Schematic of the hypothesized platelet production mechanisms in the bone marrow and the lung vasculature. Left-hand side: platelet production in the bone marrow. Right-hand side: platelet production in the lung vasculature. (I) HSCs differentiate and mature into MKs within the bone marrow niche. (II) Thrombopoiesis is hypothesized to occur via 3 different mechanisms in the bone marrow. (II_a) Proplatelet formation in which long, fine protrusions are extended from the bone marrow niche into the sinusoidal vasculature. Shear forces aid in the release of whole proplatelets or large preplatelets that interconvert into barbell platelets that pinch off to form 2 individual platelets. (II_b) Cytoplasmic (explosive) fragmentation in which case preformed platelet territories are released upon MK eruption. (II_c) Membrane budding in which case platelets are formed and released from the MK plasma membrane. (III) Whole MKs migrate out of the bone marrow niche, retaining or leaving behind their nucleus (as indicated by the dotted horizontal line in the nucleus), in the form of large protrusions driven by multiple membrane fusion events. MKs may generate platelets intravascularly as they passage within the venous vasculature. (IV) Thrombopoiesis occurring in the lung vasculature. (IV_a) Immobilized MKs extend proplatelets and undergo similar platelet release mechanisms as seen in (II_c), (IV_b) cytoplasmic fragmentation, and (IV_c) membrane budding. ∗MKs may enucleate within the bone marrow niche²⁶ or within the systemic vasculature⁵⁰ before thrombopoiesis. Figure created with BioRender.com.