In this episode, Neutrophil meets Backward Cap Platelet who is training alone to become stronger. Backward Cap Platelet struggles to work with the other platelets to form a primary blood clot, but she receives encouragement from Neutrophil to use her positive attitude to motivate the other platelets. Walking along the temporal vein in the head, they are struck by a head bump which ruptures the capillaries, sending the cells flying in zero gravity. The platelets, including Backward Cap Platelet, try unsuccessfully to form a primary blood clot. They are spurred on by Megakaryocyte; though, to form the primary blood clot and the fibrin mesh, with Backward Cap Platelet risking her life to save a stray coagulation factor. The platelets save the day as they seal the damage and are rewarded for their hard work.
Following on from previous blog posts where I describe how red and white blood cells and T cells develop in the body, in this blog post I will talk about how platelets develop in the body, how platelets assist in repairing the damage produced by bruises and head bumps and the factors that can enhance platelet activity.
The development of platelets
| Schematic | Microscopic | Anime |
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Megakaryocytes are bone marrow cells that produce membranes and proteins to form platelets. They are mostly found in the bone marrow, specifically near the blood vessels where they release proplatelets, the precursors of platelets, into the bloodstream.
Megakaryocytes are derived from haematopoietic stem cells (HSCs). Similar to the development of red blood cells, HSCs differentiate into common myeloid progenitors (CMPs) and megakaryocyte-erythroid progenitors (MEPs). From there, some MEPs commit to becoming megakaryocytes by expressing certain factors such as von Willebrand Factor (vWF). There are three types of megakaryocytes in the bone marrow:
- Promegakaryoblast: the earliest form of a megakaryocyte.
- Megakaryoblast (stage I megakaryocyte): these cells possess a large kidney-shaped nucleus to fit numerous copies of the genome. The cytoplasm has a large amount of ribosomes to mediate massive protein production but do not have granules, the intracellular stores of secretory proteins. Lastly, there is some blebbing on the plasma membrane of the megakaryoblast.
- Promegakaryocyte (stage II megakaryocyte): these are larger megakaryocytes with granules containing secretory proteins. At this stage, the promegakaryocyte splits off cytoplasm to the separating proplatelets.
Megakaryocytes undergo a number of stages in the bone marrow and the bloodstream to produce platelets:
- Endomitosis: megakaryocytes replicate or copy their DNA many times without undergoing cell division. This results in multiple sets of chromosomes being stored in one nucleus (known as polyploidy). Possessing multiple copies of the genome allows the megakaryocyte to produce a lot of proteins to facilitate platelet development.
- Maturation: the megakaryocyte rapidly expands to fit the numerous internal structures required to produce platelets. The most important internal structure in the megakaryocyte is the invaginated membrane system (IMS), an extensive network of intracellular membranes. The IMS acts as a membrane reservoir in which to form proplatelets. The megakaryocyte also has tubules that produce prostaglandin and thromboxane and granules that store proteins and substances essential for platelet activation and blood clotting.
- Proplatelets: proplatelets are cells consisting of beads of cytoplasm (which eventually become platelets) joined by thin cytoplasmic bridges. Proplatelets are derived from cytoplasmic extensions of a megakaryocyte that elongate, branch off and separate from the cell body. Eventually, almost all of the megakaryocyte cytoplasm are sectioned off into proplatelets which surround the naked megakaryocyte nucleus. Combined with the fact that DNA and chromosomes are not allocated to separate cells during endomitosis, proplatelets and platelets do not have a nucleus.
- Bloodstream: proplatelets squeeze in between the endothelial cells of the bone marrow blood vessels and enter the blood stream. In the bloodstream, the cytoplasmic bridges of the proplatelets break, cutting up the proplatelets into platelets.
Did you know? In the episode, Megakaryocyte appeared outside the bone marrow to motivate the platelets to form a primary blood clot. In real life, some megakaryocytes can appear outside the bone marrow by squeezing in between endothelial cells of a blood vessel to enter the blood stream. In particular, megakaryocytes can be found in the lung where they can produce a small number of platelets.
The role of platelets in bruises and head bumps
Blood vessels underneath the skin, particularly the capillaries, can break if the person experiences a high-force injury such as a fall or collision. In these cases, blood and tissue fluid can accumulate underneath unbroken skin, causing discolouration and swelling. Depending on where the injury is, this can result in a bruise or a bump. A bruise occurs when blood leaks underneath unbroken skin, causing discolouration associated with a black or blue area. The leaked blood can also compress the nerves around the area, resulting in pain and tenderness. A bump is similar to a bruise, but it is associated with swelling with or without discolouration. Bumps typically appear on the forehead when it hits on a hard object such as the ground. This is known as a head bump.
When blood vessels are ruptured in a bruise or bump, platelets are activated to aggregate into a primary blood clot. The activated platelets then form a fibrin mesh to close the hole, giving the blood vessels time to repair the damage. These processes occur via primary and secondary haemostasis respectively which are described in a previous blog post from season 1 of the anime. Eventually, repair of the blood vessels stops blood leaking into the area. The lymphatic vessels drain the blood and tissue fluid away from the area, allowing the bruises and bumps to subside.
Further stimulation of platelet activity
In the episode, the platelets struggle to form a primary blood clot as the blood cells continue to get flown around. They get scolded by Megakaryocyte for not quickly forming the primary blood clot. However, Megakaryocyte motivates the platelets by showing them a gold medal which would be rewarded to the hardest working platelet. This spurs the platelets to form a primary blood clot which forms the foundation for repairing the damage.
In reality, megakaryocytes do not go out of the bone marrow to promote platelet activity around the body. However, similar to the gold medal in the episode, there are numerous substances that can promote platelet activity by binding to receptors on platelets. For example, thrombin, an enzyme that converts soluble fibrinogen into insoluble fibrin to form the fibrin mesh, is also a potent platelet activator. By cleaving the outside of protease-activated receptors (PARs) on platelets, thrombin can promote the aggregation of platelets, allowing them to form a primary blood clot. Adenosine diphosphate (ADP) is also a substance that can promote platelet activity. Released from damaged blood vessels and activated platelets, they act on purinoceptors such as P2X1 and P2X12 receptors. This interaction stimulates platelets to release proteins from granules, change its shape and aggregate with other platelets.
Conclusion
Platelets are essential for sealing broken or damaged blood vessels, stopping not only mild and severe bleeding but also internal bleeding associated with bruises and bumps. Platelets are derived from megakaryocytes which undergo numerous stages to produce enough membranes and proteins to form platelets. From there, platelets circulate around the body, where on contact with damaged blood vessels become activated via the coagulation cascade (explained in a previous blog post). They are further activated by external substances such as thrombin and ADP which drives them to build a primary blood clot and form a fibrin mesh. This gives the blood vessels time to repair the damage, sealing the holes which stops the bleeding and allows the bruise or bump to subside.
I will be doing two blog posts covering the two halves of the next episode. In the first blog post, I will talk about the role of vaccines in preparing the body to fend off a common preventable infectious disease. In the other blog post, I will talk about the role of Peyer’s Patches in fending off a certain gastrointestinal infection. See you then!
References
Most of what I have learnt about platelet development comes from Machlus’ and Italiano’s excellent chapter on Megakaryocyte Development and Platelet Formation from the academic book Platelets (2019, edited by Alan Michelson, Marco Cattaneo, Andrew Frelinger and Peter Newman). They also published a review on the same topic which is free to the public. Check either of them out if you want to learn more about how platelets develop in the human body.