sickling of circulating sickled red blood cells in vivo.

Study of Dense Red Blood Cells in Children with Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4870-4870
Author(s):  
Basil Coulon ◽  
Gaetana Di Liberto ◽  
Orianne Wagner Ballon ◽  
Roberto Motterlini ◽  
Xavier Decrouy ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Univariate Analysis ◽  
Organ Damage ◽  
Cell Disease ◽  
Hemoglobin F ◽  
Distribution Method ◽  
Hemoglobin S

Abstract Many Sickle cell disease (SCD) manifestations begin at an early age and with wide inter-individual variability. High Density Red Blood Cells (DRBCs) are a specific feature of SCD, assessed with phthalate density distribution method. RBCs dehydration causes higher polymerisation of hemoglobin S and sickling, and their percentage is associated to chronic organ damage and hemolysis in adults. The spleen is one of the first altered organs, with considered complete asplenia around the age of five. We assessed the percentage of DRBCs (%DRBCs) in 50 children followed in the Créteil Paediatric Sickle Cell Referral Centre. Eligible patients had hemoglobin SS or Hemoglobin S-β0 thalassemia, without recent blood transfusion. Endpoints were the %DRBCs, its correlation with hemolytic parameters, with splenic function, with clinical manifestation. In this first prospective study in pediatric population, %DRBCs was associated with age, with particular low rate before the age of four. %DRBCs was significantly associated with enhanced haemolysis: higher total bilirubin, higher reticulocytes count, and lower hemoglobin. The results concerning LDH and ASAT were more questionable. A higher %DRBCs was associated with a lower hemoglobin F percentage. The percentage of Pitted cells, reflecting spleen function, was correlated with %DRBCs in a univariate analysis. There was no association between %DRBCs and vaso-occlusive symptoms, as expected. No statistical correlation has been found between intracranial velocity and %DRBCs. Among the five patients suffering from chronic complications related to hemolysis (kidney disease, priapism), 4 had high %DRBCs. Thus, DRBCs appearance seems to be related to the impairment of the spleen function. As in SCD adults, anemia and hemolytic markers are associated with high %DRBCs. Longitudinal analysis, with DRBC measurements before any treatment intensification, in a larger population, will be the key to evaluate the prognostic value of DRBCs for organ damage. Disclosures No relevant conflicts of interest to declare.

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.

Microfluidic electrical impedance assessment of red blood cell mediated microvascular occlusion

Lab on a Chip ◽  
2021 ◽  
Author(s):  
Yuncheng Man ◽  
Debnath Maji ◽  
Ran An ◽  
Sanjay Ahuja ◽  
Jane A Little ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cell ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Blood Cells ◽  
Electrical Impedance ◽  
Cell Disease ◽  
Blood Disorders

Alterations in the deformability of red blood cells (RBCs), occurring in hemolytic blood disorders such as sickle cell disease (SCD), contributes to vaso-occlusion and disease pathophysiology. However, there are few...

Sign in / Sign up

Export Citation Format

Share Document