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 homozygous sickle cell disease: steady and crisis states.

One of the common complications of sickle cell disease is the vaso-occlusive crisis or sickle cell crisis which could result in impaired oxygen delivery to the tissues. This study investigates the oxygen delivery index (ODI) in 38 patients with homozygous sickle cell anaemia. Thirty-three patients were in the steady state and five were experiencing crisis at the time of recruitment. Whole blood viscosity was measured with a Wells Brookfield viscometer at a shear rate of 230 sec(-1) and haematocrit was measured with an AC Tron Coulter Counter. The ODI, which is an indirect measure of the capacity of blood to deliver oxygen to tissues, was calculated as the ratio of haematocrit to whole blood viscosity values. There was no statistically significant difference in the ODI between the steady and crisis states, suggesting that tissue oxygenation is not the only factor involved in the sickle cell crisis.

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.

Increased incidence of adverse perinatal outcome with low maternal blood viscosity in preeclampsia.

Hyperviscosity of the maternal blood has been reported to be associated with an increased incidence of adverse perinatal outcome in preeclampsia. We related the changes in maternal blood viscosity to perinatal outcome in 47 preeclamptic, nulliparous, black Jamaican women. A group of 49 non-preeclamptic, nulliparous, gestation-matched women acted as controls. Perinatal outcome was also compared between the women with high blood viscosity (> or = 5 mPa.s) and those with low blood viscosity (< 5 mPa.s) in both the preeclamptic and non-preeclamptic groups. Data was analysed by the comparison of two proportions, the chi-squared test, the Fisher's exact test and the Pearson's correlation method. The level of statistical significance was taken at p < 0.05. The incidence of adverse perinatal outcome was significantly (p < 0.001) higher in the preeclamptic women as compared with that of the non-preeclamptic controls. However, of interest, was the fact that within the preeclamptic group, the incidence of adverse perinatal outcome was significantly (p = 0.001, Fisher's exact test) higher in those with low blood viscosity as compared with those with high blood viscosity. These results suggest that low maternal blood viscosity may be related to increased incidence of adverse perinatal outcome in Jamaican women with preeclampsia.

Erythrocyte deformability and erythrocyte aggregation in preeclampsia.

One of the features of preeclampsia is impaired blood rheology due to altered erythrocyte aggregation and erythrocyte deformability. We investigated these two parameters which affect the viscosity of blood, along with serum and intraerythrocytic magnesium concentrations, immunoglobulin titres and fibrinogen concentration in 12 preeclamptic women. Eighteen (18) other non-preeclamptic, gestation-matched women acted as controls. Erythrocyte deformability, expressed as elongation index (EI), and erythrocyte aggregation expressed as aggregation half-time (t 1/2) were measured with the Laser-assisted Optical Rotational Cell Analyser (LORCA). Serum and intraerythrocytic magnesium concentrations were analysed by atomic absorption spectrometry, immunoglobulin titres by radial immunodiffusion and fibrinogen concentration by a clot weight technique. There was no statistically significant difference in these parameters between preeclamptics and controls suggesting that erythrocyte deformability and aggregation as well as serum and intraerythrocytic concentrations, fibrinogen levels and immunoglobulin titres are not altered in preeclampsia. Further investigations are required in severe preeclampsia and in preeclamptic women taking magnesium sulphate supplement.

The influence of persistent hyperglycaemia on hyperfibrinogenaemia and hyperviscosity in diabetes mellitus

The effect of hyperglycaemia on hyperfibrinogenaemia and its consequence on plasma viscosity was investigated in 69 diabetic patients during the course of hypoglycaemic treatment. Glycaemic control was assessed by measurement of glycosylated haemoglobin (HbA1). Plasma fibrinogen concentration (PFC) was determined by a clot-weight method. The relative plasma viscosity (RPV) was measured by capillary viscometry. The mean PFC and RPV were significantly (p < 0.001) elevated in the diabetic patients as compared with a non-diabetic control group. Both PFC and RPV showed a distinct, step-wise increase with progressively poorer glycaemic control. The data strongly indicate that persistent hyperglycaemia is associated with a frank hyperfibrinogenaemia and hyperviscous plasma in most of the diabetic patients studied. These abnormal haemorrheological changes could impact adversely on both the haemostatic process and circulation in diabetic patients.

Is there hyperviscosity in pre-eclampsia?

There are conflicting reports on blood viscosity and its determinants in pre-eclampsia. We investigated the presence of hyperviscosity and its determinants in 25 nulliparous, pre-eclamptic Jamaican women. An equal number of non-pre-eclamptic, gestation-matched women served as controls. There was no statistically significant difference in whole blood, plasma and serum viscosities, as well as in their determinants, namely, haematocrit, fibrinogen, IgM and IgG concentrations between the pre-eclamptic and control groups. This suggests that hyperviscosity is not a feature of pre-eclampsia in this Jamaican population.

Abnormal venous function in patients with homozygous sickle cell (SS) disease and chronic leg ulcers.

Chronic leg ulceration is a major cause of morbidity in homozygous sickle cell (SS) disease in Jamaica. These ulcers have features in common with venous ulcers in patients with a normal haemoglobin genotype (AA). Thus we sought to determine whether there is abnormal venous function in the legs of patients with SS disease who have ulcers. Experiments were performed on 15 SS patients with ulcers, and on 15 SS patients and 15 AA subjects with no history of leg ulcers. Changes in venous blood volume of the bottom one-third of the leg induced by venous occlusion and release were studied by air plethysmography, providing indices of segmental venous capacitance (SVC), maximal venous outflow (MVO) and venous emptying time (VET). The changes in volume (ambulatory volume change; AVC) induced by a period of leg exercise were also measured at the ankle (AVCa) and calf (AVCc); venous refilling times at these sites (RTa and RTc respectively) were also measured. Finally, cutaneous red blood cell flux recovery time (FRT) after ankle exercise was assessed by laser Doppler flowmetry. Measurements were also made of haematological variables. SVC, MVO and VET did not differ between the groups, indicating no deep venous obstruction in the SS patients with ulcers. AVCc, AVCa and RTc did not differ among the three subject groups. However, compared with AA subjects, SS patients with ulcers had reduced RTa and FRT. Moreover, RTa and FRT were further shortened in SS patients with ulcers relative to SS patients without ulcers. Since the levels of anaemia were similar in SS patients with and without ulcers, these differences cannot be attributed to differences in arterial flow secondary to anaemia. These results suggest abnormal venous function in SS patients with ulcers, relative to both AA subjects and SS patients without ulcers. We propose that there is incompetence of venous valves draining the ankle region of SS patients with ulcers: the consequent raised venous pressure contributes to the slow healing and, possibly, to the onset of leg ulceration in SS disease.

The influence of persistent hyperglycaemia on hyperfibrinogenaemia and hyperviscosity in diabetes mellitus.

The effect of hyperglycaemia on hyperfibrinogenaemia and its consequence on plasma viscosity was investigated in 69 diabetic patients during the course of hypoglycaemic treatment. Glycaemic control was assessed by measurement of glycosylated haemoglobin (HbA1). Plasma fibrinogen concentration (PFC) was determined by a clot-weight method. The relative plasma viscosity (RPV) was measured by capillary viscometry. The mean PFC and RPV were significantly (p < 0.001) elevated in the diabetic patients as compared with a non-diabetic control group. Both PFC and RPV showed a distinct, step-wise increase with progressively poorer glycaemic control. The data strongly indicate that persistent hyperglycaemia is associated with a frank hyperfibrinogenaemia and hyperviscous plasma in most of the diabetic patients studied. These abnormal haemorrheological changes could impact adversely on both the haemostatic process and circulation in diabetic patients.

Peripheral occlusive arterial disease in diabetic clinic attendees.

Peripheral occlusive arterial disease occurs with a greater frequency in the diabetic population than in the general population. It can have debilitating effects and so early detection and intervention are important. The aim of this study was to investigate the prevalence of peripheral occlusive arterial disease (POAD) among a sample of diabetic patients attending the out-patient clinic at the University Hospital of the West Indies (UHWI), Mona. A sphygmomanometer was used to measure arm and ankle blood pressures in 80 diabetic patients, and the ankle-brachial systolic pressure index (ABI) was determined. The presence or absence of peripheral pulses was detected with the Multi-dopplex (model 1). POAD was defined by the absence of one or more peripheral pulses and/or an ABI < 0.9. Of the 80 diabetic patients examined, 18 (22.5%) were found to have POAD. Seventy-eight per cent of diabetics with POAD had the disease in both legs. Intermittent claudication was diagnosed in 27.7% of patients with POAD. A significantly larger proportion of diabetics with POAD were hypertensive and/or neuropathic (p < 0.05). The results suggest that serious attention should be given to the quantitative screening for POAD in the diabetic patients attending the clinic at the UHWI.

Peripheral occlusive arterial disease in diabetic clinic attendees

Peripheral occlusive arterial disease occurs with a greater frequency in the diabetic population than in the general population. It can have debilitating effects and so early detection and intervention are important. The aim of this study was to investigate the prevalence of peripheral occlusive arterial disease (POAD) among a sample of diabetic patients attending the out-patient clinic at the University Hospital of the West Indies (UHWI), Mona. A sphygmomanometer was used to measure arm and ankle blood pressures in 80 diabetic patients, and the ankle-brachial systolic pressure index (ABI) was determined. The presence or absence of peripheral pulses was detected with the Multi-dopplex (model 1). POAD was defined by the absence of one or more peripheral pulses and/or an ABI < 0.9. Of the 80 diabetic patients examined, 18 (22.5) were found to have POAD. Seventy-eight per cent of diabetics with POAD had the disease in both legs. Intermittent claudication was diagnosed in 27.7of patients with POAD. A significantly larger proportion of diabetics with POAD were hypertensive and/or neuropathic (p < 0.05). The results suggest that serious attention should be given to the quantitative screening for POAD in the diabetic patients attending the clinic at the UHWI.

Abnormal plasma and serum viscosity in systemic lupus erythematosus (SLE): a Jamaican study.

Vascular complications occur frequently in SLE, and their development may be related to haemorheological derangements. However, the range of rheological abnormality in Jamaican SLE patients have not been studied. The present investigation was aimed at determining the changes in the three major blood proteins, namely fibrinogen, albumin and globulin, and their effect on plasma and serum viscosity in SLE patients during the course of treatment. The concentrations of fibrinogen and globulin were significantly increased (p<0.001), while albumin was decreased (p<0.05) in the SLE patients as compared with the control group. This increase in the fibrinogen and globulin contributed significantly to the rise of both serum and plasma viscosity. SLE patients with more severe disease had higher serum viscosity values, suggesting that serum viscosity values may provide an important marker for disease severity.

Some clinical factors contributing to the development of the diabetic foot.

Clinical neurological studies, blood pressure measurements and some haematological investigations were performed on a random sample of forty-four patients, at the Diabetes Out-Patient Clinic of the University Hospital of the West Indies (UHWI), to examine some of the factors that predispose to the development of the diabetic foot. Our results revealed that 86% of the patients had elevated glycosylated haemoglobin (HbA1 > 9.0%), 82% had clinical signs of peripheral sensory neuropathy, 29% had signs of autonomic neuropathy in addition to peripheral sensory neuropathy. Sixty-one per cent (61%) of the patients had ankle/arm systolic blood pressure ratio less than 1.0 and were diagnosed as having peripheral vascular disease (PVD). The group with neuropathy was found to have a significantly lower diastolic blood pressure (p < 0.0005) than the group without neuropathy. We believe that hyperglycaemia-induced vasodilation (indicated by a lower diastolic blood pressure) in a significant number of diabetics resulted in compensatory shunting of blood from the deeper tissues, including nerves, to the periphery. The resulting endoneural hypoxia could be responsible for the unusually high incidence of peripheral sensory neuropathy detected in this sample of diabetic patients. Metabolic factors may also play a role.

Peripheral vascular response to mild indirect cooling in patients with homozygous sickle cell (SS) disease and the frequency of painful crisis.

1. In homozygous sickle cell (SS) disease, skin cooling is a common precipitating factor of the painful crisis which is associated with avascular necrosis of active bone marrow. Since skin cooling does not directly induce sickling, we have investigated the nature of the reflex vascular responses to mild cooling in SS patients in a steady state of the disease and compared them with their history of painful crises. 2. Experiments were performed in Jamaica on 60 male SS patients and 30 matched control subjects with normal haemoglobin (AA) genotype. Forearm blood flow (FBF) was measured by venous occlusion plethysmography and mean arterial pressure (MAP) by a Finapres device: forearm vascular resistance (FVR) was calculated as MAP/FBF. Cutaneous erythrocyte flux in forearm and hand was monitored by a laser Doppler meter. The contralateral hand was immersed in cool water at 16 degrees C for 2 min, 6 times, at random intervals of 0.5-3 min. 3. The first cool immersion evoked an increase in MAP, cutaneous vasoconstriction and a net increase in FVR in both AA and SS subjects. However, the direction of change in FVR varied between individuals such that 18 AA subjects showed an increase in FVR (constrictor group) while 12 showed a decrease in FVR, indicating vasodilatation in forearm muscle (dilator group). In contrast, 50 SS subjects showed an increase in FVR and only 10 showed a decrease in FVR. The proportion of subjects who showed net vasoconstriction was significantly greater in the SS than in the AA group (83% versus 60%, P = 0.03, chi 2 test). 4. By the sixth cool stimulus, the 'dilator' group of AA subjects showed no change in FVR while the 'dilator' group of SS patients showed an increase in FVR. We suggest that forearm muscle vasodilatation was the characteristic component of the alerting/defence response to novel or noxious stimuli which habituates on repetition. 5. In the whole group of SS patients, baseline values of cutaneous vascular resistance and FVR increased between stimuli, indicating persistent vasoconstriction, and the sixth cool stimulus still evoked cutaneous vasoconstriction and a net increase in FVR. In contrast, AA subjects showed an increase in baseline FVR between stimuli, but the sixth cool stimulus had no significant effect on cutaneous vascular resistances, or FVR. 6. In SS patients there were no associations between the direction of change in FVR evoked by the first cool stimulus and forearm circumference or skinfold thickness, concentrations of haemoglobin or fetal haemoglobin. However, the frequency of painful crises was significantly greater in the 'constrictor' group than in the 'dilator' group (0.36 versus 0.12/year, P = 0.04, Mann-Whitney test). 7. These results indicate that the primary reflex vasoconstrictor response evoked by mild cooling is stronger and more persistent in SS patients than in AA subjects and is particularly strong in SS patients who are most prone to painful crises. The results are consistent with the hypothesis that skin cooling may precipitate the painful crisis by causing reflex vasoconstriction in muscle, and possibly in bone marrow, so diverting blood flow away from the active marrow.

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 30s 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 an increase 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 an increase 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.

Postural vasoconstriction and leg ulceration in homozygous sickle cell disease.

1. Chronic leg ulceration is a major cause of morbidity in patients with homozygous sickle cell disease; the ulcers commonly resolve on bed rest. We have therefore compared the cutaneous vascular response to dependency in three groups of eight patients with sickle cell disease (those with an active ulcer, with an ulcer scar and with no history of ulceration) and in eight subjects with normal haemoglobin and no history of leg ulceration. 2. We monitored, with a laser Doppler flowmeter, the change in red cell (erythrocyte) flux induced in the skin of the leg, at two sites proximal to the malleoli, with the leg horizontal and 5 and 10 min after moving the leg to the dependent position. 3. With the leg horizontal, mean cutaneous red cell flux was substantially higher in normal skin of patients with sickle cell disease than in normal subjects and was higher still at the site of the ulcer or scar. On dependency, red cell flux fell not only in normal subjects but also in the patients with sickle cell disease, both in the normal skin and at the site of the ulcer or scar; there was no difference in any group between the 5- and 10-min values. The fall in red cell flux in normal skin of patients with sickle cell disease was smaller than in normal subjects when considered as a percentage of the control values (32%, 36%, 30% and 61% respectively in sickle cell patients with an active ulcer, with an ulcer scar and with no history of ulceration and in normal subjects), but in absolute terms the falls in red cell flux were similar in sickle cell patients and normal subjects. By contrast, the fall in red cell flux at the ulcer or scar site was greater than in normal skin from sickle cell patients whether considered as a percentage of the control value (48% and 49% respectively in those with an active ulcer or ulcer scar) or in absolute terms. 4. We propose that high resting perfusion is important in patients with sickle cell disease to maintain normal integrity of cutaneous tissue and that pronounced vasoconstriction on dependency hinders the healing and encourages recurrence of leg ulcers.

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 approximately 12 and 10%, respectively) forearm vascular resistance (by approximately 17 and 27%) and hand cutaneous vascular resistance and hand cutaneous resistance (by approximately 2240 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 approximately 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.

Efficacy of growth hormone replacement therapy in children with organic growth hormone deficiency after cranial irradiation.

We evaluated the growth response of 20 childhood cancer survivors who received growth hormone (GH) replacement therapy (0.3 mg/kg/week) for at least 12 months. In all subjects, GH deficiency was associated with cranial irradiation and was documented with growth charts, bone age, and somatomedin C levels; at least one GH stimulation test was available for 14 children. Pretreatment overall growth velocity was 3.3 +/- 0.5 cm/year (mean +/- SE) over a 3-year period. After GH replacement, growth velocity was 8.6 +/- 0.6 cm/year during the first year (n = 20), 7.2 +/- 0.5 cm/year during the second year (n = 17), 5.9 +/- 0.6 cm/year during the third year (n = 11), and (6.1 +/- 0.6 cm/year during the fourth year (n = 7). Growth response, tabulated by age at onset of GH replacement, was compared with the response in GH-naive children with idiopathic GH deficiency (data obtained through the Genentech Inc. National Cooperative Growth Study Summary, September 1991); the growth velocity fell within the range described for idiopathic GH deficiency adjusted for either chronological or bone age. We conclude that children with GH deficiency after cranial irradiation for neoplastic diseases respond to GH replacement therapy as well as children with idiopathic GH deficiency.