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)

The placental-umbilical unit in sickle cell disease (SCD) pregnancy was used to explore hypoxia in vivo, an important factor in the pathophysiology of this disease. Gross examination and microscopic analysis of the placentas, taken immediately after delivery, indicate good concordance between maturity and term as controls, but higher frequency of vascular injuries such as excess syncytial knots, excess fibrin deposits, congestion and villous necroses. Unexpectedly, neither leukocyte recruitment nor alteration in extraplacental membrane was observed, suggesting the absence of inflammation. Additionally, interleukin (IL)-6 and IL-8 concentrations, measured by enzyme-linked immunosorbent assay (ELISA), were similar in the placental maternal blood from controls and SCD. There were also no significant differences found in IL-6 vein blood concentrations between controls and SCD, IL-8 being not detected. Immunostaining of umbilical vein endothelium in SCD pregnancies showed redistribution of PECAM-1 (CD31), von Willebrand factor (vWF), and P-selectin to the cell surface, controls exhibiting the classical pattern. Staining quantification indicated increases in vWF (+36.2%; P=.006) and vascular endothelial growth factor (VEGF) expression (+96.0%; P=.006) over control, but a reduction in endothelial nitric oxide synthase (eNOS) (-45.5%; P=.029). These results document, for the first time, direct functional adjustments in response to hypoxia in human in vivo. The mechanism for these changes has not been clearly established, but it may reflect increased tolerance to SCD hypoxic conditions and hypoxia in general.
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PMID:The placental-umbilical unit in sickle cell disease pregnancy: a model for studying in vivo functional adjustments to hypoxia in humans. 1566 92

Complications of sickle cell anaemia include vascular occlusion triggered by the adherence of sickle erythrocytes to endothelium in the postcapillary venules. Adherence can be promoted by inflammatory mediators that induce endothelial cell adhesion molecule expression and arrest flowing erythrocytes. The present study characterised the effect of histamine stimulation on the kinetics of sickle cell adherence to large vessel and microvascular endothelium under physiological flow. Increased sickle cell adherence was observed within minutes of endothelial activation by histamine and reached a maximum value within 30 min. At steady state, sickle cell adherence to histamine-stimulated endothelium was 47 +/- 4 adherent cells/mm(2), 2.6-fold higher than sickle cell adherence to unstimulated endothelial cells. Histamine-induced sickle cell adherence occurred rapidly and transiently. Studies using histamine receptor agonists and antagonists suggest that histamine-induced sickle cell adhesion depends on simultaneous stimulation of the H(2) and H(4) histamine receptors and endothelial P-selectin expression. These data show that histamine release may promote sickle cell adherence and vaso-occlusion. In vivo histamine release should be studied to determine its role in sickle complications and whether blocking of specific histamine receptors may prevent clinical complications or adverse effects from histamine release stimulated by opiate analgesic treatment.
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PMID:Histamine increases sickle erythrocyte adherence to endothelium. 1641 24

Activated platelets have been identified in patients with sickle cell disease. However, the association of platelet P-selectin expression and automated red cell exchange procedures in these patients is not well known. We hypothesized that altered whole platelet P-selectin expression is associated with automated red cell exchange. Flow cytometric quantification of platelet P-selectin expression was carried out in 23 patients with sickle cell disease before and after automated red cell exchange. P-selectin expression was quantified as a binding index for platelet P-selectin (the percentage of positive platelets multiplied by the mean fluorescence of positive platelets). The patients were divided into two groups: individuals with painful vaso-occlusive crises (four women and five men; group 1) and those in a steady state (six women and eight men; group 2). The 33 exchange procedures were evaluated prospectively and used acid-citrate-dextrose A solution (whole blood to anticoagulant ratio = 14:1). Platelet P-selectin expression did not significantly change after automated red cell exchange. Clinical factors such as the volume of replacement fluid and the citrate infusion rate did not correlate with postapheresis platelet P-selectin expression. In addition, the association of platelet P-selectin expression and automated red cell exchange was independent of other laboratory factors (hematocrit level, hemoglobin S level, platelet count, and nitric oxide level). Finally, the difference between the study groups regarding platelet P-selectin expression before and after apheresis was insignificant. In conclusion, automated red cell exchange procedures do not induce platelet P-selectin expression in patients with sickle cell disease in the steady state or in vaso-occlusive crisis.
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PMID:Platelet P-selectin expression in patients with sickle cell disease who undergo apheresis. 1766 30

Homozygous sickle cell disease (SCD) is characterised by increased soluble P-selectin (sP-selectin), suggesting increased platelet activation, and high non-transferrin-bound iron (NTBI), reflecting iron overload, possibly due to blood transfusion. Hypothesising a relationship between these processes, we measured both markers in 40 SCD patients and 40 age/gender/race-matched controls, finding increased levels of each marker in the patients (both P<0.001), but more pertinently a significant NTBI/sP-selectin correlation (r=0.52, P<0.001). Both indices were increased in the blood of 15 recently-transfused patients compared with 25 three-month transfusion-free patients (P<0.001), but only sP-selectin was higher in present sickle crisis (P<0.001). We suggest that increased NTBI associated with blood transfusion iron overload in SCD may promote platelet activation.
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PMID:Increased levels of soluble P-selectin correlate with iron overload in sickle cell disease. 1791 Feb 82

The alphaIIbbeta3 antagonist eptifibatide is an effective treatment for patients with acute coronary syndromes (ACS). Platelet reactivity and CD40 ligand (CD40L) may play a role in the pathophysiology of sickle cell anaemia (SCA) similar to that in ACS, suggesting that inhibition of platelet aggregation and CD40L release by eptifibatide may benefit patients with SCA. Following eptifibatide infusion, safety and pharmacodynamic data were obtained from four SCA patients in their non-crisis, steady states. Eptifibatide was well tolerated, with no adverse changes in the haematological, biochemical or coagulation parameters studied. Eptifibatide did not increase plasma levels of platelet factor 4 or beta-thromboglobulin, P-selectin exposure or platelet:leucocyte aggregate formation. Moreover, decreases in platelet aggregation and soluble CD40L (sCD40L) levels achieved in SCA patients were comparable to those observed in the treatment of ACS. Finally, indicators of inflammation, macrophage inflammatory protein-1alpha, tumour necrosis factor-alpha and myoglobin were reduced following eptifibatide infusion, while vasodilation correlatives, matrix metalloproteinases (MMP-2 and MMP-9) and leptin were increased. Based on these phase I results, eptifibatide may benefit SCA patients by inhibiting platelet aggregation, decreasing sCD40L levels and favourably altering plasma levels of inflammatory mediators.
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PMID:Phase I study of eptifibatide in patients with sickle cell anaemia. 1791 3

Sickle cell disease (SCD) is characterised by abnormal coagulopathy and angiogenesis although their relationships in two common genotypes, homozygous (HbSS) SCD and sickle-haemoglobin C disease (HbSC), are unexplored. We measured markers of platelet activation (soluble P-selectin [sP-selectin]), fibrinolysis (D-dimer) and angiogenesis (vascular endothelial growth factor [VEGF]) in 27 HbSS patients, 37 HbSC patients and in 42 age and race matched subjects with normal haemoglobin (AA). sP-selectin (P = 0.025) and D-dimers (P < 0.001) were higher in HbSS than in HbSC but there was no difference in VEGF. In HbSC, sPselectin correlated with VEGF (P = 0.012) and D-dimers (P = 0.021). There were no significant correlations in health or in HbSS. Platelet and coagulation activation, but not angiogenic activity, is elevated in HbSS disease compared to the clinically milder HbSC genotype. The correlation between sP-selectin and VEGF in SCD and HbSC disease is consistent with the view that VEGF is released from platelets during in vivo activation.
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PMID:Soluble P-selectin and vascular endothelial growth factor in steady state sickle cell disease: relationship to genotype. 1808 Aug

Berkeley sickle cell mice are used as animal models of human sickle cell disease but there are no reports of platelet studies in this model. Since humans with sickle cell disease have platelet abnormalities, we studied platelet morphology and function in Berkeley mice (SS). We observed elevated mean platelet forward angle light scatter (FSC) values (an indirect measure of platelet volume) in SS compared to wild type (WT) (37+/-3.2 vs. 27+/-1.4, mean+/-SD; p<0.001), in association with moderate thrombocytopenia (505+/-49 x 10(3)/microl vs. 1151+/-162 x 10(3)/microl; p<0.001). Despite having marked splenomegaly, SS mice had elevated levels of Howell-Jolly bodies and "pocked" erythrocytes (p<0.001 for both) suggesting splenic dysfunction. SS mice also had elevated numbers of thiazole orange positive platelets (5+/-1% vs. 1+/-1%; p<0.001), normal to low plasma thrombopoietin levels, normal plasma glycocalicin levels, normal levels of platelet recovery, and near normal platelet life spans. Platelets from SS mice bound more fibrinogen and antibody to P-selectin following activation with a threshold concentration of a protease activated receptor (PAR)-4 peptide compared to WT mice. Enlarged platelets are associated with a predisposition to arterial thrombosis in humans and some humans with SCD have been reported to have large platelets. Thus, additional studies are needed to assess whether large platelets contribute either to pulmonary hypertension or the large vessel arterial occlusion that produces stroke in some children with sickle cell disease.
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PMID:Morphological and functional platelet abnormalities in Berkeley sickle cell mice. 1837 11

Pulmonary hypertension (PH), a risk factor for mortality in sickle cell disease (SCD), has pathologic features of both pulmonary arterial hypertension (PAH) and PH related to left-sided heart disease (LHD) suggesting a link between these two entities. We hypothesized that both are characterized by endothelial dysfunction and increased adhesion molecule expression. SCD patients and normal volunteers underwent a screening questionnaire, echocardiogram, and blood donation for preparation of platelet-poor plasma. PAH was defined as a tricuspid regurgitant jet (TRJ) velocity > or =2.5 m/sec and/or the presence of isolated right ventricular hypertrophy or decreased systolic function. LHD was defined as either left-sided systolic/diastolic dysfunction or significant valvular disease. Plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P- and E-selectin, nitric oxide (NO(x)), erythropoietin, and vascular endothelial growth factor (VEGF) levels were assayed by enzyme-linked immunoassay. Forty-three percent of sickle cell anemia (HbSS) and 28% of hemoglobin SC disease (HbSC) disease patients had PAH. Additionally, 10-15% of SCD patients had LHD. VCAM-1 levels were significantly increased in HbSS patients compared with HbSC patients and normal volunteers. VCAM-1 and P-selectin levels correlated positively with TRJ velocity in HbSS patients (r = 0.45, P = 0.03, r = 0.2, P = 0.05, respectively). ICAM-1, E-selectin, NO(x), erythropoietin, and VEGF levels were similar across subject groups. PH is common in SCD and, at times, due to LHD. Increased VCAM-1 and P-selectin expression was associated with TRJ elevation regardless of etiology suggesting a similar effect on endothelial gene expression and possibly providing a pathologic link between PAH and PH related to LHD in SCD.
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PMID:Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression. 1838 29

Leucocytes are emerging as critical determinants in the severity of the pathology associated with sickle cell disease (SCD) and recent studies have shown that they can bind to sickle red blood cells (SS RBCs). However, the mechanism of this interaction is unclear. The alpha4beta1 integrin on monocytes and SS reticulocytes was found to mediate the interaction of these cells in in-vitro adhesion assays and in the blood of SCD patients. Plasma fibronectin (Fn), a ligand for alpha4beta1, could link SS RBCs to monocytes, as peptides derived from both the Arg-Gly-Asp-Ser (RGDS) and CS-1 site in Fn disrupted the reticulocyte/monocyte interaction. It was further shown in whole blood that 70% of the interacting monocytes were also bound to platelets, suggesting the existence of multi-cellular aggregates in SCD. Platelet inclusion in these aggregates was mediated by a P-selectin/P-selectin glycoprotein ligand-1 interaction, which has been demonstrated to activate the monocyte. These results suggest a new model for understanding the mechanism of attachment of SS RBCs to monocytes and implicate the platelet as a component and contributor to potentially occlusive aggregates that circulate in the blood of SCD patients.
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PMID:Fibronectin bridges monocytes and reticulocytes via integrin alpha4beta1. 1842 98

Phosphatidylserine (PS)-dependent erythrocyte adhesion to endothelium and subendothelial matrix components is mediated in part via thrombospondin (TSP). Although TSP exhibits multiple cell-binding domains, the PS-binding site on TSP is unknown. Because a cell-binding domain for anionic heparin is located at the amino-terminus, we hypothesized that PS-positive red blood cells (PS(+ve)-RBCs) bind to this domain. We demonstrate that both heparin and its low-molecular-weight derivative enoxaparin (0.5-50 u/mL) inhibited PS(+ve)-RBC adhesion to immobilized TSP in a concentration-dependent manner (21% to 77% inhibition, P < 0.05). Preincubation of immobilized TSP with an antibody against the heparin-binding domain blocked PS(+ve)-RBC adhesion to TSP. Antibodies that recognize the collagen- and the carboxy-terminal CD47-binding domain on TSP had no effect on this process. Although preincubation of PS(+ve)-RBCs with TSP peptides from the heparin-binding domain that contained the specific heparin-binding motif KKTRG inhibited PS(+ve)-erythrocyte adhesion to matrix TSP (P < 0.001), these peptides in the immobilized form supported PS-mediated erythrocyte adhesion. A TSP-peptide that lacks the binding motif neither inhibited nor supported PS(+ve)-RBC adhesion. Additional experiments show that soluble TSP also interacted with PS(+ve)-RBCs via its heparin-binding domain. Our results demonstrate that PS-positive erythrocytes bind to both immobilized and soluble TSP via its heparin-binding domain and that both heparin and enoxaparin, at clinically relevant concentrations, block this interaction. Other studies have shown that heparin inhibited P-selectin- and soluble-TSP-mediated sickle erythrocyte adhesion to endothelial cells. Our results, taken together with the previously documented findings, provide a rational basis for clinical use of heparin or its low-molecular-weight derivatives as therapeutic agents in treating vaso-occlusive pain in patients with sickle cell disease.
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PMID:Phosphatidylserine-positive erythrocytes bind to immobilized and soluble thrombospondin-1 via its heparin-binding domain. 1894 Jul 19


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