doi: 10.1161/01.ATV.0000227595.97898.3f
© 2006 American Heart Association, Inc.
Editorials |
Vasoocclusion in Sickle Cell Anemia
Are Platelets Really Involved?
From the Hematology-Oncology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia.
Correspondence to Joel S. Bennett, MD, 914 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. E-mail bennetts{at}mail.med.upenn.edu
After reviewing a peripheral blood smear from a patient with sickle cell anemia, one might predict that the clinical consequences of sickle hemoglobin would result simply from vascular obstruction by misshapen red cells. In fact, the pathophysiology of sickle cell disease is far more complex. Besides red cell adhesion to vascular endothelium, it includes the participation of leukocytes, blood coagulation proteins, and platelets.
See page 1626
More than 25 years ago, Hebbel et al observed that sickle red cells adhere to cultured endothelial cells regardless of their state of oxygenation.1 It was found subsequently that sickle red cells, and in particular sickle reticulocytes, express a number of adhesion receptors including the integrin 
4ß1, the immunoglobulin receptor family member ICAM-4, basal cell adhesion molecule/Lutheran (BCAM/Lu), and CD36 that are normally present on red cell progenitors in the bone marrow, but disappear as the progenitors mature into circulating red cells.2,3 Their presence on sickle red cells may be a consequence of the accelerated rate of red cell production in sickle cell anemia and the absence of a functioning spleen. But why these proteins are more prevalent on sickle red cells than on red cells of patients with other kinds of chronic hemolytic anemia is not clear. Nonetheless, these proteins can mediate sickle cell adherence by interacting with ligands present on endothelial cells such as vascular cell adhesion molecule (VCAM)-1 and v-family integrins, as well as proteins present in plasma such as thrombospondin, fibronectin, and von Willebrand factor (vWF). A notable feature of these interactions is that they can be regulated. Thus, thrombospondin binding to CD47 expressed by sickle red cells can enhance 4ß1-mediated red cell adherence of VCAM-1, and epinephrine binding to ß2-adrenergic receptors on sickle red cells enhances both ICAM-4- and BCAM/Lu-mediated red cell adhesion to v integrins.4,5
Prospective studies have suggested that an elevated leukocyte count is an adverse risk factor in patients with sickle anemia, perhaps because leukocytes can adhere to inflamed endothelium and release cytokines and reactive oxygen species that could augment the damage induced by adherent sickle cells. Whether reducing the number of circulating leukocytes in patients with sickle cell anemia is beneficial is not clear from trials of hydroxyurea therapy. In the recently reported Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), there was no apparent correlation between leukocyte count and outcome, suggesting that the previously observed benefit of decreasing leukocytosis could simply have been a surrogate for a beneficial effect of larger hydroxyurea doses.6 On the other hand, circulating activated monocytes have been detected in sickle cell patients and decline with hydroxyurea therapy. Activated monocytes secrete proinflammatory cytokines that can in turn induce endothelial cells to express ligands for sickle adhesion receptors, as well as tissue factor, thereby providing a link between sickle cell–mediated vascular occlusion and activation of blood coagulation.
Markers of ongoing platelet activation, such as P-selectin expression on circulating platelets, increased plasma concentrations of platelet factor 4 and ß-thromboglobulin, and increased numbers of circulating platelet microparticles, have been detected in patients with sickle cell anemia both in the absence and presence of vasoocclusive crises.7 Apropos of these observations, in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Lee and coworkers provide further evidence for a role of platelets in the pathophysiology of sickle cell anemia.8 They report that plasma from patients with sickle cell anemia contained significantly increased amounts of soluble CD40 ligand (sCD40L) compared with plasma from normal controls and patients with anemia not attributable to sickle cell disease. Moreover, the amount of sCD40L increased during sickle cell crises, although not by a statistically significant amount. CD40L (CD154) is a transmembrane protein homologous to tumor necrosis factor (TNF)- that binds to a receptor, CD40, that among other things, induces isotype switching in B lymphocytes, induces an inflammatory phenotype on endothelial cells, and induces tissue factor expression on monocytes.9 CD40L is present in platelets and appears rapidly on the platelet surface after platelet stimulation by agonists, thereby becoming available to interact with CD40 on leukocytes and endothelial cells.10 CD40L is also cleaved from cell surfaces, including the platelet surface, with the resulting soluble product retaining the ability to stimulate CD40-mediated processes.11 Lee et al found that the CD40L content of platelets from patients with sickle anemia was less than half that of control platelets, a difference sufficient to account for the increased amount present in sickle cell patient plasma. Further, they confirmed the presence of increased tissue factor levels in sickle cell plasma and found that CD40L in plasma from sickle cell patients augmented tissue factor production by monocytic THP-1 cells, induced the expression of intercellular adhesion molecule-1 (ICAM-1) on human umbilical vein endothelial cells, and induced the proliferation of Ramos B lymphocytes in culture.
These studies provide a possible way to connect vascular inflammation with vasoocclusion and thrombosis in sickle cell disease, as well as a possible therapeutic target to interrupt the process (Figure). They also raise a number of mechanistic questions. What is the stimulus for platelet activation? Where in the cycle of vasoocclusion and vascular inflammation does CD40L operate? How important is it in initiating vascular inflammation, or is it one of several factors that function to reinforce the cycle it has started? Finally, one is left to marvel at how a single A
G nucleotide substitution could produce a disease as devastating and complex as sickle cell anemia.
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Disclosure(s)
None.
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References |
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Related Article:
- Biologically Active CD40 Ligand Is Elevated in Sickle Cell Anemia: Potential Role for Platelet-Mediated Inflammation
- Sheritha P. Lee, Kenneth I. Ataga, Eugene P. Orringer, David R. Phillips, and Leslie V. Parise
Arterioscler. Thromb. Vasc. Biol. 2006 26: 1626-1631.[Abstract] [Full Text] [PDF]
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