Response of platelet production to stresses. (A) Under steady-state conditions, early MK precursors develop over several days in the bone marrow into mature MKs that move to sinusoids and extend proplatelets through the endothelium into the bloodstream to shed platelets. Progression of early MKs is determined by the levels of TPO coming from blood, where most is bound by receptors (Mpl) on circulating platelets. (B) When circulating platelet numbers drop, the resulting rise in TPO reaching early MKs stimulates increased numbers to complete development and produce platelets, restoring steady-state levels after several days. (C) In a response proposed by Machlus et al, physiologic stress stimulates activated platelets and other cells to release CCL5/RANTES, which can directly stimulate mature MKs to rapidly increase platelet production, creating increased levels associated with reactive thrombocytosis. (D) Acute systemic inflammation and/or immune-modulated platelet loss produces increased levels of IL-1α, which, according to Nishimura et al,⁹  can directly stimulate mature MKs to undergo a rupture mode that allows them to rapidly shed large numbers of platelets that are somewhat larger than normal but otherwise functional. Illustration by Fred G. Pluthero.