Artificial Organs 33(12):1103–1108, Wiley Periodicals, Inc. © 2009, Copyright the Authors Journal compilation © 2009, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.
LDL Apheresis: A Novel Technique (LIPOCOLLECT 200) Claudia Stefanutti, Serafina Di Giacomo, Bruno Mazzarella, and Alessandro Castelli Department of Clinical and Medical Therapy—Plasmapheresis Unit, University of Rome “La Sapienza,” Policlinico “Umberto I,” Rome, Italy
Abstract: Therapeutic means to lower Lp(a) are limited. The most effective method to reduce plasma Lp(a) concentration significantly is therapeutic apheresis, namely, lowdensity lipoprotein (LDL) lipoprotein(a) (Lp(a)) apheresis. A novel technique based on reusable LDL adsorber called Lipocollect 200 (Medicollect, Rimbach, Germany) allows the removal of both LDL and Lp(a) from plasma.Two male patients with hyperLp(a)lipoproteinemia and angiographically established progressive coronary heart disease, without rough elevation of LDL-cholesterol, who did not respond to diet and medication were submitted to 50 LDL Lp(a) aphereses with Lipocollect 200 LDL Lp(a)-adsorber at weekly and biweekly intervals.Total cholesterol and LDL cholesterol plasma levels fell significantly by 48.3% (⫾6.7) to 61.6% (⫾12.7) (first patient), and 42.5% (⫾6.3) to 60.6% (⫾14.3) (second patient), respectively (all differences: P ⱕ 0.001). High-density lipoprotein (HDL)-cholesterol concentration in plasma did not show statistically significant change. Plasma triglycerides were also significantly reduced by 43.6% (⫾24.4) (first patient) and 42.3% (⫾13) (second patient) (both differences: P ⱕ 0.001). Plasma Lp(a)
showed a statistically significant percent reduction in plasma as expected:64.7 ⫾ 9.5 (first patient),and 59.1 ⫾ 6.7 (second patient) (both differences: P ⱕ 0.001). Plasma fibrinogen concentration was decreased by 35.9% (⫾18.7) (P ⱕ 0.05) (first patient) and 41.8% (⫾11.5) (second patient) (P ⱕ 0.005). Considering the reduction rate between the first and the last procedures, we have compared the mean percent reduction of the first five treatments (from session #1 to #5) with the last five treatments (from session #21 to #25). We have observed an increasing reduction of all activity parameters on both patients apart from HDLcholesterol (first patient) and triglyceride (second patient) that showed a decreasing reduction rate. Both patients followed the prescribed schedule and completed the study. Clinically, all sessions were well tolerated and undesired reactions were not reported. The Lipocollect 200 adsorber proved to have a good biocompatibility. In this study, the adsorber reusability for several sessions was confirmed. Key Words: Adsorption—Lp(a) apheresis—Cholesterol— Low-density lipoprotein—Hypercholesterolemia—Hyper Lp(a) lipoproteinemia—Coronary heart disease.
The merit of having been the first to introduce a therapeutic extracorporeal technique called plasmaexchange in the treatment of grave genetically determined dyslipidemia goes to De Gennes et al. (1). The successful clinical use of plasma exchange, to treat severe hypercholesterolemia was further and widely described in 1975 by Thompson et al. (2). Over two decades low-density lipoprotein (LDL) apheresis has been proven useful in the treatment of severe geneti-
cally determined hyperlipoproteinemia, which cannot be managed by diet and medication (3,4). Today, besides the five well-known methods based on immunoadsorption, dextran sulfate/cellulose adsorption, heparin extracorporeal LDL precipitation, direct adsorption of lipoproteins using hemoperfusion and cascade filtration (5–7), there is a new technique called Lipocollect 200 (Medicollect, Rimbach, Germany), based on reusable LDL lipoprotein(a) (Lp(a)) adsorber that removes apo B100-containing lipoproteins, LDL and Lp(a) from plasma. Lipocollect 200 is a new nonbiologic, polyanionic, heatsterilized LDL adsorber, which is intended for multiple use in a single patient. It is not based on immunologic adsorption to remove LDL and Lp(a) from plasma. Thus, this system cannot change any immunologic variable of the patient. We tested this
doi:10.1111/j.1525-1594.2009.00959.x Received July 2008; revised December 2008. Address correspondence and reprint requests to Prof. Claudia Stefanutti, Dipartimento di Clinica e Terapia Medica, Plasmapheresis Unit, University of Rome “La Sapienza,” Policlinico “Umberto I,” 155 Viale del Policlinico, 00161 Rome, Italy. E-mail:
[email protected]/
[email protected]
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adsorber (composed of porous silicagel) in combination with the ADAsorb system (Medicap, Ulrichstein, Germany), a new open apheresis system. The ADAsorb technique is designed for the programmable repetitive cyclic adsorption–desorption procedure with any size and kind of adsorbers. ADAsorb can work with different column types and with different setups related to the recommended manufacturer’s procedure. Within the standard procedure, it may be possible to change some parameters such as plasma volume to be processed, number of adsorption–desorption cycles, and priming volume. The system alternatively loads and elutes Lipocollect columns with plasma and hypertonic saline within each treatment. At the end of the session, the adsorbers are stored in blue-colored 0.01% sodium azide solution at 2–6°C and are ready to be reused. Rinsing– loading–regenerating–preserving steps are fully automated by the ADAsorb device. In this study, the ADAsorb system was used in combination with the COBE Spectra cell separator (COBE Laboratories, Inc., Lakewood, CO, USA). The latter is a centrifugal system that allows the best primary separation of the plasma and a consequent plasma free of small particles and platelets. Two male patients with hyperLp(a)lipoproteinemia and CHD who did not respond to diet and medication were submitted to 50 LDL Lp(a) aphereses with Lipocollect 200 LDL Lp(a) adsorber at weekly and biweekly intervals. PATIENTS AND METHODS A total of 50 LDL Lp(a) aphereses were performed in two male patients aged 42 and 44 years, respectively, with hyperLp(a)lipoproteinemia. Both patients are affected by coronary heart disease, which was confirmed by coronary angiography. They were submitted to our attention from a cardiology center for hemodynamics where they had been received as they were symptomatic for the abovementioned illness. The first patient was submitted to percutaneous transluminal coronary angioplasty (PTCA) and stenting after a myocardial infarction occurred in 2004 (main angiographic evidence: critical stenosis of the anterior descending coronary artery). In 2006, the patient was submitted again to PTCA and stenting, as the stent positioned in the first intervention was occluded. The severity of the clinical timeframe required us to treat the patient with extracorporeal cholesterol elimination. The second patient had exertional angina. In 2002, the patient was submitted to PTCA and stenting (main angiographic evidence: critical stenosis of the anterior descending coronary artery). In 2008, a cardiac Artif Organs, Vol. 33, No. 12, 2009
catetherization confirmed that the stent was still open, but a critical stenosis (85%) of the II diagonal branch has developed. The failure of any conventional therapeutic approach supported the decision to submit even this patient to extracorporeal cholesterol elimination. The lipid and lipoprotein values of the first patient at baseline were total cholesterol (TC), 187 mg/dL; LDL-cholesterol (LDLC), 120 mg/ dL; high-density lipoprotein (HDL)-cholesterol (HDL), 72 mg/dL; triglycerides (TG), 123 mg/dL; Lp(a), 125 mg/dL. The second patient had the following basal values: TC, 123 mg/dL; LDLC, 100 mg/ dL; HDLC, 14.6 mg/dL; TG, 42 mg/dL; Lp(a) 85 mg/ dL. The patients recruited in the study had been treated in the past with hypolipidemic drugs (statins, ezetimibe, second-generation fibrates, w-3 fatty acids) and diet such as Step 2 of the National Cholesterol Education Program of the American Heart Association, without success. Otherwise, they would not have been recruited in a trial devoted to therapeutic apheresis. We performed a treatment every 15 days on the first patient and every week on the second. All patients were asked at every treatment to report undesired reactions. PLASMA VOLUME TREATED First patient Within a mean time of 120 min, a mean of 3000 mL of plasma was processed by the LDL adsorbers from session #1 to #16, a mean of 3800 mL from session #17 to #19, and a mean of 4020 mL from session #10 to #25. We reached the standards of 150 min and 4020 mL of plasma treated, after procedure #19. We used anticoagulant citrate dextrose solution A for anticoagulation in a ratio of 1:30 to allow the best performance of the columns and to avoid excess dilution. The plasma was separated by the cell separator and pumped continuously at a flow rate of 15–35 mL/min. In each cycle, an adsorber was loaded with 670 mL of plasma (for six cycles). Second patient We began with a mean time of 120 min, 3000 mL of plasma treated, and 4% sodium citrate in a ratio of 1:30. The plasma had a flow rate of 15–30 mL/min, and five cycles of 600 mL of plasma were performed. Before starting the procedure, a bolus of 1250 IU heparin was given intravenously to the patients. Elution of LDL and Lp(a) was performed automatically on ADAsorb by using an hypertonic saline during the treatment. Between the treatments, the columns were stored in blue-colored 0.01% sodium azide solution at 2–6°C.
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TABLE 1. Plasma TC, LDLC, HDLC, TG, and Lp(a) mean percent differences and mean absolute differences vs. basal values after LDL Lp(a) apheresis (25 sessions) Patient 1
TC LDLC HDLC TG Lp(a)
Mean percent reduction 48.3* 61.6* 22.9 ns 43.6* 64.7*
Patient 2
SD
Mean absolute reduction
6.7 12.7 10.8 24.4 9.5
91.6* 66.7* 13.6 ns 56.0* 58*
SD
Mean percent reduction
17.9 15.8 6.8 43.8 14.1
42.5* 60.6* 21.3 ns 42.3* 59.1*
SD
Mean absolute reduction
SD
6.3 14.3 7.3 13.0 6.7
73.0* 49.7* 16.8 ns 33.4* 56*
14.7 14.9 7.7 16.7 10.8
* P ⱕ 0.001. ns, not significant.
Instrumentation Laboratory, Lexington, MA, USA). Plasma HDLC level was determined with a combined immune and enzymatic assay (HDL Cholesterol Test, Instrumentation Laboratory). Plasma LDLC level was calculated according to the formula of Friedewald: LDLC = TC - (HDLC + TG / 5). The concentration of Lp(a) in plasma was determined with quantex Lp(a) immune assay (Instrumentation Laboratory). Plasma fibrinogen (FBG) concentration was determined in citrated plasma with Fibrinogen-C Test according to the Clauss method (HemosIL, Instrumentation Laboratory). Prespecified key laboratory safety variables were determined by usual enzymatic and chemical methods. Blood cell counts were determined with a Beckman Coulter ACT Diff Hematology Analyzer (Beckman Coulter, Fullerton, CA, USA).
Laboratory methods Analyses of samples for clinical laboratory measurements were performed at a certified central university hospital laboratory. Baseline blood samples were taken directly from the antecubital venous access immediately prior to the start and at the end of the session. The blood samples for lipid and lipoprotein measurements were obtained before LDL Lp(a) apheresis, that is, at the time of the venipuncture, a little before the connection of the venous accesses in line with the instrument, and immediately after. Instead, the determining of Ca/fibrinogen was carried out immediately before connection to the instrument and at the conclusion of the reinfusion, after carrying out the discarding of an aliquot of blood, and after taking a second sample of blood to be sent to the laboratory. The hematobiochemical determination was always carried out in real time, given the experimental nature of the extracorporeal procedure. The levels of all laboratory parameters reported in Tables 1 and 2 were calculated by average concentration ⫾ standard deviation (SD), according to chronological criteria and the procedures of samples taken as mentioned above. The concentrations of plasma TC and TG were determined by enzyme assay (Cholesterol and Triglycerides Tests,
Safety Safety was assessed on the basis of potential clinical side effects that had been objectively recorded (arterial blood pressure variations, heart rate variations, fever reactions) or subjectively reported by patients as symptoms that occurred during and after each session of LDL Lp(a) apheresis with Lipocollect 200. In addition, safety was assessed by evaluating selected labo-
TABLE 2. Plasma TC, LDLC, HDLC, TG and Lp(a) mean percent reduction of the first 5 treatments (1st–5th) vs. mean percent reduction of the last 5 treatments (21st–25th) Patient 1
TC LDLC HDLC TG Lp(a)
Mean percent reduction of the first 5 treatments 47.3 59.7 27.7 39.0 53.2
Patient 2
SD
Mean percent reduction of the last 5 treatments
4.9 4.2 6.7 24.9 7.0
49.7 62.7 14.9 72.0 72.7
SD
Mean percent reduction of the first 5 treatments
10.3 17.2 3.7 8.8 4.3
40.9 43.2 20.0 44.9 59.8
SD
Mean percent reduction of the last 5 treatments
SD
12.2 20.4 6.6 14.7 5.3
45.3 66.5 21.6 42.7 60.6
5.9 6.5 5.6 14.1 8.9
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ratory parameters that indicate specific adverse reactions related to the apheretical procedure (i.e., hemolysis, blood cell loss, coagulation, biochemistry). We have not considered any immunologic parameter, as Lipocollect 200 is not based on immunologic adsorption to remove LDL and Lp(a) from plasma. The manufacturer has proved the lack of significant change of any immunologic variable of the patient.
Ethics Informed consent was obtained from all patients, according to the recommendations of the Declaration of Helsinki, Tokyo Amendment 1975, and Venice Amendment 1983.
Statistical data analysis Differences in baseline characteristics were tested for statistical significance by conventional Student’s t-test. Statistical analysis was performed according to parametric tests, depending on the parameters under evaluation.
RESULTS First patient The relative data to the variations observed in TC, LDLC, HDLC, TG, and Lp(a) expressed as absolute values and in percentages are reported in Table 1. All the differences observed, apart from the exception of HDLC, were statistically significant (P ⱕ 0.001). FBG concentration in plasma showed a percent reduction of 35.9 ⫾ 18.7 (P ⱕ 0.05). Plasma FBG level at baseline was 227 mg/dL and was significantly reduced to 85 ⫾ 53.56 mg/dL (P ⱕ 0.05) after extracorporeal cholesterol elimination. We have considered the reduction rate between the first and the last procedures, comparing the mean percent reduction of the first five treatments (from session #1 to #5) to the last five treatments (from session #21 to #25). We have observed an increasing reduction of all activity parameters, apart from HDLC that showed a decreasing reduction rate. In detail, TC reduction rate shifts from 47.3 ⫾ 4.9 (mean ⫾ SD) to 49.7 ⫾ 10.3, LDLC shifts from 59.7 ⫾ 4.2 to 62.7 ⫾ 17.2, HDLC shifts from 27.7 ⫾ 6.7 to 14.9 ⫾ 3.7, TG shifts from 39 ⫾ 24.9 to 72 ⫾ 8.8, and Lp(a) shifts from 53.2 ⫾ 7 to 72.7 ⫾ 4.3. Data are reported in Table 2. We also had to take into account that we have processed a mean of 3000 mL during the first five treatments and a mean of 4020 mL in the last five treatments. Artif Organs, Vol. 33, No. 12, 2009
TABLE 3. Safety parameters: mean plasma total proteins, albumin, and total Ca+ absolute changes after LDL Lp(a) apheresis Variations (mg/dL)
SD
1.15 1.05 0.8
0.9 0.35 0.85
Total proteins Albumin Total Ca+ All differences: not significant.
Second patient The relative data to the variations observed in TC, LDLC, HDLC, TG, and Lp(a) expressed as absolute values and in percentages are reported in Table 1. All the differences observed, apart from the exception of HDLC, were statistically significant (P ⱕ 0.001). FBG concentration in plasma after apheresis was reduced to 41.8 ⫾ 11.5 (P ⱕ 0.005). Plasma FBG level at baseline was 271 mg/dL and was significantly reduced to 117 ⫾ 49.68 mg/dL (P ⱕ 0.005) after extracorporeal cholesterol elimination. We have considered the reduction rate between the first and the last procedures, comparing the mean percent reduction of the first five treatments (from session #1 to #5) to the last five treatments (from session #21 to #25). We have observed an increasing reduction of all data, apart from TG that showed a decreasing reduction rate. In detail, TC reduction rate shifts from 40.9 ⫾ 12.2 (mean ⫾ SD) to 45.3 ⫾ 5.9, LDLC shifts from 43.2 ⫾ 20.4 to 66.5 ⫾ 6.5, HDLC shifts from 20 ⫾ 6.6 to 21.6 ⫾ 5.6, TG shifts from 44.9 ⫾ 14.7 to 42.7 ⫾ 14.1, and Lp(a) shifts from 59.8 ⫾ 5.3 to 60.6 ⫾ 8.9. Data are reported in Table 2. We processed a mean of 3000 mL during all treatments. As safety variables are concerned, we focused our analysis on total proteins, albumin, and total Ca+ levels in plasma. We have observed a reduction of 15.4% (⫾12) in total protein, of 22% (⫾7.9) in albumin, and of 8% (⫾7.9) in total Ca+. Total protein and albumin levels in plasma at baseline were 7.5 mg/dL and 4.6 g/ mL, respectively. After apheresis, the observed reductions were 1.15 ⫾ 0.9 and 1.05 ⫾ 0.35 mg/dL, respectively. Total Ca+ concentration in plasma at baseline was 9.25 mg/dL. The absolute reduction after apheresis was 0.8 ⫾ 0.85 mg/dL. The abovereported differences were not statistically significant (Table 3). DISCUSSION Elevated plasma levels of atherogenic lipoproteins such as LDL and Lp(a) constitute major risk factors for the development of atherosclerotic disease (8). It has been postulated that lipid-modifying therapies
LDL APHERESIS: A NOVEL TECHNIQUE (LIPOCOLLECT 200) including statins, ezetimibe, and fibrates potentially could lower all lipid particles in plasma. However, in a severe, genetically determined metabolic disorder such as hyper Lp(a) lipoproteinemia, it is generally accepted that most of currently available lipidlowering drugs fail to lower Lp(a) level in plasma (9,10). Plasmapheresis was the initial extracorporeal method used in clinical practice to lower lipid and lipoprotein levels when usual medical therapy failed to attain desirable values of the above-mentioned lipid particles. In relatively recent years, LDL apheresis (immunoapheresis), discovered 26 years ago by Stoffel, and introduced as a clinical application by Borberg, has also emerged as an effective and more selective method of lipid-lowering in familial hypercholesterolemia and hyper Lp(a) lipoproteinemia (11,12). The present study showed high efficacy and selectivity of TC, LDL, TG and Lp(a) removal by Lipocollect 200 adsorber. Lipocollect 200 can provide major reduction of LDLC and Lp(a), up to almost 70% of the basal values. However, in this study, we did not deem it necessary to increase the quantity of treated plasma, as the initial levels of LDL in both patients were low, making the reduction less essential. Moreover, the effectiveness of Lipocollect 200 in reducing significantly the levels of apoB100containing lipoproteins in plasma is evident in the results. The aim of the study was also to verify the possibility of a new method in nonextreme operative conditions. The adsorber proved its good biocompatibility with lack of adverse effects although the management of the system was not very easy as far as the setup time is concerned. We guess that the system (COBE Spectra plus ADAsorb) is characterized by a relative technical complexity and could be handled easily only by experienced staff. However, once begun, the treatment time was not different from other available systems for extracorporeal cholesterol elimination. At present, it is to be recognized that there is no existing proof of published work in international literature, relative to the fact that the system described does not change immunologic variables (13). Nevertheless, an indirect immunologicrelated parameter such as the white cell count and differential leukocyte count did not show significant changes during the study. The adsorbers demonstrated a good reusability; this implies that they are cost saving as a pair of columns could work for approximately 50 apheresis sessions. Moreover, we failed to observe side effects related to the reuse of the columns. Neither deterioration of the adsorbent nor change of LDL and Lp(a) removal efficiency on consecutive sessions were demonstrated during the study. We did not observe significant adverse events
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such as infections or related symptoms during the investigation. We observed a statistically significant reduction of plasma FBG. However, we guess this finding is not directly related to a specific removal by the adsorber. Probably, a certain level of hemodilution must be taken into account to explain the abovementioned finding. The method of Clauss, even though frequently used in many laboratories to determine FBG concentration in plasma, might be misleading, as it may be submitted to the influence of heparin given intravenously as bolus at the beginning of apheresis. Thus, this finding must be considered as to be further investigated and should be confirmed by using an immunologic method to avoid heparin influence in the measurement of FBG level in plasma. At least in this study, the Lipocollect 200 adsorber in combination with the ADAsorb system and the COBE Spectra cell separator has demonstrated to be safe and effective. It should be emphasized that Lipocollect 200 is not the unique technique effective in removing Lp(a) from plasma. Lp(a) columns, for instance, reduce Lp(a) by more than 80% of the initial value, and filtration by up to 70%. Even other already cited extracorporeal techniques are effective in removing apolipoprotein B100–containing lipoproteins, such as LDL and Lp(a), from plasma (14–17). CONCLUSIONS Regular extracorporeal cholesterol elimination using Lipocollect 200 adsorber allows mean TC, LDLC, TG, and Lp(a) concentrations in plasma to be maintained at levels closer to those recommended by international guidelines for primary and secondary prevention of atherosclerotic disease and its ischemic complications (18). In the light of recent guidelines of the American Society for Apheresis, we can suggest a reasonable possibility of utilizing LDL Lp(a) apheresis Lipocollect 200 as a therapeutic instrument that is the widest technique of LDL apheresis indicated in extracorporeal treatment in grave genetically determined dyslipidemia (19). The above-mentioned technique, at least in the patients of this study, demonstrated compatibility as a long-term treatment according to the criteria of safety and tolerability described by other authors (20). Acknowledgments: The skillful technical assistance of Ms. O. Macciocca, Ms. D. Cudalb, and Mr. P. Lamberti is gratefully acknowledged. REFERENCES 1. De Gennes JL, Touraine R, Maunand B, Truffert J, Laudat P. Homozygous cutaneo-tendineous form of hypercholesterArtif Organs, Vol. 33, No. 12, 2009
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12. Stoffel W, Borberg H, Greve V. Application of specific extracorporeal removal of low-density lipoprotein in familial hypercholesterolemia. Lancet 1981;2:1005–7. 13. Thies K. Selective removal of low-density lipoproteins from plasma by polyacrylate-coated Fractogel in vitro and in experimental extracorporeal perfusion. Artif Organs 1988;12:320–4. 14. Pokrovsky SN, Adamova IY, Afanasieva O, Benevolenskaya GF. Immunosorbent for selective removal of lipoprotein (a) from human plasma: in vitro study. Artif Organs 1991;15:136– 40. 15. Pokrovsky S, Straube R, Afanasieva O, Kukharchuk V, Konovalov G. Lp(a) apheresis for the treatment of severe CHD patients with Lp(a) hyperlipidemia. Ther Apher Dial 2005;9:A40. 16. Bambauer R, Schiel R, Klinkmann J, Latza R. Low-density lipoprotein-apheresis in two patients with extremely elevated lipoprotein (a) levels. J Clin Apher 1998;11:78–80. 17. Schenck Ch, Keller S, Hailer S, Wolfram G, Zöllner N. Reduction of Lp(a) by different methods of plasma exchange. J Mol Med 1988;66:1197–201. 18. Journal of the American Heart Association. New Cholesterol Treatment Guidelines: ATP III Guideline Summary of Updates. Available at: http://www.nhlbi.nih.gov/new/press/0407-12.htm 19. Szczepiorkowski ZM, Bandarenko N, Kim HC. Guidelines on the use of therapeutic apheresis in clinical practice: evidencebased approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2007; 22:106–75. 20. Bláha M, Cermanová M, Bláha V, et al. Safety and tolerability of long lasting LDL-apheresis in familial hyperlipoproteinemia. Ther Apher Dial 2007;11:9–15.
