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Separation and fractionation of plasma by double-filtration technique
Journal of Membrane Science, 44 (1989) 47-54 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands
SEPARATION AND FRACTIONATION DOUBLE-FILTRATION TECHNIQUE
47
OF PLASMA BY
TETSUZO AGISHI and MICHIO MINESHIMA Departments of Surgery and Therapeutic Engineering, Kidney Center, Tokyo Women’s Medical College, 8-l Kawada-cho, Shinjuku-ku, Tokyo 162 (Japan) (Received October 28,1987; accepted in revised form November 23,1988)
Summary Double-filtration plasmapheresis utilizing the differential filtration principle was devised in an attempt to reduce the amount of the supplementation fluid of human blood products in plasmaexchange therapy. Effective removal of the pathogenetic substances is achieved by selective separation and selective concentration of the solutes in the fractionated plasma. Although apparent clinical benefits of this technique have been confirmed, there still remain problems in selective separation of the plasma protein solutes due to imperfections in the current membrane production technology.
Introduction
It was almost seventy years ago that Abel et al. suggested that “plasma removal with return of corpuscles (plasmapheresis)” could be useful in the treatment of toxemia [ 11. Many reports on the clinical usefulness of plasma exchange, or therapeutic plasmapheresis utilizing the centrifugation principle had been published as early as the late 1960’s. Plasma exchange became popular in the 1970’s, when membrane plasma separators utilizing the filtration principle were developed [2]. It is presently recognized as one of the blood purification modalities by which macromolecular pathogenetic substances can be effectively removed from the blood. A major drawback of simple or standard plasma exchange, by applying either centrifugation or filtration, is the subsequent necessity to replace 3000-5000 ml of human blood products. In an attempt to minimize the amount of replacement fluid, double-filtration plasmapheresis, by which pathogenetic substances are selectively removed, was devised in 1979 [3] and then clinically applied [ 4,5]. Clinical effectiveness of double-filtration plasmapheresis depends on the interrelation between the filtration properties of the filters and the plasma concentration of the pathogenetic substances, that depend upon the stage of the
0376-7388/89/$03.50
0 1989 Elsevier Science Publishers B.V.
48
specific diseases. While the filtration properties of most currently available filters are well defined, the plasma concentration of the pathogenetic substances targeted for removal is determined by as yet undefined multifactorial conditions. In this paper a selected overview of the current status of doublefiltration plasmapheresis is presented from the standpoint of the filtration properties of the membrane. Theory
The principle of double-filtration plasmapheresis is based on selective differential filtration, which utilizes the difference in the membrane pore size of two filters installed in an extracorporeal circulation line. The first filter, a plasma separator, separates plasma from whole blood, while the second filter, a plasma fractionator, allows only small molecular solutes to permeate, thereby rejecting the larger ones. The rejected substances, which are believed to contain macromolecular pathogenetic substances such as the viscosity-increasing molecules in hyperviscosity syndrome or antibodies and immune complexes in immune diseases, are thus removed from circulation (Figs. 1 and 2 ) . Theoretically, an area bounded by two curves, one being a plot of the sieving coefficient of the plasma separator as a function of molecular weight and the other a similar plot for the plasma fractionator, indicates the range of pathogenetic substances that can be removed by double filtration. More simply, while
\I
from
plasma
separator
plasma
fractionator
,
removed
0 blood
corpuscles
n large
molecules
A middle
Fig. 1. Principle
of double-filtration
plasmapheresis.
- small
molecules
Fig. 2. Clinical application of double-filtration plasmapheresis.
a plasma separator restricts the upper limit, a plasma fractionator restricts the lower limit in the molecular size of the plasma solute fraction to be removed. This is the concept of selective separation of plasma fractions. Selective separation of plasma fractions
The plasma fraction is selectively separated according to the filtration performance of a plasma separator and a plasma fractionator. Plasma separator
A plasma separator, which rejects blood cells and separates whole plasma components directly from whole blood in simple-filtration plasmapheresis, is used as the first filter for double-filtration plasmapheresis. The plasma separator module is designed for a plasma flux of approximately 1000 ml/hr. Membrane materials such as cellulose acetate, polyvinylalcohol, polymethylmethacrylate, polyethylene, polypropylene and polysulphone allow even
lo4 M.W.
/’ lo5 !tlgA Albumin IgG
+. Flbrtnogen
/“”
p-dpopri;.
‘lat.*
RBC’ WBC
IgM
Size of Molecules& Blood Cells Fig. 3. Sieving coefficients of plasma separators and fractionators. Shaded area is targetted to be removed.
macromolecules such as /?-lipoproteins with a molecular weight of 2,400,OOO dalton to easily penetrate with a sieving coefficient larger than 0.95. Most of the currently available plasma separators are considered acceptable for clinical use. However, even though theoretically a plasma separator with a lower cut-off point for the upper limit would be better in the treatment of immunological diseases for which the molecular size of the removal target is supposedly less than l,OOO,OOO dalton (e.g., IgM: 950,000 dalton), a plasma separator as described above is still used. More appropriate plasma separator modules are not currently available (Fig. 3 ) . Plasma fractionator Several kinds of plasma fractionators with different filtration properties are on the market in Japan. Membrane materials used for plasma fractionators include polyethylenevinylalcohol, polymethylmethacrylate, and cellulose acetate. Depending upon the filtration porperty of the membrane material, each plasma fractionator has its own specific sieving coefficients for the various plasma solutes, some of which are supposed to be pathogenetic (Fig. 3). As mentioned previously, the filtration property of a plasma fractionator defines the lower molecular size limit of the plasma components that can be effectively removed. Thus, an appropriate plasma fractionator should be chosen based on the molecular size of the pathogenetic substances targeted for removal. A general rule for selection of a plasma fractionator will be discussed below.
51
Hyperviscosity syndrome, represented by familial hypercholesterolemia, and immunological diseases, represented by malignant rheumatoid arthritis, myasthenia gravis or systemic lupus erythematosus, are considered to be suitable for treatment by double-filtration plasmapheresis. The targeted molecules are /3-lipoproteins with a molecular weight of 2,400,OOOdalton in the former, and immunoglobulins with a molecular weight ranging from 170,000 to 950,000 dalton in the latter. Albumin, with a molecular weight of 67,000 dalton, has no relationship with the pathogenesis of these diseases and should not be removed as it is better left in the patient’s blood to maintain the colloidal osmotic pressure. Albumin, inadvertently discarded as a component of the separated plasma, is therefore supplemented in conventional, simple plasmapheresis. Currently available plasma fractionators are basically divided into two groups. One consists of plasma fractionators with relatively large membrane pores and large sieving coefficients (for example in Fig. 3, Evaflux 4A, AC 1760; Group A), and the other consists of those with relatively small pores and smaller sieving coefficients (for example in Fig. 3, Evaflux 2A, XK 30; Group B ). Group A should be chosen for the treatment of hyperviscosity syndrome. While the targeted pathogenetic substances are selectively rejected and removed, albumin is returned to the patient. Double-filtration plasmapheresis can be repeatedly performed without albumin supplementation, since no serious hypoalbuminemia develops [ 61. If a membrane from Group B was used, the pathogenetic substances might be more effectively removed. However, a certain amount of albumin would also be discarded and hypoalbuminemia would inevitably develop. Therefore, albumin supplementation will probably be necessary during a series of frequent double-filtration plasmapheresis treatments using Group B membranes Group B is recommended for the treatment of immunological diseases. It has been confirmed in clinical settings that 600-1000 ml of the plasma fractionated by double-filtration technique contain amounts of pathogenetic substances comparable to those contained in 2000-4000 ml of the plasma separated by simple standard plasmapheresis techniques [ 5,7]. However, as sieving coefficients of Group B membranes for the targeted pathogenetic substances are close to those for albumin, a certain amount of albumin is discarded simultaneously. Albumin supplementation is therefore indicated in order to avoid severe hypoalbuminemia, especially during an induction phase in which frequent plasmapheresis procedures are usually performed. If Group A is used for the treatment of immunological diseases, sieving coefficients for albumin are large enough not to reject albumin and hypoalbuminemia is consequently not likely to develop. However, as a result of the large sieving coefficients for the pathogenetic immunoglobulins, a certain amount of pathogenetic substances is returned to the patient.
52
Selective concentration of plasma fractions
Usually 2500-4000 ml of plasma are separated from whole blood by a plasma separator and then 500-1000 ml of unfiltered plasma are fractionated by a plasma fractionator. The fractionated plasma is discarded, as it is believed to contain the pathogenetic substances. Initially, it was noticed incidentally that concentrations of the pathogenetic substances in the fractionated plasma were greater than those in the blood flowing into the system. The increases in concentrations of larger molecules was more pronounced [ 81. This phenomenon, which was not initially expected to occur in the double-filtration technique, is called selective concentration. The existence of the effect of selective concentration has been evidenced by an analysis of kinetic modelling [ 91. The extent of selective concentration, or S.C.
sieving coefficient plasma fractionator Evaflux
0.8
Evaflux
4 A
AC-1760
XK-30
___~_r52___jn_~l)___-T(r_=_5_)___!n_f_52___
5
C.C.,
2A
for
??“I < SoOi
TA-IQQ (n =8) ----_-_
r g
Fig. 4. Relationship coefficients.
concentration
between
coefficient
sieving
coefficient
of plasma
fractionators
and concentration
53
the concentration coefficient, is expressed as follows: Concentration coefficient =
[l-
(l-k)
SCpf] SCps k
where SCps is a sieving coefficient of a plasma separator, SCpf a sieving coefficient of a plasma fractionator and k the discard ratio (the amount of discarded plasma fraction divided by the amount of separated plasma). As mentioned previously, most of the currently available plasma separators have sieving coefficients very close to 1.0, even for large molecules. The discard ratio is usually constant during one plasmapheresis procedure, for example 0.2, when 3000 ml of plasma are separated and 600 ml of fractionated plasma are discarded. In this case, the concentration coefficient is simply expressed as follows: Concentration coefficient = 5 - 4 SCpf According to this formula, the concentration coefficient becomes larger as the sieving coefficient of a plasma fractionator becomes smaller, but is never larger than 5.0. Subsequently, more efforts have been made to verify the similarity between the theoretical and clinically obtained concentration coefficient values. As shown in Fig. 4, a concentration coefficient very close to 5.0 is obtained for clinical &lipoprotein concentration measurement [lo]. Conclusion Double-filtration plasmapheresis was developed with the intent to reduce the amount of supplementation fluid. For this reason, only the plasma fraction containing the pathogenetic substances is removed by selective separation directly from whole blood. However, in addition to selective separation, selective concentration was found to augment the efficacy of the removal of pathogenetic substances by double-filtration plasmapheresis. One of the best clinical indications for double-filtration plasmapheresis is hyperviscosity syndrome, in which macromolecules are involved in the pathogenesis. In most cases, no supplementation of blood products is necessary. On the contrary, for the treatment of immunological disease, the necessity of albumin supplementation still must be considered to avoid possible hypoalbuminemia. This results from the imperfections of current membrane technology, in that no membrane material for plasma fractionations presently available has a sharp enough lower molecular weight cut-off to recover all the albumin in the plasma. However, there is still a possibility that as membrane technology progresses, plasma fractionation membranes with more selective filtration properties can be produced.
54
References 1 2
3
4
5
6
7 8
9
10
J. Abel, L.G. Rowntree and B.B. Turner, Plasma removal with return of corpuscles (plasmapheresis), J. Pharmacol. Exp. Ther., 5( 1914)626. N. Inoue, Z. Yamazaki, Y. Fujimori, K. Sanjo, M. Sugiura, T. Wada, T. Sakai, K. Fujiwara, T. Oda, T. Abe, T. Furata, K. Inagaki, N. Tsuda, N. Kominami and Y. Fujusaki, Clinical trial of plasma exchange utilizing a membrane plasma separator with celllulose acetate hollow fibers, Jinkozoki (Artif. Organs), 7(1978)1095. T. Agishi, I. Kaneko, Y. Hasuo, E. Kumagaya, Y. Hayasaka, K. Ota, N. Sugino, M. Abe, T. Ono, S. Kawai and T. Yamane, Double filtration for selective removal or retrieval of plasma fraction, Abstracts Am. Sot. Artif. Intern. Organs, 8( 1979)70. T. Agishi, I. Kaneko, Y. Hasuo, Y. Hayasaka, T. Sanaka, K. Ota, M. Abe, T. Ono, S. Kawai and K. Yamane, Double filtration plasmapheresis, Trans. Am. Sot. Artif. Intern. Organs, 26(1980)406. T. Agishi, I. Kaneko, Y. Hasuo, T. Takuma, H. Amemiya, K. Ito, H. Kawaguchi, H. Hashimoto, J. Yamagata, N. Koga and Y. Yamagata, Semi-controlled multicentre study of double filtration plasmapheresis in systemic lupus erythematosus, Proc. Eur. Dial. Transplant Assot.-Eur. Ren. Assoc., 22 (1985) 1200. N. Koga, G. Nomura, Y. Yamagata, S. Takada, T. Nishimura, A. Sanada, S. Kanaya and T. Fujino, Double filtration plasmapheresis in the treatment of two cases of homozygous familial hypercholesterolemia, in: T. Oda (Ed.), Therapeutic plasmapheresis III, Schattauer, Stuttgart, New York, 1983, p. 113. H. Amemiya, Plasma exchange therapy in systemic lupus erythematosus, Jpn. J. Nephrol., 26(1982)205. T. Agishi, I. Kaneko, Y. Hasuo, K. Ota, H. Amemiya, N. Sugino and M. Abe, Automatic control apparatus for membrane plasmapheresis, in: Y. Nose, P.S. Malchesky, J.W. Smith and R.S. Krakauer (Eds.), Plasmapheresis, Raven Press, New York, NY, 1983, p. 169. T. Agishi, M. Mineshima, Y. Kagawa and M. Oshikawa, A trial of a standardized in vitro evaluation of double filtration plasmapheresis (DFPP) using dextran solution, in: T. Oda (Ed.), Therapeutic Plasmapheresis IV, Schattauer, Stuttgart, New York, NY, 1985, p. 39. T. Agishi, Progress in plasma separation technology, J. Clin. Sci., 22 (1986) 175 (in Japanese).
SEPARATION AND FRACTIONATION DOUBLE-FILTRATION TECHNIQUE
47
OF PLASMA BY
TETSUZO AGISHI and MICHIO MINESHIMA Departments of Surgery and Therapeutic Engineering, Kidney Center, Tokyo Women’s Medical College, 8-l Kawada-cho, Shinjuku-ku, Tokyo 162 (Japan) (Received October 28,1987; accepted in revised form November 23,1988)
Summary Double-filtration plasmapheresis utilizing the differential filtration principle was devised in an attempt to reduce the amount of the supplementation fluid of human blood products in plasmaexchange therapy. Effective removal of the pathogenetic substances is achieved by selective separation and selective concentration of the solutes in the fractionated plasma. Although apparent clinical benefits of this technique have been confirmed, there still remain problems in selective separation of the plasma protein solutes due to imperfections in the current membrane production technology.
Introduction
It was almost seventy years ago that Abel et al. suggested that “plasma removal with return of corpuscles (plasmapheresis)” could be useful in the treatment of toxemia [ 11. Many reports on the clinical usefulness of plasma exchange, or therapeutic plasmapheresis utilizing the centrifugation principle had been published as early as the late 1960’s. Plasma exchange became popular in the 1970’s, when membrane plasma separators utilizing the filtration principle were developed [2]. It is presently recognized as one of the blood purification modalities by which macromolecular pathogenetic substances can be effectively removed from the blood. A major drawback of simple or standard plasma exchange, by applying either centrifugation or filtration, is the subsequent necessity to replace 3000-5000 ml of human blood products. In an attempt to minimize the amount of replacement fluid, double-filtration plasmapheresis, by which pathogenetic substances are selectively removed, was devised in 1979 [3] and then clinically applied [ 4,5]. Clinical effectiveness of double-filtration plasmapheresis depends on the interrelation between the filtration properties of the filters and the plasma concentration of the pathogenetic substances, that depend upon the stage of the
0376-7388/89/$03.50
0 1989 Elsevier Science Publishers B.V.
48
specific diseases. While the filtration properties of most currently available filters are well defined, the plasma concentration of the pathogenetic substances targeted for removal is determined by as yet undefined multifactorial conditions. In this paper a selected overview of the current status of doublefiltration plasmapheresis is presented from the standpoint of the filtration properties of the membrane. Theory
The principle of double-filtration plasmapheresis is based on selective differential filtration, which utilizes the difference in the membrane pore size of two filters installed in an extracorporeal circulation line. The first filter, a plasma separator, separates plasma from whole blood, while the second filter, a plasma fractionator, allows only small molecular solutes to permeate, thereby rejecting the larger ones. The rejected substances, which are believed to contain macromolecular pathogenetic substances such as the viscosity-increasing molecules in hyperviscosity syndrome or antibodies and immune complexes in immune diseases, are thus removed from circulation (Figs. 1 and 2 ) . Theoretically, an area bounded by two curves, one being a plot of the sieving coefficient of the plasma separator as a function of molecular weight and the other a similar plot for the plasma fractionator, indicates the range of pathogenetic substances that can be removed by double filtration. More simply, while
\I
from
plasma
separator
plasma
fractionator
,
removed
0 blood
corpuscles
n large
molecules
A middle
Fig. 1. Principle
of double-filtration
plasmapheresis.
- small
molecules
Fig. 2. Clinical application of double-filtration plasmapheresis.
a plasma separator restricts the upper limit, a plasma fractionator restricts the lower limit in the molecular size of the plasma solute fraction to be removed. This is the concept of selective separation of plasma fractions. Selective separation of plasma fractions
The plasma fraction is selectively separated according to the filtration performance of a plasma separator and a plasma fractionator. Plasma separator
A plasma separator, which rejects blood cells and separates whole plasma components directly from whole blood in simple-filtration plasmapheresis, is used as the first filter for double-filtration plasmapheresis. The plasma separator module is designed for a plasma flux of approximately 1000 ml/hr. Membrane materials such as cellulose acetate, polyvinylalcohol, polymethylmethacrylate, polyethylene, polypropylene and polysulphone allow even
lo4 M.W.
/’ lo5 !tlgA Albumin IgG
+. Flbrtnogen
/“”
p-dpopri;.
‘lat.*
RBC’ WBC
IgM
Size of Molecules& Blood Cells Fig. 3. Sieving coefficients of plasma separators and fractionators. Shaded area is targetted to be removed.
macromolecules such as /?-lipoproteins with a molecular weight of 2,400,OOO dalton to easily penetrate with a sieving coefficient larger than 0.95. Most of the currently available plasma separators are considered acceptable for clinical use. However, even though theoretically a plasma separator with a lower cut-off point for the upper limit would be better in the treatment of immunological diseases for which the molecular size of the removal target is supposedly less than l,OOO,OOO dalton (e.g., IgM: 950,000 dalton), a plasma separator as described above is still used. More appropriate plasma separator modules are not currently available (Fig. 3 ) . Plasma fractionator Several kinds of plasma fractionators with different filtration properties are on the market in Japan. Membrane materials used for plasma fractionators include polyethylenevinylalcohol, polymethylmethacrylate, and cellulose acetate. Depending upon the filtration porperty of the membrane material, each plasma fractionator has its own specific sieving coefficients for the various plasma solutes, some of which are supposed to be pathogenetic (Fig. 3). As mentioned previously, the filtration property of a plasma fractionator defines the lower molecular size limit of the plasma components that can be effectively removed. Thus, an appropriate plasma fractionator should be chosen based on the molecular size of the pathogenetic substances targeted for removal. A general rule for selection of a plasma fractionator will be discussed below.
51
Hyperviscosity syndrome, represented by familial hypercholesterolemia, and immunological diseases, represented by malignant rheumatoid arthritis, myasthenia gravis or systemic lupus erythematosus, are considered to be suitable for treatment by double-filtration plasmapheresis. The targeted molecules are /3-lipoproteins with a molecular weight of 2,400,OOOdalton in the former, and immunoglobulins with a molecular weight ranging from 170,000 to 950,000 dalton in the latter. Albumin, with a molecular weight of 67,000 dalton, has no relationship with the pathogenesis of these diseases and should not be removed as it is better left in the patient’s blood to maintain the colloidal osmotic pressure. Albumin, inadvertently discarded as a component of the separated plasma, is therefore supplemented in conventional, simple plasmapheresis. Currently available plasma fractionators are basically divided into two groups. One consists of plasma fractionators with relatively large membrane pores and large sieving coefficients (for example in Fig. 3, Evaflux 4A, AC 1760; Group A), and the other consists of those with relatively small pores and smaller sieving coefficients (for example in Fig. 3, Evaflux 2A, XK 30; Group B ). Group A should be chosen for the treatment of hyperviscosity syndrome. While the targeted pathogenetic substances are selectively rejected and removed, albumin is returned to the patient. Double-filtration plasmapheresis can be repeatedly performed without albumin supplementation, since no serious hypoalbuminemia develops [ 61. If a membrane from Group B was used, the pathogenetic substances might be more effectively removed. However, a certain amount of albumin would also be discarded and hypoalbuminemia would inevitably develop. Therefore, albumin supplementation will probably be necessary during a series of frequent double-filtration plasmapheresis treatments using Group B membranes Group B is recommended for the treatment of immunological diseases. It has been confirmed in clinical settings that 600-1000 ml of the plasma fractionated by double-filtration technique contain amounts of pathogenetic substances comparable to those contained in 2000-4000 ml of the plasma separated by simple standard plasmapheresis techniques [ 5,7]. However, as sieving coefficients of Group B membranes for the targeted pathogenetic substances are close to those for albumin, a certain amount of albumin is discarded simultaneously. Albumin supplementation is therefore indicated in order to avoid severe hypoalbuminemia, especially during an induction phase in which frequent plasmapheresis procedures are usually performed. If Group A is used for the treatment of immunological diseases, sieving coefficients for albumin are large enough not to reject albumin and hypoalbuminemia is consequently not likely to develop. However, as a result of the large sieving coefficients for the pathogenetic immunoglobulins, a certain amount of pathogenetic substances is returned to the patient.
52
Selective concentration of plasma fractions
Usually 2500-4000 ml of plasma are separated from whole blood by a plasma separator and then 500-1000 ml of unfiltered plasma are fractionated by a plasma fractionator. The fractionated plasma is discarded, as it is believed to contain the pathogenetic substances. Initially, it was noticed incidentally that concentrations of the pathogenetic substances in the fractionated plasma were greater than those in the blood flowing into the system. The increases in concentrations of larger molecules was more pronounced [ 81. This phenomenon, which was not initially expected to occur in the double-filtration technique, is called selective concentration. The existence of the effect of selective concentration has been evidenced by an analysis of kinetic modelling [ 91. The extent of selective concentration, or S.C.
sieving coefficient plasma fractionator Evaflux
0.8
Evaflux
4 A
AC-1760
XK-30
___~_r52___jn_~l)___-T(r_=_5_)___!n_f_52___
5
C.C.,
2A
for
??“I < SoOi
TA-IQQ (n =8) ----_-_
r g
Fig. 4. Relationship coefficients.
concentration
between
coefficient
sieving
coefficient
of plasma
fractionators
and concentration
53
the concentration coefficient, is expressed as follows: Concentration coefficient =
[l-
(l-k)
SCpf] SCps k
where SCps is a sieving coefficient of a plasma separator, SCpf a sieving coefficient of a plasma fractionator and k the discard ratio (the amount of discarded plasma fraction divided by the amount of separated plasma). As mentioned previously, most of the currently available plasma separators have sieving coefficients very close to 1.0, even for large molecules. The discard ratio is usually constant during one plasmapheresis procedure, for example 0.2, when 3000 ml of plasma are separated and 600 ml of fractionated plasma are discarded. In this case, the concentration coefficient is simply expressed as follows: Concentration coefficient = 5 - 4 SCpf According to this formula, the concentration coefficient becomes larger as the sieving coefficient of a plasma fractionator becomes smaller, but is never larger than 5.0. Subsequently, more efforts have been made to verify the similarity between the theoretical and clinically obtained concentration coefficient values. As shown in Fig. 4, a concentration coefficient very close to 5.0 is obtained for clinical &lipoprotein concentration measurement [lo]. Conclusion Double-filtration plasmapheresis was developed with the intent to reduce the amount of supplementation fluid. For this reason, only the plasma fraction containing the pathogenetic substances is removed by selective separation directly from whole blood. However, in addition to selective separation, selective concentration was found to augment the efficacy of the removal of pathogenetic substances by double-filtration plasmapheresis. One of the best clinical indications for double-filtration plasmapheresis is hyperviscosity syndrome, in which macromolecules are involved in the pathogenesis. In most cases, no supplementation of blood products is necessary. On the contrary, for the treatment of immunological disease, the necessity of albumin supplementation still must be considered to avoid possible hypoalbuminemia. This results from the imperfections of current membrane technology, in that no membrane material for plasma fractionations presently available has a sharp enough lower molecular weight cut-off to recover all the albumin in the plasma. However, there is still a possibility that as membrane technology progresses, plasma fractionation membranes with more selective filtration properties can be produced.
54
References 1 2
3
4
5
6
7 8
9
10
J. Abel, L.G. Rowntree and B.B. Turner, Plasma removal with return of corpuscles (plasmapheresis), J. Pharmacol. Exp. Ther., 5( 1914)626. N. Inoue, Z. Yamazaki, Y. Fujimori, K. Sanjo, M. Sugiura, T. Wada, T. Sakai, K. Fujiwara, T. Oda, T. Abe, T. Furata, K. Inagaki, N. Tsuda, N. Kominami and Y. Fujusaki, Clinical trial of plasma exchange utilizing a membrane plasma separator with celllulose acetate hollow fibers, Jinkozoki (Artif. Organs), 7(1978)1095. T. Agishi, I. Kaneko, Y. Hasuo, E. Kumagaya, Y. Hayasaka, K. Ota, N. Sugino, M. Abe, T. Ono, S. Kawai and T. Yamane, Double filtration for selective removal or retrieval of plasma fraction, Abstracts Am. Sot. Artif. Intern. Organs, 8( 1979)70. T. Agishi, I. Kaneko, Y. Hasuo, Y. Hayasaka, T. Sanaka, K. Ota, M. Abe, T. Ono, S. Kawai and K. Yamane, Double filtration plasmapheresis, Trans. Am. Sot. Artif. Intern. Organs, 26(1980)406. T. Agishi, I. Kaneko, Y. Hasuo, T. Takuma, H. Amemiya, K. Ito, H. Kawaguchi, H. Hashimoto, J. Yamagata, N. Koga and Y. Yamagata, Semi-controlled multicentre study of double filtration plasmapheresis in systemic lupus erythematosus, Proc. Eur. Dial. Transplant Assot.-Eur. Ren. Assoc., 22 (1985) 1200. N. Koga, G. Nomura, Y. Yamagata, S. Takada, T. Nishimura, A. Sanada, S. Kanaya and T. Fujino, Double filtration plasmapheresis in the treatment of two cases of homozygous familial hypercholesterolemia, in: T. Oda (Ed.), Therapeutic plasmapheresis III, Schattauer, Stuttgart, New York, 1983, p. 113. H. Amemiya, Plasma exchange therapy in systemic lupus erythematosus, Jpn. J. Nephrol., 26(1982)205. T. Agishi, I. Kaneko, Y. Hasuo, K. Ota, H. Amemiya, N. Sugino and M. Abe, Automatic control apparatus for membrane plasmapheresis, in: Y. Nose, P.S. Malchesky, J.W. Smith and R.S. Krakauer (Eds.), Plasmapheresis, Raven Press, New York, NY, 1983, p. 169. T. Agishi, M. Mineshima, Y. Kagawa and M. Oshikawa, A trial of a standardized in vitro evaluation of double filtration plasmapheresis (DFPP) using dextran solution, in: T. Oda (Ed.), Therapeutic Plasmapheresis IV, Schattauer, Stuttgart, New York, NY, 1985, p. 39. T. Agishi, Progress in plasma separation technology, J. Clin. Sci., 22 (1986) 175 (in Japanese).