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)

Adherence of erythrocytes to vascular endothelium likely contributes to the pathophysiology of episodic vascular occlusion in patients with sickle cell disease (SCD). In addition, coagulation activation has been reported in sickle patients during complications such as pain episodes. To test the hypothesis that platelet activation contributes to sickle erythrocyte binding, we investigated whether factors released from activated sickle platelets promote adherence of sickle erythrocytes to human microvascular endothelial cells (MEC) under flow conditions. Activated sickle platelet supernatant (ASPS) promoted high levels of sickle erythrocyte adherence to MEC (55.4 +/- 3.9 erythrocytes/mm2) but only moderate adherence of normal erythrocytes to MEC (14.1 +/- 0.7 erythrocytes/mm2). When MEC were incubated with an antibody (OKM5) against CD36 (a thrombospondin [TSP] receptor), platelet supernatant mediated sickle erythrocyte adherence was inhibited 86%, suggesting that TSP participated in the adherence. To further define the role of TSP in adherence, additional studies using purified TSP were performed. At a concentration of 0.2 micrograms/mL TSP in serum-free media (SFM), sickle erythrocyte adherence to MEC was 33.9 +/- 2.7 erythrocytes/mm2 and sixfold greater than either sickle erythrocyte adherence in the absence of TSP or normal erythrocyte adherence in the presence of TSP. Doubling the concentration of TSP to 0.4 micrograms/mL proportionally increased adherence of sickle erythrocytes. Incubation of MEC with OKM5 or anti-alpha v monoclonal antibodies inhibited TSP-mediated sickle erythrocyte adherence more than 95%. These data suggest that activated platelet release factors, including alpha-granule TSP, which promote receptor-mediated sickle erythrocyte adherence to microvascular endothelium. Such factors released during in vivo platelet activation could contribute to vaso-occlusive complications by promoting erythrocyte adherence and microvascular occlusion.
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PMID:Thrombospondin from activated platelets promotes sickle erythrocyte adherence to human microvascular endothelium under physiologic flow: a potential role for platelet activation in sickle cell vaso-occlusion. 847 71

Vasoocclusive episodes in sickle cell anemia may be initiated by adherence of erythrocytes to endothelium, one mechanism of which involves thrombospondin binding to CD36 on the red blood cell (RBC). We compared CD36 expression and its relationship to stress reticulocytosis in patients with sickle cell anemia and other chronic hemolytic disorders, including some after splenectomy. Adults with sickle cell anemia had significantly more CD36-positive cells (4.1% +/- 3.4%, mean +/- SD, n = 12) in unfractionated blood than did normal adults, who had almost none (0.13% +/- 0.15%, n = 8, p < 0.05). In density-fractionated blood, sickle samples contained significantly more CD36-positive cells (39.8% +/- 21.9%, n = 10) in the lowest density layers than did splenectomized high-reticulocyte controls (8.5% +/- 6.4%, n = 4, p < 0.05). "Stress" reticulocytes (identified by their unique morphology) were significantly more frequent in low-density layers from sickle blood (44.3% +/- 23.9%, n = 10) than from nonsplenectomized high-reticulocyte controls (10.5% +/- 14.8%, n = 5, p < 0.05). There was a strong correlation (r = 0.92) between stress reticulocyte count and number of CD36-positive cells for all patients except thalassemics, in whom CD36-positive cells were more frequent than stress reticulocytes. Flow cytometry confirmed that the maximal CD36 signal was found on immature reticulocytes. We conclude that CD36-positive stress reticulocytes occur more frequently in sickle cell anemia than in other chronic hemolytic states, even after surgical splenectomy, suggesting that this enhanced CD36-positive stress reticulocytosis does not simply reflect absent splenic function. These results explain why RBCs from high-reticulocyte control patients fail to show the significant CD36-dependent thrombospondin-mediated adhesion to endothelium that is exhibited by sickle red cells.
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PMID:CD36-positive stress reticulocytosis in sickle cell anemia. 865 32

Sickle cell disease (SCD) is characterized by repeated vaso-occlusive events, which result in substantial morbidity. Abnormal adhesion of sickle red blood cells (RBC) to the vascular endothelium is postulated to play a role in the pathogenesis of vaso-occlusion. Two adhesion receptors, very late activation antigen-4 (VLA-4) and CD36, are found in unusually high numbers on sickle cell reticulocytes and do mediate adhesion of sickle RBC to endothelium. Hydroxyurea (HU) therapy results in fewer vaso-occlusive episodes, and we postulated that HU-related modulation of VLA-4 and CD36 receptors may contribute to its clinical benefit. Using flow cytometry, eight patients were followed from the onset of HU treatment through a mean treatment length of 200 +/- 49 days. Mean corpuscular volume and percent fetal hemoglobin (Hb F) increased from 87% +/- 6% to 98% +/- 9% and 6.6% +/- 3.9% to 12.7% +/- 5.6%, respectively. The percentage of reticulocytes expressing VLA-4 decreased from 29.0% +/- 5.9% to 14.9% +/- 2.3% (P = .0003). Two thirds of the total decrease in VLA-4 expression occurred after 10 weeks of HU and plateaued by 20 weeks. Changes in VLA-4 expression occurred before substantial increases in Hb F. The percentage of reticulocytes expressing CD36 decreased from 55.3% +/- 6.4% to 42.6% (P = .0046). Changes in adhesion receptor expression were not caused by a decrease in reticulocytosis with HU therapy. This report is the first to associate a decrease in adhesion receptor expression with a therapy known to reduce the clinical severity of SCD.
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PMID:Decrease of very late activation antigen-4 and CD36 on reticulocytes in sickle cell patients treated with hydroxyurea. 911 2

Blood cells are in continuous contact with the vascular endothelium. Endothelial cell culture, intravital videomicroscopy allowed the investigation of blood cell-endothelium interactions in dynamic conditions. In the various diseases, diabetes mellitus, sickle cell anemia and malaria, erythrocytes have an increased adhesion to endothelial cells. The presence of advanced glycation end products (AGE) on erythrocytes of diabetics is responsible for their binding to the receptor RAGE present on the endothelium. The AGE-RAGE binding provokes an oxidant stress and induces the expression of the adhesion molecule. Furthermore, erythrocyte AGE induce an increase in vascular permeability. In sickle cell anemia, the increased adhesiveness and the sickling of red blood cells are responsible for thrombosis. Plasmodium falciparum infestation of erythrocytes induces knob formation at the cell surface and the P. falciparum protein binding to CD36, ICAM-1 and thrombospondin present on the endothelium, and facilitates the parasite dissemination.
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PMID:[Erythrocyte adhesion to the vascular endothelium]. 1066 97

To assess whether fetal hemoglobin (HbF) modulates the adhesion of sickle erythrocytes to endothelium, children with homozygous sickle cell anemia (SS disease) were studied, using this physiologically crucial period to evaluate the relationships between HbF and the major erythrocyte adhesion markers. The mean level of CD36(+) erythrocytes was 2.59% +/- 2.15% (+/- SD, n = 40) with an inverse relationship between CD36 positivity and F cells (R = -0.76, P < .000 00 002). In univariate analyses, significant correlations with various hematologic parameters and age were noted. Multiple regression analyses, however, revealed a relationship solely with F cells. Minimal levels of very late activation antigen-4(+) (VLA4(+)) erythrocytes (0.31% +/- 0.45%, n = 40) with relationships similar to those noted for CD36(+) cells were also observed. The subpopulation of strongly adhesive stress reticulocytes was further assessed, using CD71 as their marker. The mean level of CD71(+) erythrocytes was 5.81% +/- 4.21%, with statistical correlates in univariate and multivariate analyses similar to those discussed above. When adhesion ratios were evaluated, inverse correlations were noted between basal and plasma-induced adhesion and F-cell numbers (R = -0.54, P < .0005; R = -0.53, P < .0006, n = 39). In addition, in analyses where basal or plasma-induced adhesion was the dependent variable and the independent variables included F cells and the various adhesion-related parameters, significant relationships solely with F cells were noted. The results demonstrate that SS patients with higher levels of F cells have concomitant decreases in the numbers of CD36(+), VLA4(+), and CD71(+) erythrocytes and that these findings translate into less adherent erythrocytes. These findings extend knowledge regarding the protective effects of HbF in the pathophysiology of sickle cell disease.
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PMID:Fetal hemoglobin in sickle cell anemia: relationship to erythrocyte adhesion markers and adhesion. 1131 43

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

Phosphatidlyserine (PS) exposure on the erythrocyte surface endows the cell with the propensity of adhering to vascular endothelium. Because individuals with sickle cell disease (SCD) manifest loss of erythrocyte membrane asymmetry with PS exposure, we have assessed the contribution of this marker to the process of sickle erythrocyte-microendothelial adhesion. Assays for plasma-induced adhesion were conducted on unactivated endothelium, in the absence of immobilized ligands, such that PS was compared to the erythrocyte adhesion receptor CD36. Blocking studies with erythrocytes pretreated with annexin V (to cloak PS) or anti-CD36 or both revealed an inhibitory effect on adhesion of 36% +/- 10% and 23% +/- 8% with blocking of both sites suggestive of an additive effect. We next evaluated 87 blood samples from patients with SCD and grouped them into 4 categories based on adhesion marker (CD36 and PS) levels. Results revealed a striking correlation between erythrocyte PS positivity and adhesion. Analyses of the individual patient data demonstrated a positive correlation between PS and adhesion (R = 0.52, P <.000 001), whereas none was noted between adhesion and CD36 (R = 0.2, P >.07). The effect of PS on adhesion appears to be related to the quantitative differences in erythrocyte markers in SCD, with PS the predominant marker when compared to CD36 both in the total erythrocyte population, and when the adherence-prone erythrocyte, the CD71(+) stress reticulocyte, was evaluated. Our study signals the entrance of an important new contributor to the field of sickle erythrocyte-endothelial adhesion. The implications of erythrocyte PS exposure in relation to the vascular pathology of SCD need to be assessed.
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PMID:Role of erythrocyte phosphatidylserine in sickle red cell-endothelial adhesion. 1186 Dec 69

Erythropoietin is a growth factor for endothelial cells as well as for erythroid cells. In contrast to their proliferative response to physiological levels of erythropoietin, endothelial cells may respond to decreased levels by triggering a process called neocytolysis. Neocytolysis is the selective destruction of the youngest circulating red cells, which may be prompted by endothelial cells communicating with macrophages to stimulate phagocytosis of this unusual cell subset. We speculate that this is due to decreased production by endothelial cells of the macrophage-deactivating transforming growth factor-beta. The resulting proinflammatory phenotype may include macrophage production of thrombospondin, which forms bridges between adhesion molecules selectively expressed on young red cells (CD36) and the CD36/alphavbeta3 complex on macrophages that triggers phagocytosis. Alternatively, inflammatory mediators secreted by endothelial cells and macrophages during erythropoietin withdrawal may signal young red cells to expose phosphatidylserine, which would mark them for elimination via the normal pathway for aged red cell destruction. Neocytolysis has been demonstrated in returning astronauts and in polycythemic individuals at high altitude on descent to sea level. It contributes to the anemia of renal disease, is triggered by the rapidly falling levels of erythropoietin seen after intravenous administration, and may be the normal mechanism for reduction of red cell mass in newborns. It may play a role in chronic diseases including malaria and sickle cell anemia. New erythropoietin products and methods of administration avoid the intermittent rapid decreases associated with the stimulus for neocytolysis, but study of this phenomenon may yield further improvements in drug design.
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PMID:Erythropoietin withdrawal leads to the destruction of young red cells at the endothelial-macrophage interface. 1475 97

Propagation of the vaso-occlusive process in sickle cell anaemia (SCA) is a complex process involving the adhesion of steady-state SCA patients red cells and reticulocytes to the vascular endothelium. The effect of hydroxyurea therapy (HUT) on the adhesive properties of sickle cells and the expression of adhesion molecule genes by erythroid cells of SCA individuals is not yet fully understood. The expressions of the CD36 gene and the VLA-4-integrin subunit genes, CD49d (alpha-subunit) and CD29 (beta-subunit), were compared in the reticulocytes of steady-state SCA patients and patients on HUT using real-time PCR. Basal adhesion of red cells from these subjects was also compared using static adhesion assays, as was surface protein expression, using flow cytometry. Basal sickle red cell adhesion to fibronectin was significantly greater than that of normal cells (P < 0.01); in contrast, HUT was associated with significantly lower levels (P < 0.01) of red cell adhesion that were similar to those of control cells; this decrease could not be justified solely by altered reticulocyte numbers in this population. Accordingly, flow cytometry demonstrated that reticulocytes from patients on HUT had significantly lower CD36 and CD49d surface expressions (P < 0.01) and, importantly, significantly lower expressions of the CD36, CD49d and CD29 genes (P < 0.05) than reticulocytes of SCA patients not on HUT. Taken together, data support the hypothesis that HUT reduces the adhesive properties of sickle cells and that this decrease appears to be mediated, at least in part, by a decrease in the gene and, consequently, surface protein expression of adhesion molecules such as VLA-4 and CD36.
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PMID:Therapy with hydroxyurea is associated with reduced adhesion molecule gene and protein expression in sickle red cells with a concomitant reduction in adhesive properties. 1731 60

Anti-CD36 antibodies are known to cause a platelet refractory state. We describe a previously unreported case of a 16-year-old female sickle cell disease patient with anti-CD36 antibodies, detected on routine screen prior to hematopoietic stem cell transplantation (HSCT). CD36 platelet antigen typing was negative for both the patient and her HLA-identical donor sibling. Patient plasma was compatible with 48 of 49 apheresis platelets, which were untested and presumably positive for the CD36 antigen. The patient responded adequately to transfusion of crossmatch compatible platelets and successfully underwent HSCT. The presence of anti-CD36 antibodies does not exclude potential candidates from HSCT.
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PMID:CD36 immunization in a patient undergoing hematopoietic stem cell transplantation. 1733 Aug 34


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