Kinetics of platelets, megakaryocytes and their precursors: what to measure?

A sequential exploration of the kinetics of platelets, megakaryocytes, and their progenitors is devised, wherein abnormalities at one level of differentiation are the subject of further analysis at the preceding level. Platelet kinetics yield estimates of mean platelet life span, fraction of platelet mass in circulation and daily production, making it possible to recognize the disorders of hyperdestruction, hypersequestration, hypoproduction, and hyperproduction. Theoretical considerations and regression analysis of a variety of computer-simulated survival tests show that sufficient information is contained in the first four days of the disappearance curve of population labeled platelets to provide an estimate of mean life span with an error of 9%--15%. Identifying the type of destruction disorder depends on developing tests and parameters which will make it possible to integrate into a coherent model such indices as the rate of senescence, the rates of reversible and irreversible aggregation, and the rates of adhesion to and phagocytosis by the reticuloendothelial system. Foremost among the existing models is the multiple-hit theory, although its validity rests on the unproved assumption that platelets keep a permanent memory of their injuries. Identifying the type of production disorder is the purpose of megakaryocyte kinetics. The daily production of megakaryocytes could be derived from the daily platelet production and the number of platelets released per megakaryocyte; determining megakaryocyte number would also yield the mean megakaryocyte maturation time. All these parameters could be obtained by combining a simple radioiron dilution method with cytochemical identification of megakaryocytes and with advanced, automated morphometric techniques. Abnormalities of megakaryocyte number and size can be further analyzed by studying the kinetics of thrombocytic precursors in tissue culture, i.e., by recording the distribution of precursor doublings and megakaryocyte ploidy histograms. The application of these techniques to cultures of bone marrow suggest that endomitosis may be initiated by any megakaryocyte precursor and that the kinetics of this process influence the number and final ploidy level of megakaryocytes.