Julien Tripette

Red blood cell aggregation, aggregate strength and oxygen transport potential of blood are abnormal in both homozygous sickle cell anemia and sickle-hemoglobin C disease

Recent evidence suggests that red cell aggregation and the ratio of hematocrit to blood viscosity, an index of the oxygen transport potential of blood, might considerably modulate blood flow dynamics in the microcirculation. The findings of this study indicate that patients with sickle cell disease and those with sickle cell hemoglobin C disease have low ratios of hematocrit to blood viscosity as compared to normal controls. This may play a role in tissue hypoxia and clinical status of these patients. Background Recent evidence suggests that red blood cell aggregation and the ratio of hematocrit to blood viscosity (HVR), an index of the oxygen transport potential of blood, might considerably modulate blood flow dynamics in the microcirculation. It thus seems likely that these factors could play a role in sickle cell disease. Design and Methods We compared red blood cell aggregation characteristics, blood viscosity and HVR at different shear rates between sickle cell anemia and sickle cell hemoglobin C disease (SCC) patients, sickle cell trait carriers (AS) and control individuals (AA). Results Blood viscosity determined at high shear rate was lower in sickle cell anemia (n=21) than in AA (n=52), AS (n=33) or SCC (n=21), and was markedly increased in both SCC and AS. Despite differences in blood viscosity, both sickle cell anemia and SCC had similar low HVR values compared to both AA and AS. Sickle cell anemia (n=21) and SCC (n=19) subjects had a lower red blood cell aggregation index and longer time for red blood cell aggregates formation than AA (n=16) and AS (n=15), and a 2 to 3 fold greater shear rate required to disperse red blood cell aggregates. Conclusions The low HVR levels found in sickle cell anemia and SCC indicates a comparable low oxygen transport potential of blood in both genotypes. Red blood cell aggregation properties are likely to be involved in the pathophysiology of sickle cell disease: the increased shear forces needed to disperse red blood cell aggregates may disturb blood flow, especially at the microcirculatory level, since red blood cell are only able to pass through narrow capillaries as single cells rather than as aggregates.

Effect of strenuous physical exercise on circulating cell-derived microparticles.

Strenuous exercise is associated with an inflammatory response involving the activation of several types of blood cells. In order to document the specific activation of these cell types, we studied the effect of three maximal exercise tests conducted to exhaustion on the quantitative and qualitative pattern of circulating cell-derived microparticles and inflammatory molecules in healthy subjects. This study mainly indicated that the plasma concentration of microparticles from platelets and polymorphonuclear neutrophils (PMN) was increased immediately after the strenuous exercise. In addition, the increase in plasma concentration of microparticles from PMN and platelets was still observed after 2 hours of recovery. A similar pattern was observed for the IL-6 plasma level. In contrast, no change was observed for either soluble selectins or plasma concentration of microparticles from red blood cells, monocytes and endothelial cells. In agreement, sVCAM-1 and sICAM-1 levels were not changed by the exercise. We conclude that a strenuous exercise is accompanied by platelet- and PMN-derived microparticle production that probably reflects the activation of these two cell types.

Blood rheology abnormalities and vascular cell adhesion mechanisms in sickle cell trait carriers during exercise

Sickle cell trait (SCT) is usually considered a benign disorder compared with sickle cell anemia (SS hemoglobinopathy). However, several authors have reported cases of exercise-related sudden death in this population. Among the mechanisms that could be involved in these fatal complications, vaso-occlusive processes, such as those occurring in SS hemoglobinopathy, may play a role. In sickle cell anemia, these vaso-occlusive processes involve inflammatory and adhesion molecules such as the cell adhesion molecules (CAM family), which play a role in the firm adhesion of reticulocytes and leukocytes to endothelial cells, and the selectins, which play a role in leukocyte and platelet rolling on the vascular wall. Recent results suggest that adhesion phenomena could be amplified in SCT carriers during exercise compared with non-carriers. Other mechanisms like alterations in blood coagulation and/or hemorheological properties can also favor the occurrence of vaso-occlusive processes. Although few studies have reported coagulation disturbances in SCT carriers at rest, we recently observed no difference between this population and control subjects in response to exercise. In contrast, by studying the behavior of several hemorheological parameters in response to several types of exercise, we detected hemorheological abnormalities in individuals with SCT. These abnormalities included higher red blood cell rigidity and higher blood viscosity in the SCT carriers compared with the non-carriers, particularly during the late recovery period (24 and 48 h after exercise). Therefore, we can suggest that the risks for microvascular complications in SCT carriers in response to exercise could be dependent on alterations in blood rheology and vascular adhesion processes.

Effects of hydration and dehydration on blood rheology in sickle cell trait carriers during exercise

This study compared the hemorheological responses of a group of sickle cell trait (SCT) carriers with those of a control (Cont) group in response to 40 min of submaximal exercise (exercise intensity, 55% aerobic peak power) performed in two conditions: one with water offered ad libitum, i.e., the hydration (Hyd) condition, and one without water, i.e., the dehydration (Dehyd) condition. Blood and plasma viscosities, as well as red blood cell rigidity, were determined at rest, at the end of exercise, and at 2 h recovery with a cone plate viscometer at high shear rate and 37 degrees C. The SCT and Cont groups lost 1 +/- 0.7 and 1.6 +/- 0.6 kg of body weight, respectively, in the Dehyd condition, indicating a significant effect of water deprivation compared with the Hyd condition, in which body weight remained unchanged. Plasma viscosity increased with exercise and returned to baseline during recovery independently of the group and condition. As previously demonstrated, resting blood viscosity was greater in the SCT carriers than in the Cont group. Blood viscosity increased by the end of exercise and returned to baseline at 2 h recovery in the Cont group in both conditions. The blood viscosity of SCT carriers did not change in response to exercise in the Dehyd condition and remained elevated at 2 h recovery. This extended hyperviscosity, in association with other biological changes induced by exercise, could be considered as a risk factor for exercise-related events in SCT carriers, similar to vasoocclusive crises, notably during the recovery. In contrast, the Hyd condition normalized the hyperviscosity and red blood cell rigidity of the SCT carriers, with blood viscosity values reaching the same lower values as those found in the Cont group during the recovery. Adequate hydration of SCT carriers should be strongly promoted to reduce the clinical risk associated with potential hyperviscosity complications.

Effects of storage duration and temperature of human blood on red cell deformability and aggregation

Blood samples used in hemorheological studies may be stored for a period of time, the effects of storage have yet to be fully explored. This study evaluated the effects of storage temperature (i.e., 4 degrees C or 25 degrees C) and duration on RBC deformability and aggregation for blood from healthy controls and from septic patients. Our results indicate that for normal blood, RBC deformability over 0.3-50 Pa is stable up to six hours regardless of storage temperature; at eight hours there were no significant differences in EI but SS1/2 calculated via a Lineweaver-Burk method indicated impaired deformability. Storage temperature affected the stable period for RBC aggregation: the safe time was shorter at 25 degrees C whereas at 4 degrees C aggregation was stable up to 12 hours. Interestingly, blood samples from septic patients were less affected by storage. Blood can thus be stored at 25 degrees C for up to six hours for deformability studies, but should be limited to four hours for RBC aggregation; storage at 4 degrees C may prolong the storage period up to 12 hours for aggregation but not deformability measurements. Therefore, the time period between sampling and measurement should be as short as possible and reported together with results.

Sickle cell disease: Selected aspects of pathophysiology

Sickle cell disease (SCD), a genetically-determined pathology due to an amino acid substitution (i.e., valine for glutamic acid) on the beta-chain of hemoglobin, is characterized by abnormal blood rheology and periods of painful vascular occlusive crises. Sickle cell trait (SCT) is a typically benign variant in which only one beta chain is affected by the mutation. Although both SCD and SCT have been the subject of numerous studies, information related to neurological function and transfusion therapy is still incomplete: an overview of these areas is presented. An initial section provides pertinent background information on the pathology and clinical significance of these diseases. The roles of three factors in the clinical manifestations of the diseases are then discussed: hypoxia, autonomic nervous system regulation and blood rheology. The possibility of a causal relationship between these three factors and sudden death is also examined. It is concluded that further studies in these specific areas are warranted. It is anticipated that the outcome of such research is likely to provide valuable insights into the pathophysiology of SCD and SCT and will lead to improved clinical management and enhanced quality of life.

Relationships between hemodynamic, hemorheological and metabolic responses during exercise ∗

Aerobic performance is dependent on both cardio-respiratory and peripheral factors with hemodynamic parameters playing a major role. However, whether blood rheology might affect aerobic performance through an effect on hemodynamic factors is not known. The aim of the present study was to assess the relationships between hemodynamic, hemorheological and metabolic parameters in response to a sub-maximal cycling exercise protocol consisting of three successive levels of nine min duration (50, 100 and 150 W). Ten young sportsmen participated in the present study. Mean arterial pressure (MAP) was measured manually, with thoracic impedance used to monitor cardiac output (Qc): systemic vascular resistance (SVR) was then calculated. Whole blood viscosity (etab) was measured and used to calculate systemic vascular hindrance. Hematocrit (Hct) was determined by micro-centrifugation and red blood cell (RBC) deformability (EI) was determined by ecktacytometry. A breath-by-breath gas analyzer was used to measure oxygen uptake (VO2); the Fick equation was used to calculate arterio-venous oxygen difference [(a-v)O(2)] from VO(2) and Qc. All measurements were performed at rest, during exercise and during recovery. Compared to baseline, Qc, MAP, Hct, EI, VO(2), and (a-v)O(2) increased during exercise. etab increased above baseline only at 150 W and remained elevated during recovery; the increase in etab during the last level of exercise was associated with a decrease of SVR and systemic vascular hindrance. There was a significant negative correlation between EI and SVR (r=-0.35, p<0.01) and a significant positive relationship between EI and (a-v)O(2) (r=0.35, p<0.01) and between EI and VO(2) (r=0.37, p<0.01) across all exercise workloads, thus suggesting a potential role for RBC deformability as a factor affecting aerobic performance via oxygen delivery to tissues. These data lend support to the concept that hemorheological parameters may contribute to hemodynamic and cardio-respiratory adaptations in response to exercise in moderately trained sportsmen.

Red blood cell deformability and aggregation, cell adhesion molecules, oxidative stress and nitric oxide markers after a short term, submaximal, exercise in sickle cell trait carriers

The present study investigated the hemorheological and endothelial alterations in sickle cell trait (SCT) carriers in response to a submaximal exercise. Eleven SCT carriers and 11 subjects with normal hemoglobin performed submaximal exercise for 15 min. Blood was sampled at rest, at the end of exercise, and at 2 and 24 h of recovery. Hemorheological alterations observed in the SCT group were as follows: 1) lower RBC deformability at high shear stress at all time-points, with no relation to oxidative stress, 2) higher disaggregation threshold at all time-points, suggesting RBC hyper-aggregation, and 3) higher blood viscosity at the end of exercise and during recovery. Exercise had a specific influence on the levels of the soluble cell adhesion molecules P and L-selectin in the SCT carriers, with higher P-selectin levels at all time-points and a greater increase in L-selectin levels during recovery. SCT carriers had slightly decreased nitrite levels at 24h of recovery, which might be clinically insignificant. In conclusion, the hemorheological alterations in association with lower NO production found in the SCT carriers are probably not sufficient to explain the medical complications sometimes reported in SCT carriers after exercise.

Does repeated and heavy exercise impair blood rheology in carriers of sickle cell trait

Objective:To determine if the time courses of hemorheologic parameters are different between carriers of sickle cell trait (SCT) and subjects with normal hemoglobin in response to exercise. Design:Observational and comparative study. Setting:Testing was conducted in a laboratory of exercise physiology. Participants:Nine carriers of sickle cell trait (SCT group) and 7 subjects with normal hemoglobin (CONT group) performed an exercise protocol of the repetition of 3 successive maximal ramp exercise tests. Interventions:Blood was sampled at rest (TR), at the end of each of the 3 tests (T1, T2, T3), and during the immediate (T2h) and late (T24h, T48h) recovery periods. Main Outcome Measurements:Blood and plasma viscosity (&eegr;b and &eegr;p, respectively), hematocrit (Hct), and red blood cell (RBC) rigidity (Tk and k indexes) were determined. Results:In both groups, &eegr;b significantly increased in response to exercise but the SCT group had significantly higher &eegr;b at T3 and T2h. &eegr;b then returned to baseline value at T2h in the CONT group and at T24h in the SCT group. Tk and k were not changed by exercise but significantly increased above baseline value in both groups at T24h and T48h. The increase in Tk and k during late recovery was higher in the SCT group than in the CONT group, indicating that SCT carriers had significantly higher RBC rigidity than the CONT group at that time. Conclusions:The hemorheologic changes induced by exercise in the SCT carriers could trigger microcirculatory disorders during the recovery.

Plasma levels of adhesion molecules ICAM-1 and VCAM-1 in athletes with sickle cell trait with or without α-thalassemia during endurance exercise and recovery

The aim of the study was to examine the effects of endurance exercise on circulating vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in sickle cell trait (SCT) athletes with or without alpha-thalassemia. Five athletes with SCT, 7 athletes with both SCT and alpha-thalassemia (SCTAT) and 8 control athletes (CONT) performed an incremental test on cycloergometer followed 72 hours later by a 60-min endurance exercise with a workload set at 70% P(peak) (peak power). We assessed levels of sICAM-1, sVCAM-1 and TNF-alpha at rest, immediately after endurance exercise and 1, 2, and 24 hours of recovery. Although, CONT and SCTAT groups exhibited similar basal plasma levels of adhesion molecules and TNF-alpha, SCT group had higher sVCAM-1 basal concentrations. No significant variation in sVCAM-1, sICAM-1 and TNF-alpha was measured following endurance exercise. Consequently, sVCAM-1 remained elevated in the SCT group after exercise and during the recovery period. In conclusion, our findings support the concept that SCT athletes might be at risk for microcirculatory disturbances, but these adhesive processes were not further impaired in response to endurance exercise. In addition, alpha-thalassemia co existing trait may be protective both at rest and after endurance exercise in SCT subjects.