Evolution of blood platelets
50,000 platelets are produced in our body every second, split off from their mother cells called megakaryocytes in the bone marrow. To maintain a balance 50,000 platelets are also used up or removed every second. Why do mammals produce so many blood platelets? Why is there such a rapid turnover?
In a previous blog I talked about the role of platelets as special cells of the innate immune system and their function as first line of defense. Something happened about 100-120 million years ago that is uniquely mammalian: the change from large, nucleated thrombocytes to small, numerous, and platelets that have no nucleus. All vertebrates—animals with back bones or spinal columns—that evolved before mammals, such as fishes, amphibians, reptiles, and birds, have nucleated thrombocytes. Only mammals have platelets without nucleus. Blood—in contrast to hemolymph—evolved in vertebrates because blood requires bone marrow for its production. Consequently, both nonmammalian thrombocytes and mammalian platelets are produced in the bone marrow. The evolutionary change from thrombocytes to platelets means that the cell nucleus is left behind within the relative safety of the bone and only the parts necessary for immune and hemostatic function are released – why?
Here is a theory. It is illustrated in the figure below. Leaving the nucleated mother cells of platelets—megakaryocytes—in the shelter of the bone marrow protects them from viruses that need a nucleus for replication. So-called DNA viruses such as herpes and chickenpox can replicate in thrombocytes but not in blood platelets.
Another advantage of producing a large number of small platelets is the large surface area. The immune and blood clotting functions of platelets require interactions on the cell surface. Viruses bind to receptors on the cell surface.1 One trillion platelets provide a large surface area with many receptors and an increased probability for binding viruses.
Interestingly, erythrocytes evolved to red blood cells also losing their nuclei. Again, evolution provided protection from viral replication in anucleated red blood cells. In addition, many small, specialized red blood cells are able to deliver more oxygen to mammalian tissues.
Model of blood cell production in nonmammalian and mammalian vertebrates adapted from Svoboda & Bartunek.2 In nonmammalian vertebrates (fishes, amphibians, reptiles, and birds) and mammalian vertebrates blood is produced in bones starting with similar common parent cells—homologous progenitors. Thus, thrombocytes and erythrocytes as well as platelets and red blood cells have common parent cells that mature through stages until they are specialized cells. Mammals require more clotting function3 and more oxygen than nonmammalian vertebrates. However, simply increasing the number of thrombocytes and erythrocytes would have dramatically increased the susceptibility for DNA virus replication.
Platelet interaction with viruses
Human platelets have no nuclei and are therefore protected from DNA virus replication within the cells. But how do platelets interact with DNA viruses and what about RNA viruses that don’t require a nucleus for replication? The viruses that are on the news lately such as Dengue virus, severe acute respiratory syndrome (SARS) virus, influenza viruses like H1N1, and the new coronavirus are RNA viruses. In addition, HIV, coxsackie, hepatitis A, C, D, and E are also RNA viruses. What are blood platelets doing with them?
The quick answer is: Platelets catch all viruses, take them to the spleen and together they get removed.
Platelets interact with many viruses through their surface receptors—proteins on the surface that send signals into the cell once a virus has bound. Platelets have to be in their resting, non-activated state in order for the receptors to be expressed on the surface and be functional. Both DNA viruses such as cytomegalovirus (CMV), Epstein-Barr virus and hepatitis B virus as well as RNA viruses interact with receptors on the surface of blood platelets. The binding of viruses has been shown to cause platelet activation.4 Resting platelets engulf some viruses such as dengue5 and influenza6 which are both RNA viruses; in the process the platelets get activated. During activation platelets also release substances from their granules which can modulate the immune response. Serotonin, which is released from dense granules of platelets, produces fever. The activated state of platelets is a trigger for the macrophages in the spleen to remove these platelets together with the viruses. Consequently, the platelet count of patients with infections goes down. In severe cases this phenomenon is known as thrombocytopenia.
In summary, platelets are not susceptible to DNA virus replication because they lack a nucleus. Platelets have to be in their resting state—discoid and not activated—to be ready to fight both DNA and RNA viruses. Platelets capture viruses with their surface receptors, sometimes also take them up, and activate during this process. The activated state signals the spleen to remove these platelets including their cargo. By this mechanism viruses are cleared however with the consequence that the platelet count decreases. It is important that platelets are not already activated when they get into the fight with viruses. Activated platelets are being challenged already with other pathophysiological conditions.