Automated RBC Exchange has a greater effect on whole blood viscosity than manual whole blood exchange in adult patients with sickle cell disease

Vox Sanguinis ◽  
2020 ◽  
Vol 115 (8) ◽  
pp. 722-728
Author(s):  
Nassim Ait Abdallah ◽  
Philippe Connes ◽  
Gaetana Di Liberto ◽  
Lucile Offredo ◽  
Jean Louis Beaumont ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Viscosity ◽  
Whole Blood ◽  
Adult Patients ◽  
Cell Disease ◽  
Whole Blood Viscosity ◽  
Blood Exchange

scholarly journals Whole blood viscosity and red blood cell adhesion: Potential biomarkers for targeted and curative therapies in sickle cell disease

2020 ◽  
Vol 95 (11) ◽  
pp. 1246-1256 ◽  
Author(s):  
Erdem Kucukal ◽  
Yuncheng Man ◽  
Ailis Hill ◽  
Shichen Liu ◽  
Allison Bode ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Sickle Cell Disease ◽  
Blood Cell ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Blood Viscosity ◽  
Whole Blood ◽  
Cell Disease ◽  
Whole Blood Viscosity ◽  
Potential Biomarkers

scholarly journals Rheological Effects of L-Glutamine in Patients with Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3567-3567
Author(s):  
Celeste K. Kanne ◽  
Varun Reddy ◽  
Vivien A. Sheehan
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Viscosity ◽  
Whole Blood ◽  
Blood Cells ◽  
Cell Disease ◽  
Phase 3 ◽  
Whole Blood Viscosity

Background: ENDARITM (oral pharmaceutical L-glutamine powder) received FDA approval in 2017 as a treatment for sickle cell disease (SCD). A pivotal phase 3 clinical study conducted by Emmaus Medical, Inc. showed that L-glutamine resulted in a lower incidence of vaso-occlusive crises (VOC) as well as a lower rate of hospitalizations and shorter hospital stays. No changes in standard clinical laboratory values were noted. The clinical improvements associated with sickle cell complications are believed to be due to an increase in the proportion of the reduced form of nicotinamide adenine dinucleotides in the red blood cells (RBC) of patients with SCD, reducing the oxidative stress. While the endpoints in the phase 3 study are clinically important, it is essential that we identify biomarkers or measurable laboratory changes that can serve as endpoints for future clinical trials assessing dose optimization and the efficacy and safety of L-glutamine in SCD individuals, including those with hepatic and renal dysfunction. RBC rheology is markedly abnormal in SCD; blood is more viscous for a given hematocrit than normal individuals, dense red blood cells (DRBC) are packed with HbS, potentiating sickling, and RBCs are less deformable than those of HbAA or HbAS individuals. High whole blood viscosity, high DRBCs, and poor RBC deformability are associated with higher rates of VOC. Given the demonstrated reduction in pain events, we hypothesized that L-glutamine might improve RBC rheology and sought to test this in vitro and in vivo using a battery of rheological tests. Methods: For the in vitro study, 6 mL of whole blood was drawn into an EDTA vacutainer from ten pediatric patients with sickle cell anemia (HbSS or HbSβ0) during routine clinical checkups under an IRB approved protocol. The cohort included 3 female and 7 male patients, ages 2-19 years old. All patients were on a steady dose of hydroxyurea and did not receive a transfusion within the 3 months prior to sample collection. A 200 mM stock solution of L-glutamine and water was mixed and filtered under light-protected conditions. Aliquots were stored at -20°C to avoid multiple freeze/thaw cycles. L-glutamine was added to 3 mL of whole blood for a final concentration of 1 mM (average in vivo L-glutamine plasma concentration in patients with SCD treated with L-glutamine); 3 mL of the same patient sample with water added served as a control. After a 24-hour incubation period at 4°C, whole blood viscosity was measured using a cone and plate viscometer at 37°C (DV3T Rheometer, AMETEK Brookfield, USA), %DRBCs were measured on an ADVIA 120 Hematology System (Siemens Healthcare Diagnostics, Inc., USA), and deformability measured using a Laser Optical Rotational Red Cell Analyzer (Lorrca®) (RR Mechatronics, the Netherlands) with the Oxygenscan module. The Oxygenscan measures RBC deformability at normoxia (Elmax), deformability upon deoxygenation (EImin), and point of sickling (PoS), the oxygen tension at which deformability begins to decline, reflecting the patient-specific pO2 at which sickling begins. Paired samples (with and without added L-glutamine) were analyzed using Student's t-test. For the in vivo study, rheological tests were performed on peripheral blood from one patient (18-year-old male on hydroxyurea) at baseline and treated with L-glutamine as part of his routine clinical care. Results and conclusions: Addition of L-glutamine in vitro significantly reduced the PoS, meaning RBCs incubated with L-glutamine could tolerate a lower pO2 before sickling compared to the control. RBCs incubated with L-glutamine also had significantly higher EImin, meaning deoxygenated RBCs were more flexible and deformable. Whole blood viscosity at 45s-1 and 225s-1 did not change significantly following incubation with L-glutamine; %DRBCs also did not change significantly (Table 1). The in vivo patient sample tested exhibited a similar improvement in PoS and EImin (Figure 1). We therefore propose to further test the performance of the PoS and EImin as possible biomarkers of response to L-glutamine in vivo. If validated, these biomarkers may also help further elucidate the mechanisms of action of L-glutamine in SCD. Disclosures No relevant conflicts of interest to declare.

New Views of Sickle Cell Disease Pathophysiology and Treatment

Hematology ◽  
2000 ◽  
Vol 2000 (1) ◽  
pp. 2-17 ◽  
Author(s):  
Wendell F. Rosse ◽  
Mohandas Narla ◽  
Lawrence D. Petz ◽  
Martin H. Steinberg
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Viscosity ◽  
Whole Blood ◽  
Cell Disease ◽  
Whole Blood Viscosity ◽  
Diagnosis And Management ◽  
Clinical Consequences ◽  
Areas Of Concern

This review addresses several areas of concern in the care of patients with sickle cell disease. In Sections I and II, the fundamental pathogenetic mechanisms of sickle cell disease and their clinical consequences are discussed. Dr. Narla presents the evidence for abnormal cell adhesiveness by SS cells and Dr. Rosse examines the role of the increased whole blood viscosity. In Section III, Dr. Petz reviews common and uncommon alloimmune consequences of transfusion in sickle cell disease and discusses the diagnosis and management of sickle cell patients with hyperhemolysis after transfusion. In Section IV, Dr. Steinberg gives an update on the use of hydroxyurea in the treatment of sickle cell disease, including the SC and S-β thalassemia variants.

New Views of Sickle Cell Disease Pathophysiology and Treatment

Hematology ◽  
2000 ◽  
Vol 2000 (1) ◽  
pp. 2-17 ◽  
Author(s):  
Wendell F. Rosse ◽  
Mohandas Narla ◽  
Lawrence D. Petz ◽  
Martin H. Steinberg
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Viscosity ◽  
Whole Blood ◽  
Cell Disease ◽  
Whole Blood Viscosity ◽  
Diagnosis And Management ◽  
Clinical Consequences ◽  
Areas Of Concern

Abstract This review addresses several areas of concern in the care of patients with sickle cell disease. In Sections I and II, the fundamental pathogenetic mechanisms of sickle cell disease and their clinical consequences are discussed. Dr. Narla presents the evidence for abnormal cell adhesiveness by SS cells and Dr. Rosse examines the role of the increased whole blood viscosity. In Section III, Dr. Petz reviews common and uncommon alloimmune consequences of transfusion in sickle cell disease and discusses the diagnosis and management of sickle cell patients with hyperhemolysis after transfusion. In Section IV, Dr. Steinberg gives an update on the use of hydroxyurea in the treatment of sickle cell disease, including the SC and S-β thalassemia variants.

Erythrapheresis Improves Blood Viscosity Compared to Manuel Procedure in Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2449-2449 ◽  
Author(s):  
Ait Abdallah Nassim ◽  
Connes Philippe ◽  
Di Liberto Gaetana ◽  
Offredo Lucile ◽  
Ranque Brigitte ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Viscosity ◽  
Exchange Transfusion ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Blood Exchange ◽  
Genotype 2 ◽  
Blood Exchange Transfusion ◽  
The Impact

Abstract Blood transfusion is a cornerstone of the treatment in sickle cell disease (SCD). Guidelines and clinical trials indicate their use in several acute and chronic SCD manifestations such as cerebral vasculopathy prevention and acute chest syndrome. Two methods of blood exchange transfusion are available for physicians and patients: manual exchange transfusion (MET) and erythrapheresis, i.e. an automated exchange transfusion (AET). MET consists in a phlebotomy followed by a transfusion while erythrapheresis corresponds to the replacement of only sickle RBCs by healthy RBCs by controlling hematocrit. To our knowledge, no study has compared the impact of these two methods on blood viscosity and the ratio of hematocrit to blood viscosity (HVR); i.e., an index of red blood cell oxygen transport effectiveness (Alexy et al, 2006). Herein we aimed to compare those two procedures in term of biological parameters and blood viscosity, in order to offer new physiological parameters to guide the therapeutic management of SCD patients. This prospective, monocenter, observational study included sickle cell patients, ≥18 years old, treated by Blood Exchange Transfusion (BET) in our university hospital's Adult Sickle-Cell Referral Center. The primary end point was the change in blood viscosity during the BET procedure. Secondary end-points included the change in HVR, blood viscosity and HVR at the end of the procedure. Blood viscosity was measured after full oxygenation of the blood, at native hematocrit and at a shear rate of 225 s-1using a cone/plate viscometer (Brookfield DVII+ with CPE40 spindle, Brookfield Engineering Labs, Natick, MA, USA) (Baskurt et al, 2009). This study was approved by the local Institutional Review Board. All patients gave their signed informed consent for the genetic studies in accordance with the Declaration of Helsinki. All data were rendered anonymous to protect patients' privacy and confidentiality. Twelve patients in AET group and 31 patients in MET group were included. Thirty-nine patients had a SS genotype, three patients had a S-β0 thalassemia genotype (2 AET, 1 MET) and one had a S-β+thalassemia genotype (AET). The proportion of hydroxyurea-treated patients was not different between the two groups (20/31 in MET group and 5/12 in the AET group; p=0.17). The BET indication was cerebral vasculopathy in 11/12 and vaso-occlusive crisis in 1/12 in the AET group. BET indications in the MET group were: frequent vaso-occlusive crisis (10/31), severe organ dysfunction or organ transplant (12/31), provisory hydroxyurea interruption due to pregnancy, breastfeeding, paternity desire (4/31) and leg ulcers (3/31). Differences between groups before BET were only a higher percentage of HbF in the MET group and a higher percentage of HbA in the AET group. Both AET and MET procedures decreased HbS level, leucocytes and platelets counts, and increased HbA level (p ranging from < 0.01 to < 0.001). The decrease in HbS (p < 0.001), HbF (p < 0.05), HbA2 (p < 0.05), leucocytes (p < 0.001) and platelets (p < 0.001) levels was higher in the AET than in the MET condition. MET caused a significant rise in hematocrit and hemoglobin (p < 0.001). In contrast, AET did not change hematocrit and induced a slight increase in hemoglobin (p < 0.05). The percentage of change in hemoglobin and hematocrit was higher in the MET than in the AET condition (p < 0.01 and p < 0.05, respectively). The median blood viscosity after AET was significantly lower (3.77 cP [3.78-4.25]) compared to before (4.47 cP [3.88-5.22 ]; (p=0.0001)), whereas there was no difference before (4 cP [3.7-4.25]) and after (4.15 cP [3.73-4.88]) BET in the MET group (p=0.11). The percentage of variation in blood viscosity between AET and MET was significantly different (p < 0.01). Both AET and MET significantly increased HVR (p < 0.001 and p < 0.01, respectively) and the percentage of variation was not significantly different between the two procedures (p = 0.138). Conclusion: Automated exchange transfusion and not manual exchange transfusion improved blood viscosity. This might be due to the control of hematocrit allowed by the automated procedure, while decreasing the HbS percentage. Automated exchange transfusion should be preferred in acute and chronic SCD manifestations to improve blood rheology. Disclosures No relevant conflicts of interest to declare.

scholarly journals SOD3-Mimetic As a Complement for Genetic Therapy in Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2355-2355
Author(s):  
Carleton JC Hsia ◽  
Li Ma
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Whole Blood ◽  
Dose Range ◽  
Breakdown Product ◽  
Cell Disease ◽  
Genetic Therapy ◽  
Shed Blood ◽  
Blood Exchange

Abstract Background and Objectives: Genetic therapy relieves transfusion-dependence in patients 12 years and older with ß-Thalassemia (1) There is an urgent need to develop a complementary approach to genetic therapy for children younger than 12 years of age. The objective of this report is to describe the potential development of an extracellular superoxide dismutase-mimetic (SOD3-mimetic) to relieve sickle cell disease (SCD) children susceptible to stroke from being transfusion-dependent in order to avoid stroke. SanFlow [aka polynitroxylated pegylated hemoglobin (PNPH)], a SOD3-mimetic has been evaluated and approved by the FDA for further development as drug for the treatment of traumatic brain injury (TBI) complicated by hemorrhagic shock (HS), stroke, and SCD. PK&PD studies demonstrated that SanFlow works as a macromolecular SOD3-mimetic by protecting the endogenous vascular nitric oxide (NO) leading to enhanced blood flow. SanFlow has been shown to protect against superoxide induced hypoxia and inflammation in transgenic SCD and rat model of ischemic stroke as well as a mouse model of TBI+HS. In a rat middle cerebral artery occlusion (MCAO) model of stroke the spreading of the hypoxic core of the ischemic brain as measured by Pial arterial diameter is maintained over 2 hours post onset of stroke with associated reduction in inflammatory markers and brain infraction (3). In a mouse TBI+SH model, SanFlow was shown to be superior to fresh shed whole blood. The safety and efficacy of SanFlow was tested over a 50 fold dose range (i.e. from 0.1 to 5 times the shed blood volume). SanFlow was shown to work at extremely low volume in conjunction with volume replacement crystalloid to substitute whole blood resuscitation (3). Experimental Results: Using Berkeley model of sickle mice (Hba0/0 Hbb0/0Tg (HuminiLCRα1GγAγδβS) we have measures the PK&PD of SanFlow as a complementary or a substitute for genetic therapy. We have non-invasively measured the blood flow and vasoconstriction using transgenic SS mice (N=7) against WT littermates (N=4) as control. A single bolus dose of SanFlow (20ml/kg at hemoglobin of 4g/dl) significantly corrected the aortic stiffness and pulmonary flow of the SS mice to that of WT littermates (P<0.05). This is also correlated with the decrease of superoxide level in the lung as measure by Luminol activity assays (which fluoresces in the presence of superoxide) (P<0.05). Plasma cGMP (downstream effector of NO and natriuretic peptide activity) and NOx (breakdown product of NO and a measure of NOS activity) concentrations were measured in plasma of mice after infusion of SanFlow. SanFlow infusion was shown to significantly increased plasma cGMP concentrations in plasma. SanFlow infusion also resulted in a significant increase in NOx in plasma after infusion (P<0.05). SanFlow resulted in an increase in plasma cGMP and NOx in SS mice. Thus, the pathophysiological defects or difference of SS mice and WT littermates are corrected by SanFlow infusion. Conclusions:The present results support development of SanFlow, delivered through continuous infusion, for anemic SCD children to prevent the development of blood transfusion dependency in order to avoid stroke and painful vaso-occlusive crisis (VOC). These results also demonstrated that SanFlow can be used safely and effectively in the elimination of serious painful vaso-occlusive crisis and protect silent and major strokes. Clinical trials of SanFlow in SCD children, prior to their transfusion dependence, as well as in transfusion-dependent teenagers and adults with SCD patients are warranted. By extension, ß-Thalassemia patients can also be treated like SCD patients using SanFlow to relieve them from dependence on life-long blood exchange transfusion. However, these patients would be treated with SOD3-mimetic while waiting for genetic therapy. References: Thompson AA., et.al. Eng. J. Med 2018; 398: 1479-1493 Brockman EC., et. al. 2017 Neurotrauma, 34(7):1337-50 Cao S., et. al. 2017 J. Am Heart Assoc., 6(9):e006505. Disclosures Hsia: AntiRadical Therapeutics LLC: Employment.

Quality Metrics and Health Care Utilization for Adult Patients with Sickle Cell Disease

2019 ◽  
Vol 111 (1) ◽  
pp. 54-61 ◽  
Author(s):  
Monica Ter-Minassian ◽  
Sophie Lanzkron ◽  
Alphonse Derus ◽  
Elizabeth Brown ◽  
Michael A. Horberg
Keyword(s):  
Health Care ◽  
Sickle Cell Disease ◽  
Health Care Utilization ◽  
Sickle Cell ◽  
Quality Metrics ◽  
Adult Patients ◽  
Care Utilization ◽  
Cell Disease
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