Immediate, intravascular destruction of recipient red cells should be avoidable. In practice, the main cause is error, when the incorrect blood component is transfused. The most severe reactions occur in major incompatibility, when a group O recipient with high-titre anti-A and/or anti-B, is transfused with group A, B or AB red cells. Less severe intravascular haemolysis occurs when group A red cells are transfused to a group B recipient, or vice versa, because group B and A subjects have less potent ABO antibodies than those of group O. More rarely, intravascular red cell destruction may occur when group O plasma is transfused, by mistake, to A, B or AB recipients. For this reason, group O blood should not routinely be used for non-O recipients; furthermore, this practice leads to unnecessary shortages of group O blood. If unavoidable, the group O blood must first be screened for the presence of high-titre haemolysins or be devoid of plasma.
In the UK, screening for high-titre ABO antibodies is routinely carried out at the blood centre and marked on the bag. ABO-compatible cryoprecipitate, FFP and platelet transfusions should be selected for all recipients, especially for children because of their smaller blood volume. Group A, B or AB plasma components are safe for group O recipients.
Occasionally, there is a laboratory error when antibodies in the recipient's plasma are not detected (or there is insufficient time to complete an antibody screen or compatibility test). In the UK haemovigilance system (SHOT), 30% of reported cases of incorrect blood components transfused were due to clerical or technical errors that originated in the hospital laboratory. The remainder of reports (70%) relate to clerical or admin istrative errors in the ward, collection of the blood from the blood bank, failure to confirm the identity of the patient when taking samples, mislabelling of the sample of blood or failure to perform proper checks before removing the units from the fridge or transfusing the blood. The serious consequences of such failures emphasize the need for set protocols for meticulous checks at all stages. If an identification mistake has been made, it is important to check, as a matter of urgency, that the units intended for the patient under study have not been misdirected to another recipient.
Intravascular red cell destruction is the most dangerous type of haemolytic transfusion reaction; it is associated with activation of the full complement cascade by IgM antibodies and is practically always due to ABO-incompatible blood transfusions (haemolytic anti-A,B, anti-A or anti-B present mainly in the recipient or, rarely, in the donor plasma). Most of these ABO incompatible transfusions are due to identification errors, and occur with an approximate frequency of 1 in 100 000 patients transfused. The mortality rate in such ABO-incompatible cases is 5-10%. In a further 10-15% of cases there is some morbidity.
The symptoms in the recipient are usually dramatic and severe; most are due to anaphylatoxins C3a and C5a that are liberated during complement activation (see Chapter 14), although the cytokines interleukin 1 (IL-I), IL-8 and tumour necrosis factor also play an important role. These molecules cause smooth muscle contraction, platelet aggregation, increased capillary permeability, and release of vasoactive amines and hydrolases from mast cells and granulocytes respectively. Typically, within less than 1 h of the start of the transfusion, when the reaction is symptomatic, the patient complains of heat or pain in the cannulated vein, throbbing in the head, flushing of the face, chest tightness, nausea and lumbar pain. These symptoms are
Table 16.8 Antibodies associated with haemolytic transfusion reactions.
Blood group system
Antibodies implicated in intravascular haemolysis
Antibodies implicated in extravascular haemolysis
K, k, Kpa, Kpb, Jsa, Jka, Jkb, Jk3 Fya,Fyb, Fy3 M, S, s, U (some) Lub (some)
Jsb usually accompanied by tachycardia and hypotension. In severe cases, there is profound hypotension and collapse. Rigors and pyrexia usually follow. Intravascular destruction of red cells brings about liberation of thromboplastin-like substances that activate the coagulation cascade and lead to DIC. The bleeding diathesis and increased destruction of red cells (which may eventually involve the recipient's cells) further exacerbates the problem.
Intravascular destruction of red cells liberates Hb into the circulation. Once haptoglobins are saturated, Hb will also appear in the urine. If haemoglobinuria is very severe, haemosiderinuria may be seen. Renal complications consist of acute renal failure with oliguria and anuria, possibly the result of hypotension and/or the action of activated complement.
The initial symptoms may of course be modified or abolished in anaesthetized or heavily sedated patients, in whom evidence of DIC, hypotension or the presence of haemoglobinuria may be the first signs.
Haemoglobinaemia and haemoglobinuria may also be seen in severe extravascular haemolytic transfusion reactions (see below) and, occasionally, after the transfusion of lysed red cells. This may occur in the following circumstances: inappropriate warming and overheating ofblood; exposure to extreme cold due to faulty storage conditions; lysis due to mechanical problems during administration; or due to the injection of 5% dextrose with the transfused red cells. Severe fulminant toxic symptoms leading to death, similar to those of intravascular haemolytic transfusion reactions, can be seen after the transfusion of bac-terially infected blood, especially if it contains endotoxin-producing organisms (e.g. Staphylococcus and Yersinia species). Haemoglobinaemia and haemoglobinuria may also follow transfusion of blood to a patient with severe autoimmune haemolytic anaemia, due to an increase in the number of red cells in the circulation which will be subject to immune lysis.
Extravascular red cell destruction is mediated by IgG antibodies (Table 16.8). Mononuclear phagocytic cells have receptors for the Fc fragment of IgG1 and IgG3; the binding of IgG-coated cells to these receptors is inhibited by free IgG in plasma. There are no receptors for IgM on macrophages. Red cells sensitized with IgGI and/or IgG3 antibodies, may or may not activate complement up to C3b only. If they do not, they are removed extravascularly (phagocytosis or cytotoxicity) by mononuclear phagocytic cells, predominantly in the red pulp of the spleen, where the plasma is largely excluded and the IgG on the red cells can compete with free IgG in the plasma. However, cells coated with IgG antibodies, which activate complement up to C3b, adhere to the C3b receptor on macrophages and mono-cytes. The presence of C3b on red cells greatly enhances the extravascular destruction of IgG-coated cells. This is because the binding to C3b receptors is not inhibited as there is no native C3b in plasma and consequently IgG-/C3b-coated cells are destroyed by phagocytosis or cytotoxicity, predominantly in the liver, where there are abundant macrophages (Kupffer cells) and a generous blood flow. As C3b is rapidly inactivated by the actions of factors H, I and proteases, a proportion of the cells reenter the circulation coated with C3dg and are resistant to further lysis (Figure 16.3). Red cells coated with potent IgG antibodies, especially if they are C3b-binding, are destroyed mainly by cyto-toxicity. Very rarely, red cell alloantibodies too weak to be detectable by routine pretransfusion testing may destroy donor red blood cells carrying the corresponding antigen.
The features of an immediate haemolytic transfusion reaction vary according to a number of factors: whether the red cells are destroyed within the circulation or in the reticuloendothelial (RE) system; the strength, class and subclass of antibody; the nature of the antigen; the number of incompatible red cells transfused; and the clinical state of the patient. When antibodies are present in the circulation in low titres and a large volume
of incompatible blood is given, all circulating antibody will bind to the incompatible red cells, coating them weakly without destroying them. There will then be no antibody detectable in the serum for a number of days until secondary antibody production is stimulated by the immune challenge. In the presence of an overloaded or poorly functioning RE system, large volumes of IgG-sensitized incompatible red cells can be present in the circulation with minimal or no premature removal, so the Hb level may be stable with little evidence of haemolysis. The DAT will be positive, but as there is no free antibody, elution techniques will be necessary for antibody identification.
Immediate extravascular destruction of red cells may be accompanied by hyperbilirubinaemia, occasionally haemoglo-binaemia due to antibody-dependent cytotoxicity (in severe cases), fever and failure to achieve the expected rise in Hb level. The signs and symptoms are less severe and dramatic than in intravascular haemolysis and usually appear more than 1 h after the start of transfusion (Table 16.8). There may be no signs or symptoms at all. Renal failure is very rare, even when the antibody binds the earlier components of the complement cascade. The symptoms are attributed in a large degree to liberation of cytokines from mononuclear phagocytic cells after binding to
IgG-coated red cells and to liberation of C3a when complement is bound up to C3b. The mortality is extremely low, but, in an already sick patient, the added complication of destruction of transfused red cells may contribute to death.
The management of immediate haemolytic transfusion reactions should be to terminate the transfusion immediately the patient develops the appropriate signs or symptoms. The identity of the patient and the units transfused should be checked against the appropriate documentation. Blood samples must be taken for investigation as in Table 16.9.
The circulating blood volume should be restored and the blood pressure and urinary flow maintained using fluid challenges and furosemide (frusemide) infusion. Monitoring on a high-dependency unit may be required. The renal team should be involved early if urine output is poor (< 1 mL/kg/h) and haemo-filtration may be necessary. Appropriate blood component therapy will be required if there is DIC.
All packs of transfused units should be returned to the blood bank. Pretransfusion samples should be tested in parallel. If no identification mistake is discovered immediately, a sample should be sent for bacteriological testing and all urine passed during the first 24 h should be measured and examined for Hb. Subsequent management depends upon awareness of the possible complications and prompt therapy if these occur. If the patient develops only a rise in temperature, unaccompanied by other symptoms, red cell incompatibility is unlikely and the transfusion should be slowed, under strict monitoring, but need not be stopped.
New technologies to prevent patient identification errors are under investigation in a number of countries. These generally involve bar-coded patient ID details on the patient's wristband and the use, both on the wards and in the laboratory, of a handheld bar-code reader with all data collated by the transfusion computer system. These systems are likely to be developed in tandem with similar arrangements for pharmacy and drug prescriptions, as well as ordering of blood tests and other investigations for patients.
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