Leukemia takes center (late) stage.

on the activated platelets can bind PSGL-1, strengthening the association between the activated neutrophil microparticle and the platelets. It has been previously established that GPIb directly binds activated leukocyte Mac-1,5 as well as P-selectin expressed on activated platelets/endothelial cells,3,6 enabling GPIb -mediated plateletleukocyte-endothelial cell crosstalk; for example, platelets strongly promote vascular adhesion of leukocytes in atherogenesis.7 Binding of P-selectin on activated platelets or platelet microparticles to leukocyte PSGL-1 initiates signals activating Mac-1, thereby enabling integrin-dependent adhesion to endothelial cells via intercellular adhesion molecule-1 (ICAM-1), or to mural platelets via GPIb (see figure). One of the key findings from this study is that, whereas microparticles derived from unstimulated neutrophils contain relatively low levels of Mac-1 in an inactive state, microparticles derived from PMAor PAFactivated neutrophils contain approximately10-fold enrichment of Mac-1 present in an activated state, where the insert or “I” domain in the M subunit is in a highaffinity ligand-binding form. This was established by binding of conformationdependent antibodies or the Mac-1 ligand, fibrinogen. These relative levels of inactive/ active Mac-1 in microparticles are thought to depend on lipid raft constituency before or after stimulation. This is because microparticles are likely derived from these membrane domains, and activated Mac-1 is enriched in rafts following neutrophil stimulation. There is thus a built-in differential adhesive capacity of microparticles from unstimulated versus activated neutrophils to facilitate interaction with either activated platelets (via PSGL-1/P-selectin) or resting platelets (via active Mac-1/GPIb ), respectively. This implies that microparticledependent platelet activation occurs under conditions where neutrophils are also activated; conversely, microparticles generated from quiescent neutrophils (expressing inactive Mac-1) would be limited to interacting only with activated platelets (expressing surface P-selectin). What, then, is the relevance of these new findings to inflammation and thrombosis, and is there potential diagnostic value in measuring the proportion of total neutrophil-derived microparticles expressing activated Mac-1 as a biomarker for pathological inflammation/ thrombosis? This remains to be determined, but the new discoveries by Pluskota and colleagues demonstrate a clear prothrombotic functional pathway for this microparticle subtype. Conflict-of-interest disclosure: The authors declare no competing financial interests. ■