Proceeding of the LAVC Latin American Veterinary Conference Oct , 2011 Lima, Peru

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1 Close this window to return to IVIS Proceeding of the LAVC Latin American Veterinary Conference Oct , 2011 Lima, Peru Next LAVC Conference: Apr , 2012 Lima, Peru Reprinted in the IVIS website with the permission of the LAVC

2 TRANSFUSION MEDICINE FOR THE GENERAL PRACTITIONER Elisa M. Mazzaferro, MS, DVM, PhD, DACVECC Wheat Ridge Veterinary Specialists Wheat Ridge, Colorado, USA HISTORY OF TRANSFUSION MEDICINE In the early 1600's, Richard Lower first described blood being taken from the femoral artery of a dog, and infusing it into the jugular vein of a second dog. Further experimentation with blood taken from and instilled into different species was found to be associated with several abnormal physiologic reactions, leading to the proposition that "like transfuses like". In fact, transfusion of cow and sheep blood into human patients caused documentation of the first known transfusion reaction, characterized by injection site discomfort, tachycardia, diaphoresis, nausea, renal pain, and black discoloration of the urine. Further research in 1910 allowed the discovery of four agglutinins and hemolysins on canine red blood cells (RBC's). By 1949, a total of six blood groups had been identified in dogs. Advances and progress in veterinary medicine have led to a more routine need for and use of canine and feline blood products as therapy for a variety of diseases. CANINE AND FELINE BLOOD TYPES Cell membrane receptors on the surface of RBC's serve the purpose of self- versus non-self recognition during states of health. The presence or absence of various glycoprotein and glycolipid moieties on the RBC surface help to define blood groups or "types" within an animal species. In dogs, six cell surface dog erythrocyte antigens (DEA's, 1.1, 1.2, 3, 4, 5, and 7) have been identified. Dogs that are negative for DEA 1.1, 1.2, and 7, but positive for DEA 1.4, are know as "universal donors" and in the past, were known as Type A- negative blood. DEA 1.1 and 1.2 are the most immunogenic RBC antigens known in canine transfusion medicine. Transfusion of DEA 1.1 or 1.2 positive blood to a DEA 1.1 and 1.2 negative dog can result in immediate hemolysis or a delayed-type hypersensitivity reaction. Additionally, viability of DEA 1.1 and 1.2 positive cells in a DEA 1.1 and 1.2 negative recipient is short-lived, ultimately defeating the long-term goal of increasing oxygen carrying capacity and oxygen delivery in the recipient. Like dogs, feline blood groups are defined by specific carbohydrate moieties attached to lipids (glycolipids) and proteins (glycoproteins) on the RBC surface. Three blood types (A, B, and AB) have been identified in cats. Type A, defined by the presence of N-glyconylneuraminic acid, is the most common blood type in cats. Type B, defined by the presence of N-acetylneuraminic acid, most commonly occurs in Abyssinian, Persian, Devon Rex, and British Shorthair cats, but can be found in domestic shorthair and longhair cats (DSH, DLH) as well. The incidence of Type B cats is higher than the normal population throughout the Pacific Northwest portion of the United States, and areas of Australia. Type A is completely dominant over Type B by simple Mendelian genetics. Type AB is an extremely rare blood type that has been infrequently identified in DSH, Birman, Abyssinian, Somali, British Shorthair, Scottish Fold, and Norwegian Forest Cats. Unlike dogs, cats possess naturally occurring antibodies against other feline blood types. The presence of naturally occurring auto-antibodies is of paramount importance, necessitating blood typing with or without crossmatch prior to any feline transfusion, as hemolytic transfusion reactions can potentially be fatal. Type B cats possess large quantities of anti-a antibodies, primarily of the IgM subclass. Type A blood infused into a Type B cat will be destroyed within minutes to hours, as little as 1 ml of incompatible blood can cause a life-threatening reaction. Type A cats typically possess weak Anti-B antibodies of both IgG and IgM subtypes. Transfusion of Type B blood into a Type A cat will result in milder clinical signs of reaction, and a markedly decreased survival half-life of the infused RBC's to just 2 days. Since Type AB cats possess both moieties on their cell surface, they lack naturally occurring alloantibodies; transfusion of Type A blood into a Type AB cat can be performed safely if a Type AB donor is not available. BLOOD BANKING AND SELECTION OF DONORS Blood donors should receive annual physical examinations and general health screens, including a complete blood count, serum biochemistry panel, and occult heartworm antigen test. A recent consensus panel of the American College of Veterinary Internal Medicine divided various categories of conditional testing and mandatory testing for vector-borne and nonvectorborne diseases. Organisms that can be transmitted to recipients from donor blood, can cause subclinical infection in a donor, can be cultured from the blood of an infected animal, or can results in a significant difficult to treat infection should be tested for in all canine and feline donors. Canine donors should also be screened initially for Babesia canis and gibsoni, Leishmaniasis, Ehrlichiosis, Anaplasmosis, Neorickettsiosis, and Brucellosis. Other vector-borne diseases that should be considered are Bartonellosis, Hemoplasmosis, and in dogs from Texas or the Southwest United States, Trypanosoma cruzi, or Chagas disease. Routine testing for Rickettsia rickettsii (Rocky Mountain Spotted fever)

3 or Borrelia burgdorferi (Lyme disease) is not recommended. There have been documented reports of donor blood causing the following infections in recipient dogs: Babesiosis and Leishmaniasis. Dogs should ideally weigh greater than 50 pounds (27 kg), be between 1-8 years of age, have a PCV of at least 40%, be spayed and/or nulliparous, and have never received a transfusion. If a potential donor s breeding history is unknown, a serum antibody test directed at specific red blood cell membrane antigens can be performed. If the potential donor does not have antibodies directed against red blood cells, it can be used as a donor. Feline blood donors should ideally weigh greater than 10 pounds, be between 1-8 years of age, are spayed and have never received a transfusion. Additionally, donor cats should be screened for FeLV, FIV, Hemoplasmosis (Hemobartonella felis/mycoplasma haemofelis), and Bartonellosis prior to donations. Cytauxzoon felis, Ehrlichiosis, Anaplasmosis, and Neorickettsia testing is not routinely recommended in cats. Because feline infectious peritonitis testing is often equivocal in cats, routine antibody titers to coronavirus (FIP) is not recommended. Further routine screening for Toxoplasma gondii is also not routinely recommended in feline donors. Each cat donor should have a minimally acceptable PCV of 30%, although between 35-40% is preferred. INDICATIONS FOR TRANSFUSION THERAPY There are many indications for administering transfusions of whole blood and component blood products. A step-wise approach should be taken for every patient that may require a transfusion. If a patient is at risk for blood loss, or is anemic, a transfusion should be considered. A decision should be made on the type of transfusion therapy appropriate for each particular patient. Once a decision is made about which components need to be administered, the clinician should calculate a volume to be delivered. Caution should be exercised when administering larger volumes to small patients or those with cardiac insufficiency, as volume overload with subsequent pulmonary edema can potentially occur. If red blood cell products are to be administered, a minimum of a blood type should be performed before giving type-specific blood. The gold standard is to perform a cross-match for each unit administered, to decrease the risk of a transfusion reaction or sensitizing the patient to foreign RBC antigens. In some cases of severe hemorrhage when there is not enough time even for performing a blood type, universal blood (DEA 1.1, 1.2 and 7 negative) can be administered. CROSS-MATCH PROCEDURE Prior to administering blood products, knowledge of the donor and recipient's blood types, and a crossmatch procedure should be performed, as time allows. At minimum, a blood type should be performed prior to administration. Rapid blood typing cards are available for use in dogs and cats (Rapid-Vet Feline and Canine blood typing cards, DMS Laboratories, Flemington, NJ). The card test appears to be accurate for identifying DEA 1.1 positive and DEA 1.1 negative dogs, although some cross-reactivity with DEA 1.2 can occur, causing equivocal results. In cats, the card test appears to be sensitive for identification of Type A or Type B, but is less sensitive for Type AB cats. If equivocal results occur, the donor or recipient s blood should be sent to an outside laboratory such as Easter Blood Bank of University of Pennsylvania for more definitive testing and typing. A cross-match procedure simulates in vitro the response of a recipient to donor plasma and red blood cell antigens. The cross match procedure is performed to decrease the risk of transfusion reactions in patients that have been previously sensitized, that have naturally occurring alloantibodies, or in situations of neonatal isoerythrolysis. Other indications for cross-matching include decreasing the risk of sensitizing a patient if more than one transfusion is anticipated. Cross-matching can be divided into major and minor categories. The major cross-match mixes the donor's RBC's with recipient's plasma, thus testing whether the recipient contains antibodies against donor RBC's. A minor cross-match mixes donor plasma with recipient RBC's, testing for the unlikely occurrence that the donor serum contains antibodies directed against recipient RBC's. The crossmatch procedures do not check for other sources of immediate hypersensitivity transfusion reactions, including white blood cell and platelets. There is a commercially available kit for cross-matching, but is not as sensitive or specific as the more labor-intensive in-house laboratory mixing of donor and recipient blood cells and plasma. It is a common misconception that administration of whole blood or packed RBC's (prbc's) should occur when patient PCV decreases to a certain number. In fact, no absolute "transfusion trigger" number actually exists. A transfusion should be administered whenever a patient demonstrates clinical signs of anemia, including lethargy, anorexia, weakness, tachycardia, and/or tachypnea. Indications for fresh whole blood transfusion include disorders of hemostasis and coagulopathies including disseminated intravascular coagulation, von Willebrand's disease, and hemophilia. Fresh whole blood and platelet rich plasma can also be administered in cases of severe thrombocytopenia and thrombocytopathia. Stored whole blood and prbcs can be administered in patients with anemia. If PCV drops to be low 10% or if rapid hemorrhage causes the PCV to drop below 20% in the dog or less than 12-15% in the cats, a transfusion is advocated. Fresh frozen

4 plasma or cryoprecipitate administration should be considered in cases of coagulopathy, including Von Willebrand's disease, rodenticide intoxication with depletion of activated Vitamin K dependent coagulation factors, hemophilia, or in cases of severe hypoproteinemia with albumin concentrations < 2.0 g/dl. Frozen plasma also will suffice in cases of severe hypoproteinemia, warfarin-like compound intoxication, and Factor IX deficiency (Hemophilia B). ADMINSTRATION OF BLOOD PRODUCTS Blood products should slowly be warmed to 37 C before administering to the patient. Blood warmer units are available for use in veterinary medicine to facilitate rapid transfusion without decreasing patient body temperature. Red blood cell and plasma products should be administered in a blood administration set containing a 170 um in-line filter (Product, Manufacturer). Smaller in-line filters (18 um, Hemo-Nate blood filter, Utah Medical Products, Midvale, UT) can also be used, in cases where extremely small volumes are to be administered. Blood products should be administered over a period of 4 hours, whenever possible, according to guidelines set by the American Association of Blood Banks. As a general rule, administration of 1 ml fresh of stored whole blood per pound (2 ml/kg) will raise the recipient PCV by 1%. Administration of half that volume of prbc's will have a similar effect on recipient PCV, unless ongoing loss or hemorrhage is present. Fresh frozen plasma, frozen plasma, and cryoprecipitate should be administered at a volume of 10 ml/kg until bleeding is controlled or source of ongoing albumin loss ceases. The goal of transfusion therapy should be to raise the PCV to 25-30% in dogs, and 15-20% in cats, or to raise the albumin to a minimum of 2.0 g/dl, or until bleeding stops as in the case of coagulopathies. Monitoring of the patient to insure that bleeding has stopped, coagulation profiles (ACT, APTT, and PT) have normalized, hypovolemia has stabilized, and/or total protein is normalizing are indications for discontinuing ongoing transfusion therapy. TRANSFUSION REACTIONS The exact overall incidence and clinical significance of transfusion reactions in veterinary medicine are unknown. Several studies have been performed which document the incidence of transfusion reactions in dogs and cats. Overall, the incidence of transfusion reactions in dogs and cats are 2.5% and 2%, respectively. Transfusion reactions can be immune-mediated and non-immune mediated in nature, and can happen immediately, or can be delayed after a transfusion. Acute reactions usually occur within minutes to hours of the onset of transfusion, but may occur up to 48 hours after the transfusion has been stopped. Acute immunologic reactions include hemolysis, acute hypersensitivity including RBCs, platelets, and leukocytes. Signs of a delayed immunologic reaction include hemolysis, purpura, immunosuppression, and neonatal isoerythrolysis. Acute nonimmunologic reactions include donor cell hemolysis prior to onset of transfusion, circulatory volume overload, bacterial contamination, citrate toxicity with clinical signs of hypocalcemia, coagulopathies, hyperammonemia, hypothermia, air embolism, acidosis, and pulmonary microembolism. Delayed nonimmunologic reactions include the transmission and development of infectious diseases, and hemosiderosis. Clinical signs of a transfusion reaction typically depend on the amount of blood transfused, the type and amount of antibody involved in the reaction, and whether the recipient has had previous sensitization. Monitoring the patient carefully during the transfusion period is essential in recognizing early signs of a transfusion reaction, including those that may become life-threatening. A general guideline for patient monitoring is to first start the transfusion slowly during the first 15 minutes. Temperature, pulse, and respiration should be monitored every 15 minutes for the first hour, 1 hour after the end of the transfusion, and every 12 hours minimally thereafter. The most common documented clinical signs of a transfusion reaction include pyrexia, urticaria, salivation/ptyalism, nausea, chills, and vomiting. Other clinical signs of a transfusion reaction may include tachycardia, tremors, collapse, dyspnea, weakness, hypotension, collapse, or seizures. Severe intravascular hemolytic reactions may occur within minutes of the start of the transfusion, causing hemoglobinemia, hemoglobinuria, disseminated intravascular coagulation, and clinical signs of shock. Extravascular hemolytic reactions typically occur later, and will result in hyperbilirubinemia and bilirubinuria. Pre-treatment of patients to help decrease the risk of a transfusion reaction remains controversial, as in most cases, pre-treatment with glucocorticoids and antihistamines is ineffective at preventing intravascular hemolysis and other reactions, should they occur. The most important component of preventing a transfusion reaction is to carefully screen each recipient and carefully process the donor component therapy before the administration of any blood products. Treatment of a transfusion reaction depends on its severity. In all cases, the transfusion should be immediately stopped when a clinical signs of a reaction occurs. In most cases, discontinuing the transfusion and administering drugs to stop the hypersensitivity reaction will be sufficient. Once the medications have taken effect, the transfusion can be started slowly and the patient monitored carefully for further signs of reaction. In more severe cases in which a patient's cardiovascular or respiratory system become compromised, and hypotension, tachycardia, or tachypnea occurs, the transfusion should be immediately discontinued, and the patient administered diphenhydramine, dexamethasone-sodium phosphate,

5 and epinephrine. The patient should have a urinary catheter and central venous catheter placed, for measurement of urine output and central venous pressures. Aggressive fluid therapy may be necessary to avoid renal insufficiency or renal damage associated with severe intravascular hemolysis. Overhydration with subsequent pulmonary edema can generally be managed with supplemental oxygen administration and intravenous or intramuscular furosemide (2-4 mg/kg). Plasma products with or without heparin can be administered for disseminated intravascular coagulation. Following infusion of blood products, it is important to evaluate the patient's clinical response to therapy. Guidelines for monitoring depend on the clinical condition for which the transfusion was required. A baseline patient PCV should be performed prior to the start of any transfusion. Following administration of prbc's or whole blood, a packed cell volume should be performed 1after the transfusion is complete, and every 12 hours thereafter. A general guideline is that the PCV should raise 1% for each 1 ml/pound administered. If the PCV is markedly lower than that calculated volume, ongoing loss in the form of hemorrhage or lysis should be considered. Coagulation parameters such as an ACT and platelet count should be monitored at least daily in patients requiring transfusion therapy. When plasma products (FFP, FP, Cryoppt, Cryo-poor plasma) have been administered for coagulation abnormalities, coagulation testing in the form of Prothrombin time (PT), Activated Partial Thromboplastin Time (APTT), Activated Clotting Time (ACT) should be performed after the transfusion finishes. Blood product administration can also be associated with dilutional coagulopathies and hypocalcemia. An ionized calcium should be performed whenever large volumes of blood products have been administered to a small animal patient, and the patient monitored closely for signs of hypocalcemia (facial twitching, seizures, refractory hypotension, prolonged QT interval on ECG).