Xenotransfusion: Crossing species boundaries in blood transfusion

Introduction

Xenotransfusion-the transfusion of blood or blood components between different species is an evolving and intriguing field at the crossroads of clinical urgency and scientific innovation. It stands as a remarkable yet controversial chapter in the evolution of transfusion medicine. Emerging from early, rudimentary attempts in the 17th century, the practice has transitioned from a curiosity rooted in desperation to a scientifically grounded, albeit still experimental, therapeutic strategy. Historically rooted in early medical experimentation, it now holds renewed relevance in both human and veterinary medicine, especially where persistent challenges exits associated with allogeneic transfusion, including donor shortages, blood group incompatibilities, and logistical limitations particularly in emergencies and rural or resource-limited environments (Johnson et al., 2022; Lewis et al., 2019; Martinez et al., 2021; Smith et al., 2020) [15,18,19,25] . In veterinary medicine, the urgency of clinical scenarios involving acute hemorrhage, anemia, or trauma often demands rapid decision-making, and xenotransfusion offers a critical lifeline when compatible same-species donors are unavailable. Therefore, xenotransfusion is carried out to meet the requirement of blood in emergency situations where allotransfusion is either not available or not feasible due to many reasons (Nguyen et al., 2018). Dog-to-cat transfusions or equine-to-donkey xenotransfusions in field conditions, underscore its practical value. Likewise, in human medicine, the concept has been reinvigorated by cutting-edge research into porcine red blood cells and genetically modified donor animals designed to minimize immunogenicity and disease transmission risks. It is a reflection of progress in immunology, biotechnology, and translational research (Walker et al., 2017) [29]

History

The first documented xenotransfusion to humans was performed on June 15, 1667 by Jean-Baptiste Denis, a French physician, and Paul Emmerez, a surgeon. The transfusion occurred between a lamb and a 15-year-old young Swedish boy. The patient was presented with loss of his ability to speak and was practically unconscious. Carotid artery blood from the lamb was introduced to a vein in the patient's inner elbow, and the procedure ultimately resulted in a successful recovery. Shortly after the transfusion began, the patient was able to speak again (Mollison et al., 1997) [20] . His health was improving until his condition grew progressively worse. A second transfusion took place in another patient, but it was unsuccessful, and the patient died. On November 23, 1667, an English physician named Richard Lower also performed a similar procedure and successfully transfused the blood of a lamb to a 22-yearold man and documented in his book (Starr [26] 1998).

Some examples of xenotransfusion are 1. Dog-to-cat blood transfusion

In cats the small size of cat makes blood collection technically more difficult than in other species, and sedation is frequently required or even they are anaesthetized for blood donation. Cats usually need 30 to 80 mL of blood during a single transfusion. It represents 25-30% of a donor cat's blood volume while it is only about 2% of a Labrador's blood volume, but one dog can often provide enough blood for a cat, but if we use only cat donors (allotransfusion), we may need blood from several cats. Which increases the risks and difficulties of the procedure. Thus, large volumes of blood needs may be met by a single dog (Giger et al., 2011) [9] . Another reason is blood group type in allotransfusion. One of the feline blood types, type B, is relatively rare among cats, and finding a donor for such cats is sometimes difficult. An allotransfusion with incompatible blood causes transfusion reactions like haemolysis (in the case of a type-B donor and a type-A recipient), or at the worst death within a few minutes (in the case of a type-A donor and a type-B recipient). A cat must therefore not be transfused without prior blood typing, and ideally cross-matching, not even for the first transfusion. Use of canine blood does not expose the feline recipient to these dangers. The risk of transfusion reaction with canine blood is much lower than that associated with the use of blood from a cat chosen at random. Most researchers agree on the absence of natural antibodies in cats against dog erythrocyte antigens (and vice versa) and thus confirm the value of canine blood. Because of these reasons and despite interspecies transfusions being abandoned in all other species since the early 1900s, reports can be found, mostly from the late 1960s, about the effects of canine whole blood transfusions to cats (Knottenbelt et al., 1999).

Blood transfusion in equines

Due to scarcity of typed and cross-matched equine blood, horse-to-donkey or donkey-to-horse transfusions may be performed in mules (horse-donkey hybrids), blood from either parent species may be considered, with careful monitoring.(Taylor et al., 2022) [27] .

Blood Transfusion in Ruminants and Small Ruminants (Cattle, Sheep, Goats)

In rare settings (remote rural areas, wildlife care), temporary xenotransfusions from closely related species (e.g., goat to sheep) may be considered. (Smith et al., 2019).

Domestic-to-wild animals blood transfusion

A similar situation of non-availability of same species blood can be dealt with wild species, captive or free. The lack of or impossibility of finding a donor of the same species, has led to the successful practice of xenotransfusions using blood from a closely-related domestic species. Xenotransfusion of blood from domestic dogs can be considered for captive non-domesticated canids. A blood transfusion from domestic sheep to a wild antelope in zoo medicine. (Isaza et al., 2014).

Pig to human

Genetically future modified pigs show strong potential as a source of red blood cells (pRBCs) for clinical transfusion (Cooper et al., 2016). Pig to human RBCs are similar to human RBCs in size and count, though they have a shorter lifespan (Ezzelarab et al., 2012) [8] . Despite only 85% amino acid sequence similarity between porcine and human haemoglobin, their structural and functional compatibility is sufficient (Ekser et al., 2012). Pig blood groups, particularly the A-O (H) system, have been studied, and type O pig herds can ensure ABO compatibility with humans. Transgenic pigs have even been developed to express human hemoglobin. Their high reproductive rate and the possibility of raising them in pathogen-free environments reduce infectious risks. Since pRBCs lack nuclei, they do not carry porcine endogenous retroviruses (PERV), and leukocyte filters can further reduce contamination and immune risk. With proper screening and biosecurity, the risk of disease transmission from pig RBCs is considered minimal, making them a promising alternative to human donors future. Since pig to human sensitization to pig antigens does not hinder future human allografts, pRBCs could be used in emergencies until human blood is available. pRBCs are expected to become viable alternatives for human RBCs, especially for patients with acute blood loss or transfusiondependent conditions like sickle cell disease. In highly -Sensitized patients, pRBC use alongside immunosuppression might be considered.

A tuberculosis patient receiving a direct blood transfusion from a goat at Dr Bernheim's clinic, 1891 Engraving Private collection. [9] .

Advantages of Xenotransfusion

Temporary but Effective Support:

Red blood cells of one species can circulate in other species for 2-7 days post-transfusion, providing crucial oxygen-carrying support and temporary life-saving support until the patient stabilizes or compatible blood is found (Davidow, 2013).

Disadvantages of xenotransfusion 1. Short Lifespan of

Few Tested Examples of Xenotransfusion Case report no (1)

A one-month-old kitten with severe anemia, likely due to flea infestation and Mycoplasma hemofelis infection, showed no improvement with initial treatment but after a xenotransfusion of 5 ml canine packed red blood cells drastic improvement was seen. The kitten tolerated the transfusion well, with no signs of reaction, hemolysis, or icterus. Its condition improved, PCV increased, and it recovered fully within a few days. After two weeks of monitoring, the kitten was discharged in good health.

Case report No (2)

An 11-year-old captive island fox showing signs of rattlesnake envenomation, including anemia and thrombocytopenia, was treated with anti-venom and supportive care. Due to worsening anemia, an emergency xenotransfusion of 45 ml whole blood from a domestic dog was administered. The fox showed no transfusion reactions and fully recovered within five days. This case demonstrates that canine-to-fox xenotransfusion can be successful and potentially lifesaving in critical situations. (Isaza et al., 2014).

Case report no (3)

A 10-month-old male domestic shorthair cat with severe non-regenerative anemia (PCV 6%) and negative for FeLV and FIV, experienced an acute transfusion reaction after receiving a small amount of type A feline blood, despite being typed as type A. Crossmatch tests showed incompatibility with multiple type A cat donors, deciding for a xenotransfusion with 60 ml of DEA 1-canine blood. (Weingart et al., 2004). [2] . • Prevention of xenozoonosis (cross-species infections).

(Denner et al., 2020) [5] . • Control of hyperacute rejection via complement inhibitors. (Cooper et al., 2016) [2] . • Control of hyperacute rejection via complement inhibitors.

• Immunosuppressive protocols to allow repeat xenotransfusions (Ekser et al., 2015) [6] . • Synthetic or recombinant blood alternatives inspired by xenotransfusion insights • Alternative oxygen carriers (like-Hb) to reduce need for donor blood. (Giger et al., 2023) [11] .

Conclusions

Xenotransfusion in veterinary medicine is a powerful tool for emergency intervention, particularly when conspecific donors are not available. While its use remains limited by immunologic and ethical constraints, advancements in genetic engineering and biotechnology may broaden its potential. With careful application, xenotransfusion can serve as a critical bridge in lifesaving care.

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