A Review of Common Blood Replacement Alternatives Advantages of Blood Substitutes/Alternatives Although notable progress has been made in the development of oxygen-carrying solutions that will someday bring effective replacements for whole Blood into clinical practice, most experts still consider artificial Blood to be at or near the frontier of research and development. Non-oxygen-carrying substitutes for human Blood, such as Ringer's lactate and other colloidal solutions, currently provide an effective treatment for Blood losses on the order of 50%, with few if any negative side effects. The effort to find an effective Blood substitute is both important and slow. There remain unanswered questions on their safety and efficacy relative to real human Blood. This group of compounds is unlikely to make a significant contribution to transfusion practice for some time. There are three primary reasons driving the quest for a substitute for Blood: quantity, a replacement the lost volume of Blood; storage, Blood is perishable, and both long and short term storage is an expensive problem; and purity, non-tainted Blood of the correct Blood type is not always available when needed. It is generally possible for humans to survive very low hematocrit levels (red Blood cell volume as a percentage of Blood volume) resulting from losses of up to 70% of red Blood cell mass; however, the body's ability to compensate for much smaller losses of Blood volume is surprisingly quite limited. A loss of only 30% of Blood volume can lead to irreversible shock if not treated rapidly enough. Various fluids have been found to be appropriate for increasing the Blood volume and are classified as crystalloid solutions, colloidal solutions, or oxygen-carrying solutions. Crystalloid solutions, such as Ringer's lactate or saline, and colloidal solutions, including use of albumin as a plasma expander, have proven valuable as a Blood substitute on the basis of volume replacement. Oxygen-carrying solutions, on the other hand, have posed much greater challenges, and the object of most research efforts has not been to find a replacement for whole Blood, but to duplicate its oxygen-carrying capabilities. Replacement of lost human Blood with an oxygen-bearing substitute is essential for extreme Blood loss. Although differing oxygen-carrying replacements have demonstrated numerous positive features, their use has been associated with certain limiting side effects. Hemoglobin-Based Oxygen Carriers (HBOCs) capable of effectively treating hypovolemia are intrinsically capable of providing oxygen for tissues, yet the feasibility of successfully introducing large volumes of a hemoglobin-based substitute to the body is, for sure, a work in progress. There are very important factors pressing this effort. They include an increasing need for Blood, potential risks associated with donated Blood such as infection, allergic reaction, and hemolytic reaction, and the potential benefits of a substitute offering extended shelf life. Ultimately, the use of Blood substitutes may require a balance between the need for the substitutes' life-giving properties and the potential severity of their side effects. In most situations, patients requiring Blood replacement because of Blood loss need only a short-term replenishment of the oxygen-carrying capacity of hemoglobin until their own bodies synthesize replacement red Blood cells. It is the hemoglobin, however, that requires refrigeration, has a relatively short shelf life, and must be carefully matched for correct Blood type and other factors. Efforts to develop a viable Blood substitute have thus focused on creating a hemoglobin alternative that can be stored for a long period of time at room temperature and can be transfused to restore the oxygen-carrying function of hemoglobin without the need for type matching. According to FDA estimates, over ten companies have Blood substitute products publicly disclosed and under development in preclinical and end stages of clinical trials. By the beginning of 1999, four different hemoglobin-based oxygen carriers (HBOCs), developed by four separate companies, had entered the late stages of clinical development. Following is a short, and sometimes technical, commentary and definition set of common products made from donated Blood. There are others, however, these are the ones that most often are needed in the United States. Researchers are reporting the creation of a new process for camouflaging the surface of red Blood cells that, in effect, would create a universal Blood type. This procedure for antigen camouflage, when proven, will have significant potential in transfusion and transplant medicine, as well as in veterinary medicine. The process involves coating the red Blood cell with a biocompatible polymer called polyethylene glycol (PEG). The PEG molecules form permanent covalent bonds on the surface of the cell. This coating effectively hides the antigenic molecules on the surface of the red Blood cells so that the foreign cells are not recognized by the Blood recipient's antibodies. For example, a person who has type A Blood will naturally have antibodies that attach to the antigens on the surface of type B Blood cells and destroy the foreign Blood. The attachment of PEG to the surface of type B Blood camouflages the surface of the cell so the antigens can no longer be recognized and thus would prevent the destruction of the antigenically foreign red Blood cells. A number of diseases, including thalassemia, that require repeated Blood transfusions are often complicated by the development of antibodies to "minor" red cell antigens. This "allosensitization" can render these patients almost impossible to transfuse. It can be a life-threatening situation. In vitro testing, the PEG-modified red cells appear not to trigger allosensitization and may also be useful in clinical situations where allosensitization has already occurred. When tested in a transfusion, the modified cells, while antigenically "silent," remain structurally and functionally normal and had normal survival. PERFLUOROCARBON-BASED SUBSTITUTES One firm in the United States, specializing in perfluorocarbon technologies, is developing a Blood substitute based on that technology. Because Blood gases such as oxygen and carbon dioxide are highly soluble in perfluorocarbons, SYBD's Oxycyte is intended to provide an effective means of transporting oxygen to tissues and carbon dioxide to the lungs. Compared with hemoglobin, Oxycyte has been found to be capable of carrying at least five times more oxygen. Additionally, perfluorocarbons are considered to be more effective than hemoglobin for delivering oxygen at the tissue level. According to the company, the perfluorocarbon microdroplets that carry the oxygen are 1/70th the size of the red cells. They can therefore reach many areas of the body that human red Blood cells cannot. The product is inert and can be fully sterilized. It can be stored at room temperature and does not require typing and cross-matching prior to use. The firm considers Oxycyte to be an all-purpose synthetic Blood product, with potential uses including surgery, trauma, angioplasty, open heart surgery, and oxygenation of tumors during radiation or chemotherapy. The product can also be made available on the battlefield, at the scene of accidents, and stored in emergency vehicles and emergency departments. RECOMBINANT PLASMA PROTEINS Although the official Blood establishment in the United States has not been directly and intimately involved in the development of synthetic coagulation factor concentrate products, such as factors VIII and IX, these products are mentioned here for the sake of completeness. The technology is adaptable to other therapeutic proteins such as albumin. A great advantage is that recombinant factors can be assumed to be free of the typical Blood-borne pathogens, provided those are not introduced by plasma-derived excipients. TRANSGENIC THERAPEUTIC PROTEINS Researchers at the Holland Lab, under the direction of William Drohan, Ph.D., have pioneered the development of technologies for producing synthetic human proteins in the milk of animals. By inserting the genes for human coagulation factors (protein C and factor VIII to date) into pig embryos, they showed that the adult pigs synthesized the corresponding human proteins in their milk, which then could be purified for therapeutic use. This model can serve as a source of other therapeutic proteins, which have the advantage of virtually unlimited production, low cost and freedom from human infectious diseases. Recently, this research has led to the Red Cross signing an agreement with a major biopharmaceutical company for further development and commercialization of these products. BOVINE-DERIVED HEMOGLOBIN SUBSTITUTES A company in Cambridge, MA, U. S. A. recently announced results of clinical studies involving its investigational oxygen therapeutic, Hemopure, a bovine-derived HBOC product. The results suggest that the product can eliminate the need for allogeneic red Blood cell transfusions in a significant number of patients undergoing vascular surgery. According to Glenn M. LaMuraglia, MD, the principal investigator at the division of vascular surgery, Massachusetts General Hospital, one of eight hospitals that participated in the study, "This oxygen therapeutic solution eliminated intra and postoperative red Blood cell transfusions in more than a quarter of these high-risk patients despite study design restrictions on the total dose and number of days over which the product could be administered." Specifically, the results indicated that the Blood substitute "totally eliminated the need for red Blood cell transfusions in 27% of patients throughout the entire 28-day follow-up period," according to the firm. "Moreover, 39% of Hemopure patients did not require allogeneic Blood during the 96-hour treatment period and 66% did not require allogeneic Blood on the day of surgery, further supporting the product's use as an oxygen bridge." Hematocrit levels were similar for both the Hemopure group of patients and the control group at the time of discharge from the hospital. The company believes that Hemopure may support the production of the patient's own red Blood cells. To date, Hemopure has been administered to more than 600 patients in 21 completed or ongoing clinical trials. One unit of Hemopure contains 30 g of ultrapurified, chemically cross-linked hemoglobin in 250 ml of a balanced salt solution. When infused, this linked hemoglobin circulates in the plasma, and has a lower viscosity and more readily releases oxygen to tissues than to Blood. Hemopure has been shown to be stable at room temperature for at least 30 months. The product is compatible with all Blood types, and is purified through patented techniques that are validated to remove infectious agents, including bacteria, viruses, prions, and other potential contaminants, the company states. HEMOGLOBIN SOLUTIONS Research into finding safe, effective red cell substitutes has been going on for many years, and now is being pursued mainly by biopharmaceutical companies. The two main classes of oxygen-carrying agents are stroma-free hemoglobin solutions and non-hemoglobin solutions, notably perfluorohydrocarbon emulsions. Toxicity of the latter has limited its use to support oxygen delivery during some limited surgeries. Hemoglobin solutions appear very attractive, offering the advantages of a product devoid of red cell antigens, capable of being virally inactivated, stored for long periods of time, and available in the field for use in mass trauma situations. However, because of its high oxygen affinity and rapid renal excretion, however, it requires chemical modification with crosslinking and polymerizing agents such as pyridoxal phosphate. Toxicity remains a major challenge. There are risks of bacterial sepsis, due to the effect of iron on bacterial growth and vasoconstriction due to binding of nitric oxide by the hemoglobin. A few products have reached the clinical trial stage. The most promising of these to date being a pyridoxalated polymerized hemoglobin solution ("PolyHeme") developed by a company in Illinois, U. S. A. If successful, this product, and others likely to follow, may replace red cells for many of the current indications such as acute Blood loss. PLATELET SUBSTITUTES FOR CANCER PATIENTS In addition to efforts to find Blood substitutes, research focusing on platelet substitution is being driven by potential use in treating certain conditions that are common among cancer patients. One of the side effects of cancer therapy is the drastic reduction in platelets, or thrombocytopenia. The condition is currently treated with a transfusion of Blood-derived platelets. As of 1998, it was estimated that 18 million units of platelets are transfused each year worldwide; 80% goes to patients who are thrombocytopenic as a result of chemotherapy. As chemotherapy regimes become ever more aggressive and as the use of bone marrow transplantation increases, the requirement for platelets will grow. Among the products being considered specifically to treat thrombocytopenia are 'Synthocytes', in development by a British company. Synthocytes are microcapsules to which fibrinogen has been chemically linked. Acting as a replacement for human Blood platelets in the prevention of bleeding, the Synthocytes are capable of selectively targeting the site of hemorrhage, according to the company. The product is believed to offer certain key advantages over Blood-derived platelets, that have the potential to transmit viral infections, suffer from instability during storage, and cause immune reactions. By fragmenting the membrane of outdated platelets, investigators at a company located in the United States have extracted key hemostatic components of platelets (factor 3 and the glycoprotein 1b receptor), a process called "Infusible Platelet Membranes." After a viral inactivation (heat) step and lyophilization, they infused the product into thrombocytopenic rabbits and demonstrated a reduction in the bleeding time. The Company has assumed further development of this product (now named "Cyplex Platelet Alternative"). In human volunteers with aspirin induced prolongation of the bleeding time, Cyplex caused shortening of the bleeding time. This has resulted in control of mucosal bleeding in thrombocytopenic patients. Interestingly, this also occurred in two thirds of patients refractory to platelet transfusions. To date, no significant toxicity has been observed; in particular, there were no antibodies to platelets, HLA or Cyplex. REDUCING THE NEED FOR DONOR BLOOD Earlier this year, a Canadian company announced positive results from a clinical trial of its hemoglobin replacement product involving 60 patients undergoing coronary artery bypass grafting (CABG) procedures. Hemolink is an HBOC derived from human red Blood cells. In surgical applications, the product is used in conjunction with intraoperative autologous donation (IAD). IAD is a Blood conservation strategy in which up to four units of a patient's Blood are removed just prior to undergoing surgery. This harvested Blood volume is replaced with Hemolink instead of conventional volume expanders that do not deliver oxygen to tissue. The patient's harvested Blood is subsequently returned as needed, as well as Blood recovered by cell salvage methods. The result is a reduction or complete elimination of patient exposure to donated Blood. CONTINUING RESEARCH Research into the development of Blood
substitutes is continuing at numerous centers. At the University of Pittsburgh Medical
Center's McGowan Center for Artificial Organ Development, researchers are focusing on
artificial Blood components that can function as an all-purpose Blood substitute. The
McGowan artificial Blood components are being designed to combine the high oxygen-carrying
and nutrient supplement capability of natural Blood with superior fluid properties.
According to the researchers, "The significant novelty of our research is to achieve
maximal oxygen delivery to tissues with minimal concentration of oxygen carrier via the
superior mechanical and physical properties of the product. Additional advantages of the
product are low toxicity and a low cost due to significantly reduced concentration of the
oxygen carrier." The McGowan artificial Blood components are being tested in vitro
for their effectiveness and stability. The first phase of the functionality, toxicity, and
general biocompatibility testing preparations is still in progress, and the patent
application on the novel artificial Blood was filed in September, 1998. One possible
application of artificial Blood is protection of Blood cells from mechanical damage in
Blood-wetting artificial organs
Advantages of Blood Substitutes
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