OXYGENATED BLOOD SUBSTITUTES, PLASMA EXPANDERS, ERYTHROPOIETIN AND OTHER GROWTH FACTORS
H. Franklin Bunn, M.D.
From: 1995 Bloodless Medicine and Surgery National Conference Abstracts
Conventional treatment of patients who have a clinically significant decrement in red cell mass is transfusion with stored compatible human red cells. Current anxieties notwithstanding, red cell transfusions have reached a remarkably high level of safety and efficacy. Nevertheless, there is growing interest in the development of alternate strategies, owing to both limitations in our voluntary blood donation programs and an increase in complex surgical procedures that require extensive blood replacement. This shortfall coupled with widespread concerns about transmission of HIV and other blood borne infections has spurred the development of autologous and directed donations, with augmentation of the patient's endogenous red cell production by administration of cytokines. An alternative approach is the use of a blood substitute capable of transporting oxygen to tissues.
Erythropoietin and other hematopoietic growth factors
Erythropoietin (Epo) is a glycoprotein hormone that regulates the production of red blood cells. The cloning of the Epo gene has permitted large-scale production of recombinant human Epo (rhepo) that is nearly identical to the endogenous hormone. Extensive clinical experience clearly documents the efficacy and safety of rhepo in the treatment of the anemia of renal failure. Patients with chronic inflammatory disorders such as cancer and rheumatoid arthritis may also derive benefit from therapy and in some cases, the need for transfusions is obviated. Anemias associated with primary bone marrow disorders are generally not responsive to rhepo but a substantial minority of patients with myelodysplasia have a significant increment in red cell mass, especially if rhepo is combined with granulocyte colony stimulating factor.
There is considerable interest in the use of rhepo in preoperative and postoperative settings to stimulate the patient's red blood cell production. In certain settings, this may permit a greater volume of autologous blood to be collected in anticipation of elective surgery. Even in the absence of preoperative phlebotomy, rhepo appears to be of value. A large randomized placebo-controlled study from Canada demonstrated the efficacy of pre- and postoperative administration of rhepo (days -10 to +3) in decreasing transfusion requirements of patients undergoing elective hip replacement. In addition, administration of rhepo may be of benefit in more acute surgical settings. rhepo may permit more rapid recovery in the post-operative period. In particular, it may be a useful adjunct following perioperative hemodilution. In these different applications, patients serve as their own blood banks.
Oxygen carrying blood substitutes
A cell-free oxygen transporting blood substitute would obviate many of the current concerns about conventional red cell transfusion therapy. Moreover, a stable oxygen-carrying solution could have benefits and applications not possible with red cell transfusions. Such a solution would be ideal for the treatment of acute hypovolemic shock both in domestic emergency rooms as well as in the battlefield. A colloid that delivers oxygen would also be invaluable in third world countries where the cost and logistics of blood donations and banking are formidable. More restricted applications include the treatment of patients such as Jehovah's Witnesses who refuse blood transfusions, the priming of blood oxygenation pumps, ex vivo organ perfusion prior to transplantation, and in vivo perfusion in order to enhance sensitivity to radiation therapy.
Among potential blood substitutes that transport oxygen, attention has focused on perfluorocarbons and a variety of hemoglobin preparations, either in free solution or encapsulated into lipid vesicles. Perfluorocarbons are synthetic compounds that reversibly bind oxygen, but non-cooperatively and at high O2 tension. As such, they depart substantially from the physiological role of red cells. In contrast, hemoglobin sealed into membranes comes closest to mother nature, but the obstacles in the development of such artificial red cells are formidable.
An alternative approach which has attracted considerable attention is the preparation of hemoglobin solutions designed to meet the following criteria: low toxicity and antigenicity; efficacy as a plasma expander; prolonged survival in the circulation; adequate oxygen carrying capability and efficient oxygen unloading to tissues; long shelf life. Extensive preclinical testing and recent clinical trials have been performed on human hemoglobin through the kidneys. Bovine hemoglobin has intrinsically low oxygen affinity simulating that of human hemoglobin in red cells. An alternative and attractive strategy is the production of human hemoglobin in E. Coli, thus enabling appropriate genetic mutations to optimize function. These include creation of peptide linkers to enhance plasma survival and amino acid replacements that permit a finely regulated lowering of oxygen affinity.
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