Selective extraction of plasma constituents

Plasma exchange or therapeutic plasmapheresis, introduced as a new treatment in the early 1970s, was considered an intermediate technology, one that was nonspecific and wasteful of valuable plasma constituents. As the therapy gained popularity, in large part because of its nonspecific character, concerns were raised about the loss of useful plasma components, such as coagulants, mediators of inflammatory response, and proteins. These losses, as well as volume depletion, made it imperative to use replacement solutions such as fresh-frozen plasma, a strategy that resulted in the introduction of a host of complications, notably disease transmission and allergic reactions. Thus, there was early recognition of the need for alternatives that provided selectivity as well as the possibility of autologous volume replacement. An intellectual challenge was also associated with the use of a more targeted and specific therapy with a potential for scientific gains and a pragmatic cost gain. Within a few years of the early reports of therapeutic success with plasma exchange, partially selective procedures for the removal of plasma constituents were reported. ' . ' Early efforts pursued selectivity and the use of modified autologous plasma as replacement as the means to a more physiologic and potentially less costly alternative to plasmapheresis. Techniques that selectively removed target plasma material used the principles of chemistry or physics with either onor off-line systems. Whole blood perfusion (hemoperfusion) and plasma perfusion were explored with affinity columns or filters containing immobilized ligands. Alternatively, plasma constituents were complexed, precipitated, or removed by filtration onor off-line. Principles of affinity chromatography and cryogelation with filtration propelled those early pioneering efforts. Then, as today, the limiting factor was not technology but rather identification of the undesirable plasma constituent targeted for extraction. Although a few conditions treated with plasmapheresis had a single identifiable pathogenic plasma constituent, most did not. This situation provided a basis for applying broadly specific ligands such as staphylococcal protein A to remove IgG antibodies and immune complexes, which theoretically could be useful for treating autoimmune disorders. It was also recognized that, for the treatment of autoimmune conditions, the broad specificity of plasmapheresis might be a desirable feature for removing medimune reactants of potential therapeutic value. Also at issue was the removal efficiency of plasmapheresis as aided by the dilution caused by the replacement solution. Thus, the original procedure, plasmapheresis, became the standard against which alternatives would be measured in terms of efficiency, efficacy, and economics. With time, two basic techniques were pursued, one semiselective and the other specific. In this issue of TRANSFUSION, Leitman, Smith, and Gregg3 describe a semiselective technique of low-density lipoprotein (LDL) removal by filtration for the treatment of familial hypercholesterolemia. This disorder lends itself to specific removal because it is characterized pathogenically by a single offending factor, the LDL. The ideal treatment for familial hypercholesterolemia is one that lowers the LDL level while maintaining or raising that of high-density lipoproteins. Plasmapheresis, like other current therapies, sometimes achieves only one or the other goal. Despite its drawbacks, plasmapheresis has yielded reproducible benefits in patients with homozygous hypercholesterolemia, including regression of xanthomas, stabilization of aortocoronary atherosclerosis, and prolongation of survival. Conventional drug and dietary therapy and major surgical procedures have been of limited or no efficacy. Techniques for specific extraction of LDL have been applied successfully in humans for many years. One technique uses a polyclonal antibody, which is directed against apoprotein B, the antigenic determinant of LDL and very low-density lipoproteins, covalently linked to sepharose. Improvement of this system is foreseeable as mass production of monoclonal antibodies accelerates. This system effectively matches the efficiency of plasmapheresis, but to be cost-effective, it requires reuse and sterilization with sodium azide. It is used extensively in Germany in combination with a microprocessor-driven piece of hardware that automatically directs plasma flow from a saturated column to a freshly desorbed companion column in a continuous on-line procedure. Clinical studies have demonstrated that, on average, 67 percent of LDL cholesterol is removed in a 3-hour procedure, for an equivalence of 7 to 15 g of LDL extraction, with minimal (26.5%) removal of high-density lipoprotein^. ^ Another system uses dextran sulfate covalently linked to cellulose beads for the specific removal of LDL. Like the previous system, it requires that plasma be separated