The biogenesis of platelets from megakaryocyte proplatelets

Abstract

Platelets are formed and released into the bloodstream by precursor cells called megakaryocytes that reside within the bone marrow. The production of platelets by megakaryocytes requires an intricate series of remodeling events that result in the release of thousands of platelets from a single megakaryocyte. Abnormalities in this process can result in clinically significant disorders. Thrombocytopenia (platelet counts less than 150,000/microl) can lead to inadequate clot formation and increased risk of bleeding, while thrombocythemia (platelet counts greater than 600,000/microl) can heighten the risk for thrombotic events, including stroke, peripheral ischemia, and myocardial infarction. This Review will describe the process of platelet assembly in detail and discuss several disorders that affect platelet production.

Figure 1

Anatomy of a proplatelet. Differential interference contrast image of proplatelets on a mouse megakaryocyte in vitro. Some of the hallmark features of proplatelets, including the tip, swellings, shafts, and a branch point, are indicated. Scale bar, 5 μm.

Figure 2

Localization of microtubules within proplatelets. (A) Immunofluorescence studies on murine megakaryocytes grown in culture and labeled with β₁-tubulin antibodies indicate that microtubules line the entire length of proplatelets, including shafts and the tip. (B) Immunofluorescence studies further show that microtubule coils similar to those seen in mature platelets occur in both proplatelets and released platelet-sized particles (arrow). Scale bar, 5 μm.

Figure 3

Proplatelet amplification. Megakaryocytes increase their proplatelet number through formation of branched extensions off of existing proplatelets. Initially, the shaft of the parent proplatelet (A) is sharply bent (B). This bend then folds back on itself to form a loop (C). The loop elongates to form a new proplatelet with a novel tip (D).

Figure 4

Overview of megakaryocyte production of platelets. As megakaryocytes transition from immature cells (A) to released platelets (E), a systematic series of events occurs. (B) The cells first undergo nuclear endomitosis, organelle synthesis, and dramatic cytoplasmic maturation and expansion, while a microtubule array, emanating from centrosomes, is established. (C) Prior to the onset of proplatelet formation, centrosomes disassemble and microtubules translocate to the cell cortex. Proplatelet formation commences with the development of thick pseudopods. (D) Sliding of overlapping microtubules drives proplatelet elongation as organelles are tracked into proplatelet ends, where nascent platelets assemble. Proplatelet formation continues to expand throughout the cell while bending and branching amplify existing proplatelet ends. (E) The entire megakaryocyte cytoplasm is converted into a mass of proplatelets, which are released from the cell. The nucleus is eventually extruded from the mass of proplatelets, and individual platelets are released from proplatelet ends.