Lipid apheresis

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The apheresis (also: Lipoproteinapherese) is an extracorporeal blood purification process for the removal of LDL cholesterol and other factors of arteriosclerosis such as lipoprotein (a) and triglycerides from the blood. Lipid apheresis is used in various severe lipid metabolism disorders, especially in patients suffering from the homozygous form of familial hypercholesterolemia (HoFH), as these patients do not respond adequately to dietary and drug therapy to lower LDL cholesterol. Lipid apheresis is also indicated in patients with severe hypercholesterolemia in whom the LDL cholesterol cannot be sufficiently reduced with a maximum dietary and drug therapy documented for over twelve months. Furthermore, patients with isolated lipoprotein (a) elevation and LDL cholesterol in the normal range as well as progressive cardiovascular disease ( coronary heart disease , peripheral arterial occlusive disease , cerebrovascular disease ) documented clinically and by imaging methods are treated with lipid apheresis.

Procedure

Since the use of plasma exchange in 1974, six different methods of lipid apheresis have been developed, all of which are used in medical practice: heparin-induced extracorporeal LDL precipitation (HELP), lipid filtration, and dextran sulfate cellulose adsorption (DSA) Plasma, immunoadsorption (IA) and the two whole blood processes, dextran sulfate cellulose adsorption (lipid adsorption) and polyacrylate adsorption (direct adsorption of lipoproteins, DALI process). Various physicochemical blood-plasma-surface interactions as well as intraplasmic interactions take place in vivo, which lead to the elimination of a number of plasma proteins in all lipid apheresis processes. In addition to LDL cholesterol, the treatment with lipid apheresis also eliminates immunoglobulins , coagulation factors and HDL cholesterol to varying degrees . In the long term, however, an increase in HDL cholesterol and a simultaneous decrease in the LDL / HDL quotient can be observed.

Plasma therapy procedures

In the first step of plasma therapy procedures, a plasma separator is used to separate humoral blood components from cellular components, which are then immediately returned to the patient. In a second step, LDL cholesterol and other factors of arteriosclerosis such as lipoprotein (a) and triglycerides are removed from the plasma obtained . The plasma treated in this way is finally returned to the patient together with the cellular components.

Heparin-induced extracorporeal LDL precipitation, HELP method

The HELP process, developed in 1985, eliminates LDL cholesterol, lipoprotein (a) and fibrinogen from the plasma by precipitation at an acidic pH value (pH 5.12) in the presence of heparin . The blood plasma separated by means of a plasma filter is mixed with a mixture of sodium acetate buffer and heparin in a ratio of 1: 1 . The heparin-protein complexes precipitated in this way, which contain LDL cholesterol, lipoprotein (a) and fibrinogen, are then filtered off with a polycarbonate precipitation filter. The purified plasma finally passes through a polyanion exchanger ( DEAE cellulose ) to remove excess heparin and a dialyzer to remove the buffer before it is reinfused into the patient. Since the HELP procedure also reduces fibrinogen, it lowers blood viscosity and thus improves blood flow, particularly in the fine capillary vessels . Studies show the effectiveness in cardiovascular diseases.

According to a study, the HELP procedure has been used in the treatment of acute acute hearing loss since 2002 . Only patients with increased plasma fibrinogen levels above 295 mg / dl benefited significantly compared to standard therapy. There are no long-term reliable data on efficacy; the 2010 AWMF guideline on the treatment of acute acute hearing loss does not mention this method (an updated guideline is expected in 2014).

Temperature-optimized double filtration plasmapheresis, lipid filtration

Lipid filtration, which has been used in clinical practice for more than 20 years, is a size-selective filtration of high molecular weight plasma components. Technically, it is also known as temperature-optimized double filtration plasmapheresis (DFPP). In the first step, cellular components are separated from the blood plasma with a plasma separator. The plasma obtained in this way is fed through an upstream heater into the lipid filter, which retains high molecular substances such as LDL cholesterol, lipoprotein (a), fibrinogen and triglycerides. The basic principle here is a filtration depending on size, molar mass and geometry. Molecules and molecular complexes with a diameter of 25 to 40 nm are retained, while smaller molecules such as HDL cholesterol can theoretically pass the filter unhindered. The membrane of the filter is made of polyethylene . Filters with different pore sizes are available. The method has proven to be safe and well tolerated in clinical studies. The duration of treatment is around two hours, depending on the blood flow and plasma volume. The anticoagulation can be done with either heparin or citrate.

Double filtration plasmapheresis, Monet method

The Monet process developed later is essentially identical to lipid filtration; the membrane of the secondary filter in this process consists of polysulfone and the temperature of the blood plasma is not adjusted.

Dextran sulfate cellulose adsorption (DSA) from plasma, liposorber LA

Dextran sulfate is a negatively charged molecule on its surface that selectively binds positively charged molecules such as the Apo-B domain of LDL or VLDL cholesterol and lipoprotein (a). HDL cholesterol, which lacks this domain, is not adsorbed. In the case of dextran sulfate cellulose adsorption (DSA) from plasma, the solid blood components are first separated off using a plasma separator. The plasma is passed alternately over two small columns that contain dextran sulfate bound to cellulose beads and which bind lipoproteins containing apo-B by adsorption. After every 600 ml of treated plasma volume, a switch is made to the other column and the previous one is regenerated.

ApoB100 immunoadsorption, Therasorb process

The immune adsorption system for LDL apheresis consists of an adsorber with polyclonal apoprotein B antibodies from sheep, which are immobilized on Sepharose Cl-4B and adsorb the ApoB-containing lipoproteins LDL cholesterol and lipoprotein (a) from the plasma. Two immunoadsorption columns are used, which are regenerated several times during the treatment with acidic glycine solution while the other column is in operation. Because of the high costs of the adsorbers, they have to be reused, so that each patient receives their own pair of columns, which are regenerated after the treatment and stored at 4 ° C with the addition of sodium azide as a bacteriostat. Pyrogen tests are necessary before each use. The effectiveness of the columns decreases over time, on average approx. 50 treatments are possible per column pair.

Hemoperfusion procedure

In hemoperfusion or whole blood procedures, atherogenic substances are removed directly from the blood in the extracorporeal circuit with the aid of adsorbing substances that are in granulated form in an adsorber cartridge. The size of the adsorber cartridge must ensure a sufficient exchange surface and contact time of the adsorbent .

Polyacrylate adsorption, DALI process

The direct adsorption of LDL, VLDL cholesterol and lipoprotein (a) from whole blood is also possible with the DALI system (direct adsorption of lipoproteins) developed in 1996. The single-use adsorption cartridges contain negatively charged polyacrylate ligands that are immobilized on polymetacrylamide and electrostatically bind the atherogenic lipoproteins. Fibrinogen is only removed to a small extent (up to a maximum of 30%). DALI configurations of different capacities (500/750/1000/1250) are available. The anticoagulation is done with citrate. The system structure is also simple with the DALI system because there is no plasma separation and the treatment time is short. The simultaneous use of antihypertensive ACE inhibitors can lead to side effects (bradykinin release).

Dextran-Sulphate-Cellulose Adsorption (DSA), Liposorber DL

Based on the technology of the system for dextran sulfate cellulose adsorption from plasma, the Liposorber D system was developed, which enables the adsorption of LDL, VLDL cholesterol and lipoprotein (a) from whole blood. An essential advantage of the Liposorber D-System is the simple system structure by eliminating the plasma separation and the possibility of higher blood flows (up to 150 ml / min) with a shortening of the treatment time. The liposorber D is available in different adsorber volumes. The standard anticoagulant is citrate. Simultaneous use of antihypertensive ACE inhibitors is also contraindicated here.

Effectiveness of lipid apheresis

All methodical solutions for extracorporeal LDL apheresis meet the quality criterion required by the Federal Joint Committee of at least 60% lowering of LDL cholesterol per therapy session. Treatment is usually carried out weekly to two weeks. For all procedures it can be stated that they significantly improve the atherogenic lipid profile of the patient. LDL cholesterol is reduced by an average of 60-75%, within the LDL cholesterol there is also a relative decrease in the small, dense and particularly atherogenic LDL particles, whereas the HDL cholesterol is only removed to a small extent (average 6 up to 29%) and even increases in the course of regular treatments. HDL species with an inflammatory effect are reduced in the course of this. Lipid filtration and the HELP process also lower fibrinogen (on average 52 to 59%) and, due to their additional rheological effectiveness, can therefore be preferred for patients when fibrinogen is to be assessed as a major risk factor for overall morbidity. Fibrinogen is an independent risk factor for coronary heart disease and plays an important role in the pathogenesis of atherosclerosis. Lp (a) is lowered by all methods to a comparable extent to that of LDL cholesterol. By lowering the Lp (a) plasma level, the proportion of oxidized phospholipids is also preferably eliminated. Oxidized phospholipids are preferentially transported by Lp (a) in the plasma and contribute to its atherogenic and proinflammatory properties. A consistent lowering of lipoproteins in the plasma leads to an improvement in their cardiac prognosis and overall mortality in patients with coronary artery disease. For some of the patients with hereditary hypercholesterolemia in homozygous or severe heterozygous manifestations and a particularly serious cardiac prognosis, maximum drug therapy is also insufficient. For them, lipid apheresis is vital and life-extending. This applies equally to patients with increased Lp (a) and progressive coronary artery disease, in whom the LDL cholesterol is in the target range. In September 2013, a study on patients with lipoprotein (a)> 60 mg / dl reported significantly reduced event rates for arteriosclerotic events during the observation period of two years, e.g. T. over 80%. A follow-up of this study after five years showed the lasting effect of regular lipid apheresis. During this period, no renewed increase in cardiovascular events was found. As part of the Odyssey Escape study, drug therapy with the PCSK9 inhibitor alirocumab was able to reduce the frequency of lipid apheresis sessions in some of the patients in whom the lowering of LDL cholesterol was the main focus . A combination of lipid apheresis and PCSK9 inhibitors can be used in patients with severe familial hypercholesterolemia and correspondingly high LDL cholesterol. Lipoprotein (a) is only reduced to a small extent by PCSK9 inhibitors, so that lipid apheresis remains the only effective treatment option in patients with increased Lp (a).

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  1. ↑ H. Greten, W. Bleifeld, FU Beil et al .: LDL apheresis - a therapeutic method for severe hypercholesterolemia . In: Deutsches Ärzteblatt . 89, 1992, p. 48 f.
  2. ↑ SM Grundy, JI Cleeman, CN Merz, HB Brewer Jr., LT Clark, DB Hunninghake, RC Pasternak, SC Smith Jr., NJ Stone: National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines . In: Circulation . 110, 2004, pp. 227-239. PMID 15249516 .
  3. ↑ a b c G. R. Thompson and UK Heart: LDL Apheresis Working Group: Recommendations for the use of LDL apheresis . In: Atherosclerosis . 198, 2008, pp. 247-255. PMID 18371971 .
  4. ↑ GR Thompson, M. Barbir, D. Davies, P. Dobral, M. Gesinde, M. Livingston, P. Mandry, AD Marais, S. Matthews, C. Neuwirth, A. Pottle, C. le Roux, D. Scullard, C. Tyler, S. Watkins: Efficacy criteria and cholesterol targets for LDL apheresis . In: Atherosclerosis . Epub ahead of print, 2009. PMID 19589528 .
  5. ^ T. Eisenhauer, VW Armstrong, H. Wieland, C. Fuchs, K. Nebendahl, F. Scheler: Selective continuous elimination of low density lipoproteins (LDL) by heparin precipitation: first clinical application . In: Trans Am Soc Artif Intern Organs . 32, 1986, pp. 104-107. PMID 3778691 .
  6. ↑ JW Park, M. Merz, P. Braun: Effect of HELP-LDL-apheresis on outcomes in patients with advanced coronary atherosclerosis and severe hypercholesterolemia . In: Atherosclerosis . 139, 1998, pp. 401-409. PMID 9712348 .
  7. ^ WO Richter, MG Donner, P. Schwandt: Three low density lipoprotein apheresis techniques in treatment of patients with familial hypercholesterolemia: a long-term evaluation . In: Ther Apher . 3, 1999, pp. 203-208. PMID 10427616 .
  8. ↑ M. Suckfüll: Fibrinogen and LDL apheresis in treatment of sudden hearing loss: a randomized multicentre trial . In: The Lancet . 360, 2002, pp. 1811-1817. PMID 12480357 .
  9. ↑ AWMF guidelines for hearing loss 2014 , accessed on May 18, 2017
  10. ↑ U. Julius, W. Metzler, J. Pietzsch, T. Faßbender, R. Klingel: Intraindividual comparison of two extracorporeal LDL apheresis methods: Lipidfiltration and HELP . In: Int J Artif Organs . 25, 2002, pp. 1180-1188. PMID 12518963 .
  11. ↑ U. Julius, KG Parhofer, A. Heibges, S. Kurz, R. Klingel, HC Geiss: Dextran-Sulfate-Adsorption (DSA) of Atherosclerotic Lipoproteins from Whole Blood or Separated Plasma for Lipid-Apheresis - Comparison of Performance Characteristics with DALI and lipid filtration . In: J Clin Apher . 22, 2007, pp. 215-223. PMID 17455220 .
  12. ↑ U. Julius, W. Metzler, J. Pietzsch, T. Faßbender, R. Klingel: Intraindividual comparison of two extracorporeal LDL apheresis methods: Lipidfiltration and HELP . In: Int J Artif Organs . 25, 2002, pp. 1180-1188. PMID 12518963 .
  13. ↑ Kim JY, Park JS, Park JC, Kim ME, Nahm DH: Double-filtration plasmapheresis for the treatment of patients with recalcitrant atopic dermatitis. In: Ther Apher Dial. Band 17 , no. 6 , December 2013, p. 631-637 , PMID 24330559 .
  14. ↑ U. Julius, KG Parhofer, A. Heibges, S. Kurz, R. Klingel, HC Geiss: Dextran-Sulfate-Adsorption (DSA) of Atherosclerotic Lipoproteins from Whole Blood or Separated Plasma for Lipid-Apheresis - Comparison of Performance Characteristics with DALI and lipid filtration . In: J Clin Apher . 22, 2007, pp. 215-223. PMID 17455220 .
  15. ^ R. Nowack, G. Wiedemann: Pancytopenia with severe Thrombocytopenia in a patient treated with twice weekly LDL apheresis by polyacrylate adsorption from whole blood . In: J Clin Apher . 25, 2010, pp. 77-80. PMID 20101676 .
  16. ^ S. Schmaldienst, S. Banyai, TM Stulnig, G. Heinz, M. Jansen, WH Hörl, K. Derfler: Prospective randomized cross-over comparison of three LDL-apheresis systems in statin pretreated patients with familial hypercholesterolemia . In: Atherosclerosis . 151, 2000, pp. 493-499. PMID 10924726 .
  17. ↑ U. Julius, KG Parhofer, A. Heibges, S. Kurz, R. Klingel, HC Geiss: Dextran-Sulfate-Adsorption (DSA) of Atherosclerotic Lipoproteins from Whole Blood or Separated Plasma for Lipid-Apheresis - Comparison of Performance Characteristics with DALI and lipid filtration . In: J Clin Apher . 22, 2007, pp. 215-223. PMID 17455220 .
  18. ^ S. Banyai, J. Streicher, W. Strobl, H. Gabriel, M. Gottsauner-Wolf, M. Rohac, F. Weidinger, WH Hörl, K. Derfler: Therapeutic efficiency of lipoprotein (a) reduction by low-density lipoprotein immunoapheresis . In: Metabolism . 47, 1998, pp. 1058-1064. PMID 9751233 .
  19. Jump up ↑ H. Borberg, A. Gaczkowski, V. Hombach, K. Oette, W. Stoffel: Treatment of familial hypercholesterolemia by means of specific immunoadsorption . In: J Clin Apher . 4, 1988, pp. 59-65. PMID 3294230 .
  20. ↑ T. Bosch, B. Schmidt, W. Kleophas, V. Otto, W. Samtleben: LDL hemoperfusion - a new procedure for LDL apheresis: biocompatibility results from a first pilot study in hypercholesterolemic atherosclerosis patients . In: Artif Organs . 21, 1997, pp. 1060-1065. PMID 9335362 .
  21. ↑ M. Jansen, S. Banyai, S. Schmaldienst, A. Goldammer, M. Rohac, WH Hörl, K. Derfler: Direct adsorption of lipoproteins (DALI) from whole blood: first long-term clinical experience with a new LDL- apheresis system for the treatment of familial hypercholesterolemia . In: Wien Klin Wochenschr . 112, 2000, pp. 61-69. PMID 10703153 .
  22. ↑ C. Otto, P. Kern, R. Bambauer, S. Kallert, P. Schwandt, KG Parhofer: Efficacy and safety of a new whole-blood low-density lipoprotein apheresis system (Liposorber D) in severe hypercholesterolemia . In: Artif Organs . 27, 2003, pp. 1116-1122. PMID 14678426 .
  23. ↑ C. Otto, J. Berster, B. Otto, KG Parhofer: Effects of two whole blood systems (DALI and Liposorber D) for LDL apheresis on lipids and cardiovascular risk markers in severe hypercholesterolemia . In: J Clin Apher . 22, 2007, pp. 301-305. PMID 17935245 .
  24. ↑ BM Schamberger, HC Geiss, MM Ritter, P. Schwandt, KG Parhofer: Influence of LDL apheresis on LDL subtypes in patients with coronary heart disease and severe hyperlipoproteinemia . In: J Lipid Res . 41, 2000, pp. 727-733. PMID 10787433 .
  25. ↑ AA Kroon, WR Aegevaeren, T. van der Werf et al .: LDL-Apheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis . In: Circulation . 15, 1996, pp. 1826-1835. PMID 8635262 .
  26. ↑ P. Meier, E. Blanc: Long-term efficacy of lipoprotein apheresis in homozygous familial hypercholesterolemia . In: Nephrol Dial Transplant . 15, 2000, pp. 738-740. PMID 10809830 .
  27. ^ IO Opole, JM Belmont, A. Kumar, PM Moriarty: Effect of low-density lipoprotein apheresis on inflammatory and non-inflammatory high-density lipoprotein cholesterol . In: Am J Cardiol . 100, 2007, pp. 1416-1418. PMID 17950800 .
  28. ↑ U. Julius, W. Metzler, J. Pietzsch, T. Faßbender, R. Klingel: Intraindividual comparison of two extracorporeal LDL apheresis methods: Lipidfiltration and HELP . In: Int J Artif Organs . 25, 2002, pp. 1180-1188. PMID 12518963 .
  29. ↑ C. Bergmark, A. Dewan, A. Orsoni et al .: A novel function of lipoprotein (a) as a preferential carrier of oxidized phospholipids in human plasma . In: J Lipid Res . 49, 2008, pp. 2230-2239. PMID 18594118 .
  30. ↑ S. Kiechl, J. Willeit, M. Mayr et al .: Oxidized Phospholipids, Lipoprotein (a), Lipoprotein-Associated Phospholipase A2 Activity, and 10-Year Cardiovascular Outcomes. Prospective Results From the Bruneck Study . In: Arterioscler Thromb Vasc Biol . 27, 2007, pp. 1788-1795. PMID 17541022 .
  31. ↑ Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) . In: Lancet . 344, 1994, pp. 1383-1389. PMID 7968073 .
  32. ↑ J. Leebmann, E. Roeseler, U. Julius, F. Heigl, R. Spitthoever, D. Heutling, P. Breitenberger, W. Maerz, W. Lehmacher, A. Heibges, R. Klingel: Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein (a) -hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. In: Circulation. Volume 128, Number 24, December 2013, pp. 2567-2576, ISSN  1524-4539 . doi : 10.1161 / CIRCULATIONAHA.113.002432 . PMID 24056686 .
  33. ↑ The effectiveness of lipoprotein apheresis in study proves Deutsches Ärzteblatt | Volume 110 | Issue 49 | December 6, 2013 | Accessed March 29, 2016.
  34. ^ E. Roeseler, U. Julius, F. Heigl, R. Spitthoever, D. Heutling, P. Breitenberger, J. Leebmann, W. Lehmacher, PR Kamstrup, BG Nordestgaard, W. Maerz, A. Noureen, K. Schmidt , F. Kronenberg, A. Heibges, R. Klingel; Pro (a) LiFe-Study Group: Lipoprotein apheresis for lipoprotein (a) -associated cardiovascular disease: Prospective 5 years of follow-up and apolipoprotein (a) characterization. . In: Arterioscler Thromb Vasc Biol. . 36, No. 9, September 2016, pp. 2019–2027. doi : 10.1161 / ATVBAHA.116.307983 . PMID 27417585 .
  35. ↑ G-BA decision 2016 [1]
  36. ^ PM Moriarty, KG Parhofer, SP Babirak, MA Cornier, PB Duell, B. Hohenstein, J. Leebmann, W. Ramlow, V. Schettler, V. Simha, E. Steinhagen-Thiessen, PD Thompson, A. Vogt, B Von Stritzky, Y. Du, G. Manvelian: Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. In: European heart journal. Volume 37, number 48, December 2016, pp. 3588-3595, doi : 10.1093 / eurheartj / ehw388 , PMID 27572070 , PMC 5233802 (free full text).
  37. ↑ Spitthöver R, Röseler T, Julius U, Heigl F, Schettler VJJ, Kühn R, Leebmann J, Raabe A, Knittel M, Schürfeld C, Moesenthin M, Bernhardt WM, Röseler E, Ketteler M, Heibges A, Bell R: Real -world study: Escalating targeted lipid-lowering treatment with PCSK9-inhibitors and lipoprotein apheresis. In: J Clin Apher. tape 34 , no. 4 , August 2019, p. 423-433 , PMID 30817043 .