Biomedical subjects
Publications and source records attributed to N Chetty.
Protein C is a vitamin K-dependent anticoagulant that functions by inhibiting the activity of factors Va and VIIIa. An inherited deficiency of this protein may enhance the risk of thrombosis. The first kindred with levels of protein C that averaged 50% of normal in association with recurrent thrombotic events were described in 1981. A black South African family with an inherited deficiency of this protein is reported.
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The occurrence of myocardial infarction (MI) in Black South Africans, while poorly documented, is believed by many to be approximately one-tenth that of White South Africans. Recently, this disease has been reported to be increasing in the urban Black South African population. In order to determine if variations in dietary habit within the urban black community are contributing to the disease occurrence, the fatty acid content of whole platelets and red blood cells (RBC) were measured in 25 urban Black Africans with documented history of MI. These values were compared to an asymptomatic Black African control group. Total saturated fatty acids were increased and total polyunsaturated fatty acids (PUFA) were decreased in the patient's platelets. Stearic acid (18:0) was significantly increased and eicosapentaenoic acid (20:5 n-3) was slightly but significantly decreased in the patient's platelets. No difference was seen in the total saturated and total unsaturated fatty acid levels of red blood cells (RBCs). Only 20:5n-3 and 22:5n-3 were slightly but significantly decreased in the patient's RBCs. Similarities in RBC fatty acids indicate that the progression of MI in this population may not be related solely to changes in dietary habits.
Eicosapentaenoic acid (EPA) inhibits platelet responsiveness to aggregating agents. To investigate the reactions that are affected by EPA, we examined the effect of preincubating aspirin-treated rabbit platelets with EPA on stimulation of inositol phosphate formation in response to the TXA2 analogue U46619. Stimulation of platelets with U46619 (0.5 microM) caused aggregation and slight release of dense granule contents; aggregation and release were inhibited by preincubation of the platelets with EPA (50 microM) for 1 h followed by washing to remove unincorporated EPA. Incubation with EPA (50 microM) for 1 h did not cause a detectable increase in the amount of EPA in the platelet phospholipids. When platelets were prelabelled with [3H]inositol, stimulation with U46619 of control platelets that had not been incubated with EPA significantly increased the labelling of inositol phosphates. The increases in inositol phosphate labelling due to U46619 at 10 and 60 s were partially inhibited by preincubation of the platelets with 50 microM EPA. Since the activity of cyclo-oxygenase was blocked with aspirin, inhibition of inositol phosphate labelling in response to U46619 indicates either that there may be inhibition of signal transduction without a detectable change in the amount of EPA in platelet phospholipids, that changes in signal transduction require only minute changes in the fatty acid composition of membrane phospholipids, or that after a 1 h incubation with EPA, activation of phospholipase C is affected by a mechanism that is not directly related to incorporation of EPA.
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Because of the antithrombotic and anti-inflammatory properties of the n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are found in large quantities in marine fish, the fatty acid composition of the flesh of 18 different species of fresh-water fish found in South Africa was analysed by capillary gas chromatography. In general all the fish studied had low percentages of EPA and DHA and fairly high percentages of arachidonic acid and linoleic acid when compared with some marine fish. The saturated fats constituted 33% of total fatty acids and the mono-enes averaged 35%. The fish studied are therefore not as good a source of n-3 fatty acids as marine fish.
We examined platelet aggregability during nocturnal sleep and daytime wakefulness in patients with a history of sleep-related stroke onset (SOS) and compared it to that of matched awake-onset stroke (AOS) patients and controls without evidence of vascular disease. Aggregability was evaluated in-vitro at least seven weeks following stroke onset. Platelets were more aggregable to ADP, collagen and arachidonic acid (AA) during both sleep and wakefulness in patients with AOS (p less than 0.01). No significant difference in the mean aggregation thresholds during sleeping or waking periods were found between SOS and control groups. However, platelets were significantly more responsive to AA during sleep than during wakefulness in the SOS patients (p less than 0.01). This difference was confined to the subgroup of SOS patients who had experienced nocturnal as opposed to daytime sleep-related stroke onset, suggesting that the observed difference in platelet responsiveness to AA may be related to a circadian fluctuation in platelet aggregability rather than to a sleep-related fluctuation. Significant sleep-related changes in platelet aggregability were not identified in the other two groups.
The relationship between mean platelet volume (MPV) and platelet count was evaluated in 259 patients with rheumatoid arthritis and 311 patients with various haematological disorders. Platelet volume-number relationships determined in a previous study on normal subjects were used as a reference range. There was a significant inverse relationship between MPV and platelet count in patients with rheumatoid arthritis (r = -0.49; P less than 0.0001), which by interval analysis was shown to be non-linear. In the patients with haematological disorders, the platelets were found to be disproportionately small for number in patients with aplastic anaemia, chemotherapy-induced marrow suppression and some cases of acute idiopathic thrombocytopenic purpura (ITP). In subjects with chronic ITP followed longitudinally, the inverse platelet volume-number relationship was retained. MPV was appropriate for platelet number in myelodysplastic syndromes, variable in iron deficiency anaemia and disproportionately large in myeloproliferative syndromes, most notably in agnogenic myeloid metaplasia. The observation that the MPV was disproportionately large in comparison with the platelet count was used in establishing the diagnosis of an hereditary giant platelet syndrome in a family of British origin.
Forty-five patients were randomly divided into three groups of 15 and within each group patients were given iothalamate, iopamidol or ioxaglate intravenously during radiological investigations. The plasma leukotriene C4 level was measured before and 30 s and 3 min after the administration of the respective contrast media. In patients demonstrating non-idiosyncratic contrast reactions, a consistent decrease in plasma leukotriene concentration was noted at both 30 s and 3 min following the administration of all three contrast media. A statistically significant decrease in plasma leukotriene occurred at 30 s with ioxaglate, but not with the other two agents. In the limited number of patients who experienced idiosyncratic reactions, the decrease in plasma leukotriene concentration was less apparent. This decrease in plasma leukotriene concentration has been attributed to changes in plasma volume following administration of hyperosmolar contrast media. The inability to demonstrate an increase in plasma leukotriene levels following the administration of both conventional and new, low-osmolar radiographic contrast media supports the cumulative evidence against an allergic mechanism in the majority of non-idiosyncratic and some idiosyncratic contrast reactions.
Platelet fatty acids, platelet aggregations, and coagulation factors were measured in 27 rural blacks, 27 urban blacks and 39 urban whites. Platelets were significantly less aggregable to collagen and arachidonic acid in in both black groups as compared to whites (p less than 0.01), but there were no significant differences in ADP or epinephrine aggregation between these groups. Factor VIII coagulant activity was much higher in rural and urban blacks than whites (p less than 0.001), and the partial thromboplastin times were shorter (p less than 0.005). Platelet arachidonic acid showed a marked difference between the groups, being 16.4 +/- 5.4% of total platelet fatty acids in the rural blacks, 19.9 +/- 4.2% in the urban blacks and 22.6 +/- 3.3% in the whites (p less than 0.001). Whites had higher LDL and lower HDL cholesterol than blacks (p less than 0.005). These findings suggest that in addition to the well known association of raised LDL cholesterol and acute myocardial infarction, platelet aggregation patterns and platelet arachidonic acid levels may be associated risk factors in coronary thrombosis.
Fatty acid composition of mature human milk of rural and urban black South African mothers was determined by gas-liquid chromatography. Rural mothers consumed traditional diets low in animal protein and fat, and high in carbohydrate and fibre. Urban mothers consumed more varied, partially westernized diets, and two-thirds were overweight. Plasma cholesterol concentrations were significantly lower in the rural group (3.64 vs 4.75 mmol/l, P less than 0.01). Milk of rural mothers contained significantly higher percentages of C10:0, C12:0, and total saturated fatty acids. Fatty acids C8:0-C14:0 synthesized de novo in the mammary gland were substantially higher in the milk of the rural mothers (24.7 vs 15.9 per cent). Conversely, the milk of the urban group contained higher percentages of monounsaturated fatty acids, 18:3 omega 3 and 20:2 omega 6. The ratio of polyunsaturated to saturated fatty acids in rural samples was 0.36 +/- 0.13 compared to 0.41 +/- 0.15 in urban samples (P greater than 0.1). It is concluded that maternal dietary intake significantly affects milk composition, as demonstrated by the high percentages of fatty acids synthesized de novo in the mammary gland of rural mothers habituated to low-fat, high-carbohydrate intakes.
Eight healthy subjects consumed a diet in which all animal products were replaced by 750 g/day of freshwater trout. Platelet eicosapentaenoic acid (EPA) as a percentage of total platelet fatty acids rose from a prediet level of 0.2 +/- 0.4% to 3.4 +/- 1.6% after 4 weeks on the diet. Platelet arachidonic acid remained unchanged. Platelets became more hyperaggregable to collagen (p less than .025) but became hypoaggregable to arachidonic acid (p less than .05). The Ivy bleeding time became prolonged rising from a mean of 148 seconds before the diet to 168 seconds at 2 weeks and 202 seconds at 4 weeks. Serum lipids, coagulation profiles, and blood pressure remained unchanged. The changes induced by this diet were much less marked than changes induced by marine fish diets and diets supplemented by marine fish oil extracts, despite the fact that an equivalent amount of EPA was consumed and incorporated into platelets. These findings suggest that other substances, in addition to n-3 unsaturated fatty acids, may be responsible for the antithrombotic properties of marine fish.
The incidence of reactive thrombocytosis in active pulmonary tuberculosis was studied in 122 patients. Thrombocytosis was common, platelet counts often exceeding 1 X 10(12)/1. A significant inverse correlation was noted between the mean platelet volume and the platelet count (r = -0.54, p less than 0.0001). Interval estimation suggested that this relation was non-linear. Further studies were done in a small group of six patients. Platelet survival was considerably shortened, the platelets aggregated excessively in vitro, serum concentrations of thrombopoiesis stimulating activity were raised, and serotonin uptake and release were within normal limits. The degree of thrombocytosis correlated significantly with the degree of inflammation measured by the erythrocyte sedimentation rate (r = 0.40, p less than 0.003) and serum C-reactive protein concentration (r = 0.35, p less than 0.008).
Ketamine hydrochloride, 10 mg/kg by intramuscular injection, inhibited aggregation of platelets from three out of three baboons. Aggregation to ADP, arachidonic acid, epinephrine, and collagen was inhibited but aggregation to ristocetin was normal. Two baboons anaesthetised with the related drug phencyclidine, 1.0 mg/kg intramuscularly, had delayed aggregation. Ketamine inhibition of human platelets was irreversible in that aggregation could not be restored by either gel filtration of inhibited platelets and the re-addition of normal plasma, or by increasing the concentrations of agonists. Mixtures of human ketamine inhibited and aspirinised platelets failed to aggregated. Thromboxane B2 production was reduced to 3% of the amount produced by non inhibited platelets but the oxygen burst was not inhibited.
The effect of ultra-low-dose aspirin on platelet aggregation and thromboxane B2 (TXB2) production was studied in two groups of normal subjects. Group 1 received 162 mg/d and group 2 received 20 mg/d for 4 weeks. For the first 2 weeks the effects were similar in the two groups, namely inhibition of aggregation and inhibition of TXB2 production. However, after 4 weeks there was significantly less inhibition of platelet aggregation in those receiving 20 mg/d. Inhibition of TXB2 production in the two groups was not significantly different. Two of 9 individuals receiving 20 mg/d showed an escape from the aspirin effect by the 4th week. When 40 mg/d was given to these 2 individuals they again responded. A daily dose of 20 mg aspirin is therefore too small to maintain adequate inhibition of platelet function in normal subjects.
Since the platelets of patients with familial hypercholesterolaemia (FH) are hyperaggregable, the inhibitory effect of low-dose aspirin on platelet aggregation in response to adenosine diphosphate, collagen, adrenaline and arachidonic acid was tested in 9 young adult patients with FH and compared with that in 9 normal subjects. After a single oral dose (150 mg) of aspirin the degree of inhibition of platelet aggregation was the same in the two groups, as was the recovery time (in days) for full restoration of platelet aggregation . In a second experiment in which 162 mg aspirin was administered daily for 28 days, inhibition of platelet aggregation was sustainable in both the patient and the control groups. These results suggest that despite the recognized hyperaggregability of platelets from patients with FH, daily low-dose aspirin ingestion effectively inhibits their in vitro aggregation and may therefore prove beneficial as supplemental therapy to reduce the rate of myocardial infarction in this high-risk group.
Nine healthy subjects taking an average mixed "Western" diet were placed on a vegetarian diet poor in arachidonic acid for four weeks. All animal and marine foods except for cows milk and milk products were excluded. Platelet aggregation responses to arachidonic acid and epinephrine increased slightly whereas responses to ADP and collagen were unchanged. Platelet thromboxane production, platelet counts, serum LDL cholesterol and triglycerides did not change but total and HDL serum cholesterol levels fell significantly. There was a significant rise in platelet arachidonic acid content but other platelet fatty acids did not change significantly. A reduction in dietary arachidonic acid did not inhibit platelet aggregation or thromboxane production.
Eight healthy subjects were fed a diet containing 1-4 g eicosapentaenoic acid (EPA) daily for 8-21 days. The EPA was derived from 300-400 g per day of sardines, pilchards, herring and/or kabeljou. Sources of arachidonic acid (AA) in the diet were reduced. At the end of the experimental period there was an increase in the ratio of EPA to AA in the platelets and a decrease in platelet aggregation to ADP, epinephrine and collagen. Aggregation to AA was not reduced. Thromboxane production in response to all four agonists was reduced. Serum total and HDL cholesterol levels fell significantly but platelet counts, LDL cholesterol and triglyceride values did not change. We conclude that even a relatively modest intake of EPA derived from a mixed fish diet together with a reduction in AA intake can alter in vitro platelet function and serum lipids significantly. A long term controlled trial of a palatable mixed fish diet to assess possible antithrombotic and antiatherogenic effects is justifiable.