The spleen is considered a graveyard for red blood cells. So in case of Splenectomy (complete surgical removal of the spleen), what would be the fate of red blood cells? Would this cause Polycythemia?
The spleen is not the only organ which removes "old" erythrocytes, this happens as well in the liver and the lymph nodes. The whole process is termed Eryptosis, the Apoptosis of Erythrocytes. During the aging of erythrocytes sialic acid on their outer membrane surface is removed. This leads to the recognition by macrophages and phagocytosis of this cells by macrophages which are located in liver and spleen. For more information see this article: "Physiology and Pathophysiology of Eryptosis"
Polycythemia is the state when you have an elevated number of red blood cells, characterized by an increased Hematokrit level. This is caused by the over-production of red blood cells, which can be caused by an overproduction of hematopietic cells in the bone marrow (so called myeloproliferative syndrome, which are basically cancers), the exposure to permanently low oxygen-levels (this is what athletes exploit when the do training at high altitudes) or malignancies (usually lymphoma). It is also possible due to the mis-use of Erythropoietin (EPO) which induces the production of red blood cells. Another possibility for having too much red blood cells is the over-transfusion during a blood transfusion. For further information have a look into the Wikipedia. The article there is pretty complete and contains a number of references.
So in case of Splenectomy (complete surgical removal of the spleen), what would be the fate of red blood cells? Would this cause Polycythemia?
According to wikipedia none of the side effects are related to red blood cell count (just the quality of those cells).
As splenectomy causes an increased risk of sepsis due to encapsulated organisms (such as S. pneumoniae and Haemophilus influenzae) the patient should receive the pneumococcal conjugate vaccine (Prevnar), Hib vaccine, and the meningococcal vaccine; see asplenia. These bacteria often cause a sore throat under normal circumstances but after splenectomy, when infecting bacteria cannot be adequately opsonized, the infection becomes more severe.
An increase in blood leukocytes can occur following a splenectomy.2 The post-splenectomy platelet count may rise to abnormally high levels (thrombocytosis), leading to an increased risk of potentially fatal clot formation. There also is some conjecture that post-splenectomy patients may be at elevated risk of subsequently developing diabetes.4 Splenectomy may also lead to chronic neutrophilia. Splenectomy patients typically have Howell-Jolly bodies5 and less commonly Heinz bodies in their blood smears.7 Heinz bodies are usually found in cases of G6PD (Glucose-6-Phosphate Dehydrogenase) and chronic liver disease.8
Splenectomy can be recommended by inherited blood diseases (e.g. hereditary spherocytosis, thalassemia, etc...) which cause anaemia due to the destruction of abnormal red blood cells in the spleen. After surgery the RBC count is around normal in these cases, so removing the spleen does not cause polycythemia. If you check wikipedia - polycythemia, splenectomy or other spleen related diseases do not cause polycythemia, while polycythemia can cause enlarged spleen which may be removed.
Erythropoiesis and so red blood cell count is regulated by EPO which is regulated by blood oxygen level, so spleen does not regulate the production of red blood cells directly. Removing the spleen cannot cause upregulation of EPO and so polycythemia. Mean erythrocyte age is increased, so in long term there can be a slight increase of RBC count because of a function loss by old cells, but that is not significant enough to cause disease.
- 2010 - Partial splenectomy for hereditary spherocytosis: a multi-institutional review
- 2014 - The spleen and sickle cell disease: the sick(led) spleen
- 2013 - Red blood cell vesiculation in hereditary hemolytic anemia
- 2007 - Erythropoietin after a century of research: younger than ever
- 1982 - Glycosylated hemoglobins (GHb): an index of red cell survival.
To support the speculation that macrophages might also have a function in erythropoiesis in the context of disease and to further characterize their importance in erythropoiesis in vivo, Ramos and colleagues show that macrophages regulate erythroid development in polycythemia vera, β-thalassemia and anemia (Ramos et al., 2013). Chemical depletion of macrophages by clodronate liposome administration prevents mice from recovering from induced anemia, suggesting an essential function of macrophages in promoting stress erythropoiesis in vivo. Conversely, macrophage depletion not only improves the phenotype of polycythemia vera and reverses the pathological aspects of the disease, but also alleviates anemia caused by β-thalassemia. These results propose an important dual role of macrophages in physiological and pathological erythropoiesis in vivo. Both studies suggest that macrophages exert two seemingly contradictory actions on erythropoiesis. On one hand, macrophages are indispensable for stress erythropoiesis in vivo. In their absence erythroid production in the bone marrow and spleen in response to bleeding is impaired. However, macrophages can also be deleterious in the context of polycythemia vera and β-thalassemia, since depletion of macrophages leads to a decreased disease pathology. Moreover, ex vivo cultured human macrophages from polycythemia vera patients promote proliferation of human erythroblasts and diminish differentiation. This suggests a function for macrophages in disease progression since polycythemia vera is characterized by an overactive erythron and excessive erythropoiesis (Ramos et al., 2013). These findings might pave the way to future therapies implementing macrophage depletion in the treatment of erythroid disorders like polycythemia vera and β-thalassemia.
Recovery after surgery is about 4-6 weeks. Liver and lymph nodes can take over the functions of the spleen partially. Every blood cell count may be elevated (esp. platelet count). The functions of the spleen are:
- storing iron (in the form of ferritin or bilirubin, to protect it from pathogens)
- storing blood (for the case of blood loss e.g. injury)
- filtering out damaged or old blood cells (by inherited diseases abnormal red blood cells are removed from blood as well)
- filtering out phatogens, infected blood cells, etc... (to protect the body from sepsis)
And ofc. a lot of immune cells live there. Therefore in rare cases sepsis can occur after splenectomy immediately, and can cause life threatening conditions.
- 2001 - Infectious complications in asplenic hosts
- 1996 - Overwhelming postsplenectomy infection
- 1975 - Immunological studies in the postsplenectomy syndrome
- 1995 - Preservation of the spleen improves survival after radical surgery for gastric cancer.
- 2009 - Effect of splenectomy on antitumor immune system in mice.
- 2012 - Thrombocytosis in asplenia syndrome with congenital heart disease: a previously unrecognized risk factor for thromboembolism.
- 2009 - Vascular complications after splenectomy for hematologic disorders
- 2014 - Review article of macrophages and red blood cells; a complex love story
Asplenic individuals are compromised not only in their ability to destroy infectious agents, but are at increased risk for death from autoimmune disease, certain tumors, and ischemic heart disease. Enhanced mortality is attributed to lack of phagocytes sequestered in spleen that efficiently engulf and destroy appropriate targets, although related cells are found elsewhere.
The spleen contains immune cells, from which macrophages phagocytose the senescent red blood cells. They degrade the hemoglobin into amino acids, bilirubin and iron. The iron is sent to the blood with transferrin, which can be captured and stored by the spleen or the liver or can be used to build new red blood cells in the red bone marrow. The amino acids can be used to build new proteins or they can be degraded by the liver or the kidney. The bilirubin is transported to the liver where it is conjugated and excreted into the bile. The other parts of the red blood cells are recycled as well. For the macrophages it is easier to do this kind of work if you have a dedicated organ which can help to filter out the cells for destruction, but it is not impossible without it, because macrophages live in other organs/tissues as well.
Red blood cells can get rid of damaged parts by creating microvesicles so they can elongate their lives. Vesiculation is facilitated by the spleen. These microvesicles can contain hemoglobin as well, and they are captured by the liver.
- 2004 - The red cell revisited--matters of life and death.
- 2008 - Microvesicles in haemoglobinopathies offer insights into mechanisms of hypercoagulability, haemolysis and the effects of therapy
- 2003 - Hemoglobin loss from erythrocytes in vivo results from spleen-facilitated vesiculation
- RBC Storage
- 2008 - RBC-derived vesicles during storage: ultrastructure, protein composition, oxidation, and signaling components.
The macrophages of the spleen have a remarkable function that enables them to remove unwanted damage from the RBC membrane, leaving the RBC intact (Crosby, 1957; Schnitzer et al., 1972). Removal of these intracellular inclusions seems to occur within the open circulation where the RBC are also checked for their loss of deformability to check for age. To achieve this, RBC must pass through the endothelial slits of the sinus to reenter the blood circulation. During this course, cells that are non-deformable will be removed from the circulation by residential macrophages. In the mean-time all inclusion bodies are also being removed. In splenectomized patients or in patients with a non-functional spleen, phagocytosis of the inclusion bodies fails and results in a retention of a variety of intracellular inclusions within the RBC, such as Howell-jolly bodies (inclusions of nuclear chromatin remnants) (Wilkins and Wright, 2000), Heinz bodies (inclusions of denatured hemoglobin caused by oxidative damage) (Wilkins and Wright, 2000) siderocytes (RBC containing granules of iron that are not part of the cell's hemoglobin) (Wilkins and Wright, 2000) and Pappenheimer bodies inclusion bodies formed by phagosomes that have been engulfing excessive amounts of iron (Wilkins and Wright, 2000).
The molecular mechanism that underlies the removal of inclusion bodies is largely unknown. In Willekens et al. (2003) presented an analogy to the removal of Heinz bodies when discussing RBC that lose hemoglobin through vesiculation. Via the process of RBC vesiculation the RBC loses aggregated hemoglobin, which is important to maintain the homeostasis of RBC, increases in density and becomes smaller (Piomelli and Seaman, 1993). It was suggested that this process is also facilitated by the macrophages of the spleen, in which older cells vesiculate more than younger ones. Clearly, macrophages play a pivotal role in the clearance of damaged content from circulating RBC (Crosby, 1957; Willekens et al., 2003) and vesiculation is an interesting and plausible mechanism to explain the efficient removal of damaged content while leaving the RBC intact (Wilson et al., 1987). The molecular mechanism by which macrophages in the spleen would be facilitating RBC vesiculation is still unknown.
Aged or abnormal red blood cells with exposed phosphatidylserine (PS-RBCs) are cleared from the circulation by splenic macrophages. In asplenic patients, other mononuclear phagocytic cells in tissues and in circulation may function in this capacity.
- 2010 - Activation of mononuclear phagocytes and its relationship to asplenia and phosphatidylserine exposing red blood cells in hemoglobin E/β-thalassemia patients
Suicidal death of erythrocytes (eryptosis) is characterized by cell shrinkage, membrane blebbing, activation of proteases, and phosphatidylserine exposure at the outer membrane leaflet. Exposed phosphatidylserine is recognized by macrophages that engulf and degrade the affected cells. Eryptosis is triggered by erythrocyte injury after several stressors, including oxidative stress.
CD47 on erythrocytes inhibits phagocytosis through interaction with the inhibitory immunoreceptor signal regulatory protein alpha (SIRPα) expressed by macrophages. Thus, the CD47-SIRPα interaction constitutes a negative signal for erythrocyte phagocytosis. However, we recently reported that CD47 does not only function as a ‘don't eat me’ signal for uptake but can also act as an ‘eat me’ signal. In particular, a subset of old erythrocytes present in whole blood was shown to bind and to be phagocytosed via CD47- SIRPα interactions.
- 2013 - CD47 functions as a removal marker on aged erythrocytes
- 2013 - Mechanisms tagging senescent red blood cells for clearance in healthy humans
- 2011 - Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro
- 2011 - Human red blood cell aging: correlative changes in surface charge and cell properties
- 2012 - Naturally Occurring Autoantibodies in Mediating Clearance of Senescent Red Blood Cells