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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular occlusion has a central role in the pathophysiology of sickle cell disease (SCD) and, although there is little evidence that thrombosis alone is responsible, patients with sickle cell disease are known to have an ill-defined but increased thrombotic risk. The most serious complication of this in childhood is stroke which occurs in 7-10% of children and a further 14% have asymptomatic cerebrovascular disease (CVD) on imaging. We have performed a comprehensive profile of coagulation inhibitors and markers of thrombin generation in 96 children (83 nontransfused [NTx] and 13 transfused [Tx]) with steady-state SCD and 18 healthy sibling controls. The levels of protein S (free and total) and heparin cofactor II were reduced in both the NTx and Tx groups compared to controls and protein C and APC resistance ratios were reduced in the NTx group only. Antithrombin levels were not different from controls. Thrombin-antithrombin complexes and prothrombin fragment F1+2 were increased in both patient groups. In the NTx subgroups with or without CVD there were no differences for any of the parameters measured except for lower haemoglobin levels and higher white cell counts in those with asymptomatic CVD. We conclude that children with SCD have a reduction in levels of the majority of the coagulation inhibitors and increased thrombin generation in the steady-state and these are only partially reversed by transfusion. However, these abnormalities do not appear to play a primary role in the development of cerebrovascular disease.
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PMID:Prothrombotic changes in children with sickle cell disease: relationships to cerebrovascular disease and transfusion. 988 16

The relationship between each of haemoglobin concentration (Hb), red cell count (RCC), white cell count (WBC), platelet count (PLT), mean corpuscular volume (MCV), red cell width difference (RWD), and average number of acute admissions per year (AVEADM), were determined in a cross-sectional study of 128 Afro-Caribbean sickle cell anaemia patients attending the Sickle Cell Disease Clinic of Central Middlesex Hospital in London for a mean of 7.6 patient-years. The diagnosis of sickle cell anaemia was made by both haematological and DNA analyses. The haematological parameters were determined using Coulter S automated counter during the steady state periods while the AVEADM was computed from all admissions for painful crisis, acute anaemia and acute chest syndrome, priapism, and acute stroke. Haemoglobin F level was determined by HPLC. Analysis was done in the paediatric and adult patients separately. There were no significant correlations between any of the parameters and AVEADM in the paediatric group. In adult patients, there was significant positive correlation (P < 0.05) between WBC and AVEADM. WBC has a negative correlation with Hb concentration and HbF level. WBC 10 x 10(9)/L and above is associated with Hb and HbF level below the mean for the group. WBC is lower but not significantly, in patients with single alpha-gene deletion than in those without deletion (P = 0.06). This study suggests that higher WBC count may suggest possible increased hospital admission, lower Hb concentration, and lower HbF level, in adult patients, and that, as a single parameter it can be of value in the assessment of patients with sickle cell anaemia. Possible mechanisms for these findings are also suggested.
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PMID:The predictive value of white cell count in assessing clinical severity of sickle cell anaemia in Afro-Caribbeans patients. 1137 63

Painful episodes are the most frequent complaints of patients with sickle cell disease. The Emergency Department (ED) has provided management for acute events using the usual triage format for emergencies. A prospective study evaluated the role of the ED in the care of adults with sickle cell disease (SCD). The protocol, thus, addressed issues of acute events related to SCD and provided better care for patients with SCD in the ED. Approximately 37% of ED visits were for painful events. An inciting cause was identified in 35% of painful events and 75% of these required admission to the hospital. A 15-year follow-up prospectively showed similar results and that uncomplicated pain crisis can be treated with ED protocols. Outpatient clinics and urgent centers could reduce these visits. Absolute indications for admission include sepsis, fever >102 degreeF, white cell counts >20 000, worsening anemia, hypoxemia, acute chest syndrome and new CNS events. Patient database in the ED must be revised annually to avoid extensive workup in the ED and a complete history/physical examination, and a CBC could be sufficient for triage in an uncomplicated pain crisis. An acceptable protocol for care should be available at all EDs and a registry and information system for SCD will discourage overutilization of investigational tests and visits to multiple EDs.
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PMID:Evaluation and Management of Sickle Cell Disease in the Emergency Department (An 18-year Experience): 1974--1992. 1183 5

Neutrophil activation with the release of intracellular granule contents has been observed in sickle cell disease (SCD). Because leukotriene B(4) (LTB(4)), a 5-lipoxygenase metabolite of arachidonic acid in neutrophils, is a chemoattractant and enhances neutrophil adhesion to endothelium, we assessed plasma levels of this metabolite in controls (n = 9) and individuals with SCD, SS genotype, both in basal "steady state" (n = 37) and during episodes of vaso-occlusion (n = 10) and acute chest syndrome (n = 5). Thirteen patients with SCD, SC genotype, in steady state were also studied. Although no significant differences were noted between the control (136 +/- 32 fmol/mL) and SC genotype (177 +/- 83 fmol/mL, P >.15), LTB(4) levels were markedly increased in patients with SS genotype in basal steady state (207 +/- 64 fmol/mL, P <.003) compared with those in controls. Values were further increased during vaso-occlusion (264 +/- 94 fmol/mL) and acute chest syndrome (363 +/- 124 fmol/mL). These levels were significantly different from measurements taken during steady state (P <.04 and P <.0001, respectively). No correlation was noted between LTB(4) level and total white cell or neutrophil count. Additionally, the significant correlation noted in SCD between increased levels of plasma LTB(4) and soluble L-selectin (P <.03) reflects neutrophil activation. We also observed an effect of LTB(4) on red cell-endothelial adhesion at concentrations that appear clinically relevant (1-10 pmol/mL) with concomitant up-regulation of mRNA for the endothelial vitronectin receptor. These properties of LTB(4) are relevant to disease pathophysiology, providing further evidence of the contribution of the neutrophil to the proinflammatory and proadhesive phenotype in SCD.
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PMID:Eicosanoids in sickle cell disease: potential relevance of neutrophil leukotriene B4 to disease pathophysiology. 1191 46

Microvascular complications in sickle cell disease occur as a result of obstruction of small vessels by deoxygenated sickle cells. Cerebrovascular complications are also common and result from obstruction of large blood vessels by thrombosis with changes in vessels that have some similarity to those found in arteriosclerotic vascular disease. Endothelial damage and activation from sickle cell-endothelial interactions may contribute to both. We find that endothelial cells have increased expression of VCAM-1, E-selectin, and ICAM-1 when exposed to sickle blood cells. The concentration-dependent, sickle-induced, adhesion molecule expression is significantly greater than that promoted by normal cells. The time course of Cell Adhesion Molecule (CAM) expression is similar to that induced by TNF-alpha and IL1. Studies after white cell enrichment and reduction suggest leukocytes are the primary mediators. CAM expression by endothelial cells appears stimulated by soluble factors. Antibody inhibition studies support TNF-alpha and IL-1, produced by sickle leukocytes, as the primary soluble factors responsible for the observed CAM expression. Both the induction of endothelial CAM expression and subsequent endothelial adherence of sickle erythrocytes may play significant roles in the pathophysiology of sickle-related complications, and reduction in CAM expression may provide a new approach to treatment.
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PMID:Activation of vascular endothelial cell adhesion molecule expression by sickle blood cells. 1267 44

The lifespan of sickle cell patients has increased substantially. We chose to compare the attributes of older sickle cell patients with younger ones within the confines of a single institutional study serving the local Bronx population. Laboratory and clinical assessments from 40 patients with sickle cell disease over 40 years of age were compared to 40 patients under 30 years of age. When the older group was compared to the younger group, hemoglobin, indirect bilirubin, and platelet counts were significantly lower. Creatinine clearances were lower and BUN levels were higher in the older group. Although the prevalence of radiographically measured cardiomegaly was significantly higher in the older group, systolic and diastolic blood pressures remained unchanged. The number of crises and number of admissions were higher in the younger group than in the older, but there was wide variation, and no significant differences could be detected; days spent in hospital over the previous 2 years did not differ. No statistically significant differences were observed for absolute reticulocyte count, MCV, % HbF, white cell count, liver function tests, or oxygen saturation. Comparing genders within age groups, younger males had higher hemoglobin levels and absolute reticulocyte counts than younger females, while only the older females had higher HbF levels than the corresponding males. Lower levels of hemoglobin associated with older age may reflect decreased hematopoietic potential that may in part be due to decreased renal function. Lower platelet counts in older sickle cell patients may be a consequence of this decreased hematopoietic potential but may also represent a secondary survival benefit effect in sickle cell anemia.
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PMID:The older sickle cell patient. 1649 1

The goal of elucidating the biophysical and physiological basis of pressure-flow relations in the microcirculation has been a recurring theme since the first observations of capillary blood flow in living tissues. At the birth of the Microcirculatory Society, seminal observations on the heterogeneous distribution of blood cells in the microvasculature and the rheological properties of blood in small bore tubes raised many questions on the viscous properties of blood flow in the microcirculation that captured the attention of the Society's membership. It is now recognized that blood viscosity in small bore tubes may fall dramatically as shear rates are increased, and increase (dramatically with elevations in hematocrit. These relationships are strongly affected by blood cell deformability and concentration, red cell aggregation, and white cell interactions with the red cells anti endothelium. Increasing strength of red cell aggregation may result in sequestration of clumps of red cells with either reductions or increases in microvascular hematocrit dependent upon network topography. During red cell aggregation, resistance to flow may thus decrease with hematocrit reduction or increase due to redistribution of red cells. Blood cell adhesion to the microvessel wall may initiate flow reductions, as, for example, in the case of red cell adhesion to the endothelium in sickle cell disease, or leukocyte adhesion in inflammation. The endothelial glycocalyx has been shown to result from a balance of the biosynthesis of new glycans, and the enzymatic or shear-dependent alterations in its composition. Flow-dependent reductions in the endothelial surface layer may thus affect the resistance to flow and/or the adhesion of red cells and/or leukocytes to the endothelium. Thus, future studies aimed at the molecular rheology of the endothelial surface layer may provide new insights into determinants of the resistance to flow.
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PMID:Microvascular rheology and hemodynamics. 1580 70

Children with sickle cell disease, a chronic hemolytic anemia, present with a wide variety of neurological syndromes, including ischemic and hemorrhagic stroke, transient ischemic attacks, 'soft neurological signs', seizures, headache, coma, visual loss, altered mental status, cognitive difficulties, and covert or 'silent' infarction. Those with ischemic stroke usually have stenosis or occlusion of the distal internal carotid and proximal middle cerebral arteries. Indefinite transfusion prevents recurrence in most patients who have had a stroke, and can prevent first stroke in those with high transcranial Doppler velocities. High white cell count, low hemoglobin and oxyhemoglobin desaturation predict neurological complications. Other risk factors for overt ischemic stroke include hypertension, previous transient ischemic attack, covert infarction and chest crisis. For hemorrhagic stroke, aneurysms are common in adults but not children, who often present with hypertension after transfusion or corticosteroids. Seizures are particularly common in patients with cerebrovascular disease and covert infarction; the latter is also associated with hyposplenism and infrequent pain. Factors associated with cognitive difficulties include thrombocytosis, infarction, large-vessel disease, and perfusion abnormality on neuroimaging. As well as investigating the role of genes and the possibility that hydroxyurea or blood pressure control reduce neurological complications, we should explore the modifiable effects of poor nutrition, chronic infection, hemolysis and oxyhemoglobin desaturation on stroke risk.
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PMID:Therapy insight: stroke risk and its management in patients with sickle cell disease. 1747 74

Free circulating DNA is present in the plasma of healthy subjects, and is elevated in conditions characterized by increased cell death, such as cancer and physical trauma. Analysis of circulating DNA in plasma could provide a useful biomarker in sickle cell disease (SCD) in view of the increased cell turnover through chronic ongoing haemolysis, recurrent vaso-occlusion and inflammation. Plasma DNA was determined by real-time quantitative polymerase chain reaction (PCR) amplification of the beta-globin gene (HBB) in 154 patients with SCD [105 haemoglobin (Hb)SS, 46 HbSC and three HbS/beta(0) thalassaemia] and 53 ethnically matched controls. Blood samples were obtained from all patients in steady state; 21 of the 154 patients were also sampled during admission to hospital for acute pain. Median concentration of circulating plasma DNA in acute pain was more than 10-fold that in steady state and in controls - 10070 vs. 841 and 10070 vs. 933 genome equivalents/ml respectively (P < 0.0001, in both cases). During steady state, patients had plasma DNA levels similar to controls. Plasma DNA levels in SCD correlated with C-reactive protein levels (P < 0.005) and total white cell counts (P < 0.05) in steady state. The study shows that plasma DNA concentration may have potential as a biomarker in sickle cell patients.
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PMID:Circulating DNA: a potential marker of sickle cell crisis. 1789 11

Sickle cell disease is an inherited disorder of hemoglobin (Hb) synthesis, caused by a single nucleotide substitution (GTG>GAG) at the sixth codon of the beta-globin gene, leading to the production of a defective form of Hb, Hb S. When deoxygenated, Hb S polymerizes, damaging the sickle erythrocyte and it is this polymerization that is the primary indispensable event in the molecular pathogenesis of sickle cell disease. Hb S polymerization results in a series of cellular alterations in red cell morphology and function that shorten the red cell life span and leads to vascular occlusion. Sickle cell disease vaso-occlusion is now known to constitute a complex multifactorial process characterized by recurrent vaso-occlusion, ischemia-reperfusion injury, and oxidative stress with consequent vascular endothelial cell activation that induces a chronic inflammatory state in sickle cell disease individual and is propagated by elevated levels of circulating inflammatory cytokines. Activation of the endothelium results in the induction of endothelial adhesion molecule expression that mediates red and white cell adhesion to the vessel wall and the formation of heterocellular aggregates, followed by secondary red cell trapping, all of which contribute to reduced blood flow and eventually obstruction of the micro-circulation. Reduced nitric oxide bioavailability, caused principally by its consumption by cell-free Hb, liberated during intravascular hemolysis, contributes to this process by facilitating vasoconstriction and adhesion molecule activity.
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PMID:Newer aspects of the pathophysiology of sickle cell disease vaso-occlusion. 1920 68


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