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)

Proteins are important constituents of the red blood cell plasma membrane. Several important breakthroughs have occurred in their analysis over the past few years. SDS-polyacrylamide gel electrophoresis lead to the separation of the major proteins and glycoproteins. Location of most of these proteins -- either on the external, the internal or both surfaces of the membrane -- was determined. The strenght of the binding of the protein to the membrane was established. Hydrophobicity of membrane proteins has so far hindered their purification. However, the major glycoprotein (glycophorin A) was isolated and recently sequenced. The description of several membrane-associated enzyme activities has been followed by some understanding of their specific role in the red blood cell physiology. Abnormalities of glycoproteins, Ca2+-ATPase and of membrane protein phosphorylation have been reported under various conditions: sickle cell disease, hereditary spherocytoses, progressive muscular dystrophy.
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PMID:[Erythrocyte membrane proteins]. 14 51

Erythropoietin is a glycoprotein hormone that plays a vital role in erythropoiesis. It is mainly produced in the fetal liver till the third trimester of pregnancy. At that point, the kidney interstitium takes over this function and becomes the main source of erythropoietin. Hypoxia stimulates erythropoietin production by a mechanism that may require a heme protein as a second messenger. Erythropoietin stimulates the maturation of erythroid precursors (colony-forming unit-erythroid and burst-forming unit-erythroid) via at least two types of cell surface receptors. The higher-affinity receptors appear to be more important in modulating the effects of erythropoietin in vivo. Changes in intracellular calcium may ultimately mediate the action of erythropoietin on erythroid precursors. A specific and sensitive radioimmunoassay is now available for accurately measuring erythropoietin levels. All forms of erythrocytosis except polycythemia vera are associated with elevated erythropoietin levels. Levels are also high in cord blood obtained following fetal asphyxia. Reduced levels are seen in patients with anemia due to renal diseases. The response of erythropoietin to the degree of anemia appears to be attenuated in patients with cancer, chronic diseases, and human immunodeficiency virus (HIV) infection. Erythropoietin has been successfully used for treating patients with anemia due to renal failure. Its use has also been approved for the treatment of anemia patients receiving zidovudine for HIV infection. Encouraging results have been observed when erythropoietin was used to treat anemia due to rheumatoid arthritis, hematological malignancies, and prematurity. It has also been used to increase the yield of autologous blood collected prior to an elective surgical procedure. However, it has not proved to be useful in sickle cell anemia and myelodysplastic syndromes.
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PMID:Erythropoietin. Biology and clinical applications. 178 66

The chemistry, pharmacology, pharmacokinetics, clinical uses and efficacy, adverse effects, drug interactions, dosage and administration, and formulary considerations of epoetin are described. Erythropoietin, a glycoprotein hormone primarily synthesized in the kidney, is the chief regulator of red blood cell production. Erythropoietin concentrations increase in response to a hypoxic state, resulting in increased red blood cell formation, accelerated hemoglobin production, and premature movement of reticulocytes into the circulation. The human gene responsible for the production of erythropoietin recently was cloned, and the recombinant product--epoetin--has been made available through mass production. The apparent volume of distribution of i.v. epoetin approximates the assumed plasma volume both in healthy volunteers and in patients with chronic renal failure. Little is known about the metabolism and route of elimination of epoetin and erythropoietin. Epoetin recently was approved by the FDA for treatment of anemia associated with chronic renal failure. Clinical trials in patients receiving hemodialysis or peritoneal dialysis and in predialysis patients with renal dysfunction demonstrate epoetin's efficacy. Other potential indications include augmentation of blood production in patients enrolled in autologous blood donation programs and treatment of anemias associated with rheumatoid arthritis, sickle cell disease, acquired immunodeficiency syndrome, cancer, and premature birth. The most frequent adverse effect associated with epoetin therapy is the worsening or development of hypertension. Other adverse effects include thrombocytosis, hyperkalemia, rise in serum urea concentration, iron deficiency, and flu-like symptoms. No drug interactions with epoetin have been reported in humans. The recommended starting epoetin dosage in patients with chronic renal failure is 50-100 IU/kg three times weekly. Epoetin is available only as an injection for i.v. or s.c. administration. Epoetin provides a new therapeutic approach to the treatment of anemia associated with chronic renal failure in hemodialysis, peritoneal dialysis, and predialysis patients. Benefits of epoetin therapy include reduced need for blood transfusions, the amelioration of anemic symptoms, and an improved quality of life.
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PMID:Epoetin: human recombinant erythropoietin. 268 Feb 41

The abnormal adherence of red blood cells, especially circulating reticulocytes (erythrocyte precursors), to the endothelium is believed to contribute to vascular occlusion observed in patients with sickle cell disease. Although several plasma proteins including von Willebrand factor and fibronectin have been proposed to mediate this adhesion, the mechanism of sickle cell adhesion to the endothelium remains unknown. Using flow cytometry, we screened sickle red blood cells with monoclonal antibodies (MoAbs) against known adhesion receptors and detected integrin subunits alpha 4 and beta 1 and the nonintegrin glycoprotein IV on reticulocytes but not on erythrocytes. No reactivity was detected against integrin subunits alpha 2, alpha 3, alpha 5, alpha 6, alpha v, beta 2, beta 3, integrin alpha IIb beta 3, or the nonintegrin glycoprotein Ib. Immunoprecipitation of reticulocytes with either alpha 4- or beta 1-specific antibodies identified the alpha 4 beta 1 complex (alpha 4(70) and alpha 4(80) forms), a receptor for fibronectin and vascular cell adhesion molecule-1. An antibody against glycoprotein IV, a receptor reported to bind thrombospondin and collagen, immunoprecipitated an 88-kD protein consistent with its reported M(r). MoAbs against alpha 4 and glycoprotein IV bound to an average of 4,600 and 17,500 sites per reticulocyte, respectively. Identification of alpha 4 beta 1 and glycoprotein IV on reticulocytes suggests both plasma-dependent and independent mechanisms of reticulocyte adhesion to endothelium and exposed extracellular matrix.
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PMID:Integrin alpha 4 beta 1 and glycoprotein IV (CD36) are expressed on circulating reticulocytes in sickle cell anemia. 750 18

Two acute phase reactants (C-reactive protein: CRP and alpha 1-acid glycoprotein: alpha 1-AGP) and transferrin (Tf) levels change were measured in order to evaluate their clinical or prognostic value during the vaso-occlusive crisis. Measurements were performed in normal controls, painful crisis with or without treatment and during steady state. Immunochemical determinations indicate that markedly acute inflammation occurred in sickle cell painful crisis, as revealed CRP and alpha 1-AGP levels. Compared to controls, during periods of steady state in the absence of any intercurrent condition, a lesser but significative increase of alpha 1-GPA was observed. Transferrin level remained lower and did not sufficient to discriminate between crisis and steady state. Compared to the vasodilatator drug effect, non steroidal anti-inflammatory drug showed more efficiency in the sickle cell disease inflammatory process. Taken together, these findings indicate that serial determinations of CRP, alpha 1-GPA and Tf may be helpful in monitoring the course of sickle cell disease and response to treatment. Then, non steroidal anti-inflammatory drugs appear necessary to reduce the length of the sickle cell crisis.
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PMID:[Clinical value of C-reactive protein, alpha 1-glycoprotein acid and transferrin assay in homozygous sickle cell disease]. 829 21

To identify a possible acute phase response during the steady state of sickle cell disease, we estimated the serum alterations of acute phase proteins, beta2-microglobulin (beta2M), kappa and lambda light chains, interleukins (ILs) and tumor necrosis factor-alpha (TNFalpha) in 21 patients. Increased concentrations of C-reactive protein (CRP) were found in 5 patients, alpha-1-acid-glycoprotein (AGP) in 3, alpha-1-antitrypsin (AAT) in 8, ceruloplasmin (CER) in 2, alpha-2-macroglobulin (AMG) in 14 and decreased haptoglobin (HPT) and transferrin (TFR) in 11 and 9, respectively. Increased beta2M was found in 10 patients and kappa and lambda light chains in 11. IL-1beta, IL-2, IL-4, IL-10 and TNFalpha were not detected in any of the patients. However, significantly increased values of IL-6 and sIL-2r were found. This study has demonstrated increased serum levels of some of the acute phase proteins in patients during the steady state of sickle cell disease. This may be a result of a subclinical vaso-occlusion which in turn leads to a covert inflammatory response. Cytokines, and in particular IL-6, produced after this response, seem to be responsible for the high levels of acute phase proteins in the steady state of this disease.
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PMID:Acute phase proteins and interleukins in steady state sickle cell disease. 968 92

Heparin Cofactor II (HCII) is a glycoprotein in human plasma which inactivates thrombin rapidly in the presence of dermatan sulfate. Inhibition occurs by formation of a stable equimolar complex between HCII and thrombin. HCII association with thrombotic events has not always been observed, thus decreased HCII does not appear to be a strong risk factor for thromboembolic events. Reduced HCII levels have been detected in different clinical conditions, such as hepatic failure, disseminated intravascular coagulation, thalasemina, sickle cell anemia. Increased physiological levels have been found in pregnant women and oral contraception. In our laboratory, we measured HCII plasmatic levels in the normal Buenos Aires city population and in patients under different clinical conditions, such as sepsis, diabetis, burns, oral anticoagulation and in patients treated with heparin, hyperhomcysteinemia in whom septic and diabetic patients showed decreased values. HCII thrombin inhibition possibly takes place in extravascular sites where dermatan sulfate is present. HCII activity would be important in the regulation of wound healing, inflammation, or neuronal development.
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PMID:[Heparin cofactor II, a thrombin inhibitor with a still not clarified physiologic role]. 1034 31

The Lutheran and LW glycoproteins are blood group-active proteins found at the surface of human red cells. The Lutheran glycoprotein (Lu gp) is a member of the immunoglobulin superfamily (IgSF) that binds the extracellular matrix protein laminin, in particular, laminin isoforms containing the alpha 5 subunit. The LW glycoprotein (LW gp), also an IgSF member, has substantial sequence homology with the family of intercellular adhesion molecules (ICAMs). LW gp binds the integrin very late antigen-4 (VLA-4, alpha 4 beta 1) and alpha V-containing integrins. Studies on the expression of LW and Lu gps during erythropoiesis utilizing in vitro cultures of haemopoietic progenitor cells have shown that LW gp expression precedes that of Lu gp. These observations have led to the suggestion that LW gp on erythroblasts may interact with VLA-4 on macrophages to stabilize erythroblastic islands in normal bone marrow and that Lu gp may facilitate trafficking of more mature erythroid cells to the sinusoidal endothelium where alpha 5-containing laminins are known to be expressed. Levels of Lu gp and LW gp expression on sickle red cells are greater than on normal red cells and sickle red cells adhere to alpha 5-containing laminins. These data suggest that the Lu and LW molecules may contribute to the vaso-occlusive events associated with episodes of acute pain in sickle cell disease.
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PMID:Erythroid cell adhesion molecules Lutheran and LW in health and disease. 1089 61

It is thought that an increase in the adhesion of circulating reticulocytes to the vascular endothelium may initiate the vascular occlusion underlying the painful crises and organ failures typical of sickle cell disease (SCD). At least 2 receptors, usually present on reticulocytes, seem to be involved in this adhesion process: glycoprotein CD36 (glycoprotein IV) and integrin alpha(4)beta(1) (very late activation antigen--4). Recently, a high frequency of the platelet CD36--deficient phenotype was reported in black Africans. The frequency of this deficiency was similar in subjects with and without SCD. The role of CD36 in vaso-occlusion was then investigated by comparing the clinical course in 2 groups of black Africans homozygous for hemoglobin S, with and without CD36 deficiency, but similar in age, sex, geographical origin, number of alpha-globin genes, and beta-globin gene haplotype. Flow cytometry showed that CD36 was absent from the circulating red blood cells and reticulocytes of platelet CD36--deficient individuals but present on those from patients with normal platelet CD36 expression, and that alpha(4)beta(1) integrin levels were similar on the reticulocytes of the 2 groups. Neither clinical severity, as evaluated by the frequency and characteristics of vaso-occlusive events, nor biological data differed significantly in the 2 groups of patients. Finally, although CD36 has been suggested to play a critical role in the pathogenesis of vaso-occlusion, this study, despite including only a small number of patients, supports the idea that the modulation of expression of a single type of adhesion molecule is insufficient to counteract the pathological process leading to vaso-occlusion in SCD patients. (Blood. 2001;98:966-971)
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PMID:The nonexpression of CD36 on reticulocytes and mature red blood cells does not modify the clinical course of patients with sickle cell anemia. 1149 40

Platelets play an important role in the pathophysiology of acute myocardial infarction, unstable angina, and ischemic stroke. The expression of the glycoprotein IIb/IIIa (alphaIIb/beta3 integrin) receptor on the surface of activated platelets constitutes the common pathway for platelet aggregation. Glycoprotein IIb/IIIa has low affinity for its soluble ligands (fibrinogen and von Willebrand factor) in resting platelets. In the setting of vascular injury, platelet activation occurs after binding of the glycoprotein Ib-IX-V receptor to von Willebrand factor in the extracellular matrix (at high shear rate) and binding of soluble agonists to specific platelet membrane receptors. The ensuing inside-out signaling increases several-fold the affinity and avidity of alphaIIb/beta3 for its ligands. High affinity ligand binding to alphaIIb/beta3 triggers outside-in signaling, causing microskeletal contraction and platelet retraction. The signaling pathways for inside-out and outside-in signaling are incompletely understood. Glycoprotein IIb/IIIa antagonists were developed under the premise that these agents would abrogate platelet aggregation while preserving platelet monolayer deposition at sites of injury. A number of parenteral and oral agents have been developed and evaluated in clinical trials. Three of them are approved in the United States and other countries: abciximab (ReoPro; the Fab fragment of a chimeric human-mouse antibody), eptifibatide (Integrelin; a cyclic heptapeptide), and tirofiban (Aggrastat; a tyrosine-derived nonpeptide molecule). The greatest clinical impact of these parenteral agents (used in conjunction with aspirin and heparin) has been in the prevention of ischemic complications after percutaneous coronary intervention. In contrast, oral agents have yielded disappointing results in the secondary prevention of acute coronary syndromes, and none of them are approved at present. Eptifibatide and tirofiban are specific for alphaIIb/beta3, whereas abciximab also exhibits cross-reactivity with the alphavbeta3 and alphaMbeta2 integrins. Although alphaIIb/beta3 is unique to platelets and megakaryocytes, alphavbeta3 is more widely distributed and mediates several functions, including endothelial cell migration, monocyte adhesion, angiogenesis, and inhibition of apoptosis. alphaMbeta2 mediates leukocyte-platelet interactions. In the percutaneous coronary intervention trials, abciximab has been more efficacious than the other parenteral agents, perhaps because of cross-reactivity with these other integrins, the pharmacodynamic profile of abciximab, or other effects. Other documented effects of abciximab include acute dethrombosis, reduction of thrombin generation, and improved flow in the coronary microcirculation after percutaneous coronary intervention. Abciximab is presently under evaluation in the treatment of acute ischemic stroke. Promising data have been obtained in experimental models of tumor angiogenesis and sickle cell anemia.
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PMID:Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions. 1200 56


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