Published online before print April 6, 2006, doi: 10.1161/01.ATV.0000220374.00602.a2
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© 2006 American Heart Association, Inc.
Thrombosis |
Biologically Active CD40 Ligand Is Elevated in Sickle Cell Anemia
Potential Role for Platelet-Mediated Inflammation
From the Departments of Pharmacology (S.P.L., L.V.P.) and Medicine (K.I.A., E.P.O.), the University of North Carolina at Chapel Hill; and Millennium Pharmaceuticals (D.R.P.), South San Francisco, Calif. D.R.P.’s current address: Portola Pharmaceuticals, Inc, 270 E Grand, Ste 22, South San Francisco, CA 94080.
Correspondence to Dr Leslie V. Parise, Department of Pharmacology, University of North Carolina, CB#7365, Chapel Hill, NC 27599-7365. E-mail parise{at}med.unc.edu
Objective— After activation, platelets expose CD40 ligand (CD40L) on their surface, then subsequently release the inflammatory mediator as a soluble fragment (sCD40L). Because sickle cell anemia (SCA) is noted for both platelet activation and chronic inflammation, we asked whether platelet-released CD40L potentially plays a role in SCA.
Methods and Results— ELISAs demonstrate that SCA patient plasma contains 30-fold more sCD40L than control plasma. Correspondingly, platelets from these patients contain less than half the CD40L found in control platelets. Platelets from patients in painful crises are further depleted of CD40L, with even higher plasma levels, suggesting a correlation to the patient’s clinical state. In addition, elevated sCD40L correlates with increased tissue factor in SCA plasma. Blockage of the CD40L receptor CD40 reduces SCA plasma-induced production of tissue factor and endothelial intercellular adhesion molecule-1 (ICAM-1). Finally, sCD40L activity in SCA plasma is confirmed by its induction of B-cell proliferation.
Conclusions— Platelet-derived sCD40L is elevated in SCA, further elevated in crises, and biologically active. The participation of sCD40L in SCA plasma-induced production of B cells, tissue factor, and ICAM-1 suggests that CD40L may contribute to the chronic inflammation and increased thrombotic activity known to occur in SCA.
CD40L is elevated in plasma but depleted from platelets in sickle cell anemia (SCA). These differences are exaggerated during painful crises. CD40L is implicated in SCA plasma-induced production of tissue factor, ICAM-1, and B cells, suggesting that platelet-derived CD40L contributes to inflammation and coagulation in SCA.
Key Words: CD40L • sickle cell anemia • platelets • inflammation • coagulation
Related Article:
Arterioscler Thromb Vasc Biol 2006 26: 1415-1416.
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