Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. (41/2332)

Abnormal interaction of sickle red blood cells (SS RBC) with the vascular endothelium has been implicated as a factor in the initiation of vasoocclusion in sickle cell anemia. Both von Willebrand factor (vWf) and thrombospondin (TSP) play important roles in mediating SS RBC-endothelium interaction and can bind to the endothelium via alphaVbeta3 receptors. We have used monoclonal antibodies (MoAb) directed against alphaVbeta3 and alphaIIbbeta3 (GPIIb/IIIa) integrins to dissect the role of these integrins in SS RBC adhesion. The murine MoAb 7E3 inhibits both alphaVbeta3 and alphaIIbbeta3 (GPIIb/IIIa), whereas MoAb LM609 selectively inhibits alphaVbeta3, and MoAb 10E5 binds only to alphaIIbbeta3. In this study, we have tested the capacity of these MoAbs to block platelet-activating factor (PAF)-induced SS RBC adhesion in the ex vivo mesocecum vasculature of the rat. Infusion of washed SS RBC in preparations treated with PAF (200 pg/mL), with or without a control antibody, resulted in extensive adhesion of these cells in venules, accompanied by frequent postcapillary blockage and increased peripheral resistance units (PRU). PAF also caused increased endothelial surface and interendothelial expression of endothelial vWf. Importantly, pretreatment ofthe vasculature with either MoAb 7E3 F(ab')(2) or LM609, but not 10E5 F(ab')(2), after PAF almost completely inhibited SS RBC adhesion in postcapillary venules, the sites of maximal adhesion and frequent blockage. The inhibition of adhesion with 7E3 or LM609 was accompanied by smaller increases in PRU and shorter pressure-flow recovery times. Thus, blockade of alphaVbeta3 may constitute a potential therapeutic approach to prevent SS RBC-endothelium interactions under flow conditions. (Blood. 2000;95:368-374)  (+info)

Prediction of adverse outcomes in children with sickle cell disease. (42/2332)

BACKGROUND: The ability to identify infants with sickle cell anemia who are likely to have severe complications later in life would permit accurate prognostication and tailoring of therapy to match disease-related risks and facilitate planning of clinical trials. We attempted to define the features of such babies by following the clinical course of 392 children with sickle cell disease from infancy to about the age of 10 years. METHODS: We analyzed the records of 392 infants who received the diagnosis of homozygous sickle cell anemia or sickle cell-Beta(0)-thalassemia before the age of six months and for whom comprehensive clinical and laboratory data were recorded prospectively; data were available for a mean (+/-SD) of 10.0+/-4.8 years. Results obtained before the age of two years were evaluated to determine whether they predicted the outcome later in life. RESULTS: Of the 392 infants in the cohort, 70 (18 percent) subsequently had an adverse outcome, defined as death (18 patients [26 percent]), stroke (25 [36 percent]) frequent pain (17 [24 percent]), or recurrent acute chest syndrome (10 [14 percent]). Using multivariate analysis, we found three statistically significant predictors of an adverse outcome: an episode of dactylitis before the age of one year (relative risk of an adverse outcome, 2.55; 95 percent confidence interval, 1.39 to 4.67), a hemoglobin level of less than 7 g per deciliter (relative risk, 2.47; 95 percent confidence interval, 1.14 to 5.33), and leukocytosis in the absence of infection (relative risk, 1.80; 95 percent confidence interval, 1.05 to 3.09). CONCLUSIONS: Three easily identifiable manifestations of sickle cell disease that may appear in the first two years of life (dactylitis, severe anemia, and leukocytosis) can help to predict the possibility of severe sickle cell disease later in life.  (+info)

In vivo production of type 1 cytokines in healthy sickle cell disease patients. (43/2332)

Interleukins (IL)-1, 2, 12, and interferon (IFN)-gamma, along with soluble IL-2 receptor (sIL-2R) were measured from sera obtained from healthy sickle cell disease (SCD) patients and comparable healthy control subjects. The cytokines were assessed by enzyme-linked immunosorbent assay (ELISA) in 60 SCD patients and 58 controls. No significant detectable levels of IL-1 or IL-12 were found in the sera of either group of patients. Significantly elevated levels of IFN-gamma were measured in 20 (33%) of 60 SCD patients and 21 (36%) of 58 controls. A large subset of 18 (41%) of 43 healthy controls and a smaller subset of 12 (21%) of 58 SCD demonstrated detectable levels of IL-2. The sIL-2R levels of the SCD group (4465 +/- 552 pg/mL) were significantly higher (P < .0001) than that of controls (3473 +/- 411 pg/mL). The results revealed comparable circulating levels of all type 1 cytokines in both healthy SCD and normal control subjects, with the exception of in vivo sIL-2R production. Elevated serum levels of both IL-6 and tumor necrosis factor (TNF)-alpha have been reported previously in a significant percentage of SCD steady-state subjects. These two cytokines are known to increase sIL-2R expression and may help explain the difference between the patient populations. Immune activation markers such as sIL-2R are produced by cells that mediate host responses to infection or inflammatory stimuli. The implication of higher levels of sIL-2R in SCD is not clear, but chronic parvovirus B19 infection, chronic polyclonal activation of B cells or defective regulation of antibodies are possible explanations for the elevated levels in SCD.  (+info)

Sickle cell disease and aortic valve replacement: use of cardiopulmonary bypass, partial exchange transfusion, platelet sequestration, and continuous hemofiltration. (44/2332)

Sickle cell disease in patients undergoing open heart procedures presents a multitude of challenges to the medical staff. With improved techniques of cardiopulmonary bypass, surgery, and anesthesia for treating patients with sickle cell disease, perfusionists will likely encounter patients with this genetic disorder on a more frequent basis. A 40-year-old black woman was admitted to our institution with recurrent Staphylococcus epidermidis and sepsis. She underwent transesophageal echocardiography and cardiac catheterization and was subsequently diagnosed with severe aortic insufficiency. The aortic valve was replaced. Herein, we report our experience in the preoperative, perioperative, and postoperative management of this patient. We present a concise update on the current literature and techniques used by others in similar cases, and we provide a brief section on future considerations to assist fellow practitioners in recognizing this disease and meeting the accompanying challenges.  (+info)

Sickle cell anemia day hospital: an approach for the management of uncomplicated painful crises. (45/2332)

Painful crisis episodes are poorly treated in sickle cell anemia, both in timeliness and appropriateness of care. Delayed treatment in Emergency Departments, unrelieved pain, frequent admissions, and prolonged hospitalizations are common. We established a Day Hospital (DH) to determine if an alternative care delivery system could improve pain relief and reduce unnecessary hospital admissions for patients with uncomplicated painful crises. Trained DH staff delivered prompt titration for pain relief based on each patient's analgesic history and qualitative and quantitative assessments. Response to therapy and comorbidities commanded disposition. During the first 5 years of DH operation there were 2554 visits; 60% of the patients had severe pain. During an average visit of 4.5 hours, 84% of the patients were titrated to relief; 90% had pain relief within 2 to 4 hours. Overall, 81% of the patients were discharged home (70% initially and 90% to 94% in the last 3 years). During the first 5 years of the DH, there were 2612 emergency department (ED) visits that averaged 13 hours each. The combined ED and DH admissions during this time represented a 40% decrease in the baseline ED admission rate of 92%, (1 year pre-DH). Patients with uncomplicated painful crisis were admitted 5 times less often from the DH (8.3%) than from the ED (42.7%). The length of stay (LOS) for inpatients followed by the DH staff decreased by 1.5 days, while the LOS for patients followed by non-DH staff remained unchanged. Reduction of admissions and LOS represented a savings of approximately $1.7 million. We conclude that a dedicated facility provides the kingpin for effective and rapid painful crisis management, reduces hospitalizations, and facilitates integration of the approach into other areas of care. (Blood. 2000;95:1130-1136)  (+info)

Adherence of phosphatidylserine-exposing erythrocytes to endothelial matrix thrombospondin. (46/2332)

Phospholipid asymmetry is well maintained in erythrocyte (RBC) membranes with phosphatidylserine (PS) exclusively present in the inner leaflet. The appearance of PS on the surface of the cell can have major physiologic consequences, including increased cell-cell interactions. Because increased adherence of PS-exposing RBCs to endothelial cells (ECs) may be pathologically important in hemoglobinopathies such as sickle cell disease and thalassemia, we studied the role of PS exposure in calcium ionophore-treated normal RBC adherence to human umbilical vein endothelial cell (HUVEC) monolayers. When HUVEC monolayers were incubated with these PS-exposing RBCs, the ECs retracted and the RBCs adhered primarily in the gaps opened between the ECs. A linear correlation was found between the number of PS-exposing RBCs in the population and the number of adhering RBCs to the monolayer. Pretreatment of RBCs with annexin V significantly decreased adherence by shielding PS on the RBCs. Similarly, PS-containing lipid vesicles decreased RBC binding by competing for the PS binding sites in the monolayer. PS-exposing RBCs and PS-containing lipid vesicles adhered to immobilized thrombospondin (TSP) and matrix TSP, respectively, and adherence of PS-exposing RBCs to EC monolayers was reduced by antibodies to TSP and to its EC receptor, alpha(v)beta(3). Together, these results indicate a role for PS and matrix TSP in the adherence of PS-exposing RBCs to EC monolayers, and suggest an important contribution of PS-exposing RBCs in pathologies with reported vascular damage, such as sickle cell anemia. (Blood. 2000;95:1293-1300)  (+info)

Height and weight reference curves for homozygous sickle cell disease. (47/2332)

OBJECTIVE: To derive height and weight growth reference curves for children with homozygous sickle cell disease. STUDY DESIGN: Subjects (n = 315) were participants in a population based, longitudinal cohort study of sickle cell disease in Kingston, Jamaica. Regular measurements of height and weight were made from enrollment into the study at birth up to 22 years of age. RESULTS: Sex specific growth reference curves for height for age and weight for age covering the age range 0-18 years are presented. CONCLUSION: These growth reference curves are suitable for identifying coincidental growth problems in children with homozygous sickle cell disease.  (+info)

Volume control in sickle cells is facilitated by the novel anion conductance inhibitor NS1652. (48/2332)

A low cation conductance and a high anion conductance are characteristic of normal erythrocytes. In sickle cell anemia, the polymerization of hemoglobin S (HbS) under conditions of low oxygen tension is preceded by an increase in cation conductance. This increase in conductance is mediated in part through Ca(++)-activated K(+) channels. A net efflux of potassium chloride (KCl) leads to a decrease in intracellular volume, which in turn increases the rate of HbS polymerization. Treatments minimizing the passive transport of ions and solvent to prevent such volume depletion might include inhibitors targeting either the Ca(++)-activated K(+) channel or the anion conductance. NS1652 is an anion conductance inhibitor that has recently been developed. In vitro application of this compound lowers the net KCl loss from deoxygenated sickle cells from about 12 mmol/L cells/h to about 4 mmol/L cells/h, a value similar to that observed in oxygenated cells. Experiments performed in mice demonstrate that NS1652 is well tolerated and decreases red cell anion conductance in vivo. (Blood. 2000;95:1842-1848)  (+info)