Harvey L Reid

Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation

Background Recent evidence suggests that autonomic nervous system activity could be involved in the pathophysiology of sickle cell disease, but it is unclear whether differences in autonomic nervous system activity are detectable during steady state in patients with mild and severe disease. The aim of the present study was to compare the autonomic nervous system activity, blood rheology, and inflammation in patients with sickle cell anemia according to the frequency of acute pain crisis. Design and Methods Twenty-four healthy volunteers, 20 patients with sickle cell anemia with milder disease, and 15 patients with sickle cell anemia with more severe disease were recruited. Milder disease was defined as having no pain crisis within the previous year. More severe disease was defined as having had within the previous year three or more pain crises which were documented by a physician and required treatment with narcotics. The autonomic nervous system activity was determined by spectral analysis of nocturnal heart rate variability. Blood viscosity determination and measurements of several inflammatory markers (interleukin-6, soluble vascular cell adhesion molecule-1, soluble CD40 ligand and sL-selectin) were made on blood samples collected in steady-state conditions. Results Results showed that: 1) patients who had suffered more frequent pain crises had lower parasympathetic activity and greater sympatho-vagal imbalance than both controls and patients with milder disease. However, when adjusted for age, no significant difference was detected between the two sickle cell anemia patient groups; 2) patients who had suffered more frequent pain crises had higher blood viscosity than patients with milder disease, and this was not dependent on age. Conclusions Results from the present study indicate that both the autonomic nervous system activity and blood viscosity are impaired in patients with sickle cell anemia exhibiting high frequency of pain crisis in comparison with those who did not experience a crisis within the previous year.

Physiological Responses of Sickle Cell Trait Carriers during Exercise

Growing evidence suggests that physiological responses during exercise in sickle cell trait (SCT) carriers might differ from persons with normal haemoglobin. Epidemiological and experimental results support the view that SCT carriers could be advantaged in certain anaerobic activities, but the underlying physiological and bio-cellular mechanisms remain unknown. Maximal aerobic physical fitness (i.e. maximal oxygen consumption and maximal aerobic power) is not affected by SCT; however, recent studies suggest that SCT carriers could be characterized by a lesser aerobic capacity. Discrepancies are frequently reported in the literature concerning lactate metabolism during exercise in this population. While some studies observed higher blood lactate concentration during exercise in individuals carrying SCT compared with subjects with normal haemoglobin, others described lower concentration, which suggests a paradoxical lower lactate production by exercising muscles and/or greater ability to clear circulating lactate in SCT carriers. One of the most debated topics is the clinically benign condition of SCT, particularly during strenuous exercise. SCT carriers are usually involved in physical exercise without developing medical complications; however, several authors have presented case reports of SCT carriers who have collapsed and died unexpectedly during or after exercise. Blood rheological, haemostatic and vascular adhesion mechanism abnormalities in combination with environmental factors, such as heat strain, might play a role in the occurrence of these fatal scenarios. Several physiological differences have been observed between SCT carriers and non-SCT carriers, which make it necessary to consider the former as a specific population in response to exercise.

Exercise limitation, exercise testing and exercise recommendations in sickle cell anemia

Sickle cell anemia (SCA or SS homozygous sickle cell disease) is an inherited blood disorder caused by single nucleotide substitution in the β-globin gene that renders their hemoglobin (HbS) much less soluble than normal hemoglobin (HbA) when deoxygenated. The polymerization of HbS upon deoxygenation is the basic pathophysiologic event leading to RBC sickling, hemolysis, vasoocclusion and ultimately to chronic organ damage. The metabolic changes imposed by exercise may initiate sickling and vaso-occlusive episodes. Further, in patients with SCA, exercise limitation may be related to anemia or chronic complications such as pulmonary vascular disease, congestive heart failure and chronic parenchymal lung disease. Few studies have investigated the cardiorespiratory responses of patients with SCA during either symptom-limited maximal exercise test on cyclo-ergometer or during a six minute walk test. Therefore, patients are advised to start exercise slowly and progressively, to maintain adequate hydration during and after exercise, to avoid cold exposure or sudden change in temperature, and to avoid sports associated with mechanical trauma. There are, however, lack of evidence to allow practitioners to prescribe an exercise program for patients with SCA, and individuals are usually encouraged to exercise on a symptom-limited basis. Finally, this review will also highlight the basic principles that are often used for exercise practice and could be used for exercise prescription and rehabilitation in patients with sickle cell anemia.

Are published standards for haematological indices in pregnancy applicable across populations: an evaluation in healthy pregnant Jamaican women

BackgroundThe haematological profile of the pregnant woman has an impact on the outcome of the pregnancy. Published guidelines indicate acceptable levels for haematological indices in pregnancy but they are population specific. Indicators of haemoglobin concentration are the most commonly utilized of the indices. These published international norms are used across populations, however, there is no evidence confirming their applicability to a population such as the Jamaican pregnant woman. This study was therefore undertaken with the intent of documenting the haematological profile of pregnant primigravid Jamaican women and comparing these to the established norms to determine whether the norms apply or whether there was a need to establish local norms.MethodsThis was a longitudinal study done on a cohort of 157 healthy primigravid women ages 15 to 25 and without anaemia, and who were recruited from the antenatal clinic of the University Hospital of the West Indies, Kingston, Jamaica. The haemoglobin concentration, packed cell volume, mean cell volume, mean cell haemoglobin, mean cell haemoglobin concentration, white blood cell count, red blood cell count and platelet count were measured on samples of blood obtained from each consenting participant during each of the three trimesters. The results were analysed using SPSS for windows (Version 11) and the data expressed as means ± S.D. Means were compared using the students paired t-test. Comparison was then made with the international norms as recommended by the United States Center for Disease Control (1989). Ethical approval for this study was obtained from the University Hospital of the West Indies/University of the West Indies Ethics Committee.ResultsThe results showed changes by trimester in all measured variables. For most of the indices the changes achieved levels of significance across trimesters. These changes were however in keeping with the expected physiological response in pregnancy and the values were similar to the published international norms.ConclusionThe findings suggest that the international norms for haematological indices in pregnancy are applicable across populations and to the pregnant Jamaican primigravid woman. This finding may be reassuring to others with a similar population and stage of development as Jamaica.

Blood Viscosity and the Expression of Inflammatory and Adhesion Markers in Homozygous Sickle Cell Disease Subjects with Chronic Leg Ulcers

Objective To determine differences in TNF-α, IL-1β, IL-10, sICAM-1 concentrations, leg hypoxia and whole blood viscosity (WBV) at shear rates of 46 sec-1 and 230 sec-1 in persons with homozygous S sickle cell disease (SCD) with and without chronic leg ulceration and in AA genotype controls. Design & Methods: fifty-five age-matched participants were recruited into the study: 31 SS subjects without leg ulcers (SSn), 24 SS subjects with leg ulcers (SSu) and 18 AA controls. Haematological indices were measured using an AC.Tron Coulter Counter. Quantification of inflammatory, anti-inflammatory and adhesion molecules was performed by ELISA. Measurement of whole blood viscosity was done using a Wells Brookfield cone-plate viscometer. Quantification of microvascular tissue oxygenation was done by Visible Lightguide spectrophotometry. Results TNF-α and whole blood viscosity at 46 sec-1 and 230 sec-1 (1.75, 2.02 vs. 0.83, 1.26, p<0.05) were significantly greater in sickle cell disease subjects than in controls. There were no differences in plasma concentration of sICAM-1, IL-1β and IL-10 between SCD subjects and controls. IL-1β (median, IQR: 0.96, 1.7 vs. 0, 0.87; p<0.01) and sICAM-1 (226.5, 156.48 vs. 107.63, 121.5, p<0.005) were significantly greater in SSu group compared with SSn. However there were no differences in TNF-α (2, 3.98 vs. 0, 2.66) and IL-10 (13.34, 5.95 vs. 11.92, 2.99) concentrations between SSu and SSn. WBV in the SSu group at 46 sec-1 and at 230 Sec 1 were 1.9 (95%CI; 1.2, 3.1) and 2.3 (1.2, 4.4) times greater than in the SSn group. There were no differences in the degree of tissue hypoxia as determined by lightguide spectrophotometry. Conclusion Inflammatory, adhesion markers and WBV may be associated with leg ulceration in sickle cell disease by way of inflammation-mediated vasoocclusion/vasoconstriction. Impaired skin oxygenation does not appear to be associated with chronic ulcers in these subjects with sickle cell disease.

Optimal haematocrit in subjects with normal haemoglobin genotype (HbAA), sickle cell trait (HbAS), and homozygous sickle cell disease (HbSS)

The determination of an optimal haematocrit (H0) has important clinical implications if such a level can be attained, and more importantly, maintained. This is defined as a haematocrit level, above or below which oxygen delivery is deleteriously affected. This study is designed to determine an optimal haematocrit in normal (AA), sickle cell trait (AS) and sickle cell disease (SS) subjects. Twenty-seven apparently healthy subjects having normal haemoglobin genotype, 24 with sickle cell trait and 42 with homozygous sickle cell disease were recruited into the study. Whole blood viscosity (WBV) was measured by a Wells Brookfield Cone and Plate Viscometer at a shear rate of 230 sec-1. Haematocrit was determined by an AC.Tron Coulter Counter. The optimal haematocrit was calculated as the inverse of a constant, K, which was derived from the haematocrit and viscosity data. Our findings showed that the H0 varied significantly among the 3 haemoglobin genotypes, in the order AA vs SS and AS vs SS. Additionally, the data indicated an increased H0 in subjects with sickle cell trait, suggesting a possible impairment in oxygen delivery in these individuals.

Oxygen delivery index in subjects with normal haemoglobin (HbAA), sickle cell trait (HbAS) and homozygous sickle cell disease (HbSS)

Sickle cell disease is characterized by altered blood rheology due to a reduced haematocrit and a resulting lowered viscosity. Oxygen carriage, and consequently oxygen delivery, may be deleteriously affected if the haematocrit reduction is such as to limit oxygen uptake from the lungs and delivery to the tissues. The present study seeks to determine and compare the oxygen delivery index (ODI) in subjects with normal and abnormal haemoglobin genotypes. Thirty four apparently healthy subjects having normal haemoglobin genotype (AA), 27 with sickle cell trait (AS) and 50 with homozygous sickle cell disease (SS) were recruited into the study. Whole blood viscosity was measured at low and high shear rates of 23 s(-1) and 230 s(-1), respectively, using a Wells Brookfield Cone and Plate Viscometer. Haematocrit was determined using an AC.Tron Coulter Counter. The oxygen delivery index was calculated as the ratio of the haematocrit to whole blood viscosity. There was a statistically significant difference in the ODI in the SS group compared with both the AA and AS groups. There was no statistical significance in the ODI between the AA and AS groups. The ODI may be considered as a useful assessment of oxygen delivery in subjects with sickle cell disease.

Comparison of responses evoked by mild indirect cooling and by sound in the forearm vasculature in patients with homozygous sickle cell disease and in normal subjects

In normal individuals, novel or noxious stimuli commonly evoke the pattern of the alerting or defence response which includes cutaneous vasoconstriction, but vasodilatation in forearm skeletal muscle. We have compared cardiovascular responses evoked by sound and by indirect cooling in 60 patients with homozygous sickle cell (SS) disease and in 30 control subjects with normal haemoglobin genotype (AA). A sound of 90 dB, 1 kHz for 30 s evoked an increase in hand and forearm cutaneous vascular resistance (HCVR and FCVR) in SS patients and an increase in HCVR in AA subjects, as assessed from Doppler flowmetry. Meanwhile, a decrease in forearm vascular resistance (FVR) assessed by venous occlusion plethysmography, occurred in 14 out of 30 AA subjects and 25 out of 60 SS patients, indicating vasodilatation in forearm muscle; an increase in FVR occurred in the remainder. The proportions of SS patients and AA subjects who showed anincrease in FVR (53% vs 57%) were not significantly different. Cooling increased HCVR and FCVR in SS patients and increased FCVR in AA subjects; a decrease in FVR indicating vasodilatation, occurred in 12 out of 30 AA subjects, but in only 10 out of 60 SS patients. The proportion of SS patients who showed anincrease in FVR to cooling was greater than in AA subjects (83% vs 60%,P<0.05). Thus, SS patients are just as capable of showing the muscle vasodilatation of the alerting response to sound as AA subjects. That few SS patients showed muscle vasodilatation in response to cooling is consistent with the view that reflex vasoconstrictor responses to cooling are particularly strong in SS patients. This, in turn, is consistent with our hypothesis that the reflex vasoconstrictor response to cooling acts as a trigger for the painful crisis of SS disease by diverting blood flow away from active bone marrow.

Daily variability in resting levels of cardiovascular variables in normal subjects and those with homozygous sickle cell disease

Measurements were made of cardiovascular variables and oral temperature in 16 male subjects with homozygous sickle cell disease (SS) and in 17 matched controls (AA) at 10.00 a.m., 1.00 p.m. and 4.00 p.m. All subjects were in a rested state throughout. At 10.00 a.m., mean arterial pressure was lower, while heart rate, total forearm blood flow and cutaneous red cell flux in the forearm were higher in SS than AA. Vascular resistance in total forearm and forearm skin, calculated by dividing arterial pressure by blood flow or red cell flux, were lower in SS but hand cutaneous red cell flux and vascular resistance were not significantly different in SS and AA. In both SS and AA, there were parallel increases over the three sessions, in mean arterial pressure (by ≈ 12 and 10%, respectively) forearm vascular resistance (by ≈ 17 and 27%) and hand cutaneous vascular resistance and hand cutaneous resistance (by ≈ 240 and 350%) whereas forearm blood flow and hand cutaneous red cell flux fell. By contrast, forearm cutaneous resistance showed no change during the day in SS, but increased progressively in AA (by ≈ 75%). These results indicate that, during the day, there is progressive vasoconstriction in forearm muscle and hand skin in SS and AA and also in forearm skin of AA that contributes to a progressive rise in the resting level of mean arterial pressure. We suggest this daily variability should be considered in studies of cardiovascular function: within a given study they should be performed at the same time of day.

Segmental blood flow and rheological determinants in diabetic patients with peripheral occlusive arterial disease

Vascular abnormalities are more prevalent in the lower extremities in diabetic patients and may cause diminished perfusion to surrounding tissues. We sought to identify blood flow abnormalities in the leg of diabetic patients with peripheral occlusive arterial disease (POAD) and to determine whether these were associated with abnormalities in rheological determinants, namely, plasma fibrinogen concentration (PFC), relative plasma viscosity (RPV), hematocrit (Hct), and whole blood viscosity (WBV). Seventeen diabetic patients with POAD were compared with 40 diabetic patients without POAD and 19 nondiabetic control subjects. Blood flow was measured by venous occlusion plethysmography, RPV was measured by capillary viscometry, WBV was measured by a Wells-Brooksfield viscometer [at high (230 s(-1)) and low (23 s(-1)) shear rates], and PFC was measured by the clot-weight method of Ingram [Ingram, G. I. C. (1961). A suggested schedule for the rapid investigation of acute haemostatic failure. Journal of Clinical Pathology, 14, 356-360]. Ankle blood flow (Q(ak)) was significantly lower in diabetic patients with POAD than in diabetic patients without POAD (P<.05). PFC was higher and Hct was lower in diabetic patients with POAD than in diabetic patients without POAD (P<.05). RPV was 1.97+/-0.15 versus 1.92+/-0.15 in diabetic patients with POAD and diabetic patients without POAD, respectively (P>.05). There was no significant difference in WBV at low or high shear rates between the groups studied. There was a correlation between WBV at low shear rate and arterial flow in the calf (Q(c)) (r=.94) and great toe (r=.95) in diabetic patients with POAD, and between Q(c) and WBV at high (r=-.465) and low (r=-.472) shear rates in diabetic patients without POAD (P<.05). We conclude that vasodilatation occurring in diabetic patients without POAD is severely restricted or absent in diabetic patients with POAD. Increased plasma fibrinogen and plasma viscosity may contribute to this phenomenon.