Introduction and Overview
The Rhesus factor (Rh) refers to the red blood cell’s(RBC) surface antigen;the name Rhesus comes from the small Indian monkeys in which it was first discovered. Rh incompatibility,sometimes referred to as Rh disease, is a condition that occurs when a woman with the Rh-negative blood type is exposed to Rh- positive blood cells, leading to the development of Rh antibodies. This condition can have fatal outcomes including haemolytic disease of the foetus or newborn, autoimmune haemolytic anaemia and haemolytic transfusion reactions (HTRs). These conditions have, in the past, raised a lot of concerns, and some measures have been put in place to prevent them. Important research is also ongoing to come up with new ways to combat them. This paper aims to analysethe various factors that may cause the incompatibility of red blood cells, and methods by which unwanted cells can be cleared from the bloodstream.
It is important that doctors check the blood types of couples who are planning to have a child, patients who require a blood transfusion and women who are already pregnant, in order to determine if there is a possibility of incompatible red cells that may endanger the patients’lives. Some of the methods used to detect unexpected antibodies include LISS, PEG, solid phase adherence and column agglutination. Theseapply mainly to pregnant women, but can also be used in cross-match blood transfusion.
In cross-match-incompatible transfusion,a donor’s RBCs are infused into a patient who has antibodies that work against the antigens of the donors’ RBCs. Haemolysis of the transfused RBCs usually has fatal consequences, including HTRs. This is the first method of prevention, but there is always a chance that incompatibility has already occurred due to amnestic antibody response, or as a result of a clerical error on the part of the physician. On other occasions, incompatible transfusion can be due to anaemia, which poses an immediate risk of hypoxia. In this case,biphasic clearance can be performed to remedy the situation, as supported by the experiment conducted by (Bloch et al) (1)
HTRs usually occur when the antigen-positive donor’s RBCs are transfused to a patient with antibodiespreformed against the donor’santigens. The result could be the immediate destruction of the donor’s RBCs, a reaction which,though usually fatal,is sometimes mild, occurring after a day or two. Incompatibility of the RBCs is also likely to happen when the recipient’s RBC antigens are attacked by the antibodies of the donor’s plasma. Usually this is not critical, since the amount of antibodiestends to be very low. Incompatibility can be mild or severe, depending on factors such as: the amount of transfused incompatible antigens, determined by the amount of blood transfused; the nature of the antigen, determined by its location and size on the RBC’s membrane; the nature of the recipient’santibodies, whether 1gG or 1gM, and their subtype (1gG3); the amount of RBCs present in the circulation at the time of transfusion; and their ability to activate, complement and bind to the antigens.
Mechanisms
Band 3 and C-dependent
Intravascular haemolysis is the most severe reaction, since it leads to total destruction of the donor’s RBCs. Usually, the haemoglobin is released into the plasma and is then excreted in the urine, making the latter turn adark brown colour. The patient may experience symptoms of jaundice and shock due to the uncontrollable clotting cascade (disseminated intravascular coagulation). The most common cause of this reaction is ABO incompatibility, of which the main complicationsare a delay in engraftment of the donor’s red cells and prolonged red cell aplasia (PRCA). C-dependency can result in persistent isohaemagglutinins in the patient, which suppresshaematopoiesis in the donors’ red cells.
Alternatively,an extravascular haemolytic reaction can occur, in which the macrophages in the spleen and liver remove the donor’s RBCs from the circulation. The antibodies directed at the antigens of the Rh blood antigens usually mediate this type of RBC removal. The extravascular destruction controlsthis kind of haemolysis, and little if any haemoglobin is released into the urine.
White blood cells (WBCs) can also have effects on blood transfusion when they are incompatible. This reaction is usually referred to as a febrile non-haemolytic transfusion reaction (FNHTR). The most common indications include slight rise in body temperature and hotand cold symptoms, which are usually very mild. This condition is thought to be a result of preformed antibodies attacking the transfused WBCs and binding to their antigens. The reaction can also happen whencytokines are released during the storage of WBCs, which can cause fever. The risks of FNHTRs can be managed through removal of the WBCsfrom the blood unit prior to storage.
SC Receptors
Human complement receptor 1 (CR1, CD35) comprises of a single thransmemabrane glycoprotein chain that has a molecular weight of 160-250kd depending on the allotype, and is part of the regulators of complement activators (RCAs) family of proteins. Their main function is to prevent excessive complement activation through inhibition of the significant enzymes, C3 and C5,which have convertases in the three complementary pathways, classical, alternative and lectin. CR1 can inhibit the dependent redcell destruction,thereby reducing the effects of incompatibility.The complement receptor 2 (CR2), which is a primate gene, produces small isoforms and is usually removed during blood storage using a leucocyte removal filter, since it has the potential to cause complications during blood transfusion.
CD-47 Mechanism
CD47 is sometimes referred to as the integrin-associated protein, and is ubiquitously expressed as a 50-kDa cell glycoprotein that functions as a ligand for signal regulatory protein (SIRP),alternatively referred to as CD172a or SHPS-1. CD47 and SHPS-1 comprise a cell communication system (CD47-SIRP system) which has an important role in a variety of cellular processes such as adhesion of B cells, T cell activation and cell migration. The CD47-SIRP system is also implicated in the bad regulation of phagocytosis by macrophages.
CD47,which appears on the surface of several cell types such as platelets, leukocytes and erythrocytes, can be instrumental in offering protection against such phagocytosis through binding the inhibitory macrophage receptor.It has been established that SIRP is a significant immune inhibitory receptor for macrophages. The reaction of SIRP with CD47 leads to the prevention of autologous phagocytosis. Interspecies incompatibility of CD47 contributes to xenogeneic cell rejection by the macrophages. Porcine cells, for the expression of human CD47, can be manipulated to radically reduce the vulnerability of the cells to phagocytosis by human macrophages. In general, the interspecies incompatibility of the CD47 determines,to a great extent,whether the xenogeneic cell will be rejected by the macrophages.
Platelet incompatibility, alternately referred to as post-transfusion purpura (PTP) and thrombocytopenia in medical terms, usually occurs about 5-10 days after platelet transfusion. The risk factors for patients who suffer such an attack include excessive bleeding in the skin, causing a purplish discolouration of the skin that is sometimes referred to as purpura. The main cause of PTP is transfusion of blood to patients who have platelet-specific antibodiesthat react to the donor’sblood cells. This condition commonly occurs in women, since pregnancy increases the likelihood of forming theseantibodies. HPA-1a is frequently targeted in this reaction. The condition can be treated through intravenous injection with immunoglobin to neutralise the antibodies or to remove them from plasma through plasmapheresis.
Complement Activation
This mechanism also contributes to red cell removal and usually happens in an in vivo destruction of red cells. It is especially common during an immune-mediated HTR,in which case the antibodies that bind to red cells contribute to the activation of the complement. The process of activation leads to the haemolysis of intravascular valve. The free haemoglobin is left freely to move into the plasma; should this happen, the end result of complement activation is lysis of red cells. In this way, incompatible red cells can be removed through the introduction of IgM antibodies (Slonim et al)(2). The lysis of red cells leads to their removal. The process can also be described as informingthe removal of sensitised red cells from circulation;this is done though mononuclear phagocytes, which act as a sensitiser. The other process of in vivo cell destruction can also occur through coagulation activation, whereby the antibody-antigen complex works to trigger coagulation, leading to the dissemination of intravascular coagulation (Mamode et al)(3).
PS Exposure
When the donor’s blood is stored in the blood banks, the RBCs usually undergo various structural and biochemical changes that constitute storage lesion. Externalised phosphatidyserine (PS) is a critical indicator for fast recognition and removal of RBCs by the reticulo-endothelial system. Usually, the number of PS-exposing RBCs leads to increased storage in the blood bank. The storage automatically leads to the increase of PS exposure due to hyporosmotic stress (Sweeney)(4).
The proportion of the PS-exposing RBCs after a near-physiological stress to the stored RBCs is usually the same as the proportion that appears shortly after the transfusion. This factor clearly demonstrates that the PS exposure could be a determining factor for the survival of the RBCs within the initial 24 hours following transfusion.
The concentrate production of the RBCsthemselves has some effects on the PS exposure, in that the initial exposure is correlated with the RBCs’ susceptibility to stress-induced PS exposure. There are also certain plasma case factors that the patient may have, which predisposes them to PS exposure on the transfused donor’s RBCs.This results in accelerated clearance of the compatible Hb AA RBCs,although the mechanism that governs this is yet to be established (Moon et al)(5).
Conclusion
In conclusion, the above piece indicates that incompatibility of RBCs can be eliminated, especially if proper mechanisms are considered. This involves analysing the various factors that may cause incompatibility and the methods by which it can be cleared from the bloodstream. Incompatibility can be a result of pregnancy or blood transfusion. In most cases, several tests are performed by physicians to prevent this fatal experience. Several factors can determine the extent to which the recipient experiences severe reactions to the donor’s blood, but there is always a chance of preventing such reactions. One such instance is through extravascular and intravascular haemolytic reaction. The former can occur when the macrophages in the spleen and liver remove the donor’s RBCs from circulation. The antibodies that are directed at the Rh blood’s antigens usually mediate this type of removal. The latter is the most severe reaction, since it leads to total destruction of the donor’s RBCs. Usually, the haemoglobin is released into the plasma and is then excreted in the urine, making it turn a dark brown colour.
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