Journal of Clinical Apheresis 7: 145-146 (1992)
Artificial Surfaces in Apheresis Devices: Interactions With the Complement System Paul S. Malchesky Cleveland Clinic Foundation, Department of Biomedical Engineering and Applied Therapeutics, Cleveland, Ohio
In extracorporeal circulation procedures of apheresis, blood and its components are in direct contact with a number of synthetic materials. Further, to perform such procedures an anticoagulant is required. Blood material contacts have been known to effect changes in the various humoral and cellular systems. Changes in one system can cause further changes in others. There is a strong interrelationship among the systems. Figure 1 illustrates some of the interactions among some humoral systems. As noted, the anticoagulant and material the blood (and its components) contacts will modulate the humoral systems by their interrelationships even if a direct relationship does not exist. Regarding the humoral systems, the adsorption of plasma proteins, including complement components, proteinases, and inhibitors, will occur. Activation of complement with release of anaphylatoxins, the activation of coagulation factors, and the production of kallikrein, kinin, and bradykinin may occur to varying degrees depending upon the material type, the surface area of blood contact, and operating conditions of the procedure (i.e., flow, temperature). In a similar fashion, cellular systems may be impacted. Blood concentration changes are known to occur. Transient drops in circulating concentrations of platelets, monocytes, and neutrophils have been noted, along with transient neutrocytosis and lymphocytosis, and lymphocyte subpopulation changes. Functional changes in white blood cells and platelets have also been noted to occur, such as increased adherence and augmented superoxide generation of polyrnorphonuclear cells, phagocytosis changes of blood mononuclear phagocyte cells, blastogenesis and reactivity changes of lymphocytes, and adhesion changes of platelets. The various blood cells have been noted to show increased secretion of elastase, lactoferrin, alpha- 1 proteinase inhibitor, and peroxidase for polymorphonuclear cells; interleukin 1 , tumor necrosis factor, and other monokines for mononuclear phagocytic cells; various lymphokines for lymphocytes; and platelet factor 4, betathromboglobulin and thromboxane for platelets. Most of the above-noted reactions of blood material interactions have been demonstrated in extracorporeal Q 1992 Wiley-Liss, Inc.
circulation procedures such as hemodialysis, hemofiltration. and blood oxygenation. Similar reactions may be expected with apheresis techniques. Material blood contacts in apheresis occur in 3 areas: ( 1 ) blood access devices, (2) blood conduits, and ( 3 ) separationitreatment devices. The contacts in blood access devices are short and the area of contact relative to the total circuit area is small, making its effect difficult to assess. Further, blood conduits are typically made of polyvinyl chloride or like materials. Circuits from various manufacturers are generally not interchangeable among various hardware types, making circuits alone difficult to evaluate. With the various types of materials used in separation and treatment devices, such as varying polymer types for plasma and cell separation and membrane and sorbent devices for plasma treatment, such evaluations have been more practically carried out. The hypothesis upon which blood material reactivity is based is that the surface chemistry of the material of blood contact will affect the degree of blood humoral and cellular changes. Various in vitro animal investigations and clinical studies have shown that different materials effect different responses. Further, the responses noted can be shown to depend on the surface area of blood contact. A significant degree of interest has been focused on the complement system. Complement is one of the serum enzyme systems. It consists of 19 separate proteins which may be activated either via the classical or alternative pathways. The classical pathway is activated typically by immune complexes and the alternative pathway by surfaces or molecules including microbial products. The complement system functions include mediating inflammation, opsonization of antigenic particles (such as bacteria), and causing membrane damage to pathogens. Of considerable attention are the generation of activated components of complement C3 and C5, the anaphylatoxins C3a and
Address reprint requests to Paul S Malchaky. D Eng Corpordtion. 9450 Pineneedle Drive. Mentor. OH 44060
.
STERIS
146
Fig. I, Interactions of humoral systems in extracorporeal technology applications.
C5a. These agents are known to mediate inflammation, to cause mast cell degranulation, to cause smooth muscle contraction, and to cause increased capillary permeability. Various polymers used in apheresis devices have been shown to cause complement system activation and the generation of C3a and C5a to varying degrees. It has been shown that these 2 factors may have different effects on the immune system. C3a production has been shown to inhibit antibody formation, while C5a and its byproduct C5a des Arg enhances antibody formation. Different materials have been shown to produce C3a and C5a in different proportions, suggesting that not only the absolute concentrations of these factors may be important, but also their relative ratio. In the extracorporeal circulation of blood, an anticoagulant is required to prevent the blood from clotting during the treatment procedure. The anticoagulants used are typically either citrate or heparin. Each functions in a different way. Heparin is an antagonist of thromboplastin that reduces the formation of thrombin and prevents fibrin formation. Citrate acts by binding with calcium. The influence on the properties of blood, and specifically the coagulation and complement systems, have been shown to be different for these 2 anticoagulants. It is noteworthy that calcium is required for complement activation; the use of citrate inhibits its activation. It is important to differentiate the effects of the anticoagulant and material-blood contacts in understanding the effects of extracorporeal circulation. The extracorporeal procedure (i.e., apheresis) will effect biomodulation, that is, changes in the cellular or biochemical milieu of the body. Of course the apheresis procedure is therapeutically designed to do just that, whether it is for cell or solute removal or for treatment.
However, due to the choice of materials for blood contact and anticoagulation procedure, biomodulation will also occur. These procedure-associated events, which are not specifically intended in the design of the therapy, must be considered in the overall evaluation of the clinical effects, as their impacts may extend for days to weeks beyond the treatment period. Recognizing that material blood contacts alone can modulate the biological system, a number of investigations are under way to design and use materials for such specific purposes. Of particular note are the design of materials to activate blood cells, such as lymphocytes to become killer cells and therefore enhance cytotoxicity . While efforts to date primarily have concentrated on the development and design of materials to minimize biological response, so-called biocompatible materials, this new investigative effort is concentrated on the design of materials to effect direct humoral (biochemical) or cellular modulation. This area of development holds specific promise to the design of materials for therapeutic apheresis.
SUMMARY
Blood contacts with artificial surfaces will effect different degrees of complement activation. Associated with complement activation will be cellular concentration and functional changes. The type of anticoagulant also will effect complement activation. The noted biomodulating effect of a material in contact with blood suggests that the choice and design of materials and their “biocompatibility” can be made to effect humoral and cellular changes as the therapy may require.
Artificial Surfaces in Apheresis Devices: Interactions With the Complement System Paul S. Malchesky Cleveland Clinic Foundation, Department of Biomedical Engineering and Applied Therapeutics, Cleveland, Ohio
In extracorporeal circulation procedures of apheresis, blood and its components are in direct contact with a number of synthetic materials. Further, to perform such procedures an anticoagulant is required. Blood material contacts have been known to effect changes in the various humoral and cellular systems. Changes in one system can cause further changes in others. There is a strong interrelationship among the systems. Figure 1 illustrates some of the interactions among some humoral systems. As noted, the anticoagulant and material the blood (and its components) contacts will modulate the humoral systems by their interrelationships even if a direct relationship does not exist. Regarding the humoral systems, the adsorption of plasma proteins, including complement components, proteinases, and inhibitors, will occur. Activation of complement with release of anaphylatoxins, the activation of coagulation factors, and the production of kallikrein, kinin, and bradykinin may occur to varying degrees depending upon the material type, the surface area of blood contact, and operating conditions of the procedure (i.e., flow, temperature). In a similar fashion, cellular systems may be impacted. Blood concentration changes are known to occur. Transient drops in circulating concentrations of platelets, monocytes, and neutrophils have been noted, along with transient neutrocytosis and lymphocytosis, and lymphocyte subpopulation changes. Functional changes in white blood cells and platelets have also been noted to occur, such as increased adherence and augmented superoxide generation of polyrnorphonuclear cells, phagocytosis changes of blood mononuclear phagocyte cells, blastogenesis and reactivity changes of lymphocytes, and adhesion changes of platelets. The various blood cells have been noted to show increased secretion of elastase, lactoferrin, alpha- 1 proteinase inhibitor, and peroxidase for polymorphonuclear cells; interleukin 1 , tumor necrosis factor, and other monokines for mononuclear phagocytic cells; various lymphokines for lymphocytes; and platelet factor 4, betathromboglobulin and thromboxane for platelets. Most of the above-noted reactions of blood material interactions have been demonstrated in extracorporeal Q 1992 Wiley-Liss, Inc.
circulation procedures such as hemodialysis, hemofiltration. and blood oxygenation. Similar reactions may be expected with apheresis techniques. Material blood contacts in apheresis occur in 3 areas: ( 1 ) blood access devices, (2) blood conduits, and ( 3 ) separationitreatment devices. The contacts in blood access devices are short and the area of contact relative to the total circuit area is small, making its effect difficult to assess. Further, blood conduits are typically made of polyvinyl chloride or like materials. Circuits from various manufacturers are generally not interchangeable among various hardware types, making circuits alone difficult to evaluate. With the various types of materials used in separation and treatment devices, such as varying polymer types for plasma and cell separation and membrane and sorbent devices for plasma treatment, such evaluations have been more practically carried out. The hypothesis upon which blood material reactivity is based is that the surface chemistry of the material of blood contact will affect the degree of blood humoral and cellular changes. Various in vitro animal investigations and clinical studies have shown that different materials effect different responses. Further, the responses noted can be shown to depend on the surface area of blood contact. A significant degree of interest has been focused on the complement system. Complement is one of the serum enzyme systems. It consists of 19 separate proteins which may be activated either via the classical or alternative pathways. The classical pathway is activated typically by immune complexes and the alternative pathway by surfaces or molecules including microbial products. The complement system functions include mediating inflammation, opsonization of antigenic particles (such as bacteria), and causing membrane damage to pathogens. Of considerable attention are the generation of activated components of complement C3 and C5, the anaphylatoxins C3a and
Address reprint requests to Paul S Malchaky. D Eng Corpordtion. 9450 Pineneedle Drive. Mentor. OH 44060
.
STERIS
146
Fig. I, Interactions of humoral systems in extracorporeal technology applications.
C5a. These agents are known to mediate inflammation, to cause mast cell degranulation, to cause smooth muscle contraction, and to cause increased capillary permeability. Various polymers used in apheresis devices have been shown to cause complement system activation and the generation of C3a and C5a to varying degrees. It has been shown that these 2 factors may have different effects on the immune system. C3a production has been shown to inhibit antibody formation, while C5a and its byproduct C5a des Arg enhances antibody formation. Different materials have been shown to produce C3a and C5a in different proportions, suggesting that not only the absolute concentrations of these factors may be important, but also their relative ratio. In the extracorporeal circulation of blood, an anticoagulant is required to prevent the blood from clotting during the treatment procedure. The anticoagulants used are typically either citrate or heparin. Each functions in a different way. Heparin is an antagonist of thromboplastin that reduces the formation of thrombin and prevents fibrin formation. Citrate acts by binding with calcium. The influence on the properties of blood, and specifically the coagulation and complement systems, have been shown to be different for these 2 anticoagulants. It is noteworthy that calcium is required for complement activation; the use of citrate inhibits its activation. It is important to differentiate the effects of the anticoagulant and material-blood contacts in understanding the effects of extracorporeal circulation. The extracorporeal procedure (i.e., apheresis) will effect biomodulation, that is, changes in the cellular or biochemical milieu of the body. Of course the apheresis procedure is therapeutically designed to do just that, whether it is for cell or solute removal or for treatment.
However, due to the choice of materials for blood contact and anticoagulation procedure, biomodulation will also occur. These procedure-associated events, which are not specifically intended in the design of the therapy, must be considered in the overall evaluation of the clinical effects, as their impacts may extend for days to weeks beyond the treatment period. Recognizing that material blood contacts alone can modulate the biological system, a number of investigations are under way to design and use materials for such specific purposes. Of particular note are the design of materials to activate blood cells, such as lymphocytes to become killer cells and therefore enhance cytotoxicity . While efforts to date primarily have concentrated on the development and design of materials to minimize biological response, so-called biocompatible materials, this new investigative effort is concentrated on the design of materials to effect direct humoral (biochemical) or cellular modulation. This area of development holds specific promise to the design of materials for therapeutic apheresis.
SUMMARY
Blood contacts with artificial surfaces will effect different degrees of complement activation. Associated with complement activation will be cellular concentration and functional changes. The type of anticoagulant also will effect complement activation. The noted biomodulating effect of a material in contact with blood suggests that the choice and design of materials and their “biocompatibility” can be made to effect humoral and cellular changes as the therapy may require.
