Blood substitutes

 

In recent decades, one of the most exiting topics in haematology has centred on the efforts to develop substitutes for human blood. There are several reasons why the need for blood substitutes has become more pressing: while some are of a social nature, aimed at changing the perceived value of blood, others are more technical, in that they involve the scientific desire to produce a product with properties superior to that of normal blood, but without any of the weaknesses inherent in the original substance.

 

Firstly, recruiting and managing donors is a difficult and time-consuming task, requiring the allocation of considerable funds to tend to the administration of donor needs. To be successful, any blood substitute must be available in volumes that are abundant enough to meet all foreseeable demands at a lower cost than it takes to recruit human volunteers. Secondly, if human blood is to be properly stored and transported, then refrigerated facilities and vehicles are needed, which may present logistical difficulties in areas where basic infrastructure is lacking. Ideally, any blood substitute should be stable at room temperature and easy to handle without requiring the use of specialized and costly equipment. Furthermore, even when properly handled, we must recall that blood is a perishable item with a relatively short shelf life – while nutrient additives such as glucose can be used to prolong its life, rapid deterioration persists, so a good substitute will need to retain its usable properties for a long period of time, even when exposed to undesirable storage conditions. Safety is another consideration, as money must be spent on the testing and handling of donated blood in order to ensure that it is safe and goes to the right recipient. Ideally, any substitute should eliminate the need to conduct expensive disease screening and type matching tests. Finally, there is the issue of blood borne diseases, which have not only limited the amount of blood that could be supplied by donors, but may have also restricted the more widespread use of transfusion due to fears of infection among recipients. While screening tests have made transfusion safer than before, a substitute that can be proven to be absolutely free of any disease carrying properties or genetic defects, whilst being efficacious in clinical use, would be very successful in a commercial sense, and could restore any lost confidence in the use of blood as a medical tool. 

 

While the rate of supply of blood has, until now, managed to keep broadly in line with increases in demand, such a state of affairs may not always be possible. In order to head off any problems that may appear in future, a range of alternative blood products have been developed and tested for possible human use. What follows is a summary of the main categories of feasible substitutes, with an evaluation of their features and likely prospects for future introduction.

 

i) Human haemoglobin

Many of the efforts to develop blood substitutes involve the development of a substitute for red cells, with the focus of research being on replacing red cells with solutions that use haemoglobin (the respiratory pigment found in red cells) as their basic raw material. Ideally, the best type of haemoglobin is the one found in human red cells, as it has all the basic properties required for use in the human body. The one immediately accessible source for acquiring such raw material has traditionally been from outdated red cells present in the stocks of blood banks, but while this may have been a promising avenue in the past, in recent years, the flow has all but disappeared. This is since the quantity of outdated blood available for reprocessing has steadily decreased due to improvements made by blood banks in their handling and storage procedures and because donated blood is consumed almost as soon as it is cleared for use. In addition to this supply problem, a technical difficulty concerns the fact that the antigens that define the differences between blood groups remain functional in old red cells, which limits the potential usefulness of this raw material. While scientists have attempted to overcome this obstacle by converting all salvaged human haemoglobin to type O standards, they have had only limited success [1], which means that for the foreseeable future, all blood substitutes with this haemoglobin will continue to require cross matching and typing tests before use.

 

ii) Non-human haemoglobin extracts

Rather than depend on limited human haemoglobin stocks, an alternative approach has been to extract haemoglobin from other living organisms that also require oxygen in order to survive.

 

One potentially unlimited source is bovine haemoglobin, which can be extracted as a by-product of livestock slaughtered at abattoirs. Several experimental products prepared with red cells obtained from cattle, such as Hemopure, have been tested on human volunteers, but while the results of trials have been promising, it is unlikely that such products will be publicly acceptable in the near future [2]. This is mainly because not enough is yet known about the long-term effects on humans of repeated exposure to animal blood, although experience from the early transfusion experiments suggests that animal blood, even if treated, has the potential to harm humans. In addition, a great fear that has yet to be settled is whether or not such products can transmit mutations of animal diseases such as BSE, the so-called “mad cow disease”, to human recipients.

 

In lieu of using haemoglobin obtained from normally reared animals, an alternative source that has become available as a result of the scientific advances of recent years has been the blood of transgenic animals, which are genetically engineered before birth to produce human blood cells. Some of the apparent benefits of this technology are that the blood produced is stable, can be transmitted to the following generation of animals (helping to increase the size of the donor pool), and is relatively easy to separate from the haemoglobin belonging to the host animal (as it has slightly different identifying markers). The main disadvantage is that as this technology is still in its infancy, it is not yet clear whether large quantities of transgenic haemoglobin can be efficiently produced at a low enough cost. In addition, it is doubtful as to how long further research in this field will be allowed to continue given the present public distaste for cloning and animal experimentation.

 

Finally, recombinant haemoglobin, which is obtained by genetically modifying non-animal organisms that breathe oxygen, such as plants, bacteria and yeast, has also been considered [3]. The main advantages of obtaining haemoglobin from this source are that it may be available in large volumes, can be engineered into “tailor made” molecules suitable for specific tasks, and, as it does not rely on any human or animal blood as a building block, has the potential to be free of animal viruses (but maybe not against plant diseases). Once again, the main disadvantages are that this is a new technology that has yet to prove itself completely, plus there may be a similar outcry against it as there was against the introduction of genetically modified foods.

 

iii) Perfluorochemical emulsions

An alternative technique of developing red cell substitutes has involved the synthesis of perfluorochemical emulsions, which are organic compounds where the hydrogen atoms have been replaced with fluorine. Commercially, the most successful of these products has probably been Fluosol, which was developed by Green Cross of Japan, one of the largest players in the blood products industry. In 1990, following an extensive period of testing upon hundreds of patients, the FDA approved the limited use of this product on certain high risk patients undergoing angioplasty or receiving treatment for certain forms of cancer [4]. Despite this success, Fluosol is considered to be a “first generation” product only, as it suffers from several drawbacks, including a short lifespan, a limited oxygen carrying capacity, an unstable nature at room temperature (necessitating the use of frozen storage), and a potential for causing toxic exposure in recipients. In order to overcome these limitations, a second generation of enhanced products in this category with superior longevity and oxygen carrying properties has been proposed, although these are still in the early stages of development and have yet to be widely tested.

 

iv) Synthetic and recombinant plasma products

While researchers have had limited success in developing red cell substitutes, their efforts at developing substitute plasma products have been more fruitful. Probably the most successful of these substitutes is recombinant factor VIII concentrate, which is primarily of synthetic origin, although it does contain traces of human albumin within its cells [5]. This product is thought to have such great potential that in the UK, all haemophiliacs under the age of 16 or who have never been administered the original human product before are now being treated almost exclusively with it, resulting in its share of the applicable UK market increasing from literally zero to almost 25% in only 3 years [6]. At present, the principal disadvantage of this product is that it costs considerably more to produce than the equivalent human version, suggesting that until unit costs fall substantially, its use is likely to be restricted mainly to wealthier patients or health systems.

 

Other substitute products that have recently been introduced limited use include recombinant factor VIIa concentrate, as well as recombinant factor IX concentrate and recombinant disease vaccinations, which have the impressive advantage of having absolutely no human sourced material in them whatsoever. Along with these synthetic products, scientists have also had some success with an animal derived product known as porcine factor VIII, which, as its name implies, is a product for haemophiliacs developed from the plasma of pigs. 

 

In addition to these conventional plasma products, another set of conceivable blood substitutes worth mentioning are artificial saline solutions, which are derived via a chemical production process. These are generally used as haemodilutents or volume expanders during events such as cardiac surgery, where rapid inflows of fluid that keep the heart pumping are needed to compensate for the massive losses of blood that take place. While such fluid enhancers have proven highly successful, they may only show their true worth on the day that they are successfully coupled with red cells substitutes, in which case a very good basic imitation of natural blood will have been developed [7].

 

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