Platelet senescence is regulated by an internal timer, not damage inflicted by hits

The mechanisms responsible for the brief life span of blood platelets have been a subject of speculation since the 1950s. The most popular hypothesis to date has been the "multiple-hit" model, whereby damage inflicted by external "hits" triggers recognition and clearance by the reticuloendothelial system. Recently, it was demonstrated that platelets contain an apoptotic pathway that mediates their survival in vivo. Using a novel labeling technique to measure population and cohort survival in mice carrying mutations in this pathway, combined with mathematical modeling, we have studied the internal and external control of platelet fate. Our results cast doubt on the veracity of the multiple-hit model. An alternative model, under which platelets are born with an internal "timer," provides a more parsimonious interpretation of the data. Thus, at steady state, platelet senescence is probably the product of internal processes rather than external hits.