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Ann Hohenhaus, DVM, DACVIM Animal Medical Center, New York, New York Which Bag Do I Choose?
Important advances have occurred in veterinary transfusion medicine over the past 10 years. The major innovation has been the advent of component therapy. A survey of AAHA member hospitals indicated the predominant blood product transfused was whole blood. Another survey performed at Tufts University School of Veterinary Medicine demonstrated an increased use of packed red blood cells instead of fresh whole blood and an increase in the use of plasma between 1986 and 1989. Blood components are the products available from veterinary blood banks, but many veterinarians are not familiar with which products are optimal for their patients. Component therapy is considered the optimal method of transfusion since it allows specific hemotherapy: red blood cells for anemia or plasma to provide absent coagulation factors. The use of whole blood in anemic patients wastes the plasma, which could be used to control hemorrhage in a dog with anticoagulant rodenticide toxicity. A dog with anemia secondary to chronic renal failure does not require coagulation factor replacement and only needs a red blood cell transfusion. The plasma from this unit of blood can be used for a different dog with a bleeding disorder. By transfusing only the component required to treat the disorder, the risk of adverse reaction is decreased while maintaining efficacy. Collecting blood on demand and using fresh blood for transfusion also decreases the likelihood that adequate screening for infectious diseases will take place. To improve the ability of veterinarians to use blood components effectively, the various components available for use in veterinary patients are discussed below regarding their composition, clinical use, dosage and most common adverse reactions. Although there have been many advances in veterinary transfusion medicine, there is currently not a consensus regarding the size of a "unit" of blood. For this discussion a unit of canine whole blood with be the blood plus the anticoagulant collected from 1 dog into a standard blood bag. A "unit" of a component is the volume of a product produced from 1 unit of whole blood. This information will not apply to blood from all blood banks and the reader is referred to the product insert for information regarding a particular blood banks products. Because feline blood is collected in such a small volume and there is a lack of appropriate sized multi-bag systems, it is not typically processed into components, but it is possible to do so. Whole Blood (WB) is blood collected from the donor, plus the anticoagulant. A standard blood bag contains 63 ml of anticoagulant. It is probably the most commonly product in veterinary practice since a practitioner can produce whole blood simply, without any expensive equipment. Whole blood is typically used to transfuse cats. Feline units of blood are usually 40-50 ml of blood plus 5-9 ml of anticoagulant preservative solution. Ideally, WB would rarely be used in the dog as component therapy conserves blood and allows more dogs to be transfused from one unit of donated blood. Whole blood would be most appropriate in pediatric transfusions when it would waste an entire unit of blood to open it for 10 or 20 ml to transfuse a small puppy or kitten. Whole blood could be used for patients experiencing hypovolemic anemia from hemorrhage, but packed red blood cells and crystalloid or colloid solutions will achieve the same effect. The most common reaction associated with whole blood transfusion is fever which is not related to an acute hemolytic transfusion reaction, but is believed to be due to cytokines contained in the transfused blood or from antibodies against RBC, WBC or platelets. Whole blood should not be used in normovolemic anemia because of the risk of volume overload from the additional volume plasma adds to the transfusion. Whole blood or any blood product containing red blood cells carries a risk of causing an acute hemolytic transfusion reaction due to recipient antibodies against the donor red blood cells. The initial dosage of whole blood is 10-20 ml/kg. Packed red blood cells (pRBC) are the cells and a small amount of plasma, which remain after the plasma and anticoagulant, are removed. The PCV is approximately 80%, making pRBC very viscous. Normal (0.9%) saline is the only solution that should be added to any blood product and can be done with pRBC to improve flow. Packed red blood cells in additive solution are processed similarly to pRBCs, but after the red blood cells are separated from the plasma 100 ml of an additive solution are added to the red blood cells. PCV is 55-60%. This preserves the red blood cell function longer than the traditional anticoagulants ACD or CPDA and it eliminates the need to add saline to the pRBC to decrease viscosity and improve flow. The fresh frozen plasma obtained from this process is exactly the same as FFP produced from standard anticoagulant bags. The only indication for packed red blood cells is a clinically symptomatic anemia. Both pRBC and pRBC in additive solution are appropriate products to treat anemia caused by blood loss, hemolysis or bone marrow failure. Signs of anemia include: tachycardia, weakness, tachypnea, and collapse. The major risk of administration of pRBC is acute hemolytic transfusion reaction, although as with any transfusion, there is a risk of volume overload. The initial dosage of packed red blood cells is 6-10 ml/kg. Fresh frozen plasma (FFP) is the plasma obtained from whole blood, which has been centrifuged, and the red cells removed within 6 hours of collection. The anticoagulant remains in the plasma fraction during processing. When it is frozen at -20 C, the clotting factors maintain activity for 1 year. FFP is an excellent source of clotting factors and can be used to treat a wide variety of hemorrhagic disorders, including hemophilia, von Willebrand's disease, rodenticide intoxication and DIC. It is not a good source of albumin or nutrition and calculations indicate 45 ml/kg would be required to increase the serum albumin concentration by 1 g/dl. FFP may be used in puppies or kittens with failure of passive transfer. Plasma transfusions may cause volume overload or allergic reactions. The initial dosage is 6-10 ml/kg one to three times daily depending on the condition being treated and the response to therapy. Frozen plasma (FP) is plasma that has not been processed and frozen within 6 hours of collection. Labile coagulation factors are not preserved and are therefore FP is not a source of factors V and VIII. It may be produced from whole blood that has been stored > 6 hours. Fresh frozen plasma stored at -20C for > 1 year is considered frozen plasma since it contains reduced levels of coagulation factors. FFP may be used in puppies or kittens with failure of passive transfer. Albumin is preserved at that temperature for 5 years and frozen plasma may be used as a source of albumin. The initial dosage is 6-10 ml/kg one to three times daily depending on the condition being treated and the response to therapy. Cryoprecipitate is a concentrated source of von Willebrand's factor, fibrinogen (factor I) and factor VIII prepared from 1 unit of FFP. Fresh frozen plasma is thawed at 4C. During thawing, a white precipitate (cryoprecipitate) forms in the plasma and this precipitate contains vWf, factors VIII and I. The cryoprecipitate is separated from the liquid plasma by centrifugation. The liquid plasma is termed cryo-poor plasma. Cryoprecipitate is used to treat von Willebrand's disease, hemophilia A and fibrinogen deficiency. Storage and handling of cryoprecipitate is similar to fresh frozen plasma. It can be stored at -20C for 1 year. Like any plasma component, cryoprecipitate may cause allergic reactions. The initial dosage is 1 unit per 10 kg of body weight. Cryo-poor plasma is the plasma, which remains after the cryoprecipitate is removed. Cryo-poor plasma contains factors II, VII, IX and X which makes it useful for the treatment of rodenticide intoxication. Storage and handling of cryo-poor plasma is similar to fresh frozen plasma. Like any plasma component, cryo-poor plasma may cause allergic reactions. The initial dosage is 1 unit per 10 kg of body weight. Platelet rich plasma (PRP) is prepared from fresh whole blood by centrifugation at a slower centrifuge rate than for production of pRBC and plasma. The platelets are suspended in plasma to facilitate transfusion and transfused within hours of collection. PRP should not be refrigerated as it inactivates platelet function. Allogeneic platelet transfusions should be most useful in cases of decreased platelet production rather than cases of increases consumption or destruction of platelets. Unfortunately, increased destruction of platelets is the most common cause of thrombocytopenia in the dog. Platelet transfusions may cause allergic reactions or fever. The dosage is 1 unit of platelets per 10 kg of body weight. Frozen platelets are collected through plateletpheresis. Platelets are preserved by DMSO and also contain a small amount of fresh frozen plasma. Efficacy data on this product has not been published, but it has been suggested to use this product for the treatment of immune mediated thrombocytopenia. Because the product contains DMSO, it must be infused slowly or bradycardia will result. The dosage is 1 unit of platelets per 10 kg of body weight. This should increase the platelet counted 20,000/Ml when counted 1-2 hours post transfusion. Human immunoglobulin is a concentrated source of immunoglobulin produced from the plasma of over 1000 humans via ethanol cold fractionation technique. In a limited number of cases, it has been used to treat acute cases of canine immune mediated hemolytic anemia. It is believed that providing the large number of immunoglobulin molecules overwhelms the reticuloendothelial system and prevents it from destroying additional red blood cells. Initial therapy has been associated with thrombosis and thrombocytopenia, but these abnormalities may be a result of the primary disease not the immunoglobulin infusion. Theoretically, repeat administration could cause severe anaphylactic shock, but no reports of a second infusion have been published. The recommended dosage is 0.5-1g/kg and the reconstituted product is infused over 6-8 hours. Volume in various units of canine blood products
Available blood products
*The dosage of any blood product is simply a guideline for the initial transfusion. All transfusions are given "to effect" meaning until the RBC count is high enough to adequately improve the recipient's oxygenation or adequate coagulation factors have been transfused to correct the hemorrhagic process. HEMATOLOGY/ONCOLOGY JOURNAL CLUB 2001
PREVENTION AND MANAGEMENT OF TRANSFUSION REACTIONS
A blood transfusion is a medical therapy which is not without risk to the patient. The veterinarian must decide if the medical benefits of transfusion outweigh the potential for a transfusion reaction, as is done in the decision making process prior to the administration of any therapeutic agent. This talk will center on a classification scheme for transfusion reactions. Classification of transfusion reactions will provide a framework for institution of preventive measures designed to minimize negative effects of transfusion. Strategies for the recognition of clinical signs associated with transfusion reactions and therapeutic management of transfusion reactions, should they occur, will complete the discussion. DEFINITION: TRANSFUSION REACTION A transfusion reaction is the range of immunologic and metabolic changes which occur during or following administration of blood products. Four classes of transfusion reactions have been described in the human literature. The "classic transfusion reaction", or the acute hemolytic transfusion reaction due to transfusion of incompatible red blood cells, is an example of an acute immunologic transfusion reaction. The three other classes of transfusion reactions are acute nonimmunologic, delayed immunologic and delayed nonimmunologic transfusion reactions. Acute transfusion reactions occur during or within a few hours of a transfusion and delayed transfusion reactions occur after the completion of the transfusion. The delay may be months to years. ACUTE IMMUNOLOGIC TRANSFUSION REACTIONS The best example of an acute hemolytic transfusion reaction in veterinary medicine is the administration of type A red blood cells to a type B cat. An acute hemolytic transfusion reaction is the most feared transfusion reaction, because the sequela can be rapid, irreversible and fatal. Naturally occurring alloantibodies and complement bind to the incompatible red blood cells and cause hemolysis. Current theories on the pathogenesis of acute hemolytic transfusion reactions propose hemolysis induces the release of cytokines such as tumor necrosis factor, interleukin 1,6 and 8, complement, endothelium derived relaxing factor (nitric oxide) and endothelin which result in the clinical syndrome of disseminated intravascular coagulation, acute renal failure, and shock. Acute anaphylactic and nonhemolytic febrile transfusion reactions occur because of the presence of recipient antibodies against donor IgA and donor leukocytes, respectively. One of the milder reactions is urticaria, which is the result of antibody to donor plasma proteins. Rarely, acute immunologic transfusion noncardiogenic, pulmonary edema occurs following transfusion. Antibody from the donor to recipient's leukocytes is believed to be responsible. DELAYED IMMUNOLOGIC TRANSFUSION REACTIONS Even though compatible blood is given to a patient, the recipient may develop antibodies against any one of the hundreds of red blood cell antigens. An amnestic response to the red blood cell antigens results in a delayed hemolytic transfusion reaction which is a well described complication of red cell transfusion. They invariably occur in persons who have been previously sensitized to allogenic red blood cell antigens by transfusion or pregnancy. Controversial evidence exists in both veterinary and human medicine for immunosuppression induced by blood transfusion. Pretransplantation transfusion enhanced renal allograft survival in dogs when compared to a group of non-transfused dogs receiving rental transplants. Some studies show greater postoperative infection rates in transfused patients, but this has not been confirmed in all studies. Immunosuppression following transfusion has been implicated as the cause of a poorer prognosis in transfused patients suffering from colorectal and prostatic cancer. Proposed mechanisms of immunosuppression include, a decrease in cell-mediated immunity, a decrease in the CD4:CD8 ratio, decreased macrophage function and increased production of prostaglandins, thromboxanes, prostacyclin, and interleukin 2. Transfusion associated graft versus host disease can occur in immunosuppressed recipients. Engraftment of immunocompetent donor lymphocytes is necessary for this to occur. ACUTE NONIMUNOLOGIC TRANSFUSION REACTIONS During storage, ATP content of red blood cells falls and some cells undergo hemolysis, resulting in leakage of potassium out of the red blood cell into the storage media. Hyperkalemia in the transfusion recipient is a rare complication of transfusion unless the patient receives a massive transfusion (greater than or equal to 1 blood volume in 24 hours) and has renal failure or preexisting Hyperkalemia. In cases of massive transfusion, ionized hypocalcemia can result from citrate used as an anticoagulant. Massive transfusion of refrigerated blood may result in hypothermia. Embolism may occur from clots and other debris formed during collection and storage of blood. Venous air embolism produces the sudden onset pulmonary vascular obstruction, a precordial murmur, hypotension, and death due to respiratory failure. Circulatory overload and pulmonary edema is most likely to occur in patients with chronic severe anemia, compromised cardiac and pulmonary systems or geriatric patients. Infectious complications of transfusion are relatively rare, can result from bacteria, microfilaria, spirochetes, and protozoa. Immunocompromised patients are at greatest risk. Shock results from transfusion of blood that has heavy bacterial contamination. Physical damage to red blood cells, (freezing or heating) causes hemolysis without evidence of an acute hemolytic transfusion reaction. DELAYED NONIMMUNOLOGIC TRANSFUSION REACTIONS In man, AIDS, hepatitis virus and cytomegalovirus infections are documented late effects of transfusion. Donor cats infected with FeLV or FIV or FIP would be a source of infections in feline transfusion recipients. PREVENTION STRATEGIES Correct selection of blood donors is crucial to the administration of a successful transfusion. The exact definition of the blood type of the canine universal donor is controversial, but donor dogs should be negative for DEA 1.1, DEA1.2, and 7 are debatable, but ideally should be negative, Blood from universal canine donors would be least likely to cause either an acute or delayed hemolytic transfusion reaction. All feline donors and recipients must be blood typed and given appropriate type blood to prevent A-B mismatch transfusions, which can be fatal, even during the first transfusion. All blood donors should be screened for infectious diseases. Feline donors should not be infected with FeLV, FIV or FIP. Transmission of toxoplasmosis via blood transfusion has been documented in immunocompromised humans. Bartonella henselae is an emerging feline infectious disease, currently of unknown importance in feline transfusion medicine. Dirofilariasis, ehrlichiosis, and babesiosis can be transmitted via transfusion; consequently, donors should have negative titers against these infectious agents. Transfusion transmitted borreliosis has not been documented in man, but could theoretically occur. Donors should not donate if they are ill, have a fever, vomiting or diarrhea. This has resulted in Yersinia entercolitica contamination of human units of blood. Crossmatching is an in vitro test which detects antibodies in the plasma of the recipient or donor that may cause an acute hemolytic transfusion reaction. Crossmatching will not prevent sensitization to red blood cell antigens which may result in a hemolytic reaction during future transfusions. Crossmatching should be repeated if a second transfusion is planned. Strict aseptic technique during collection and procession of blood is essential to prevent bacterial contamination. Elimination of all multidose vials of reagents will also eliminate another source of contamination from the collection process. Multiunit donors may develop scarring over frequently used venipuncture sites. These scarred areas cause difficult venipuncture which is associated with increased risk of bacterial contamination of blood. The unit of blood should be examined before transfusion. The most common reason for an acute hemolytic transfusion reaction in human medicine is due to clerical error; the wrong unit of blood is released from the blood bank and transfused. Attention should be paid to transfusing the correct unit of blood as determined by blood typing and Crossmatching. Red blood cells should also be examined for a normal red color and consistency in the bag. Bacterially contaminated blood often appears brown. Administration of blood through a filter will remove blood clots and debris likely to cause emboli. The risk of an air embolism is greatly reduced by collecting blood in plastic bags, not glass bottles. The usage of blood warmers and infusion pumps must be limited to those devices approved for use with blood products to prevent physical damage to the blood. Stored blood does not contain any antibacterial agents; consequently, blood must be maintained under refrigeration until used. Transfusions should be completed within 4 hours of initiation to prevent bacterial overgrowth in units maintained at room temperature. Volume overload can be minimized in recipients with cardiac disease by transfusing only packed red blood cells, no whole blood in cases of anemia. Diuretics can be administered prior to institution of transfusion to decrease intravascular volume. rate of transfusion can be slowed if all the blood can be given in 4 hours. If not, the blood may be split into smaller units, one transfused slowly and the other returned to the refrigerator until the first unit is completed. Transfusion recipients should be monitored during the transfusion. Temperature, heart rate and respiratory rate should be recorded every 10 minutes during the first 1/2 hour and then every thirty minutes thereafter. The patient should be monitored for vomiting, diarrhea, urticaria and hemoglobinuria. Changes in the vital signs or clinical status may indicate a transfusion reaction. In patients receiving massive transfusion, potassium, and calcium should be monitored frequently. THERAPEUTIC MANAGEMENT In all acute transfusion reactions, the transfusion should be stopped, samples of patient blood and urine obtained and the unit of blood Gram stained and cultured. Acute, hemolytic transfusion reactions manifest as vomiting, hemoglobinuira, hemoglobinemia, fever, hypotension and shock. Olig- or anuria may ensue. Immediate infusion of crystalloids should be instituted to maintain blood pressure and urine output. A dopamine infusion may be required to attain adequate blood pressure and urine production. Intravenous administration of glucocorticoids may suppress some of the mediators of acute hemolytic transfusion reactions and lessen the clinical progression. Coagulation parameters should be measured and appropriate therapy instituted if DIC is present. If fever occurs without evidence of hemolysis, and the Gram stain is negative, the transfusion may be restarted. These acute, nonhemolytic febrile transfusion reactions do not require treatment, but antipyretics may be used if the patient is uncomfortable. Urticaria from plasma administration should be treated with short acting steroids and antihistamines. The plasma may be restarted at a slower rate and the recipient observed carefully. An acute anaphylactic transfusion reaction occurs after only a few milliliters of blood and does not have a fever. In man, it occurs in cases of IgA deficiency. IgA deficient Chinese Shar Peis and German Shepherds would be at risk for this transfusion complication; however, it has not been reported in veterinary medicine. If hyperkalemia or hypocalcemia is documented in a transfusion recipient, insulin-dextrose or calcium gluconate can be administered to correct the abnormality. Empirical administration of calcium to transfusion recipients cannot be recommended because of the risk of hypercalcemia and increased myocardial irritability. Cases of volume overload are treated with diuretics and vasodilators. Most cases respond well. Transfusion of bacterially contaminated units of blood can result in shock which is managed with volume expansion and pressor agents as well as empirical antibiotic therapy based on the Gram stain. Therapy cannot be prescribed for delayed transfusion reactions. It is important to recognize the late effects of transfusion and not mistake them for other disease process. Fever is the most common sign of a delayed hemolytic transfusion reaction. Icterus may also be noted 4-7 days after a transfusion. BLOOD TYPING AND CROSSMATCHING
The purpose of blood typing and crossmatching is to prevent transfusion reactions by identifying incompatible donors and recipients. Blood typing and crossmatching involve several disciplines of medicine including: transfusion medicine, immunology, biochemistry, genetics and laboratory techniques. A blood group is a related set of blood types; the most familiar is the ABO system in humans. A blood type is determined by species-specific markers on red blood cells. Because the markers are species specific, blood type A in a person is not equivalent to blood type A in cats. Blood Groups in Cats The blood group system in cats consists of three blood types, A, B, AB. These blood types are determined by the presence of absence of N-acetyl neuraminic acid of N-glycol neuraminic acid in the red blood cell membrane. Blood types A and B are inherited by an autosomal recessive mechanism. The inheritance mode of blood type AB is unknown. The frequency of blood types A, B, AB in the cat population vary by both breed and geographic location. In the United States, the domestic cat population is 97.5% blood type A, but a higher prevalence of blood type B is found in the West Coast domestic cat population. Certain breeds of cats have a higher prevalence of blood type B within the breed. These breeds include: Devon rex, British shorthair, Cornish rex, Persian, Exotic shorthair, Himalayan, Sphinx, Abyssinian, Maine Coon, Japanese bobtail. Only the Siamese, Burmese and Oriental shorthair have not been reported to have any members of blood type B. Knowledge of the blood type of both the donor and recipient cats is essential to a safe and effective transfusion. All blood type B cats have naturally occurring alloantibodies against type A red blood cells. If a B cat is transfused with A red blood cells, an acute hemolytic reaction will occur which can result in death. If an A cat is transfused with B red blood cells, the survival of the transfused cells is only 2 days. Matched red blood cells have a half life of 28-38 days following transfusion to the recipient cat. Blood Groups in Dogs The blood group system in dogs is more complicated than in cats. Over 12 different blood types have been described, although only 7 blood types currently have typing antisera available.. The nomenclature for canine blood types has changed through the years. Currently, they are identified by the acronym DEA (dog erythrocyte antigen) and are numbered 1-8. DEA 1 has three subtypes, 1.1, 1.2 and 1.3. A dog may have 1.1, 1.2, 1.3 or no antigen on their red blood cells. The remainder of the DEA types can be either present or absent. Breed prevalence of blood types has not been determined in the dog. Controversy exists over the clinical importance of the DEA types in transfusion reactions. DEA 1.1 is believed to be the most important type for inducing acute hemolytic transfusion reactions. DEA 1 negative dogs given red blood cells positive for DEA 1.1 could become sensitized to future transfusions. DEA 1.2 has been reported to cause a transfusion reaction in a research laboratory, but clinical evidence is lacking for DEA 1.2 mediated transfusion reactions. DEA 7 is believed to be structurally related to an antigen commonly found in the gastrointestinal tract. Some hematologists believe this could cause a clinically significant transfusion reaction without prior sensitization from a precious transfusion. Others strongly disagree. Unlike cats, dogs are believed to lack any naturally occurring alloantibodies against red blood cell antigens. This belief has lead to the recommendation not to crossmatch dogs prior to the first transfusion. Blood Typing Availabilty Veterinary reference laboratories, veterinary colleges or blood banks typically perform blood typing in cats, using anti-A serum from blood type B cats and Triticum vulgris lectin which agglutinates type B red blood cells. This method is not particularly convenient in emergency situations. Feline blood typing can be performed in-house utilizing blood typing cards available from dmslaboratories, Flemington, NJ. Veterinary reference laboratories, veterinary colleges or blood banks typically perform blood typing in dogs. A blood typing card, which can be used in clinical practice to detect dogs positive for the most important antigen 1.1, is available from dmslaboratories, Flemington, NJ. Crossmatching A crossmatch is a laboratory test which attempts to predict the response of the transfusion recipient to the donor's red blood cells and plasma. Unfortunately, the in vitro test does not always predict the in vivo response. A major crossmatch tests for incompatibility between the donor red blood cells and antibodies in the recipient plasma. A minor crossmatch tests for incompatibility between the antibodies in the donor plasma and the recipient red blood cells. In the dog, the minor crossmatch may not be performed, due to the low likelihood that a small amount of plasma in the red blood cells will cause a reaction and the lack of naturally occurring alloantibodies. The minor crossmatch is essential in feline crossmatching. Incompatibility in either the major or minor crossmatch is a strong indication of AB incompatibility. If the donor is known to be blood type B and the minor crossmatch is incompatible, the recipient is likely blood type A. Crossmatching is performed using either EDTA blood or clotted blood in a plain red top tube, samples are needed from both the donor and recipient. Be sure all tubes are labeled prior to adding the plasma and red blood cells. The plasma (serum) and red blood cells are separated. Red blood cells are washed 3 times in saline. Mix 0.2 ml red blood cells with 4.8 ml 0.9% saline. For the major crossmatch, add 0.1 ml of the diluted donor red blood cells to 0.1 ml of recipient plasma. For the minor crossmatch, add 0.1 ml diluted recipient red blood cells to 0.1 ml of donor's plasma. The tubes should be incubated for 15 minutes at room temperature. The tubes are centrifuged for 1 minute and observed. Hemolysis of the supernatant plasma indicates incompatibility. Swirl the contents of the tube. If the crossmatch is incompatible, agglutination will be visible. If no agglutination is seen, place one drop from each tube on a slide and evaluate microscopically for agglutination. Agglutination of the control sample indicates laboratory error or possibly immune mediated hemolytic anemia. Agglutination is graded 1-4. VACCINE ASSOCIATED SARCOMAS: MANAGEMENT OPTIONS
History Beginning in 1991, veterinary pathologists noticed an increase in fibrosarcomas in feline patients and commented that the tumor location coincided with common sites of vaccination. Tumors were often preceded by postvaccinal inflammatory reactions, but all reactions did not lead to development of a tumor. Speculation that the inflammation or the inflammatory mediators lead to tumor development has led to investigation of the role inflammatory mediators in vaccinal sarcomas. Furthermore, aluminum, a common component of vaccine adjuvant was identified in the tumors via electron probe technology. It was not until 1993, that strong epidemiological evidence became available to support these observations. Over time it also became evident that not only fibroscarcomas developed at sites of vaccination, but other soft tissue sarcomas as well. Development of vaccine associated sarcoma (VAS) has been most strongly linked to FeLV and rabies vaccine and in cats where multiple vaccines are administered at a single site. Initial reports of incidence ranged from 1 in 1000 cats to 2 in 10,000 cats vaccinated. A large study involving over 31,000 cats found an incidence of postvaccinal reactions of 12/10,000 vaccine doses and an incidence of 0.63 tumors/10,000 cats. No age, breed, sex predilection or association with retroviral infection has been made. Today this disease has a worldwide distribution, including countries such as Japan and Australia which have limited rabies vaccination programs. Diagnostic evaluation Pre surgical evaluation Based on anatomic location and vaccine history, it is possible to have a high degree of suspicion that a cat has a VAS. Routine CBC, biochemical profile and urinalysis are indicated to determine the health status of the cat as it may impact on the plan developed to manage the tumor. A diagnostic aspiration can be useful to help confirm the diagnosis, but most experts believe an incisional biopsy should be performed prior to the development of a therapeutic plan. Three view thoracic radiographs should be obtained to identify metastatic disease. An overall metastatic rate as high as25% has been reported and the rate of metastasis increases with prolonged survival. VAS will metastasize widely and if extensive and expensive therapy is undertaken, an abdominal ultrasound should be considered to evaluate the abdominal cavity for occult metastasis. VAS tend to follow fascial planes and the actual tumor often extends far beyond the palpable mass. Preoperative CT scanning with administration of a contrast agent has been shown to more accurately identify the extent of the tumor, and whenever possible, a contrast enhanced image should be obtained. CT scan is also useful in the planning process for radiation therapy, especially when preoperative radiation therapy is used. Histopathology The diagnosis of a VAS is based on a biopsy. Vaccine associated sarcomas have a typical histologic appearance. They are anaplastic cells with a high mitiotic rare and a necrotic center. Inflammation is a prominent feature, with multinucleated giant cells, amorphic or granular refractile material and perivascular lymphocytic-plasmacytic infiltrates observed in the tumor. Eosinophils are present. Fibrosarcoma, chondrosarcoma, malignant fibrous histiocytoma, extraskeletal osteosarcoma, undifferentiated sarcoma and myofibrosarcoma are all consistent with VAS. Therapeutic Strategies
The optimal therapy for VAS has yet to be determined. It is clear that all therapeutic modalities typically used in cancer therapy are appropriate in the treatment of VAS. Surgery and radiation therapy are treatments aimed at controlling local disease. Tumors with high metastatic potential, like VAS, may benefit from chemotherapy which is a systemic treatment aimed at controlling systemic spread of the tumor. Questions about the therapy of this tumor which remain to be answered include: Should surgery precede radiation therapy or radiation therapy precede surgery? How wide an excision is necessary to control the local tumor? What is the optimal chemotherapy protocol to aid in prevention of metastatic disease? Role of Surgery Surgery plays a three part role in the management of VAS. First, a surgical biopsy is used to confirm the diagnosis of a suspected VAS. Knowledge that the tumor is a VAS will influence the prognosis given to the owner, the diagnostic evaluation, surgical plan and if radiation therapy is anticipated, the consultation with a radiation oncologist. Secondly, the completeness of surgical resection greatly influences the ultimate prognosis for a cat with VAS. When the first surgery in the management of this tumor is a wide surgical excision, the possibility of long term survival of the cat improves. Knowledge that a tumor is a VAS will facilitate presurgical planning. Third, surgery helps in radiation therapy planning. In cases where surgery is to be followed by radiation therapy, the surgeon can place radiopaque markers that can be used to identify the location of the tumor during the radiation planning process. Overall survival for cats treated with surgical excision alone is 400-500 days and surgical treatment alone appears to control this tumor long term in only 10-15% of cats.1,2 Several factors influence the success of surgery in controlling VAS: including the surgeon, completeness of surgical margins, anatomic location of the tumor and the number of prior surgeries. Surgery resulting in margins free of malignant cells resulted in a longer median survival time than "dirty" margins in 2 retrospective studies. 1,2 Even with "complete" excision, up to 50% of tumors will recur. In a third study, amputation with complete surgical margins was the only single modality therapy reported to result in a "cure" of this disease with some cats attaining a survival of >1300 days following amputation. To attain surgical margins free of tumor, an amputation should be considered in any cat with a distal limb VAS. Davidson reported the prognosis improved if the first surgery performed was by a surgeon at a teaching hospital. 2 Role of Radiation Therapy Radiation Therapy (RT) combined with surgery has been investigated in the treatment of VAS. Increases local tumor control have been reported when these 2 modalities have been combined. Currently controversial in RT for VAS is whether preoperative or postoperative radiation is the better choice. Postoperative RT is the only choice when a patient is referred for oncologic evaluation following excisional biopsy of a VAS. Preoperative radiation therapy allows for a smaller RT field because the entire surgical field, including scars and drain holes must be included in the treatment field. Preoperative RT will, in some cats decrease the size of the tumor, making complete surgical excision possible. When preoperative RT is administered, the surgical field can be as large as necessary because there is no requirement for a large radiation field to encompass the entire surgical field and cause excessive toxicity to the cat. Preoperative RT has the disadvantage of lacking radiopaque markers placed by the surgeon to define the tumor bed, making CT scan more important in RT planning. Preoperative RT has the disadvantage of performing surgery in the radiation field, however; postoperative complications are typically minimal and easily controlled. Median survival time reported for combination of surgery and RT range from 600-700 days. 3,4,5 The best survival was attained by a conservative surgery (<3 cm margins) immediately (within 2 days) followed by electron beam radiation therapy. 4 Efficacy of Chemotherapy Anecdotal reports of response to carboplatin, doxorubicin, and mitoxantrone abound. One published study reported a response rate of 50% to a combination of doxorubicin and cyclophosphamide in cats with balky disease, but duration of response was short (median 125 days). 6 Two retrospective studies have analyzed the effect of doxorubicin in multimodality protocols. Neither was able to detect a treatment effect, but the small number of cats included in the studies and the retrospective study design does not allow definitive conclusions to be made. The optimal chemotherapy protocol has yet to be defined, but since cure of this tumor is rare and metastases are common, chemotherapy is recommended in most cats. One unpublished study of trimodality therapy indicates surgery + RT + chemotherapy resulted in a median survival of nearly 800 days. Selected References
FELINE LYMPHOMA
LYMPHOMA IN THE CAT The adage "The cat is not a little dog" is especially true when it come to the discussion of lymphoma in the cat. Although lymphoproliferative diseases are more common in the cat than the dog, the existing body of information about lymphoma in the cat is smaller. Overall, the survival times for cats treated for lymphoma with chemotherapy are shorter than in the dog, although some notable exceptions are discussed below. Another major difference between lymphoma in the two species is the common anatomic forms of the disease that occur. Over 80% of dogs with lymphoma have the multicentric or peripheral lymphadenopathy form. This means the diagnostic evaluation for dogs with lymphoma is relatively uniform consisting of a minimum data base, radiographs and a lymph node aspiration or biopsy. There is no standard diagnostic evaluation of a cat with lymphoma because the clinical presentation is related to organ system affected by lymphoma. Clinically, most cats ultimately diagnosed with lymphoma are evaluated for chronic vomiting, weight loss, renal failure, nasal discharge or a cutaneous mass and lymphoma is discovered during the diagnostic evaluation. LYMPHOMA: DEFINED Lymphoma is the most common hematopoietic tumors of all domestic animal species and occurs most frequently in the cat. It is a proliferation of malignant lymphoid cells that primarily affects lymph nodes or solid visceral organs such as the liver or spleen. Advanced stages of the disease can involve the bone marrow and be clinically indistinguishable from leukemia. ANATOMIC FORMS OF LYMPHOMA Four anatomic forms of lymphoma have been described: alimentary, multicentric, thymic and atypical. There appear to be geographic variations in the occurrence of various anatomic forms of feline lymphoma. Two large studies performed in the United States, which included 277 cats, found the alimentary form of lymphoma most common (52% of cats). An Australian study of 90 cats found an equal distribution between the 4 anatomic forms. In that study, young male Oriental shorthair cats were found to be predisposed to developing multicentric lymphoma. A similar predisposition has been reported in England. In the Netherlands, a predominance of FeLV negative mediastinal lymphoma has been reported in young Siamese cats. Multicentric Typical clinical signs in a cat with multicentric lymphoma include lethargy or an abdominal mass. Renal lymphoma is often grouped in this category, although some place it in its own category. Renal lymphoma is frequently associated with spread of lymphoma into the central nervous system. Prophylaxis with cytosine arabinoside, which penetrates into the CNS is recommended in these cats. Median age of cats with multicentric lymphoma is 8-10 years.Survival of cats with renal or multicentric lymphoma is approximately 6-9 months. Mediastinal The typical clinical signs in a cat with mediastinal lymphoma are dyspnea, coughing or dysphagia. Pleural effusion is common and analysis of the effusion is often diagnostic for lymphoma. Mediastinal lymphoma has become much less common in the United States as FeLV infection becomes less common. Median survival has been reported to be 69 days and it is likely the short survival time is influenced by the high percentage of young, FeLV positive cats in this anatomic group. Alimentary Clinical signs in cats with alimentary lymphoma include: depression, lethargy, vomiting, anorexia and massive weight loss. The majority are FeLV negative and cats with alimentary lymphoma are typically older: median age = 10-12 years. Median survival of these cats when treated with a doxorubicin containing protocol is 40 weeks. Extranodal Palpable masses, or signs referable to a mass ie exopthalmous, stridor, dysphagia, nasal discharge are typical in cats with extranodal or atypical lymphoma. The cutaneous form of lymphoma is rare, appearing in <2% of cats in two large case series from the US and Australia. Two forms of cutaneous lymphoma have been described, the nodular form which can be either B or T cells and an epitheliotrophic form typically composed of T cells. Because this tumor is rare, only antecdotal information exists regarding treatment and limited information on efficacy is available. Central nervous system involvement with lymphoma in either the brain or spinal cord is classified as atypical lymphoma. Brain lymphoma often causes blindness, ataxia and seizures with cranial nerve deficits. Spinal cord lymphoma occurs at the thoracolumbar location, has a male predilection and if complete remission is induced, a 14 week survival time. Lymphoma confined to the nasal cavity appears to carry a better prognosis than other forms of lymphoma. Median survival has been reported to be as long as 456 days. THE ROLE OF RETROVIRUSES FeLV Infections FeLV infection has been associated with the development of lymphoma for nearly 3 decades. Early reports found 50-70% of cases of lymphoma associated with FeLV. Today FeLV infection in cats treated for lymphoma seems to be less frequent with only 39/242 cats treated for lymphoma recently reported as FeLV positive. In the United States, a young cat, with an anterior mediastinal mass is the typical FeLV positive cat with lymphoma. The prevalence of FeLV infection is similar in Australian cats. Whether the decrease in FeLV infection rate reflects a decrease in the population infection or a selection bias against treating lymphoma in cats with FeLV infection is unknown. FIV Infection The risk of developing lymphoma is 5 times greater in an FIV positive cat than a negative one. Some studies have also associated the atypical form of the disease with FIV infection. Like with FeLV, there is geographic variation in FIV infection in cats with lymphoma which may be attributed to feline lifestyle. In New York City where cats are predominantly indoors, 4/132 treated cats were positive FIV, but in Australia 46% of cats with lymphoma are positive for FIV. WORLD HEALTH ORGANIZATION STAGING FOR CANINE LYMPHOMA I single lymph node or lymph tissue II regional lymphadenopathy III generalized lymphadenoathy IV lymph node and hepatic/splenic lymph node involvement V blood, bone marrow or other organ involvement Substage a without clinical signs Substage b with systemic signs, hypercalcemia This staging system does not apply well in cases of feline lymphoma, because most cats do not have peripheral lymph node involvement with lymphoma. An alternative staging system for feline lymphoma has been proposed, but is not uniformly predictive of outcome. What is useful in staging a cat with lymphoma are the results of the bone marrow aspirate. Extensive involvement of the bone marrow with tumor may indicate myelosuppression may be more problematic in certain cats. Alternative staging system I single tumor II single tumor with regional lymph node involvement or a primary resectable GI mass III two tumors on opposite sides of the diaphragm, all spinal lymphoma, unresectable abdominal disease IV Stages I-III with liver and/or splenic involvement V Stages I-IV with CNS or bone marrow involvement CLINICAL PROGNOSTIC FACTORS
ADVANCED HISTOLOGY Because there are few prognostic factors, which can be used to determine the expected outcome in cats undergoing therapy for lymphoma, advanced histologic techniques have been employed in an attempt to better define the ultimate prognosis. Immunophenotyping Lymphoma can be subclassified into the type of immune cell, which is malignant, either B or T cells. Information from 3 large studies is tabulated below. Unfortunately, this information has not yet proven to be clinically useful as prognosis has not been associated with either phenotype of lymphoma.
AgNOR AgNOR is the acronym for argyrophilic (silver staining) nucleolar region. The presence of AgNORs indicates a tumor with an increase in cellular proliferative activity and in some types of cancer the presence of AgNORs correlates with prognosis. In two separate studies, AgNOR has not proven to be predictive in feline lymphoma. RADIATION THERAPY AND LYMPHOMA Lymphoma is a very radiation sensitive tumor, but its role in the treatment of canine lymphoma is poorly defined. It may be used to palliate bulky disease, as an adjunct to chemotherapy or as primary therapy in CNS lymphoma. One of the most common uses for radiation therapy in feline lymphoma is in the treatment of nasal lymphoma. Chemotherapy drugs penetrate poorly into bulky tumors and radiation therapy is quite effective at decreasing tumor size. The optimal radiation therapy protocol has yet to be described, but veterinary oncologists commonly prescribe 3-6 treatments given 1-2 times weekly. CHEMOTHERAPY AND LYMPHOMA Chemotherapy is considered to be the most effective therapy for lymphoma in cats. Multiagent protocols are most commonly used. Cyclophosphamide, vincristine and prednisone (COP protocol) result in an 83 day median survival. Recent study from the Netherlands found a median survival of 266 days in cats treated with the COP protocol. This apparent difference from the original publication of COP in cats may be influenced by the lower predominance of FeLV in the Netherlands. The addition of doxorubicin to chemotherapy regimens (see below) significantly increases that time. A randomized clinical trial comparing chemotherapy drugs with and without the addition of prednisone has not been performed. Some limited information is available about protocols not containing prednisone and median survival was 2 months compared to 7 months for those cats receiving prednisone. Doxorubicin Doxorubicin is one of the most successful chemotherapy agents ever identified. In the dog, single agent doxorubicin can induce complete remission in approximately 75% of dogs with lymphoma and can maintain remission for 9-10 months. This appears not to be true in the cat. An Australian study showed a complete remission rate of 32% and an American study a complete remission rate of 42% using single agent doxorubicin. Median survival was 94 days. Doxorubicin is effective in multiagent protocols, and the use of doxorubicin containing multiagent protocols results in longer survival times, approximately 40 weeks. Use of doxorubicin should strongly be considered in all cats with lymphoma CCNU CCNU (Lomustine) is an "old" nitrosourea alkylating agent. There are currently no publications documenting the use of CCNU in cats with lymphoma. Clinical antedotes suggest it has efficacy in lymphoma. Dose is between 60-90mg/m2. Careful monitoring of the neutrophil count is necessary to avoid neutropenia which may be prolonged. Hepatic and renal toxicity have been reported in the dog; consequently, liver and renal function should be routinely monitored. ADVERSE EFFECTS OF LYMPHOMA THERAPY A simple method to categorize the potential complications of chemotherapy is to divide them into 3 groups: myelosuppression and sepsis, gastrointestinal toxicity and reactions specific to certain drugs. Any chemotherapy drug can cause any of these reactions, some are worse than others are. As a rule, anorexia is much more common than vomiting and diarrhea in the cat. Urinary tract infection Chronic use of steroids in chemotherapy protocols may be the cause of renal or bladder infections in cats on chemotherapy. In my opinion, sick lymphoma cats, especially ones with renal dysfunction should have a urine culture performed to identify any subclinical infection. Cyclophosphamide cystitis, which is a chemical cystitis is rare in cats. Ringworm Dermatophytosis is another common infection I see in cats undergoing chemotherapy for lymphoma. Once a cat has ringworm, it typically has it for the duration of its life. I typically treat with lime sulfur dip and miconazole topically. Because the side effects of itraconazole are significant, I typically avoid its use. A recent report suggests the use of lufenuron for reatment of ringworm in cats. The recommended dosage is 80 mg/kg. Diabetes mellitus Administration of glucocorticoids is a risk factor for the development of diabetes in the cat because glucocorticoids cause peripheral resistance to insulin. Prednisone is a common drug used in lymphoma chemotherapy protocols. Despite these 2 facts, the development of diabetes in cats on prednisone containing chemotherapy protocols in rare in my personal experience and in the veterinary literature. Of 243 cats treated with prednisone containing chemotherapy protocols published in the veterinary literature, only 1 cat was reported to have developed diabetes. Radiation complications The major concern of many owners of cats receiving lymphoma as part of cancer therapy is the side effects of the disease. Since radiation is commonly used in cats with nasal lymphoma, ocular toxicity will be seen. Most of the time, the radiation therapy plan can avoid one eye. The eye in the radiation therapy field will develop a cataract 9-12 months after radiation. Retinal atrophy from radiation is possible, but the frequency of occurrence is unknown. "Dry eye" may also occur. Fur in the radiation field will have pigment changes that are of little consequence to the cat. |
