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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000036

Red cell adhesion in human diseases

Colin, Yvesa,b,c,d; Van Kim, Caroline Lea,b,c,d; El Nemer, Wassima,b,c,d

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aInserm U1134

bUniversité Paris Diderot, Sorbonne Paris Cité, UMR_S 1134

cInstitut National de la Transfusion Sanguine

dLaboratoire d’ Excellence GR-Ex, Paris, France

Correspondence to Yves Colin, UMR_S 1134, INTS, 6 Rue Alexandre Cabanel, 75015 Paris, France. Tel: +00 33 1 44 49 30 93; e-mail:

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Purpose of review: This review discusses the unexpected role of red blood cell (RBC) adhesiveness in the pathophysiology of two red cell diseases, hereditary spherocytosis and polycythemia vera, and two ‘nonerythroid’ disorders, central retinal vein occlusion and Gaucher disease. These pathologies share common clinical manifestations, that is vaso-occlusion and/or thrombotic events.

Recent findings: Recently, the direct involvement of RBC adhesion to the vascular endothelium has been demonstrated in the occurrence of vaso-occlusive events, in particular in sickle cell disease (SCD). Several erythroid adhesion molecules and their ligands have been identified that belong to different molecular classes (integrins, Ig-like molecules, lipids…) and are activated by a variety of signaling pathways. Among these, the laminin receptor, Lutheran/basal cell adhesion molecule, which is activated by phosphorylation, appears to play a central role in several pathologies.

Summary: RBC adhesiveness might be involved in complications such as the vaso-occlusive crisis in SCD, thrombosis in polycythemia vera, splenic sequestration in hereditary spherocytosis, occlusions in central retinal vein occlusion and bone infarcts in Gaucher disease. Characterization of this pathological process at the cellular and molecular levels should prove useful to develop new therapeutic approaches based on the blockade of RBC abnormal interactions with vascular endothelium and/or circulating blood cells.

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Although expressing various adhesion molecules [1], mature RBCs are thought to be unable to adhere to other cell types under normal physiological conditions. However, under certain pathological conditions and in the presence of specific stimuli, abnormal RBC adhesion to vascular endothelium or to circulating blood cells could be initiated and participate in microvascular occlusions and/or thrombotic events. These abnormal conditions comprise hematological and nonhematological disorders such as diabetes and malaria in which the molecular bases of the abnormal RBC adhesive properties have been partially elucidated [2,3▪▪]. Yet it is certainly in sickle cell disease (SCD) that this pathological process has been the most extensively studied because it participates in the occurrence of painful vaso-occlusive crises (VOC), a hallmark of the disease. Besides the activation of endothelial cells and the alteration of RBC rheology in SCD [4,5], in-vitro studies have shown that RBCs are highly adherent to endothelial cells or to components of the vascular wall because of the abnormal expression and activation of several erythroid membrane molecules. Such molecules include integrin α4β1 and CD36, two proteins expressed on the surface of reticulocytes and involved in cell adhesion to activated endothelium through interaction with vascular cell adhesion molecule-1 and a thrombospondin bridge, respectively. Adhesion proteins of the immunoglobulin superfamily, such as intercellular cell adhesion molecule-4 (ICAM-4) and Lutheran/basal cell adhesion molecule (Lu/BCAM), are expressed on the surface of reticulocytes and mature RBCs, and activated by phosphorylation events. ICAM-4 and Lu/BCAM mediate sickle RBC adhesion to endothelium through interactions with endothelial αvβ3 integrin [6,7] and laminin 511/512 of the sub-endothelial extracellular matrix [8–12], respectively. In addition, these proteins mediate abnormal interactions between RBCs and leukocytes [13,14], which are believed to activate the latter, and trigger their interactions with the endothelial surface, contributing to VOC [14]. Finally, phosphatidylserine, which is normally maintained at the inner leaflet of the membrane lipid bilayer by the conjugated action of proteins from the flipase, scramblase and translocase families, becomes exposed on the outer leaflet of the membrane in 2–4% of SCD RBCs and may participate in their enhanced adhesion to endothelial cells [15].

Targeting these interactions, either directly by using soluble peptides in animal models [7,16] or indirectly with hydroxycarbamide in SCD patients [8,17,18], decreases RBC adhesion and reduces the frequency and severity of VOC. This shows the critical role of RBCs in clinical manifestations involving vaso-occlusion, and highlights the importance of investigating RBC adhesive properties in other pathologies characterized by unexplained vaso-occlusive or thrombotic events.

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Hereditary spherocytosis and hereditary elliptocytosis are characterized by hemolytic anemia associated with RBC membrane abnormalities. Although found worldwide, hereditary spherocytosis is more common in individuals of northern European descent, affecting approximately one in 1000–2500 individuals depending on the diagnostic criteria. In contrast, hereditary elliptocytosis is more common in individuals of African and Mediterranean descent (incidence up to 1 : 100 in parts of Africa) than in the rest of the world (incidence 1 : 2000–4000), presumably because it confers resistance to malaria.

The primary defect in hereditary spherocytosis is the loss of RBC membrane surface area leading to a spheroid shape and reduced deformability. Mutations responsible for hereditary spherocytosis can reside in the transmembrane protein band 3, the skeletal protein α and β-spectrins, or in protein 4.2 and ankyrin, two proteins mediating the attachment of transmembrane proteins to the spectrin-based skeleton. The majority of mutations leading to hereditary spherocytosis involves ankyrin and spectrins. The principal defect in hereditary elliptocytosis is a mechanical fragility of the membrane skeleton because of mutations in the transmembrane protein glycophorin C, in the junctional complex protein 4.1, or in α and β-spectrins. As in hereditary spherocytosis, the most common mutations in hereditary elliptocytosis are found in spectrin [19–21], leading to an elliptical shape.

In murine models of hereditary spherocytosis and hereditary elliptocytosis with a high incidence of thrombosis and stroke, Wandersee et al.[22] have shown that RBCs with α-spectrin deficiency exhibit abnormal adhesion to laminin and thrombospondin, which was also observed in RBC from patients with hereditary spherocytosis [22,23].

Although the molecular basis for the adhesion of hereditary spherocytosis/hereditary elliptocytosis RBCs to thrombospondin has not been fully elucidated, a recent study involving two patients with severe hereditary spherocytosis and a 40% deficiency in α-spectrin revealed that hereditary spherocytosis RBCs exhibited enhanced adhesion to laminin that was mediated by Lu/BCAM, the unique laminin receptor in RBCs. Moreover, Lu/BCAM was more easily solubilized from the membrane skeleton of hereditary spherocytosis RBCs than RBC controls. These results suggest that the increased adhesion of hereditary spherocytosis RBCs to laminin may be the result of an impaired interaction between Lu/BCAM and the spectrin-based skeleton, potentially leading to Lu/BCAM clustering or conformational change [23] (Fig. 1). Recently, RBCs from 24 nonsplenectomized hereditary spherocytosis patients were shown to exhibit significantly increased adhesion to human umbilical vein endothelial cells. In this study, the authors provided evidence that the extravascular hemolysis and the ensuing upregulation of RBC production may also contribute to increased RBC adhesive properties in hereditary spherocytosis [24▪].

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Polycythemia vera, also called Osler–Vaquez disease, is the most common myeloproliferative disorder, with a minimum incidence of 2.6 per 100 000 [25,26]. Polycythemia vera is currently considered as a sporadic disease, although very rare familial cases have been reported [27]. Polycythemia vera is characterized by the presence of a V617F activating mutation in the tyrosine kinase JAK2 [28–31]. Patients exhibit high hemoglobin levels and increased red cell mass, with a high risk of thrombosis, a major cause of mortality and morbidity in this disease [32].

Growing evidence supports a role for RBCs in thrombosis. Several mechanisms may explain the participation of RBCs in thrombus formation (reviewed in [33]), among which at least two are observed in polycythemia vera. One is the potential effect of the increased hematocrit on blood viscosity, which directly impacts blood rheological parameters. Another mechanism may involve the capacity of RBCs to activate adhesion receptors, which then initiate abnormal cellular interactions, conferring to RBCs a role in clot formation or stabilization. Adhesion of RBCs to endothelial cells has been shown to be significantly increased in polycythemia vera because of the presence of activated Lu/BCAM protein at the cell surface [34]. Although the red cell lineage is primarily affected by the JAK2V617F mutation in polycythemia vera, the impact of this mutation on the behavior of circulating RBCs in general and on their adhesive phenotype in particular had not been documented until a recent report [35▪]. Using human erythroleukemia and JAK2V617F transfected BaF3 cell lines, they showed that the active JAK2V617F triggers a signaling pathway involving the small GTPase Rap1 and the serine/threonine kinase Akt that directly phosphorylates Lu/BCAM, activating its adhesive function to endothelial laminin [35▪] (Fig. 2). This pathway was also present in RBCs from polycythemia vera patients, the first evidence that downstream pathways are activated by JAK2V617F in circulating polycythemia vera RBCs despite the absence of the erythropoietin receptor in these mature cells. Because Rap1 and Akt are ubiquitously expressed proteins that regulate cell adhesion and cell–cell interactions, one could speculate that this novel role of JAK2V617F is not only restricted to the activation of Lu/BCAM but also to other adhesion molecules such as ICAM-4, which is similarly activated in SCD through phosphorylation [6,7]. This could play a critical role in initiating abnormal interactions between RBCs, leukocytes and platelets, and between blood circulating cells and the vascular wall in polycythemia vera patients. This would open new perspectives on the role of cell adhesion in pathologies characterized by the JAK2V617F mutation or by the deregulation of JAK2-dependent signaling pathways.

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Retinal vein occlusion is a common cause of visual loss and includes central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). These two conditions seem to be mutually exclusive because their association in the same patient is exceptional. Although sharing the same risk factors, namely aging, arterial hypertension and glaucoma, CRVO differs from BRVO by a 10-year lower average age of onset (45 vs. 55 years), a lower prevalence in the general population [36] (0.5 vs. 2% for instance in France) and the existence of familial cases, and by its underlying mechanism. Although BRVO occurs almost always at arterio-venous crossings (suggesting a predominant mechanical factor in the pathophysiology), the location of venous obstruction in CRVO patients is variable [37].

CRVO has a worse prognosis than BRVO with 60 vs. 15% of patients, respectively, who exhibit a final visual acuity in the affected eye of 1/10 or less. Hence, CRVO represents the fifth cause of unilateral blindness and the seventh cause of bilateral loss of vision. Despite the great number of clinical studies on CRVO, its pathophysiology remains obscure, very few risk factors have been identified and there is no medical treatment with recognized efficacy during the acute phase or for preventing recurrence [38].

In CRVO, the acute occlusive phenomenon does not seem related to early thrombus formation, as fluorescein angiography shows a slowing of venous flow without proper shutdown, and the presence of thrombus is not constantly described in the rare pathological cases reported. This is reinforced by the lack of efficacy of conventional anticoagulant therapy in this disease [39].

The observation that 27% of patients with CRVO exhibit spontaneous in-vitro growth of erythroid precursors in the absence of any detectable myeloproliferative disorder raised the hypothesis that the erythroid cell lineage might play a role in the pathophysiology of the disease [40]. Flow cytometry analysis of more than 20 cell surface markers revealed that CRVO patients had a higher number of RBCs expressing membrane phosphatidylserine at the cell surface (1.5–2% RBCs) as compared with RBCs from normal subjects (0.5–08%) [41].

Phosphatidylserine expression at the cell surface was shown to be responsible, at least in part, for abnormal adhesion of CRVO RBCs to endothelial cells. Indeed, under flow conditions, RBCs from patients with CRVO were more resistant to washout and adhered in greater numbers (6–10 fold) than control RBCs. Interaction between CRVO RBCs and endothelial cells could be inhibited by 50–60% in the presence of annexin V (a phosphatidylserine ligand) and of antibodies against or peptide specific for the phosphatidylserine receptor (PSR). These results suggest that phosphatidylserine expressed on CRVO RBCs binds to the endothelial PSR and is largely responsible for the increased RBC adhesion (Fig. 3). However, the cellular and molecular bases of phosphatidylserine exposure at the outer surface of CRVO RBCs remain to be elucidated.

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Gaucher disease was the first lysosomal storage disease described, and has a frequency of about 1/60 000 in the general population and 1/1000 in the Ashkenazi Jewish population. Gaucher disease is caused by β-glucocerebrosidase deficiency, resulting in the accumulation of the incompletely metabolized substrate, glucocerebroside, into the monocyte/macrophage lineage of the liver, spleen, bone and bone marrow, leading to anemia, thrombocytopenia, hepatosplenomegaly, spleen infarction and bone complications [42]. Some Gaucher disease patients exhibit signs of central nervous system involvement (type 2 and 3), but more than 90% of patients belong to the subgroup of nonneuronopathic Gaucher disease (type 1).

The pathophysiology of Gaucher disease is poorly understood, and there are striking variations in its clinical presentation, severity and course. Clinically, some patients may experience painful episodes of bone crisis similar to those observed in SCD patients. Because macrophages overloaded with glycolipids infiltrate the liver, the spleen and the bone marrow, they are considered as the key factor in the pathophysiology of the disease. Although this could explain hematological and visceral manifestations, the cause of the severe debilitating skeletal manifestations, including bone infarcts, remains unknown, and recent studies question the sole role of the macrophages in Gaucher disease [43].

Previous data described accumulation of glucosylceramides in Gaucher disease RBCs, which was associated with abnormal membrane morphologies [44,45]. This led to the hypothesis that Gaucher disease RBCs could be involved in the ischemic events of the spleen and bones. RBCs from nonsplenectomized type 1 Gaucher disease patients were analyzed for their hemorheological properties and their adhesion to laminin and endothelial cells under flow conditions [46▪]. A higher proportion of Gaucher disease RBCs exhibiting abnormal morphologies (dacryocytes, elliptocytes, echinocytes and schistocytes) was observed compared with control RBCs. Hemorheological analyses revealed enhanced blood viscosity, increased aggregation and lower deformability, indicating a membrane elasticity defect. Under physiologic conditions, more Gaucher disease RBCs adhered to human microvascular endothelial cells and to laminin than control RBCs (three-fold), and resisted to shear stress. The Lu/BCAM adhesion molecule was overexpressed and activated by phosphorylation in Gaucher disease RBCs, and played a major role in the adhesion process (Fig. 3). These data suggest that accumulation of lipids in the Gaucher disease RBC membrane might disturb the distribution of membrane proteins at the cell surface, leading to abnormal expression and activation of adhesion molecules, such as Lu/BCAM, which might trigger ischemic events in Gaucher disease [46▪]. Thus, RBCs exhibiting abnormal properties could be involved in the vaso-occlusive events occurring in Gaucher disease, including infarcts of the spleen and bones, which could lead to erythrophagocytosis by macrophages and formation of pathogenic Gaucher cells in several organs. These findings uncover an overlooked aspect of Gaucher disease, and suggest that RBCs could represent most relevant cells for the pathophysiology of the disease (Fig. 4).

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Recent studies on the molecular mechanisms underlying abnormal RBC adhesion in various diseases with thrombotic and/or vaso-occlusion events revealed a complex biology as in SCD, and the unrecognized role of circulating RBC adhesion in some diseases such as those discussed in the present review in which RBCs had not been considered as significant players. Nevertheless, the mechanisms leading to enhanced RBC adhesive properties have not been fully identified.

First, the laminin receptor, Lu/BCAM, appears to play a central role in some of these diseases, but the role of the Lu/BCAM cytoplasmic domain interaction with the spectrin-based skeleton in modulating the adhesive properties of its extracellular domain is unknown; second, although phosphorylation of the Lu/BCAM cytoplasmic domain is central to its activation, the role of dimerization and/or conformational changes of its laminin-binding site in increasing RBC adhesion in polycythemia vera and hereditary spherocytosis has not been investigated; third, abnormal RBC adhesion in CRVO patients has been shown to involve phosphatidylserine, but the exact mechanism leading to phosphatidylserine exposure at the surface of CRVO RBCs, specifically the role of scramblase and/or aminophospholipid translocase alterations, remains to be established. Similarly, the link between abnormal erythropoiesis and abnormal RBC adhesion in CRVO patients has not been identified; finally, recent work showing abnormal RBC properties in Gaucher disease, in which the macrophages are recognized as the main culprit, raises the question for the role of RBCs in osteonecrosis, a common complication of this disease. Further studies correlating the abnormal RBC properties with bone crises and avascular necrosis may provide novel predictive markers for this complication in Gaucher disease.

Nevertheless, it can be expected that the interaction sites between RBCs and endothelial cells might represent general important therapeutic targets for newly designed molecules aiming at inhibiting abnormal RBC adhesion events, independently of the underlying mechanisms (Fig. 5).

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This study was supported by grants from the Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051. The LabEx GR-Ex is funded by the program ‘Investissements d’avenir’ of the French National Research Agency, reference ANR-11-IDEX-0005–02.

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Conflicts of interest

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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adhesion; Lutheran/basal cell adhesion molecule; red blood cells; vascular endothelium; vaso-occlusion

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