Unified hypothesis for the origin of aplastic anemia and periodic hematopoiesis

Abstract

The clinical and laboratory date related to periodic hematopoiesis (PH) are briefly reviewed, and it is concluded that the dynamics of PH probably originate in the hematopoietic pluripotential stem cell (PPSC) population. A model for the PPSC population is developed and analyzed. Based on the model, the simplest hypothesis for the origin of aplastic anemia (AA) ad PH is that they are both due to the irreversible loss of proliferative stem cells. In addition to offering estimates for normal PPSC parameters in man and dogs, the model offers an explanation for the rarity of PH and its obsered dynamics. The hypotheis predicts that for subjects without proliferative PPSC loss and with a normal differentiation flux M out of the PPSC, the effect of cell loss from proliferation will be hypocellularity and pancytopenia. However, in both man and dogs with an M significantly less than normal, loss of proliferating PPSC at a low rate gives mild pancytopenia, loss at a higher rate gives PH, and at an even higher rate severe pancytopenia appears. The threshold M for the appearance of PH in man is predicted to be about 3.7 x 107 cells/kg/day at a minimal period of 17 days. For mongrel dogs, the M at which PH ensues is 6.6 x 107 cells/kg/day and the period is about 9 days. Finally, the hypothesis predicts that the PPSC in subjects with AA and PH will have an increased proliferating fraction, and that stem cells should display an increased doubling time during periods of exponential growth.