Blood transfusion is a common approach used in the field of medicine especially in the treatment of chronic as well as acute illnesses such as anemia (1). Despite the significance of transfusion therapy, there are negative impacts associated with the practice such as pathophysiologies like incompatible transfusions and hemolytic transfusion reactions (HTRs). The occurrence of hemolytic transfusion reactions can lead to death in some cases since the hemolytic transfusion reactions destroy red blood cells during the transfusion process (2). However, there are cases whereby the occurrence of incompatible transfusions fails to cause pathophysiology. In other cases, mild as well as life-threatening impacts occur as a result of transfusion therapy. For example, there are other types of infectious but serious dangers associated with transfusion therapy which include iron overload, transfusion-associated circulatory overload (TACO), and Transfusion-related acute lung injury (TRALI) among others. In addition, transfusion of blood can have adverse impacts on the immune system of the recipient (3).
Even though blood transfusion has been highly practiced and used to address serious medical problems, it is important to understand the antibodies and antigens of both the donor and recipient. This is attributable to the fact that incompatible transfusion is dangerous as it involves the infusion of red blood cells (RBCs) from a donor whose antigens are against the antibodies of the recipient (4). Such a case triggers the occurrence of hemolytic transfusion reactions which are fatal. Even though there are numerous tests to prevent cases of incompatible transfusion, there are cases when such transfusion occurs and hence, requires the clearance of transfused incompatible RBCs (5).
This paper provides an overview of some of the methods that can be used to clear incompatible red blood cells from circulation. Specifically, the Phosphatidylserine (PS) exposure, SC mechanism, novel mechanism, Band 3 mechanism, the CD47 Mechanism, clearance through the use of Fc receptors, and the complement activation are discussed.
The existence of various types of blood groups on the red blood cells of human beings has led to the growth in the significance of transfusion in the field of medicine. As pointed out in the introduction, with the increased demand for blood transfusion, chances are high that incompatible transfusion of red blood cells might occur (6). However, even though incompatible transfusions are common, it is only a small percentage of the cases involving ABO-incompatible transfusion that results in hemolytic transfusion reactions. Despite this, the occurrence of such reactions varies concerning the specific blood group antigens involved in the process of any transfusion. In addition, there are cases whereby some patients involved in incompatible red blood cells transfusion do not show any response as far as HTRs are concerned.
It is not advisable to carry out incompatible red blood cells transfusion since the hemolytic transfusion reactions are very dangerous and can cause death in some cases. Even though HTRs are fatal and that they occur due to the combination of incompatible antigens, it is important to understand that not every antigen leads to the occurrence of hemolytic transfusion reactions (7). For instance, in the majority of the cases, it is only an insignificant fraction of the incompatible transfusions that lead to apparent cases of HTRs. Some incompatible red blood cells may remain for some days after the process of incompatible transfusion (8). In case incompatible transfusion is done mistakenly or even when there is no alternative, measures should be taken to ensure that the incompatible red blood cells are cleared from circulation.
Phosphatidylserine (PS) exposure
There are cases when nucleated cells undergo suicidal death through a process called apoptosis. During this process, the cellular K+ is lost followed by the shrinking of the cell, phosphatidylserine exposure, cell membrane blebbing, mitochondrial depolarization, as well as the fragmentation of the DNA. As such, as the PS expression increases, the number of aged red blood cells increases, and this correlates with the rate at which the red blood cells are removed from circulation. The PS expression enhances the elimination of the incompatible red blood cells through the help of the macrophages. Initially, it was believed that the PS receptor was only responsible for the recognition of the incompatible red blood cells but nowadays other receptors such as Stabilin-2, Tim4, Tim1 have been identified to help in the mediation of the binding as well as phagocytosis of these cells.
Incompatible red blood cells are efficiently cleared from circulation based on high molecular weight. As such, the saturable cellular mechanism can be used in this case where receptors are used on macrophages. However, the focus in this mechanism is on the use of dose-dependent mechanisms and rapid saturable mechanism but at therapeutic doses. Such an approach results in the formation of pharmacodynamics properties, which has a significant impact on the intensity as well as the action of the incompatible red blood cell hence, allowing their clearance from circulation.
Fc-receptors are known to clear HOD expressing red blood cells. Contrastingly, incompatible red blood cells can be clear by anti-hGPA antibodies through a novel biphasic mechanism. This mechanism involves the agglutination of the red blood cells by the anti-hGPA antibodies; a process that leads to their sequestering from circulation. However, in the second phase, this mechanism requires the input of the phagocytic cells to remove the red blood cells sequestered in the first phase. Unlike in the normal cases, such removal does not require the input of complement or even the Fc-receptors.
Band 3 mechanism
Incompatible red blood cells can be removed from circulation through the Band 3 mechanism, whereby, there is no need for the cells to be apostatized but instead, undergo direct phagocytosis. Band 3 refers to an integral membrane protein that has red blood cells but with separate domains. One of the domains, the cytoplasmic domain, has the capacity of binding different types of protein hence, making it possible to control the function, as well as the structure of the red blood cells. Upon band 3 clustering, a high affinity for Nabs is developed and hence, enhances the clearing of the RBCs from circulation.
Clearance through the CD47 Mechanism
The CD47 approach is considered a suitable approach to clear incompatible RBCs from circulation in case of incompatible transfusion. This clearance can be attributed to the availability of defects in blood transfusion, membrane composition, as well as changes in erythrocyte metabolism. Often, “eat me” signals can be found on the aging red blood cells’ membrane as a result of erythrocyte phagocytosis. The CD47 has undergone conformational change, and for this reason, it is considered to be an “eat me” signal. As such, the presence of CD47, alongside macrophages found in the liver or even in the spleen, helps to clear aged incompatible RBCs transfused.
Clearance through the use of Fc receptors
This is one of the highly understood mechanisms used to clear red blood cells from circulation. The process is mediated by the Fc receptors and leads to phagocytosis. Human beings have different subtypes of IgG including IgG1, IgG2, IgG3, and IgG4. Human beings have FcγR1(CD 64) types of receptors, which can be found in the human macrophages (9). Often, the FcγR1of the humans bind effectively with the IgG1 and IgG3. The macrophages used in the clearance of incompatible red blood cells have a significant role to play in the reticuloendothelial system, which can be considered to connect the lymphoid tissues, bone marrow, lungs, liver, and spleen. With the connection between these organs, it is believed that the major responsibility of clearing incompatible red blood cells is done by the spleen and the liver. As such, the majority of the transfused incompatible red blood cells, particularly the Cr51-Red Blood Cells, are found deposited on the spleen. In addition, the spleen for a long time has been used in the removal of antibody bound, abnormal, aged, as well as complement sensitized red blood cells. In other cases, the spleen’s white blood cells, whose function is to fight pathogens in the blood, as well as filter red blood cells.
On the other hand, the liver through the receptors ensures the clearance of transfused incompatible red blood cells as it is considered to be a pathogen. This is possible due to the presence of Kupffer cells in the liver’s macrophages. As such, the presence of antibodies in blood help to clear the incompatible red blood cells help in the mediation of incompatible red blood cells through the Fc receptors or in other cases through the complement cascade. This is attributable to the fact that antibodies have a damaging impact on incompatible red blood cells. In some cases, the reaction between antibodies and incompatible red blood cells leads to the generation of mechanical stress and eventually the bound RBCs die.
The other approach is the antibody-dependent clearance mechanism (10). Notably, in the process of incompatible transfusion, chances are high that preemptive red blood cells die. The use of the complement system allows the clearance of incompatible red blood cells. This is made possible through the process of intravascular hemolysis (11). The complement system can be defined as a proteolytic series of events that play a significant role in the membrane attack complex formation and comprise the osmotic homeostasis and the membrane of the target. There are three ways through which the complement can be triggered and these include the alternative pathway, which involves complement C3 activation, the lectin pathway, which involves binding through lectin, and the classical pathway, which comprises antibody binding. The IgG3 and IgM activate the classical pathway (12).
The complement proteins can lyse cells intravascularly as well as bind complement receptors (CR). In addition, when the C3 is activated, it is used in biding the majority of the receptors for clearance (13). The cascade process is possible since activated C3 becomes very reactive that it attaches itself to the red blood cells bound and the cells surface. After it is bound, there is a likely formation of C5 convertase or the degradation of C3dg and iC3b. The formation of the various types of C3 can lead to biding diverse complement receptors that are available on a variety of white blood cells.
The alternate mechanism of red blood cells clearance is successful in the presence of an IgG medium. In this case, the FcγR and complement pathways are not used (14). The mechanism focuses on the destabilization of the membrane of the red blood cells, which in turn leads to the eryptosis process (death of red blood cells).
Conclusion and future directions
According to the discussion above, it is evident that transfusion therapy is a significant process especially in chronic illnesses such as anemia. While this is the case, there are several negative impacts in case of a mismatch of blood cells. The implication is that incompatible transfusion ought to be avoided. In case it is a must, the transfusion of red blood cells should be done only in cases where the antibodies of the donor and recipients are compatible. Despite this, there are cases when incompatible transfusion might be necessary especially in a case where it is the only alternative. Nevertheless, it is important to note that such a process puts the life of the patient at a high risk of hemolytic transfusion reactions, which are fatal.
concerning the discussion about there are a few aspects that need to be addressed as far as incompatible blood transfusion and the clearance of RBC is concerned. Even though incompatible transfusion occurs as a result of transfusion of red blood cells from a donor to a recipient where the antigens and antibodies are not compatible, not every antigen leads to the occurrence of hemolytic transfusion reactions. Nevertheless, the occurrence of the hemolytic transfusion reactions is initiated by the presence of different antigens and antibodies in a given blood group system. For this reason, it is advisable to ensure compatibility during transfusion therapy to avoid such cases. However, in case incompatible transfusion occurs, some mechanisms can be used to remove the incompatible red blood cells from circulation. Some of these methods include the complement mechanism and the clearance of incompatible red blood cells through the use of Fc receptors.
There is a need for a clear understanding of the causal role of FcγRs and complement especially in cases of incompatible transfusion in human beings. These receptors have an important role to play in numerous human hemolytic treatment reactions and for this reason, there is a need for future studies that focus on alternate pathways for a complete definition of the biology of hemolytic treatment reactions. Evidence-based therapeutic interventions for the prevention of clinical consequences associated with hemolytic transfusion reactions are not available. It is important, therefore, to have a clear understanding of the rationale for the hemolytic transfusion reactions’ mechanisms. As such, there is a need for effective measures and knowledge on how to clear incompatible red blood cells from circulation. Such an approach would lead to the development of the best therapeutic interventions that can be used in the case of HTRs.
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