Platelet Activation and Inflammation

While platelets have long been known to play major roles in hemostasis and thrombosis, only recently has their role in the immune response and inflammation begun to be appreciated. Platelets contain high amounts of certain inflammatory mediators, including CD40 ligand (CD40L). Upon platelet activation, CD40L is exposed on the cell surface and then released as a soluble fragment (sCD40L). CD40L acts at one of its receptors, CD40, to induce multiple inflammatory responses that include increased adhesion receptor expression on endothelial cells, B cell proliferation, and tissue factor (TF) expression. CD40L can also bind to GPIIb-IIIa on platelets, induce platelet activation, and promote thrombosis. One disease that displays hallmarks of both platelet activation and chronic inflammation is sickle cell anemia (SCA).  We therefore asked if CD40L might contribute to the symptoms of this disease. We found that SCA plasma contains perhaps the highest levels of sCD40L ever reported in any disease. Platelets from these patients were also significantly depleted of CD40L by an amount that more than accounted for its levels in plasma. Moreover, relative loss of this molecule from platelets appeared to be an even more accurate predictor of SCA severity than the amount shed into the plasma, per se.  The sCD40L appeared biologically active since plasma from SCA patients induced TF production, adhesion receptor expression on endothelial cells and increased B-cell proliferation in a CD40L and/or CD40 dependent manner. A small phase I clinical trial showed that CD40L levels could be safely lowered in the plasma of SCA patients with the GPIIb-IIIa antagonist, eptifibatide. Preliminary studies in SCA mice suggest that blocking CD40L may improve organ pathology. We conclude that platelet-derived sCD40L is significantly elevated, biologically active, and likely to be a major contributor to the inflammatory response in SCA.