Comparison of different Lp (a) elimination techniques: A retrospective evaluation

Lipoprotein (a), abbreviated Lp (a), is accepted as a potential selective or additional risk factor for premature atherosclerosis. Though it may be considered to be closely related to low density lipoprotein, so far attempts to keep it under control with diet or cholesterol lowering medications have failed. Thus, extracorporeal elimination is the only effective treatment approach for patients with premature atherosclerosis. As different techniques for differential elimination such as precipitation, adsorption and filtration exist, it appeared of interest for us to retrospectively evaluate adsorption and filtration procedures in their capacity to lower Lp (a). Four patients with selectively elevated Lp (a) and eight patients with familial hypercholesterolaemia and additional elevated Lp (a) could be evaluated. All patients had Lp (a) values of 80–120 mg/dl without treatment in common. Different plasma or whole blood volumes were processed to obtain 30 mg/dl Lp (a) as post-treatment target values. In patients with a selective elevation Lp (a)-apheresis, as developed from Prokovski, was the most potent elimination procedure, decreasing the Lp (a) by at least 81% of the initial value after processing 6 L of plasma followed from LDL-(immune) apheresis with 71%. Plasma differential filtration using the Kuraray LA 4 filter decreased Lp (a) by 70% processing only 3.4 L, however was less selective and limited by the loss of fibrinogen and other high molecular weight proteins. In patients with familial hypercholesterolaemia and Lp (a) elevation in a range of 80–120 mg /dl LDL-(immune) apheresis removed >80% of Lp (a) processing 6 L of plasma whereas if 5 L were processed a removal of 76% was comparable to liposorption. Neither whole blood perfusion (DALI, Fresenius) nor filtration applying the Kuraray LA 5 filter was able to reach the desired target values.     

Efficacy of different low-density lipoprotein apheresis methods.

Low-density lipoprotein (LDL) apheresis is a treatment option in patients with coronary heart disease and drug resistant hypercholesterolemia. Various apheresis systems based on different elimination concepts are currently in use. We compared the efficacy of 4 different apheresis systems concerning the elimination of lipoproteins. The study included 7 patients treated by heparin extracorporeal LDL precipitation (HELP), 10 patients treated by immunoadsorption, 8 patients treated by dextran-sulfate adsorption, and 4 patients treated by cascade filtration. Ten subsequent aphereses were evaluated in patients undergoing regular apheresis for more than 6 months. Total cholesterol decreased by approximately 50% with all 4 systems. LDL cholesterol (LDL-C) (64-67%) and lipoprotein a [Lp(a)] (61-64%) were decreased more effectively by HELP, immunoadsorption, and dextran-sulfate apheresis than by the less specific cascade filtration system [LDL-C reduction 56%, Lp(a) reduction 53%]. Triglyceride concentrations were reduced by 40% (dextran-sulfate) to 49% (cascade filtration) and high-density lipoproteins (HDL) by 9% (dextran-sulfate) to 25% (cascade filtration). On the basis of plasma volume treated, HELP was the most efficient system (LDL-C reduction 25.0%/L plasma), followed by dextran-sulfate (21.0%/L plasma), cascade (19.4%/L plasma), and immunoadsorption (17.0%/L plasma). However, a maximal amount of 3 L plasma can be processed with HELP due to concomitant fibrinogen reduction while there is no such limitation with immunoadsorption. Therefore, the decision of which system should be used in a given patient must be individualized taking the pre-apheresis LDL concentration, concomitant pharmacotherapy, and fibrinogen concentration into account.     

Hemorheology and therapeutic hemapheresis

Rheological parameters (plasma and blood viscosities, erythrocyte aggregation and deformability) are very relevant to a better understanding of the changes inflicted on the properties of blood in various hematological diseases (monoclonal gammopathies in particular). This study reports the measurement of rheological parameters (plasma and blood viscosity, RBC aggregation and deformability) in hematological disorders where abnormal blood properties have been described. All these diseases are treated by means of blood separators (therapeutic haemapheresis:plasma exchange, plasma processing, or erythrocyte exchange). We monitored plasma viscosity in 50 patients with monoclonal gammopathies: before and after each exchange (PE) or plasma processing (PP) sessions. Hyperviscosity was reduced in all cases after plasma exchange. Erythrocyte aggregation in gammopathies was also tested (15 multiple myelomas) treated by PE or PP, EA abnormalities and therapy-induced changes are described. EA is also modified by erythropheresis (seven sickle cell anemias). Measurement of rheological parameters are useful to the diagnosis of rheological abnormalities, as well as to assess the impact of therapeutic hemapheresis techniques like plasma exchange, plasma treatment, erythrocytapheresis.     

Therapeutic apheresis application using membrane plasma fractionation technology: present scope and limitations.

Membrane technologies have been applied for therapeutic apheresis, such as plasma separation and plasma fractionation. Membrane used for plasma fractionation has a microporous structure with pore sizes in the range of 0.01-0.04 microm. A membrane plasma fractionator is utilized for the second filter in the double filtration plasmapheresis (DFPP) system and is applied for treatment of various diseases.This article summarizes the present scope and limitation of membrane plasma fractionation.     

Membranes for therapeutic apheresis.

Kuraray has developed many kinds of apheresis devices, such as plasma separators, plasma fractionators, and apheresis monitors. In this article, apheresis membranes, especially double filtration plasmapheresis (DFPP) and plasma fractionators used in DFPP are introduced. DFPP is both clinically and cost effective apheresis therapy, and it has been used widely for the treatment of many kinds of diseases. Several types of plasma separators with various pore sizes are available. It is important to select the proper plasma separator with suitable pore size, determined by the size of the pathogenic substances to be removed. The Evaflux 5A ethylene-vinyl alcohol copolymer plasma fractionator efficiently separates low-density lipoprotein from high-density lipoprotein. DFPP with the Evaflux 5A is effective for the treatment of familiar hyperlipidemia.     

Haemapheresis activities in Germany.

Preparative and therapeutic haemaphereses are well established in Germany. Plasma and platelets are the most often collected products by apheresis. 1,090,329l of apheresed plasma were collected for fractionation in 2002. For therapeutic purposes 410,507 transfusion units (TUs) of plasma and 227,096 TUs of platelets were harvested by apheresis. The number of allogeneic and autologous peripheral blood stem cell collections is steadily increasing and supplants more and more the harvesting of bone marrow. There is only a small market for the collection of red blood cells (RBCs) by apheresis (4982 TUs in 2002) and multicomponent donation. Unfortunately, there is no central register for the data acquisition of therapeutic aphereses which makes it impossible to gain exact data about the number of performed procedures as well as their side effects. Preparative haemapheresis are usually carried out by specialists in Transfusion Medicine, whereas therapeutic aphereses are performed by experts in Transfusion Medicine and by clinicians of different specialties. Besides the well established plasmaphereses and cell depletions, new interesting therapeutic apheresis techniques, e.g. for the treatment of sudden hearing loss and cardiomyopathy, are promising.     

The role of rheology in hemapheresis.

Rheological therapy attempts to favorably influence the blood flow mechanics for the treatment of diseases, mainly of the microcirculation but also of the macrocirculation. Hemapheresis, originally used only for the elimination of an excess of cellular or plasmatic components, was shown to also influence the hemorheology favorably. As extracorporeal therapy affects the rheology much more than conventional hemorheotherapy, not only cellular or plasmatic hyperviscosity syndromes but also many more diseases associated with organ perfusion problems due to diseases of the micro- and macrocirculation, especially in the elderly, were and are increasingly considered to be indicated. Technical progress led away from plasma exchange as an unspecific and unselective procedure to plasma differential separation using precipitation. adsorption, and filtration. With our recent development, we demonstrated that rheohemapheresis is the most advanced technical procedure. The mechanism of action can well be related to a synergetic consideration of rheology. However. one has to keep in mind that the elimination of blood components such as lipids, immunoglobulins, and endothelial factors may well contribute to the explanation and understanding of the positive clinical effects observed. These speculative aspects need further investigation.     

Leukodepletion of platelet concentrates and plasma collected with haemonetics MCS+ apheresis system. Experience of EFS-Alsace.

The prevention of transfusion reactions and transmission of infectious diseases partly relies on the systematic removal of leukocytes from blood products. Apheresis platelets and plasma collected on the Haemonetics MCS+ collection system require filtration to obtain low levels of residual leukocytes. This filtration step is automated for platelet concentrates, whereas plasma filtration requires sterile docking of a leukoreduction filter. Our experience shows residual leukocyte levels of approximately 10(5) for platelets (the French requirements are 10(6) per unit) and 10(2) for apheresis plasma (no existing standard in France). Leukocyte residuals in platelets are highly dependent on the filtration rate, which should be as slow as possible. Whereas the current method of filtration is convenient for platelets, the connection of an in-line filter for plasma causes some organizational problems and is also associated with a loss of plasma. Haemonetics' latest development, the use of a filtering core bowl, should avoid the requirement for the connection of an additional filter for plasma filtration and will ensure continuous filtration of platelets, reducing, even further, the residual leukocyte count in platelet concentrates.     

Risk of AIDS-related virus (human immunodeficiency virus) transmission through apheresis procedures

Since exposure to blood products occurs on a daily basis during hemapheresis, the acquired immunodeficiency syndrome (AIDS) epidemic has a serious impact both for patients undergoing apheresis procedures as well as for health professionals working in the field. We studied serum samples from 110 patients who underwent therapeutic plasmapheresis for a variety of diseases not related to AIDS for the presence of antibodies to human immunodeficiency virus (HIV). Exchange fluids used in the majority of the patients were plasma protein fraction and 5% human albumin. Four patients received only fresh-frozen plasma. Fifty-five patients also received IV gammaglobulin. The follow-up period exceeded 24 months. All patients who did not belong to any known high-risk group for AIDS were negative for HIV antibodies prior to treatment and remained negative at last follow-up. Seven patients were homosexual men. All seven were seropositive prior to plasmapheresis and remained so throughout the treatment period. Seven health professional working in a busy haemapheresis unit were followed for 2 1/2 years. All remain HIV seronegative with normal immune function. These data indicate that transmission of HIV is unlikely through haemapheresis procedures.     

Therapeutic apheresis in critically ill patients

Therapeutic apheresis procedures in critically ill patients comprises of therapeutic plasma exchange in most cases but also less commonly, erythrocytapheresis (red cell exchange), thrombocytapheresis, or leukocytapheresis. These procedures present a number of challenges to the apheresis healthcare team, and there are myriad beneficial and adverse effects for patients. In this patient population, one has to weigh the risks against the benefits and especially in those situations where apheresis is requested as a treatment when other alternative therapies have failed. Therapeutic plasma exchange is capable of removing toxins, pathologic auto- and allo-antibodies but will also remove beneficial medications, clotting factors and cations which are chelated by citrate anticoagulant. Herein, we review clinically significant issues that are commonly encountered in patients that are in the intensive care unit and have conditions that require therapeutic apheresis.     

Membrane plasmapheresis in the United States: a review over the last 20 years.

Plasmapheresis is a general term involving extracorporeal plasma separation by centrifugation or primary membrane plasma separator (MPS). Further plasma processing can be accomplished by the use of secondary membrane plasma fractionation (PF), as in double filtration plasmapheresis, also called cascade filtration, low-density lipoprotein pheresis, thermofiltration, and cryofiltration apheresis. Otherwise, the separated plasma is replaced by colloid solution as in plasma exchange (PE). PE is used, unselectively, to treat patients with immunological, neurological, hematological, renal, and metabolic disorders. Secondary PF may be a more selective alternative. In general, the primary MPS and secondary PF are safe, effective, and biocompatible. The advantages of the primary MPS include its simplicity to use with blood pumps and no observed white blood cell or platelet loss, compared with centrifugation. The disadvantages are lack of versatility, the need to monitor transmembrane pressure to prevent hemolysis, and possible biocompatibility issues such as use of polyvinyl alcohol membranes. The advantages of secondary PF, compared with PE, include selective removal of macromolecules according to molecular weight and filter pore size. No deficiency syndromes or sepsis are observed, nor is replacement solution required. More than 1 plasma volume may be processed, and it is less expensive than PE. Cryofiltration apheresis, using the cryoglobulin filter, selectively removes cryoproteins and is a specific treatment for cryoprecipitate-induced diseases. The disadvantages of PF include biocompatibility, especially with concomitant ACE inhibitor use, and membrane plugging. An important disadvantage is that most PFs are investigational in the United States. This article reviews the availability, safety, efficacy, and biocompatibility of primary MPSs and secondary PF in the United States.     

Low-density lipoprotein apheresis and changes in plasma components.

Several different techniques of low-density lipoprotein (LDL) apheresis are available for management of severe hypercholesterolemia. Among them, the adsorption system with a dextran-sulfate cellulose (DSC) column is most widely used. In addition to adsorption of LDL, DSC adsorbs plasma constituents that have the following characteristics: proteins containing apolipoprotein B (Lp[a]); proteins involved in the initial contact phase of the intrinsic coagulation pathway (coagulation factor XII, high-molecular-weight kininogen and prekallikrein); factors with lipophilic characteristics (coagulation factor VII, coagulation factor VIII, and vitamin E); and proteins with adhesive or other characteristics (von Willebrand factor, fibronectin, serum amyloid P component, hepatocyte growth factor). The adsorption of these proteins seems to ameliorate prevention or regression of atherosclerosis. Moreover, plasma treatment by the DSC column may be useful for treatment of inexorable diseases, such as amyloidosis. On the other hand, the DSC column generates bradykinin by activation of the initial contact phase of the intrinsic coagulation pathway. Bradykinin generation may explain the functional improvement in the circulatory system, as well as hypotension during LDL apheresis, which is observed in patients taking ACE inhibitors.     

Low density lipoprotein immunoapheresis does not increase plasma lipid peroxidation products in vivo.

Extracorporeal elimination of low density lipoprotein (LDL) is frequently used in drug-resistant hypercholesterolemia. LDL-immunoapheresis selectively removes LDL and lipoprotein(a) [Lp(a)] from plasma. Lipid peroxidation is one unwanted side effect, that occurs during extracorporeal plasma treatment. The purpose of this study was to investigate the effect of LDL immunoapheresis on lipid peroxidation. Before and after a single LDL-immunoapheresis treatment, plasma concentrations of lipid hydroperoxides, determined with two different spectophotometric assays, thiobarbituric acid-reacting substances (TBARS), determined spectrophotometrically and malondialdehyde (MDA), determined by an MDA-TBA/HPLC method, were measured in 13 hypercholesterolemic patients. In addition MDA was also determined in the eluate of the apheresis column. Before treatment, plasma cholesterol and LDL cholesterol concentrations were significantly higher in patients than in healthy control subjects, as were the lipid peroxidation products. LDL-immunoapheresis treatment of the patients led to significant decreases in total cholesterol (69+/-8%), LDL-cholesterol (79+/-7%), HDL-cholesterol (35+/-17%), triglycerides (38+/-21%), apolipoprotein-B (77+/-6%), apolipoprotein-A1 (25+/-5%) and Lp(a) concentrations (76+/-10%). Changes in plasma lipid peroxide concentrations (17+/-8 nmol/l before vs. 14+/-5 nmol/l after treatment) were not significant, neither were those in TBARS (3. 0+/-2.6 micromol/l vs. 2.3+/-1.3 micromol/l) or MDA concentrations (1.03+/-0.17 micromol/l vs. 1.0+/-0.20 micromol/l). Patients with high baseline values showed a decrease, whereas others did not. MDA was present (0.57+/-0.13 micromol/l) in the eluate of the apheresis column, suggesting that, along with LDL, lipid peroxidation products are also removed. From these results we conclude that a single LDL-immunoapheresis treatment effectively reduces LDL and Lp(a) in the absence of increases in plasma lipid peroxidation products.     

Low density lipoprotein hemoperfusion by direct adsorption of lipoproteins from whole blood (DALI apheresis): clinical experience from a single center.

The elimination of low density lipoprotein (LDL) and lipoprotein (a) (Lp[a]) by conventional LDL apheresis techniques can only be achieved in a cell-free medium and thus requires the initial separation of plasma from the blood cells. The present paper describes the first LDL hemoperfusion system which is able to adsorb LDL and Lp(a) directly from whole blood. This simplifies the procedure substantially. The adsorber consists of polyacrylate ligands linked to a modified polyacrylamide matrix. These negatively charged polyacrylate ligands interact with the positively charged apoprotein B moiety of LDL and Lp(a), which results in selective adsorption of these lipoproteins onto the column. Three hypercholesterolemic patients suffering from overt atherosclerotic complications were treated weekly by direct adsorption of lipoproteins (DALI) (n = 20 sessions each). All patients were on the highest tolerated dose of cholesterol synthesis enzyme (CSE) inhibitors. About 1.3 patient blood volumes were treated per session. The anticoagulation was performed with acid citrate dextrose (ACD-A). The following acute reductions were achieved: LDL: 66%; Lp(a): 63%; and triglycerides: 29%. High density lipoprotein (HDL) (-13%) and fibrinogen (-16%) were not substantially reduced. The sessions were essentially uneventful. Due to a low ACD-A infusion rate, no hypocalcemic episodes were registered. One patient on enalapril was treated without complications when this angiotensin converting enzyme (ACE) inhibitor was withdrawn 2 days prior to apheresis. In summary, in our hands, DALI apheresis proved to be a simple, safe, and efficient method of lipid apheresis in hypercholesterolemic patients refractory to conservative lipid lowering therapy.     

Apheresis of immune diseases and apheresis using immunological specificity.

It has been clearly shown that autoimmune diseases can be treated by apheresis by eliminating immune complexes, however, the effects of therapeutic apheresis are not limited to immune disorders. Almost all diseases are associated with immune systems. Immune systems can be regulated by advanced techniques of apheresis, including immunoadsorption and immunocytapheresis, removing immune effector molecules and various immune-associated cells selectively. Therefore, apheresis can be used as a nondrug treatment for many diseases. In addition, disease-associated proteins that cause disease or are produced in the course of diseases and accumulate in the body could be eliminated selectively by apheresis using the extremely powerful ability of the immune system to recognize polypeptide structures specifically and distinguish miniscale differences among molecules. In this article, we discuss the current status of treatment of immune diseases by apheresis and possible treatment approach of a variety of diseases by apheresis based on immune reactions.     

Low density lipoprotein apheresis by membrane differential filtration (cascade filtration).

Membrane differential filtration (MDF) is an apheresis technique with which atherogenic lipoproteins can be eliminated from plasma on the basis of particle size. In 52 patients (REMUKAST Study, 1,702 treatments), low density lipoprotein (LDL) cholesterol was decreased by 61%, high density lipoprotein (HDL) cholesterol by 42%, and fibrinogen by 54%. Our own results in 3 patients show decreases of 62%, 31%, and 59%, respectively; lipoprotein (a) (Lp[a]) was reduced by 58%. The elimination of atherogenic lipoproteins was accompanied by a loss of macromolecules (IgM: 55%, IgG: 27%, alpha 2-macroglobulin: 49%) resulting in improved hemorrheologic parameters. Although HDL is eliminated with each apheresis session, pretreatment concentrations of HDL cholesterol increased by 24% during regular apheresis for 1 year (26 patients, REMUKAST Study). However, preapheresis concentrations of other macroglobulins such as immunoglobulins remained decreased compared to concentrations obtained before the first apheresis session (IgM: 34%, IgG: 23%, and IgA: 16%). We conclude that MDF apheresis is an effective method to lower elevated concentrations of atherogenic lipoproteins. The concomitant loss of other macromolecules transiently improves hemorrheology but demands a close monitoring of immunoglobulin concentrations as a safety parameter.     

Clinical application and effectiveness of low-density lipoprotein apheresis in the treatment of coronary artery disease.

The Low-Density Lipoprotein Apheresis Coronary Atherosclerosis Prospective Study (L-CAPS) examined whether or not combined low-density lipoprotein (LDL) apheresis and drug therapy apheresis could induce the regression of coronary atherosclerotic lesions in patients with familial hypercholesterolemia. Twenty-eight patients treated with LDL apheresis and drugs and 11 patients treated with drugs alone underwent sequential coronary angiography 2.5 years apart. The frequency of cases with regression or no change was significantly higher for the apheresis group than for the control group (p = 0.004). The LDL apheresis Angioplasty Restenosis Trial (LART) investigated the hypothesis that high plasma lipoprotein (a) (Lp[a]) levels were associated with increased incidences of restenosis after coronary angioplasty. Two days before and 5 days after angioplasty, 66 patients underwent LDL apheresis. The restenosis rates were 21% in the 42 patients whose Lp(a) levels were reduced > or = 50% and 50% in the 24 patients whose Lp(a) levels were reduced < 50% (p < 0.05). LDL apheresis is effective in the prevention of the progression of coronary atherosclerosis. Its potential application in restenosis prevention should be further investigated.     

Haemorheological changes in mixed cryoglobulinaemia during apheresis treatment

Thirty-four patients affected by mixed cryoglobulinaemia have been submitted to treatment by apheresis (plasma exchange or double cascade filtration). The authors have monitored clinical, laboratory and, above all, haemorheological changes following therapy. The final results have shown mainly a reduction of plasma viscosity and consequently an improvement of the haemorheology of the affected organs. In conclusion, apheresis may be considered a successful therapy in patients with severe renal or neurological diseases due to mixed cryoglobulinaemia.     

The current state of extracorporeal haemorheotherapy: from haemodilution via cascadefiltration to rheohaemapheresis.

Rheological therapy aims at an improvement of organ perfusion however, it has to be stressed that the tonus of the blood vessels also plays an important role for both the blood distribution and the rheology in the micro- and the macrocirculation. Conventional rheotherapy consists of attempts to influence nutrition and life style, to apply drugs such as purin derivatives, vasodilatating or defibrinising substances and hypervolaemic (using infusion therapy), hypovolaemic, e.g., blood letting, erythrocytapheresis and – the most widely distributed – isovolaemic haemodilution. With the introduction of centrifugal devices, and approximately 10 years later with the introduction of hollow fibre and flat sheet membrane techniques, a considerable increase of therapeutical efficacy was achieved. These technologies were successfully applied for the treatment of cellular and plasmatic hyperviscosity syndromes. The treatment of less severe diseases of the micro- and macrocirculation, vessel stenosis, vessel wall sclerosis, malformation of the blood vessel architecture, pathological clinical–chemical blood parameters and maldistribution have hardly been taken into consideration. Our group at Köln investigated different plasma differential separation techniques and demonstrated, that adsorption as well as filtration could be applied. These different techniques being 6–10 times more effective as conventional haemodilution techniques have in common high molecular weight proteins determining the viscosity of plasma and thus whole blood viscosity is removed, however differences among the different elimination techniques do exist. The rheological and clinical importance of such differences has to be determined. Applying filtration techniques for both primary and secondary separations, the concept of Rheohaemapheresis was developed. A corresponding quality program was also introduced into our clinical routine. Rheohaemapheresis is supported from the currently introduced concept of the synergetic consideration of the microcirculation. Age related macular degeneration, so far without generally accepted therapy, is a most advanced indication based on several pilot studies and a prospective, randomised controlled trial. Other diseases of the microcirculation have also successfully been treated.