Our ability to perform blood component transfusions has become a vital therapeutic option in treating many ailments affecting our patients. One of the most common uses of blood components involves replacement of red blood cells (RBC) in the case of clinical anaemia leading to tissue hypoxia. The amount of oxygen delivered (DO2) being reduced to the point where critical oxygen exchange ratio is exceeded (signifying inadequate DO2 to meet oxygen demand, VO2) leads to reliance on anaerobic respiration for energy production, and is ultimately unsustainable. Supplementation of oxygen carrying capacity is warranted in these cases, and the most accessible method in providing this is through RBC transfusions. Thus, the demand for RBC products has historically been high, and the struggle for blood banks to meet demands still continues. The unavailability of RBC products is exacerbated by the presence of RBC antigens (blood types) and the potential for immunologic complications without careful consideration of compatibility risks. Alternative methods of transfusions are sought out in the effort to minimize our reliance on homologous transfusions to meet oxygen carrying capacity demands.
Xenotransfusions
A recent news report of a feline patient who was determined to require a RBC transfusion with the alternative being death has brought to the forefront of our minds how challenging obtaining feline blood matching our patient can be. A practice, for example, with an in-house bank that has two units of type B blood banked regularly, with a type B donor in the donor program ready to donate at beck-and-call would be considered very well prepared for a type B patient requiring transfusions. The practice still would be out of options for RBCs of this rare feline blood type if a patient requires multiple transfusions, or multiple patients come in and happen to be of the same type. Many practices face shortages of RBC products in general, regardless of the type. In this particular news report, the feline patient received canine blood as a part of his treatment; an example of xenotransfusion in practice.
Xenotransfusions, or transfusion of blood products between individuals from different species, have been recorded in literature dating back to 1667 involving transfusion of blood from lambs, calves, and dogs to humans for various reasons. Xenotransfusion has been employed in the 1800s with a good degree of success, though the discovery of blood types and improved knowledge on blood compatibility from the 1900s encouraged the practice of intraspecies, or homologous, transfusions. The practice of intraspecies transfusions has significantly improved the safety and effectiveness of RBC transfusions since varying degrees of haemolysis and shortened life span of RBCs were seen in xenotransfusions, with the development of high antibody titres against foreign RBCs leading to immunologic consequences. Veterinary transfusion largely is practiced in this manner, with adequate feline blood supply being challenging to sustain with the small donor pool and more complicated collection process. Being able to use, for example, canine donors of a typical donation volume of 450 ml to supply our feline patients with a typical (whole blood) unit volume of 50 ml would allow a single donation to give us enough blood for nine transfusions. This seems like a great opportunity for a solution to the blood shortage. Let’s discuss this further.
In order to implement xenotransfusion into our practices, we would first need to ensure the effectiveness and safety of xenotransfusions. There are several published studies specifically evaluating the effects of canine to feline transfusions, evaluating pre-transfusion predictors of immunologic complications, immunologic complication signs seen during and after transfusions, and the same on repeat xenotransfusions at varying timings.
Efficacy
The studies that have been conducted heavily focused on compatibility testing and immunologic complications, and less information on efficacy of the transfusion is available. Literature giving insight to the efficacy of canine to feline transfusion indicates a rapid improvement of clinical symptoms, leading to the conclusion that a positive effect of the transfusion is expected. In a case report involving a type B cat receiving blood from a Labrador Retriever resulted in an increase in PCV taken after the transfusion performed over 48 hours. The effect is relatively short lived, however, since the transfused RBCs seem to have an average lifespan of 4 days. In comparison, a typical life span of RBCs of homologous feline transfusion is 30 days. The loss of transfused RBC is attributed to delayed haemolytic transfusion reaction resulting from antibody production against RBC antigens introduced. The production of antibodies by the immune system when exposed to foreign antigens (sensitization) occurs in a delayed manner reaching significant titre levels 4–7 days post transfusion, allowing the transfused RBCs to persist for 4 days on average. The recipients have been observed to develop icterus from increased intravascular haemolysis and bilirubin load.
Safety
Statements regarding safety of canine to feline transfusions can be separated into three specific situations. In almost all transfusions performed in these studies, there were no acute clinical consequences to performing canine to feline transfusions as long as there was no history of previous canine blood transfusions. Subsequent transfusions performed within 4 days of the initial exposure also were performed without acute symptoms of immunologic complications. Subsequent transfusions performed more than 46 days past initial exposure resulted in anaphylaxis, which is often fatal.
Cats seem to be tolerant of the first canine blood transfusion they receive without signs of acute haemolytic or allergic reactions, indicating a lack of naturally occurring antibodies against canine RBC antigens. These observations correlate with the majority of compatibility testing methods (slide agglutination and cross match haemolysis testing) showing no signs of incompatibility. Occasional positive reactions were seen on the minor (recipient RBC mixed with donor plasma) cross match, which upon transfusion would cause some haemolysis of recipient RBC. This effect is minimized from the use of pRBC, containing very little plasma, and dilution by recipient blood volume upon transfusion. Cats in the studies rarely exhibited signs of complications, and when they did they were mild, involving tachypnoea and pyrexia during or within 24 hours of the transfusion. Delayed haemolysis occurring after 4–7 days of transfusion seems inevitable, with presence of anti-canine RBC antibodies made evident through positive slide-agglutination and cross match results when performed after this timing.
Subsequent transfusions after the initial exposure within the 4–7 day period did not result in clinical signs. Slide agglutination and cross match tests performed during this time period did not result in a positive reaction as well. This indicates a “grace period” in which antibodies are being produced to incite an anamnestic response when the next exposure occurs. Felines in the study that were given doses of canine RBC 1 and 2 days after initial exposure did not exhibit signs of immunologic complications. Test subjects having subsequent transfusions performed later than 6 days after the initial exposure showed signs of anaphylaxis with more than 66% resulting in death. Some of these cats were treated with cyclophosphamide as an immune suppressant prior to second exposure with the hypothesis of immune suppression reducing chances or severity of immunologic complications, with no positive effect seen. This serves as further evidence of the ineffectiveness of immune suppressive agents as premedication for transfusion (human studies show premedication to be ineffective).
Summary
Transfusion of canine blood, whether whole blood or packed RBC, can be performed without immediate consequences if it is the first transfusion of this kind. However, the benefit is short lasting, and should be reserved for patients that are in dire need of blood. The basic considerations in employing this therapeutic option should include situations where all of the following conditions are met. (1) The patient has no source of RBCs with compatible blood type (type B cat with no stocked blood, donor, or nearby hospital with stock, for example) or haemoglobin-based oxygen carrier solution. (2) The patient is imminently going to pass away or is thought to be in danger of sustaining irreversible hypoxic damage (certainly up to clinical judgment) without the ability to obtain compatible blood in a timely manner. (3) The patient is expected to benefit from a short-term oxygen carrying capacity gain. In this case, the patient may have a condition where the cause of anaemia can be controlled swiftly enough to allow regenerative response to take over, or allow for time to obtain sources of compatible RBCs in the meantime. (4) The patient has never received canine blood products. (5) The owner understands the risks and consequences of performing a canine to feline transfusion. As the method is non-traditional, the owner should know our exact state of knowledge and potential consequences to give fully informed consent to the procedure.
If these conditions are met, use of transfusions of canine RBC to feline patients can be a life-saving therapeutic option in true emergency situations. If a xenotransfusion is decided on, a major and minor cross match should be performed to screen donor-recipient matches resulting in any signs of immunologic complications, and a therapeutic plan formulated with the benefit lasting 4–7 days in mind. Clear understanding of outcomes of future canine to feline xenotransfusion by the owners is important in preventing a second exposure beyond the 4–7 day mark. As responsible veterinary professionals, xenotransfusion should not become common practice in its current state. Effort invested in maintaining a good source and stock of feline RBC products should not decrease simply because “we can always turn to dog blood if we really need to.”
“In its current state” it is used as a qualifier in the previous passage because there is research ongoing for the human medical field involving “immunocamouflaging,” or biochemical alteration of RBC antigens to prevent detection of the antigen as foreign by the immune system. The technique is still under development and its application to veterinary medicine would have an unknown timeline. Implementation of such techniques in xenotransfusions is theoretically beneficial in preventing immunologic consequences.
Autologous Transfusions
Several forms of autologous transfusions, or the act of infusing blood products derived from the patient themselves, are available in providing the patient with components necessary. These techniques can be useful in specific situations.
Autotransfusion
Autotransfusion is the act of recycling blood lost by the patient by collection and reinfusion. The term autotransfusion is specific to the form of autologous transfusion involving blood that is lost from the patient’s condition or injury. In veterinary medicine, autotransfusion is most commonly performed as unwashed red cells transfused through a filter. This is accomplished through transfer of suctioned blood into an intravenous fluid bag and administered with a blood administration set. An alternative method involves the use of a 3-way stopcock attached to a syringe and extension sets. The stopcock is first opened to the extension leading to the pooled blood and syringe, and blood pulled into the syringe. The stopcock is then opened to the syringe and another extension leading to an intravenous catheter, and the blood pushed through an in-line blood filter into the patient. The syringe method can also be employed prior to surgical intervention, through percutaneous insertion of a catheter into a body cavity where haemorrhage is occurring. Autotransfusion is observed to be effective in alleviating compensatory signs from anaemia and improvement in consciousness, whereas replacement of the volume with lactated Ringer’s did not result in the same effect.
An autologous RBC salvage system or cell-saver device is a piece of equipment with the capability of collecting blood lost into the patient, separating blood components through centrifugation, washing the RBC, and suspending them back into a suspension for administration. The salvage process can be discontinuous (batched) or continuous (uninterrupted reinfusion) depending on the device, and has the advantage of having the ability to provide higher concentration of RBC than collected blood containing fluid, as well as removing contaminants through the separation and wash process.
Autotransfusion has advantages, including the alleviation of blood bank demands in performing transfusions. Blood bank supply is often strained, with upkeep being a significant financial and staff training investment. In addition, by administering autologous blood, the concerns of immunologic complications are eliminated. Blood typing and cross-matching can also be omitted, since there should be no better match to a recipient than their own blood. Storage lesions, which include accumulation of hazardous levels of electrolytes, metabolites, and inflammatory mediators as well as RBC changes reducing their efficacy as oxygen carriers lead to blood stored longer than 14 days to be less effective in treatment of anaemia, have shorter survival time, and incite negative effects. These storage lesions can be virtually completely avoided through employment of autotransfusion, as no storage time is involved.
One of the main concerns with autologous transfusions is the theoretical potential for iatrogenic metastases of neoplastic cells that may be contained in the blood suspension. While no veterinary evidence is available, human studies indicate the lack of such consequences upon autotransfusion. This may be a combination of several factors, such as the thought of the cell salvage process and leukoreduction of the blood leading to effective removal of neoplastic cells. In addition, neoplastic cells may already be in circulation in many cases. Furthermore, allogenic transfusions are known to cause transfusion related immunomodulation resulting in down-regulation of the immune system, associated with increased incidences of cancer recurrence. There is potential for autologous transfusions to be more beneficial for cancer patients.
Another concern with autologous transfusions lies in the case of bacterial contamination of the blood being salvaged. In the case of blood salvaged by cell-saver devices undergoing leukoreduction, 99% of the bacterial load is seen to be removed prior to transfusion, eliminating this concern. Blood collected in clean procedures not involving obvious sources of bacterial contamination such as bowel perforation or penetrating trauma is seen to contain bacteria as well, questioning the notion of all bacterial contamination being avoidable as well. While the effect of bacterial load in blood prepared for autotransfusion without cell-saver devices and leukoreduction is uncertain, the general approach to these patients involves antibiotic therapy, and there is no evidence supporting increased incidences of bacteraemia as a result of autotransfusion. The use of cell-salvage devices may also lead to cell-salvage syndrome resulting in disseminated intravascular coagulation, acute respiratory distress syndrome, acute kidney injury, or death.
Pre-Operative Donation
Autologous transfusions may be performed as an intentional form of blood collection prior to procedures with reasonable chances of it resulting in haemorrhaging and subsequent demand for a transfusion. Preemptively collecting blood from the patient, typically a week prior to the procedure will allow for regenerative response to have helped replace the RBC lost through collection. The collected blood is stored in preparation for the anticipated blood loss, serving as a source of autologous RBC product if need arises. Advantages similar to autotransfusion techniques exist with this form of autologous transfusion, including the elimination of need for compatibility testing and alleviation of allogenic blood demand. A differing severity of storage lesion will be seen depending on the timing of blood collection and can lead to an increase in complications related to storage lesions. The risk of bacterial contamination upon blood collection should be at a rate similar to allogenic units, dependent on quality of blood collection procedures and storage.
Acute Euvolaemic Haemodilution
The detrimental effects of storage anticipated by performing autologous transfusions through pre-operative donation can be circumvented through a technique called acute euvolaemic haemodilution. The technique involves blood collection from the patient undergoing a surgical procedure with likelihood of haemorrhaging just prior to the procedure, with replacement of lost blood volume with crystalloids to prevent hypovolaemia. While the patient will have reduced circulating RBC mass as the procedure is started, the amount of blood collected is limited to tolerable amounts to meet oxygen demands. The blood lost during the procedure will be diluted in concentration of RBC (PCV), reducing the RBC mass lost when compared to the same volume of blood with the original concentration. The collected blood can be transfused if the need for a RBC transfusion arises, with the same benefits of any autologous transfusion technique, with the additional benefit of the blood being fresh. The technique serves as a method in alleviating allogenic blood transfusion need, though is often not sufficient to eliminate needs.
The quest for providing a sufficient supply of safe RBC product is an area of ongoing improvement, as the demand for blood products is ever-present, while the negative effects of blood transfusions in current practice are increasingly understood. Ensuring supply and safety in transfusions relies on methods to reduce the need for RBC transfusions (conscientious blood sampling, assertive treatment of underlying cause, proper assessment of indication), use of alternatives to RBC transfusions, proper risk assessment and compatibility testing, proper patient monitoring, and swift response to complications. Xenotransfusions and autologous transfusions are a couple of strategies increasing our supply of RBC products, each with their situational effectiveness and appropriate considerations.
References
1. Bovens C, Gruffydd-Jones T. Xenotransfusion with canine blood in the feline species: review of the literature. J Fel Med Surg. 2012;15(2):62–67.
2. Hirst C, Adamantos S. Autologous blood transfusion following red blood cell salvage for the management of blood loss in 3 dogs with hemoperitoneum. J Vet Emerg Crit Care. 2012;22(3):355–360.
3. Kellett-Gregory LM, Seth M, Adamantos S, Chan DL. Autologous canine red blood cell transfusion using cell salvage devices. J Vet Emerg Crit Care. 2013;23(1):82–86.
4. Kisielewicz C, Self IA. Canine and feline blood transfusions: controversies and recent advances in administration practices. Vet Anaesth Analg. 2014;41:233–242.
5. Prittie JE. Controversies related to red blood cell transfusion in critically ill patients. J Vet Emerg Crit Care. 2010;20(2):167–176.
6. Safaei M, Takami HM. Blood autotransfusion outcomes compared with Ringer lactate infusion in dogs with hemorrhagic shock induced by controlled bleeding. J Res Med Sci. 2011;16(10):1332–1339.