A Study of Eight Heated Plasma Protein Preparations.

Human plasma has not gained general acceptance as a therapeutic agent because of the risk of hepatitis following its use. A number of physical and chemical treatments have been tried to minimize this risk but the incidence remains about 0.5 per cent for single donor plasma and upwards of 20 per cent for some lots of pooled plasma (1, 2). Ultraviolet irradiation, which at one time seemed quite promising, proved incapable of inactivating the hepatitis virus at radiation doses which allowed preservation of the integrity of the plasma proteins. Another physical agent, heat, has demonstrated the ability to reduce markedly, if not completely eliminate, the hepatitis risk in human albumin (3). In this situation an albumin solution containing a stabilizer is heated for 10 hours at 600 C. This treatment does not modify the protein to an extent which makes it unsuitable for infusion. After more than a decade of wide use, a substantiated case of hepatitis caused by injection of heated human albumin has yet to be reported. Just as the usefulness and safety of albumin are well recognized, so also are the problems of its high cost, complexity of production, and relatively small yield as compared to plasma. Because of these factors a number of individual investigators and industrial concerns set out to develop a plasma expander which would be as useful therapeutically as albumin, but which would be less expensive and have no greater risk of transmitting hepatitis. Added impetus was given to this program by the need of the Office of Defense Mobilization and the Department of Defense for a safe plasma expander to be manufactured from their outdating stockpile of plasma. On the basis of the work of Gellis and associates (3) and of Murray (1) on the heating of albumin, most of the investigators involved decided that a major effort should be devoted to developing a plasma derivative which could be heated without adversely affecting the constituent proteins. Murray and co-workers had shown previously (4) that the heating of whole plasma for 4 hours at 60° C produced gross changes in the proteins and did not eliminate hepatitis infectivity. It was hoped, however, that the evidence for heat inactivation of virus in albumin could be extrapolated to plasma. The main problem was to develop a procedure which would stabilize the proteins, allowing the plasma derivative to be heated for at least 10 hours at 600 C without significant alteration. The problem was approached in two somewhat different ways. Some of the workers hoped to solve the dilemma by the use of whole plasma to which had been added a chemical stabilizer in order to minimize protein denaturation. Other workers used modifications of the recognized plasma fractionation procedures, intending thereby to eliminate those fractions of plasma which seemed most susceptible to heat denaturation. They hoped that the partially fractionated final product would turn out to be as heat stable and safe as albumin, but less expensive than that preparation. With the cooperation of the National Research Council, this laboratory had the opportunity of doing simultaneous analyses on these various plasma preparations in an attempt to detect and perhaps evaluate some of the physical and chemical changes which were taking place as a result of the treatments. This report will present comparative data on eight such preparations. When unheated controls were available, they were similarly studied. All materials were also compared with normal unheated citrated plasma.