Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of the high prevalence of thrombotic complications in patients with sickle cell anemia (SCA), we investigated platelet function in patients with sickle hemoglobinopathies. Platelet aggregation induced by epinephrine, ADP, and collagen, except for absent secondary wave in 3 of 10 patients with SCA, was qualitatively normal. However, ristocetin-induced platelet aggregation (RIPA) with a final concentration 1.12 mg/ml was markedly abnormal-absent or virtually absent in 9 of 10 patients with SCA, 3 of 3 patients with hemoglobin S-C disease, and 2 of 3 patients with sickle trait. All 8 controls used in these experiments repeatedly demonstrated normal RIPA. Addition of normal plasma failed to correct abnormal RIPA in sickle hemoglobinopathy patients. All patients demonstrated normal RIPA with a ristocetin dose of 2.24 mg/ml and aggregated with bovine fibrinogen. Recombinant mixing experiments demonstrated that washed SCA platelets support RIPA (1.12 mg/ml) when resuspended in normal plasma or high dilutions of SCA plasma, but not in undiluted SCA plasma. Washed normal platelets do not support RIPA (1.12 mg/ml) when resuspended in SCA plasma. These findings suggest the presence of a plasma inhibitor of RIPA in patients with sickle hemoglobinopathies.
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PMID:A plasma inhibitor of ristocetin-induced platelet aggregation in patients with sickle hemoglobinopathies. 59 69

The statistical relationships among the glycolytic intermediates (GI)) of the Embden-Meyerhof pathway, adenine nucleotides (ANs) and various hematological measures were estimated for 34 sickle cell anemia patients. Heterogeneity in linear and quadratic regressions of hemoglobin and hematocrit, both singly and jointly, on the GI and AN variables implied 1) that any single formula to standardize optical density measures of the GIs and ANs on a per gram hemoglobin or per liter cell water basis would not uniformly remove hemoglobin and hematocrit effects: 2) that ignoring significant hematological effects could bias the estimates of correlation among GIs and ANs; and 3) that hemoglobin and hematocrit measures do not reflect the same source of variability. The correlations among the GIs and ANs, after adjustment for hematological variability, were analyzed by path analysis to determine which of five proposed path models for cause and effect relationships were compatible with the data. AMP had a greater influence on ADP (coefficient of determination (CD) = 23%) than all the GIs together, while G6P and ADP influenced ATP variability the most (CD = 33% and 12%). The contributions of unknown factors to ADP and ATP variability were large for all models (CD = 56--77%) possibly due to stress of sickle cell disease. The path model with AMP and the four GIs (G6P, F6P, FDP, DHAP) influencing ADP variation, and the same GIs and ADP influencing ATP was the model most compatible with the data.
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PMID:A path analysis of the causal relationships between red cell glycolytic intermediates, ADP and ATP in sickle cell anemia. 59 96

Ticlopidine inhibits platelet aggregation induced by adenosine diphosphate (ADP) and most other platelet agonists in ex vivo studies of human platelets. The drug also improves other abnormalities of platelet function seen in patients with cerebrovascular disease, peripheral arterial disease, ischaemic heart disease or other conditions involving platelet hyperaggregation. Abnormal platelet activity has been implicated in a variety of clinical conditions in which patients are at high risk of thromboembolic events, and thus the effectiveness of ticlopidine has been investigated in such patients. Since the initial review of the drug appeared in the Journal, data from several large multicentre studies have shown that ticlopidine has a substantial benefit to offer patients who have experienced transient ischaemic attacks or stroke, and in those with peripheral arterial disease or ischaemic heart disease. Ticlopidine reduces the incidence of further stroke, myocardial infarction or vascular death, and is superior to placebo and aspirin in this regard in studies of patients with recent stroke or transient ischaemic attacks, or intermittent claudication. Ticlopidine is equally effective in both men and women and also improves symptoms of claudication in patients with peripheral arterial disease, and appears to reduce anginal pain. Patients with subarachnoid haemorrhage and sickle cell disease have shown some improvement with ticlopidine administration. The drug reduces thromboembolic events and re-stenosis in patients undergoing haemodialysis and cardiac surgery, and appears to prevent the progression of nonproliferative diabetic retinopathy. Ticlopidine in large clinical trials is associated with a higher incidence of adverse effects than placebo and an overall incidence similar to aspirin. Most adverse effects do not require withdrawal of treatment. Gastrointestinal symptoms (particularly diarrhoea) are most common, occurring almost twice as frequently with ticlopidine as with aspirin. Other adverse effects associated with ticlopidine include skin rash, haemorrhagic disorders, and haematological effects; these latter effects require careful monitoring of patients during the initial weeks of therapy. In conclusion, ticlopidine is a valuable addition to the prophylactic treatments available for the management of patients with cerebrovascular disease, peripheral arterial disease or ischaemic heart disease, who present a high risk of thromboembolic events. Although tolerability may be a problem for some patients, the overall benefit conferred by the drug would appear to outweigh this potential disadvantage. Because of its antiplatelet activity, ticlopidine has a promising role in other disorders mediated by platelet dysfunction. However, the precise role of the drug in these additional therapeutic indications awaits clarification with wider clinical experience.
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PMID:Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders. 222 15

Platelet activation at sites of enmeshed sickled red cells in the microcirculation may contribute to platelet plug formation and microinfarction in sickle cell anemia. To test this hypothesis platelets from 116 sickle cell anemia patients free of crisis, 32 patients with crisis, 16 convalescents within 1 week of crisis, and 180 normal controls were studied. Platelets store 90% of their ADP in dense secretory granules. During activation ADP is secreted and permanently lost from the cell. This leads to a decrease in cellular ADP concentration and a sharp rise in the ATP/ADP ratio. ATP and ADP were ethanol-extracted from platelet-rich plasma, measured in the luciferase-luciferin assay and expressed in nmoles per 10(8) cells. No adenine nucleotide differences were found in platelets from patients free of crisis compared with normal controls. The ADP concentration of platelets from patients in crisis was significantly lowered, indicating that in vivo platelet secretion of ADP had occurred. Total and released ADP was decreased from 2.69 to 1.66, and from 1.90 to 1.21 respectively, and the total ATP/ADP ratio was increased from 1.85 to 2.84 (P less than 0.001). ADP stores in platelets from convalescents were significantly different from sickle controls (P less than 0.001) but were less abnormal than ADP stores in platelets from crisis patients (P less than 0.01), indicating recovery. Total and released ADP was decreased to 1.97 and 1.31 respectively, and the ATP/ADP ratio was increased to 2.38. Platelets from patients in crisis were able to release their remaining granular ADP in response to thrombin as effectively as normal platelets. Thus significant platelet activation with ADP release occurs during acute sickle pain crisis. This might contribute to platelet plug formation and microvascular obstruction.
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PMID:Platelet activation during pain crisis in sickle cell anemia patients. 274 22

Measurements of the coagulation system were carried out in children with sickle cell disease (SCD) in both steady state and on the 1st day of painful crisis and were compared to age- and sex-matched healthy controls. No significant differences were found in prothrombin time, partial thromboplastin time, thrombin time, reptilase time, plasma fibrinogen, antithrombin III, factor VIII:C, ristocetin-cofactor (Ri-Cof) and platelet aggregation responses to ADP, collagen and adrenaline. Abnormal aggregation responses to ristocetin were noted in all patients with SCD when compared to controls. Daily measurements during the first 4 days of painful crisis showed significant elevation of fibrinogen and Ri-Cof and enhancement of aggregation to ADP and adrenaline by the 3rd day of crisis. It was concluded that the changes noted, rather than being primarily responsible for the onset of crisis, can only be secondary changes arising from the aetiological factors of crisis, i.e. stasis and acute-phase proteins.
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PMID:Coagulation changes in sickle cell disease in early childhood. 311 56

Ticlopidine is an inhibitor of platelet action that has been used in the treatment of a variety of disease states in which platelets play a prominent role. Studies in animals and man have demonstrated that ticlopidine is a potent inhibitor of platelet aggregation induced by adenosine diphosphate (ADP), and variably inhibits aggregation due to collagen, adrenaline (epinephrine), arachidonic acid, thrombin, and platelet activating factor. Inhibition of platelet aggregation is both dose- and time-related, with its onset of activity being 24 to 48 hours, its maximal activity occurring after 3 to 5 days, and its activity still being present 72 hours after a final dose. Ticlopidine also inhibits the release reaction of platelets, prolongs bleeding time, reduces plasma levels of platelet factor 4 and beta-thromboglobulin in patients in whom these proteins are elevated, and may also inhibit platelet adhesion, increase red cell filtrability and decrease whole blood viscosity. In a large number of animal models, ticlopidine markedly inhibits thrombus formation or graft occlusion. Ticlopidine is well absorbed after oral administration. It is extensively metabolised and at least one of its metabolites is pharmacologically active. Therapeutic trials in patients with chronic arterial occlusion due to thrombangitis obliterans or arteriosclerosis obliterans, post-myocardial infarction, cerebrovascular thromboembolic disease, subarachnoid haemorrhage, vascular shunts or fistulas for haemodialysis, and sickle cell disease have shown promise for the use of ticlopidine. However, trials of patients with intermittent claudication, angina pectoris, diabetes mellitus with microvascular disease, aortocoronary bypass grafts, and vascular prostheses have had conflicting results or have shown an unfavourable side effect profile. Further studies are clearly required to establish the role of ticlopidine in many of these areas, some of which are already in progress. Overall, side effects occur in 10 to 15% of patients receiving ticlopidine. The most common side effects are gastrointestinal disturbances and skin rashes. Neither of these necessarily require discontinuation of therapy in most patients. Agranulocytosis, thrombocytopenia, and cholestatic jaundice have also been reported. Bleeding is infrequent except possibly in patients receiving ticlopidine prior to some surgical procedures.
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PMID:Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states. 330 67

Although numerous studies have provided indirect evidence for enhanced platelet activity in sickle cell anaemia, little attention has been directed to examination of platelet alpha and dense granule release in the sickling disorders. We simultaneously measured by radioimmunoassay plasma levels of the alpha granule constituents beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) in 43 children with sickle cell anaemia in steady state and 24 patients during severe vaso-occlusive crisis. beta-TG levels during steady state (50 +/- 3.6 ng/ml, mean +/- SEM) were greater (P less than 0.001) than in normal controls (36 +/- 1.6), but there was no additional significant rise during crisis (55 +/- 5.9). PF4 levels were similar (P = 0.12) in both steady state (10 +/- 1.2 ng/ml) and crisis (9.3 +/- 2.3) to those of normal controls (6.0 +/- 0.8). The similarity of beta-TG/PF4 ratios in normal and sickle cell anaemia patients as well as the positive correlation (P less than 0.05) between platelet count and beta-TG and PF4 suggested that an artefactual in vitro platelet activation was responsible for some of the observed increased beta-TG and PF4 levels. Further evidence against enhanced platelet activity in these sickle cell patients included normal intraplatelet content of the dense granule constituent 5-HT and a normal ATP/ADP ratio. From this data we conclude that platelet activation in children with sickle cell anaemia appears minimal.
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PMID:Evidence against enhanced platelet activity in sickle cell anaemia. 622 55

Previous reports have given conflicting conclusions of the role platelets may play in initiating vaso-occlusive sickle cell crisis. Seven patients homozygous for sickle cell hemoglobin, and seven age, race and sex matched controls were each studied on at least two occasions in a six week period of normal health. The number of platelets circulating as aggregates, the plasma concentration of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF-4) were significantly elevated compared with controls. These findings were confirmed with a second series of fourteen patients and nine controls. Patient's platelets in plasma adjusted for both platelet number and citrate concentration aggregated more in response to low concentrations (0.4 and 1 microM) but less to higher concentrations (4 and 20 microM) of ADP and needed significantly more prostacyclin (PGI2) to inhibit ADP induced aggregation than did platelets from control subjects. There was no significant difference in plasma concentration of fibrinopeptide A and thromboxane (Tx)B2, nor in the platelet generation of TxB2 and release of serotonin and beta TG induced by aggregating agents. Thus, the platelets of patients with sickle cell anemia in the steady state are readily activated and respond in vivo by increased formation of aggregates and release of beta TG and PF-4.
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PMID:Platelet activation during steady state sickle cell disease. 622 76

In view of prior reports of platelet activation in the sickling disorders, platelet aggregation, malondialdehyde (MDA) production following stimulation with N-ethylmaleimide, and/or production time (survival) measurements were examined in 44 children with homozygous sickle cell disease. Aggregation in response to epinephrine, collagen, and adenosine diphosphate was similar to or only slightly less than in normal black controls, rendering highly unlikely the circulation of a sizable population of refractory or "exhausted" platelets. The platelets from the normal blacks aggregated less in response to epinephrine than those from white control subjects. MDA generation in sickle cell platelets was not increased, and platelet production time was not shortened in 6 patients studied during crisis. These observations do not support the occurrence of a marked degree of platelet activation and consumption in sickle cell anaemia.
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PMID:Platelet aggregation, malondialdehyde generation and production time in children with sickle cell anaemia. 733 Aug 19

In vitro platelet aggregation responses to epinephrine and ADP were significantly lower in patients with sickle cell disease when compared to age- and sex-matched normal subjects. Platelet aggregation responses were reduced in all patients regardless of clinical status. Measurement of circulating platelet aggregates showed normal values in patients with sickle cell disease in steady state or with infection alone, but a significant increase in others with acute vaso-occlusive crises. Recovery from vaso-occlusion was associated with a decline in circulating platelet aggregates. This study suggests that in vivo platelet activation may result in "tired" platelets which are refractory to epinephrine and ADP stimulation in vitro.
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PMID:Abnormalities of platelet aggregation in sickle cell disease. 735 81


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