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B-Harmony: Are You The Right Type For Me?
Kenichiro Yagi, BS, RVT, VTS (ECC, SAIM)
Adobe Animal Hospital, Los Altos, CA, USA
INTRODUCTION
Blood components transfusions are regularly utilized as a method of treatment for various ailments. Red blood cells (RBCs) are utilized for anemia to supplement oxygen carrying capacity; plasma and its contents are used to provide coagulation factors in coagulopathies; platelets, when available, are used to aid in hemostasis in patients with life threatening hemorrhaging due to thrombocytopenia; and supportive evidence is emerging for canine specific albumin to positively affect the outcome in hypoalbuminemic patients. Less commonly, intravenous immunoglobulin (IVIG) is administered for its immunomodulatory effect in immune-mediated hemolytic anemia (IMHA), immune-mediated thrombocytopenia (ITP), and sudden acquired retinal degeneration syndrome; in addition, specific immunoglobulins are utilized as antitoxins for snake envenomation and tetanus. Complication rates are variable depending on the component being transfused, and can be immunologic or non-immunologic in nature.
IMMUNOLOGIC R ESPONSE AND ANTIGENIC BLOOD COMPONENTS
Immunologic complications are a result of the body’s immune system responding to the foreign blood components transfused. Hypersensitivity reactions result from exposure to antigenic proteins in the transfused blood component. While a hypersensitivity response can occur at first exposure, the response may be even more severe with repeated exposures to the antigens due to the body’s ability to “remember” past exposures and elicit a secondary (“anamnestic”) immune response. Hypersensitivity reactions prompted by blood component transfusions are classified as Type I (Allergic), Type II (Cytotoxic), and Type III (Immune Complex) hypersensitivity reactions in a traditional classification scheme.
Type I Hypersensitivity Type I hypersensitivity reactions, commonly known as allergic reactions, are mediated by immunoglobulin E (IgE) resulting in the production and release of inflammatory mediators. When IgE expressed on the surface of mast cells are cross-linked with an introduced antigen, the mast cell is triggered to release its granules (degranulation). These granules contain inflammatory mediators, enzymes, and cytokines which stimulate the production of more inflammatory mediators. The release of these mediators such as histamine, serotonin, prostaglandins, and leukotrienes results in an acute inflammatory reaction. Clinical signs can arise in seconds to minutes, giving type I hypersensitivity its other name of “immediate hypersensitivity”. Symptoms of type I hypersensitivity are usually mild, and include vomiting, diarrhea, fevers, hives (urticaria), pruritus, and facial swelling. In severe cases, a type I hypersensitivity reaction may result in anaphylaxis. Anaphylaxis in dogs typically manifests as hemodynamic collapse due to the occlusion of the hepatic veins leading to a lowered venous return, cardiac output, and arterial blood pressure. These dogs can show signs of weakness or collapse, become comatose, convulse, or die in a very short time. In cats, anaphylaxis can lead to salivation, vomiting, dyspnea, collapse, and may also lead to death. Evidence of bronchoconstriction, pulmonary hemorrhage, and edema in the respiratory system are seen on necropsy of these feline patients. These reactions can be triggered by any blood product but seem most commonly triggered by antigens on donor white blood cells and platelets. In addition, RBCs that have been stored longer have a higher tendency of causing type I hypersensitivity. Cytokines produced by leukocytes having a role in the hypersensitivity reaction may be the reason for this observation. Any signs of an acute hypersensitivity reaction should prompt the staff to immediately stop the transfusion. In the case of mild reactions an H1 antihistamine such as diphenhydramine may be used for treatment, and cautious administration may be possible after the signs subside. In the case of anaphylaxis, administration of
epinephrine, a glucocorticoid such as dexamethasone, and aggressive fluid resuscitation is recommended.
Type II Hypersensitivity Type II hypersensitivity reactions can occur in response to genetically different RBCs being transfused into a recipient. Surface glycoproteins and glycolipids, which function as cell membrane components such as transport channels, serve as antigens for antibody response and complement activation, leading to intravascular hemolysis. The antibodies also serve as opsonins, which allow for phagocytosis and destruction of the RBCs. This leads to extravascular hemolysis through the mononuclear phagocyte system. The combination of this intravascular and extravascular hemolysis is known as type II hypersensitivity, or cytotoxic hypersensitivity. The time to onset depends on the existence of antibodies against the erythrocyte antigens being introduced. Presence of preexisting antibodies can result in agglutination and hemolysis of the transfused cells. When type II hypersensitivity is triggered due to preexisting antibodies, it is known as an acute hemolytic transfusion reaction (AHTR) due to its rapid onset. If there are no preexisting antibodies to the novel erythrocyte antigens, a delayed hemolytic transfusion reaction (DHTR) may still occur as the transfused cells circulate within the body while antibodies are produced against them, leading to elimination of these red cells. Any subsequent exposure to these antigens will result in AHTR. Clinical signs of type II hypersensitivity vary in severity depending on the amount of incompatible red cells transfused, and the antigenic property of the erythrocyte antigen. The mildest sign is a febrile response. Most severe cases of AHTR can be seen in incompatible transfusions to a previously sensitized patient. These transfusions result in hemolysis of the transfused cells, leading to hemoglobinemia and hemoglobinuria. A large amount of intravascular hemolysis can trigger the coagulation cascade and result in disseminated intravascular coagulation (DIC). Activation of the complement system results in degranulation of mast cells, leading to systemic release of cytokines and inflammatory mediators, ultimately resulting in circulatory consequences of hypotension, bradycardia, and resulting shock. Salivation, vomiting, and diarrhea may also be seen as a result of sympathetic response. DHTR can be symptomatic or asymptomatic. The most common sign is a significant drop in PCV or Hb after the transfusion. Less common signs are fever, hyperbilirubinemia, and reduced urine output. These signs can manifest 3–21 days post transfusion. Type II hypersensitivity reactions are of concern primarily when RBCs are transfused (whole blood, PRBC). However, a potential for red cell contamination of plasma products exist, and while rare, should not be ignored as a possibility. When a reaction is seen, the transfusion should be stopped immediately. Treatment for AHTR involves IV fluids, vasopressor and/or inotropic therapy to combat shock, glucocorticoid administration to suppress the immune response, and supportive care, especially to offset the nephrotoxic effects of hemoglobin, until the foreign red cells are eliminated from circulation.
Type III Hypersensitivity Generalized type III hypersensitivity reactions occur when antigens are introduced intravenously. Serum antibodies form immune complexes with the antigens, and these complexes are normally removed from circulation by binding to erythrocytes and platelets, or eliminated by the mononuclear phagocyte system. In the face of a large antigenic load overwhelming clearance mechanisms, complexes are deposited on vessel walls, leading to vasculitis or arteritis; sites of high blood flow resulting in glomerulonephritis or synovitis; and on blood cells themselves, causing anemia, leukopenia, or thrombocytopenia. Clinical signs of type III hypersensitivity include fever, erythema, edema, urticaria, neutropenia, lymph node enlargement, joint swelling, and proteinuria, and can be seen 1–3 weeks after exposure. The signs seem to be more severe in healthier patients, possibly because of a stronger immune response. Because type III hypersensitivity reactions are caused by formation of immune complexes, blood products containing unbound antigens are potential triggers. Type III reactions have been reported in dogs receiving human serum albumin, and are postulated to occur with IVIG, snake antivenom, tetanus antitoxin, and incompatible plasma transfusions. Patients with symptoms are treated with supportive care.
occurring anti-type B antibodies at a low titer level. When these type A cats are transfused type B red cells, a mild form of type II hypersensitivity occurs. Type B cats have naturally occurring anti-A antibodies at a high titer level, such that even transfusions of a small amount (~ 1 mL) of type A blood will cause severe, hemolytic reactions. Plasma transfusions of the incorrect type can also cause a hemolytic reaction due to the anti-A and anti-B antibodies present. Type AB cats lack both anti-A and anti-B antibodies, making them a universal recipient for pRBCs. However, hemolytic transfusion reactions can be seen in both type A and B plasma or whole blood transfusions to AB cats due to the antibodies present in the plasma. The Mik antigen is a blood group identified in cats distinct from the AB group, for which there are currently no methods to type in clinical settings. Because mismatched transfusions in the AB group system will result in mild to severe reactions, feline donors and recipients should be typed prior to both red cell and plasma transfusions. In-house agglutination based card tests are available for both canine DEA 1 and feline A/B. The DEA 1 test kit has a DEA 1 positive control, negative control, and the test well. The feline test kit has patient control, type A test, and type B test wells. The test well contains murine monoclonal antibodies against erythrocyte antigens to be tested. Agglutination occurs with antibody-antigen complex formation, indicating that the patient is positive for the blood type under evaluation. The control wells can serve to identify any presence of auto-agglutination due to auto-immune disease. However, because the test relies on agglutination for blood type detection, interpretation of blood samples obtained from a patient with auto-agglutination is unreliable. Another type of available in-house blood typing test utilizes immunochromatography to determine blood types. Immunochromatography uses a porous strip impregnated with antibodies in two locations. In the initial sample area, red cells with the target antigens form immune complexes with antibodies that are labeled with a chromatographic substance such as colloidal gold or selenium. The red cells then pass through the detection area with antibodies fixed in place, which stops the migration of the red cells by attaching to them. This results in a colored band as the indicator for the blood type if positive, and a lack of a band if negative. Immunochromatographic tests have the advantage that they can filter agglutinated cells, allowing for blood type determination even when auto-agglutination is present. A comparison study of agglutination card, immunochromatographic cartridge, and gel column (not readily available in clinical settings) blood typing kits for DEA 1 found all methods to be highly accurate (89–91%, 93%, and 100% respectively), making both cage-side test types viable options for blood typing. The immunochromatographic cartridges have the advantages of removing subjectivity on interpretation and allowing typing even with auto-agglutination present as advantages.
Cross-Matching Cross-matching is the act of exposing donor red cells to recipient plasma (major cross-match) and recipient red cells to donor plasma (minor cross-match), with agglutination or hemolysis indicating incompatibility. While the exact protocol for cross-matching is slightly variable depending on the practice, it involves suspending RBCs in saline to achieve a 3–5% solution, washing the red cells 3– times, and preparing four different combination mixtures of recipient red cells and plasma with donor red cells and plasma (major and minor cross match, recipient and donor control). The tubes are then incubated, centrifuged, and graded for the level of agglutination and hemolysis. Some protocols call for microscopic evaluation for agglutination in the absence of macroscopic agglutination, or for comparison of the degree of agglutination in the case of recipient auto-agglutination or when samples from all potential donors show a positive cross-match. This allows for determination of the least reactive match, which would indicate selection of blood least likely to cause harm, and most likely to survive the longest with the recipient. Commercial cross-matching kits are also available, which may help standardize the process, though adding expense. For first time transfusions in canines, the necessity for a cross-match is often debated due to the lack of naturally occurring antibodies for DEA 1 and the unlikelihood of an obvious incompatibility reaction. However, if there is any uncertainty in the transfusion history, or if there is a definite history of a previous transfusion, a cross-match would be in order. However, there are good reasons for feline transfusions to be cross-matched despite our ability to match the blood types through AB type testing.
There have been reports of AHTR occurring even with an AB system match, likely due to the Mik positive blood being transfused to Mik negative cats. Some evidence also exists for antigens not belonging to the AB and Mik antigen groups. Because of these observations, a cross-match prior to all feline transfusions is indicated, in addition to mandatory typing.
BEYOND THE COMPATIBILITY TESTING
While the above mentioned methods are quite effective in minimizing transfusion reactions caused by erythrocyte antigens and alloantibodies contained within plasma products, the compatibility tests available to us cannot screen for every possibility of type II hypersensitivity reactions and reduction of red cell life span. In addition, there are no readily available laboratory methods to test for compatibility of plasma component products. This leads us to think about methods to minimize transfusion-related complications in conjunction with compatibility testing. One of these approaches is appropriate blood product selection through application of concepts in blood component therapy. Reducing the transfusion of unnecessary components or the use of alternatives when available will only help minimize occurrences of immunologic complications. In addition, proper administration protocols and the technical staff’s role in the monitoring of patients receiving transfusions is invaluable in early detection and treatment of complications, should they arise.
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