Geddis's "The root of platelet production" 2007

From Biol557

• Platelets are the first line of defense when bleeding occurs.
• Platelets are pathological in atherosclerosis, acute coronary syndromes, and some cancers.
• Exactly how platelets are deposited into the blood stream was previously unknown.
• A group shows that the platelets are fragments of long proplatelets that extend from megakaryocytes, through sinusoidal endothelial cells, and into the blood vessel.
• They demonstrate this through multiphoton intravital microsocopy.
• Platelets are discoid, anucleate cells, ~2μm in diameter.
• Normally platelets flow along with no reaction to each other or cell the vessel wall. Upon injury, however, they change shape, adhere to the vessel wall and secrete cytokines which initiate vessel repair.
• Thrombocytopenia is the deficiency of blood platelets. This condition can lead to intracranial bleeding, simple bruising, gastrointestinal hemorrhage, or death.
• The body can increase platelet production (thrombopoiesis) 20-fold when needed.
• Thromopoiesis occurs in bone marrow.
• Hematopoietic stem cells generate megakaryocytes which generate platelets.
• We've learned lots about megakaryocytes recently, but we still didn't know how they produced platelets.
• For a long time there were two schools of thought: that cytoplasmic fragmentation occurred (the cytoplasm gotten separated into separate platelets) or that long proplatelet processes were generated via microtubules.
  • Both of these hypotheses had microscopic evidence.
  • Studies demonstrated factors that aided in platelet formation from long processes, but they still didn't know if they were seeing in vitro artifacts or not.
• By way of intravital fluorescence microscopy on the opened cranial marrow cavity of a mouse, Junt et al. showed pro-platelet chunks being sheered off of long, protruding processes by the flow of blood.
• They also showed that these chunks are further broken up on their occlusion of the vessel.
  • "Their findings confirm the decades-old observation that the platelet count in the pulmonary veins (leading out of the lung) is higher than in the pulmonary arteries (leading into the lung), because single proplatelet processes undergo further hydrodynamic processing in the lung into two or more platelets."
• There are, of course, more questions now:
  • How does a megakaryocyte know when to produce these processes?
  • How does the process protrude through the megakaryocyte cell cytoskeleton?
  • Does iron deficiency or inflammation change platelet size and number by affecting pro-platelet formation?
  • Since platelets are only derived from polyploidy megakaryocytes, what is the mechanism by which DNA replication and cell division are uncoupled to generate polyploidiness?