jats:titleABSTRACT</jats:title> jats:pPlatelets are found only in mammals. Uniquely, they have a log Gaussian volume distribution and are produced from megakaryocytes, large cells that have polyploid nuclei. In this Hypothesis, we propose that a possible explanation for the origin of megakaryocytes and platelets is that, ∼220 million years ago, an inheritable change occurred in a mammalian ancestor that caused the haemostatic cell line of the animal to become polyploid. This inheritable change occurred specifically in the genetic programme of the cell lineage from which the haemostatic cell originated and led, because of increase in cell size, to its fragmentation into cytoplasmic particles (platelets) in the pulmonary circulatory system, as found in modern mammals. We hypothesize that these fragments originating from the new large haemostatic polyploid cells proved to be more efficient at stopping bleeding, and, therefore, the progeny of this ancestor prospered through natural selection. We also propose experimental strategies that could provide evidence to support this hypothesis.</jats:p>