In vivo platelet production from mature megakaryocytes: does platelet release occur via proplatelets?

Although platelets are universally accepted to be born from megakaryocytes (MKs), the mechanism by which platelets are formed and released from MKs in vivo remains controversial. One theory, known as the proplatelet theory, postulates that platelets are released from proplatelet processes protruding from MKs into sinusoids located in the bone marrow hematopoietic compartment. Proplatelet formation (PPF) has been observed in in vitro experiments involving detailed analyses of related molecular events. PPF has also been used as a marker of MK maturation. However, PPF is suggested to be a nonphysiological phenomenon. On the other hand, transmission electron microscopy (TEM) analyses have revealed platelet formation via explosive fragmentation of MK cytoplasm in bone marrow and lung capillaries prepared by immersion fixation. Moreover, TEM and scanning electron microscopy studies of liquid-cultured MKs kept in suspension show that platelet formation occurs without PPF. Rather, an explosive and global fragmentation of the MK cytoplasm composed of platelet territories has been reported as the mechanism of platelet formation. In addition, in vivo and ex vivo observations of platelet release from MKs with phase-contrast microscopy strongly support the explosive-fragmentation theory. With all observations taken into account, PPF may not be a prerequisite for platelet release from MKs under real-life conditions. In this review, a new "protoplatelet" concept is proposed to support the explosive-fragmentation theory. Additionally, the role of the lungs in platelet production is reviewed and discussed.