Phosphatidylserine externalization in sickle red blood cells: associations with cell age, density, and hemoglobin F

Yasin, Zahida; Witting, Scott R.; Palascak, Mary B.; Joiner, Clinton H.; Rucknagel, Donald L.; Franco, Robert S.

doi:10.1182/blood-2002-11-3416

Cited by 100 publications

(75 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3). This reduction in retention/adherence is most likely a result of subpopulations of PS-exposed SRBCs, of which their PS was cloaked by annexin V (27,30,43). A second possible explanation is that even during steady state, some basal level of neutrophil activation exists as suggested by Lard et al (28), resulting in higher than normal numbers of PS-exposed cells.…”

Section: Discussionmentioning

confidence: 95%

“…Another potentially significant membrane property that contributes to SRBC adhesion to vascular endothelium is the presence of phosphatidylserine (PS) on the external surface of the SRBC membrane (PS-exposed) (30,34). Measurement of erythrocyte membrane PS asymmetry in sickle and normal erythrocytes using the calcium-dependent phospholipid-binding protein annexin V is well established (7,27,30,39,43). Setty et al (34) have reported that PS-exposed SRBCs exhibit increased adhesion to EC monolayers that can be blocked by annexin V. The PS role in SRBC-EC adhesion is of particular interest because every erythrocyte could potentially be involved.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Activated neutrophil-mediated sickle red blood cell adhesion to lung vascular endothelium: role of phosphatidylserine-exposed sickle red blood cells

Haynes

Obiako²,

King³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

. Activated neutrophilmediated sickle red blood cell adhesion to lung vascular endothelium: role of phosphatidylserine-exposed sickle red blood cells. Am J Physiol Heart Circ Physiol 291: H1679 -H1685, 2006. First published May 19, 2006 doi:10.1152/ajpheart.00256.2006.-Activated neutrophils (ANs) increase sickle red blood cell (SRBC) retention/adhesion in the pulmonary circulation. This study investigates the role of neutrophil activation and SRBC retention/adhesion in the pulmonary circulation through a mechanism that involves increasing phosphatidylserine (PS) exposure on the external membrane surface of the SRBCs (PS-exposed). With the use of flow cytometry, double-labeling studies were performed with a calcium-dependent phospholipidbinding protein, annexin V-fluorescein isothiocyanate fluorescence, and the erythroid-specific marker glycophorin A to assess for the percentage of PS-exposed normal and SRBCs at baseline and after coincubation with ANs. Additional studies were performed that assessed retention/adhesion of SRBCs in the isolated rat lung using 51 Cr-labeled SRBC alone, SRBC ϩ AN, SRBC ϩ AN ϩ zileuton, and SRBC ϩ AN ϩ annexin V. Specific activities of lung and perfusate were measured, and the number of retained SRBCs per gram lung was calculated. Flow cytometry demonstrated that ANs increased the percentage of PS-exposed normal and SRBCs. The 5-lipoxygenase inhibitor zileuton attenuated AN-mediated increases in PS-exposed SRBCs and decreased SRBC retention/adherence in the lung on histological sections. Similarly, in the isolated perfused lung and in histological lung sections, retention/adherence of SRBCs cloaked with annexin V was attenuated in the presence of ANs. We conclude that ANs enhance the adhesion of SRBCs to vascular endothelium by increasing red blood cell membrane externalization of PS. Zileuton attenuation of AN-mediated SRBC PS externalization suggests that a 5-lipoxygenase product(s), secreted by the AN, plays a vital role in altering the adhesive properties of PS-exposed SRBCs to vascular endothelium. zileuton; microvascular occlusion; pulmonary circulation INCREASED SICKLE red blood cell (SRBC) adhesion to vascular endothelial cells (EC) is well documented in cell culture systems (19 -21, 23, 24, 34) and is thought to be central to vasoocclusion by the SRBC. In isolated rat lung perfused with SRBC suspensions, we have shown that the retention/adherence of SRBCs was 3.5 times greater than that seen in lung perfused with normal (hemoglobin A) human red blood cells (RBCs). In isolated perfused lung, products of activated neutrophils (ANs) further enhanced SRBC retention/adherence. This effect of ANs on RBC adhesion is attenuated when neutrophils are pretreated with a 5-lipoxygenase inhibitor (16). Whereas these in vitro results suggest the involvement of leukotriene products, the cellular mechanism involved in neutrophil-mediated increased SRBC adhesion to EC has yet to be elucidated.Adhesion molecules and their ligands on the RBC membrane surface, on EC, and in plasma have been im...

show abstract

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

Activated neutrophil-mediated sickle red blood cell adhesion to lung vascular endothelium: role of phosphatidylserine-exposed sickle red blood cells

Haynes

Obiako²,

King³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Both protein S and protein C can exert their anticoagulant effects on phosphatidylserine expressing sickle red blood cell membranes [7,8,10]. In patients with lower hemoglobin levels, there are more dense cells and membrane-shed vesicles, as well as reticulocytes (which all have high phosphatidylserine exposure) [44][45][46][47][48]. As total, but not free, protein S correlates positively to hemoglobin levels, it does not seem likely that this association reflects protein S consumption on phosphatidylserine-expressing red cells and vesicles.…”

Section: Discussionmentioning

confidence: 99%

Protein C and S and inflammation in sickle cell disease

et al. 2004

View full text Add to dashboard Cite

Reduced activity of naturally occurring anticoagulants (NOAC) protein C and protein S may contribute to vaso-occlusion in sickle cell disease (SCD). We studied whether protein C and S are related to clinical vaso-occlusion, hematological markers of disease severity (hemoglobin levels, leukocyte counts, and percentage of fetal hemoglobin), and inflammation in SCD. Protein C activity, protein S (free and total) antigen, endothelial activation markers (soluble vascular cell adhesion molecule-1 [sVCAM-1], von Willebrand antigen [vWF]), and high sensitive C-reactive protein (hsCRP) levels were measured in 30 HbSS and 20 HbSC patients and in race-matched HbAA controls. NOAC levels were reduced in patients, and endothelial activation markers and hsCRP were elevated (except vWF in HbSC patients). Protein C activity and vWF levels were lower in HbSC patients who experienced painful crises compared to HbSC patients who were clinically asymptomatic. No other differences were observed between patients who did and did not experience vaso-occlusive events (painful crises, stroke, acute chest syndromes) or leg ulcers. A significant positive correlation between total protein S with hemoglobin levels and a significant negative correlation between total and free protein S and sVCAM-1 were detected in HbSS patients. Except perhaps for protein C in relation to painful crises in HbSC patients, these markers were not associated with the occurrence of clinical events. The protein S, hemoglobin, and sVCAM-1 associations may suggest decreased endothelial protein S production due to the more severe endothelial perturbation in HbSS patients with lower hemoglobin levels. Am.

show abstract

“…Inflammation is likely triggered by the abnormal erythrocyte membrane and the presence of chronic hemolysis. Dense sickle cells that become dehydrated after several rounds of sickling expose their annexin V-binding phosphatidyl serine on the outer layer of the plasma membrane (53,54). These negatively charged glycolipids can activate the coagulation cascade (55), leading to the generation of tissue factor and thrombin, which in turn promote the inflammatory response.…”

Section: Advances In the Pathophysiology Of Scdmentioning

confidence: 99%