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Comparison of different Lp(a) Elimination Techniques:

A retrospective Evaluation

  H. Borberg

German Haemapheresis Centre

ESFH Congress Düsseldorf 2008

Correspondence to:
Prof. Dr. Dr. h.c. H. Borberg
Deutsches Hämapherese Zentrum
50825 KÖLN-Braunsfeld, Maarweg 165
Tel: +49-221-954235-0
Fax: +49-221-954235-95
Key words: Lp (a) apheresis, extracorporeal elimination, apheresis therapy, Lipoprotein a, Lp (a), Lp (a) treatment


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). 4 patients with selectively elevated Lp(a) and 8 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 20 - 40 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 litres of plas-ma 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 litres, 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 litres of plasma whereas if 5 litres 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.


Lipoprotein (a) is an LDL - like particle which was described as having an atherogenic [1,2,3, 4,5,6,7,8] and thrombogenic (9,10,11,12,13,14] potential. Whether Lp(a) increased the vascular risk only in combination with other risk factors such as increased LDL-cholesterol, low HDL-cholesterol, diabetes and others or could also be considered in a selective isoform as a genetically determined independent, isolated cause of atherogenesis [15,16,17,18,19,20, 21,22, 23,24,25,26,27] is under debate. Increased Lp (a) may be of pathogenetic importance for kidney diseases [27,28,29, 30,31,32,33,34], hypertension [35], diabetes [36, 37,38], stroke [39, 40] pulmonal hypertonia [41] and aneurismal disease [42].
With the development of Lp(a) - apheresis [43,44,45] the earlier claim, that there is "no treat-ment" for an elevated Lp(a) other than the elimination of additional risk factors is not valid any more. The term Lp(a) - apheresis should not be misused for other techniques also lowering Lp(a) (comparable to the confusion observed with the term LDL - apheresis). Procedures lowering both LDL - cholesterol and Lp(a) by 50 - 60 % may clinically not suffice as it may delay progression of atherogenesis rather than preventing it. Such prevention appears more likely to be obtained by Lp(a)-apheresis decrea-sing the pre-apheresis values about 80 - 90 % and obtaining post-treatment target values of 30 - 50 mg/dl with a better promise of optimal clinical efficacy. However, the rather rapid rebound needs to be taken into consideration.


Lipoprotein (a) or abbreviated Lp(a) may be considered as an inherited, genetically determined special form of low density lipoprotein, which may explain the atherogenic potential. However differences in structure are obvious, as it also has a structural relationship to plasminogen, which may lead to an interference with the coagulation cascade.
The molecule consists of a core of cholesterol, phospholipids and apolipoprotein B 100 (apo b) which is linked to apolipo-protein a (apo a), a high molecular weight glycoprotein. Apo a is synthesized in the liver cells, but it is assumed that the binding with the LDL particle is an extracellular process. The way the particle is segregated is hardly known. The presence of apo a explains why it differs from LDL-Cholesterol. Apo a presents as an external "cringle " (cringle = Danish brezel) which surrounds the apo B core to which it is bound by a disulfide bridge. Lp (a) is a very heterogenous particle (up to 30 iso-forms) of different densities and molecular weights. The cringle structure of apolipoprotein A is homologous to plasminogen and enables the interference with the coagulation cascade.


We evaluated retrospectively 4 patients with selectively elevated Lp(a) and premature atherosclerosis treated under the following conditions:

  • Initial range of Lp(a) between 80 - 120 mg/dl
  • Application of the same procedure for each patient
    (Lp(a)-apheresis, LDL-(immune) apheresis, secondary plasma filtration)
    whereas the processed plasma volume varied from 3,4 - 6 litres.

All patients had a severe premature atherosclerosis with advanced coronary heart disease.
Also 8 patients with a combination of familial hypercholesterolaemia and elevated Lp (a) ranging from 80 - 120 mg/dl Lp(a) prior to apheresis and suffering from advanced coronary heart disease were evaluated if treated under the same conditions but with LDL-(immune) apheresis, liposorption, whole blood perfusion and secondary filtration though using a different filter.
All treatments were performed at weekly intervals (except for one patient with a selectively elevated Lp (a) who is treated every two weeks) attempting to reach Lp (a) post - treatment values of 30 - 40 mg/dl, The rebound was estimated calculating the average values after the treatments and comparing them with the average pre-treatment values.


The results are shown in Table 1 for patients with a selectively elevated Lp (a) and in table 2 for patients with familial hypercholesterolaemia and an elevated Lp (a) as an additional risk factor. It is obvious that both immune apheresis procedures are most efficacious and as they can be re-used not only during the individual treatments but also from one treatment to the other for the same patient are most economic.
The rebound as drawn from these data is similar in both groups, however the divergence is considerable and more data may be necessary to obtain a more patient oriented individual insight.


The indication for the extracorporeal treatment of patients with a selectively elevated Lp(a) is under debate.
Lp(a) values exceeding the 75th percentile are at high risk for cardiovascular disease, demonstrated from studies such as PRIME, [46], ILSA [47] and others. This information is also supported from experimental data. As patients at high risk due to an elevated Lp(a), both as co- or independent risk factor, are with-out convincing drug therapy so far, extracorporeal elimination such as regular Lp(a) - aphe-re-sis is the therapy of choice and without alternative.
For all patients with a selectively elevated Lp(a) it is obligatory to eliminate additional risk factors such as smoking, hypertonia, obesity and others to be eliminated. However this is no treatment but prerequisite. As we have seen patients with selectively elevated Lp (a) values of more than 250 mg/dl without premature atherosclerosis we recommend that such patients remain under cardio- angiological control once per year but without treatment. If the development of premature atherosclerosis with clinical relevance can be demonstrated during the observation period, early treatment should be initiated even if no further risk factors can be found. It is beyond debate that patients characterised from a selectively elevated Lp (a) e.g. > 80 mg/dl, premature atherosclerosis without further risk factors and particularly if clinically symptomatic with an early vascular disease (e.g. myocardial infarction underneath 35 - 40 years of age) must be treated with Lp (a) apheresis.
For patients with familial hypercholesterolaemia in combination with elevated Lp (a) also no treatment alternative exists, after diet and cholesterol lowering medications have exhaustively been applied.
The thrombogenic potential if of clinical relevance for such patients may also be taken into consideration.
Whether the lack of controlled trials providing for final evidence of the clinical value of an extracorporeal elimination of Lp(a) in severely sick patients and patients at high coronary risk appears to be a formality for reimbursement or justifies Lp (a) apheresis with all consequences for the maintenance of an optimal quality of life and life expectancy may not only be considered as a problem of generalised consideration and bureaucratic formalism but needs also an individualised, thoughtful decision as an issue of medical ethics.
In analogy of our 26 years experience with the original LDL - apheresis and the survival of patients under optimal treatment conditions we favour post-treatment target values of 30 - 40 mg/dl rather than referring only to a decrease expressed in percentage as this approach appears to promise a better or even an optimal clinical efficacy. Nevertheless, if such percentage is taken as a measure it should exceed a decrease of at least 70 %. However, the rather rapid rebound needs also to be taken into consideration.
For patients with a selectively elevated Lp (a), the choice of the optimal treatment technique depends on the initial level of Lp (a). Lp (a) apheresis is the most potent elimination procedure which guarantees optimal post-treatment values, but needs the procession of higher plasma volumes, whereas other techniques such as plasma differential filtration eliminate other plasma components as well and have a limited capacity suitable for the treatment of patients with lower Lp(a) values (underneath 80 mg/dl).
FH patients with an additional elevated Lp (a) are more difficult to treat, as LDL-apheresis columns if used in a repetitive cycling approach may obtain optimal post-treatment values of LDL-cholesterol but only suboptimal post-treatment Lp (a) values. Thus technical considerations for an optimal decrease of both risk factors for the best treatment of these patients are necessary.
As 30 mg/dl are considered as "normal" one should consider this value as target for an optimal patient treatment rather than restricting oneself to a limited percentage of Lp(a) elimination (e.g. 60 %). The treatment should completely eliminate Lp (a) as the risk factor, if it is technically possible, to maintain, an optimal quality of life and halting the progress of premature atherosclerosis for an optimal survival.
This evaluation cannot replace a controlled trial, particularly as it restricts itself to a retrospective approach and the comparison of different treatment techniques. Also, it comprises only a limited number of comparable procedures. Nevertheless, it contributes to the selection of the most efficient and most economic elimination procedure.
Variations of the measurement procedures [48,49,50,51,52, 53] with new insights into the importance of the size heterogeneity together with other issues raised again discussions whether Lp (a) increased the vascular risk only in combination with other risk factors such as increased LDL-cholesterol, low HDL-cholesterol, diabetes and others or could also be considered as a genetically determined independent, isolated cause of atherogenesis. Such discussion is directly related to the indication for extracorporeal Lp(a) lowering therapy.
Numerous procedures have been applied to estimate the efficacy of extracorporeal cholesterol lowering therapy. The most convincing evidence is the survival of patients under long term treatment. Patients with selectively elevated Lp (a) are of special interest.
One of the 4 patients is now under regular therapy for 15 years without obvious signs of progression, whereas the other 3 patients are treated only for 1 -1/12 years so far and do not yet allow to draw any conclusion. Thus, a controlled trial using Lp (a) apheresis for patients with Lp (a) concentrations of more than 80 mg/dl is desirable. However, due to the complexity of the problem one should not underestimate the problems of designing such trial.


  1. Lp (a) - apheresis as developed from Prokovski at the National Academy of Medical Sciences at Moscow allows for the most efficient elimination with a decrease of at least 80 % of the pre-treatment Lp (a) level. However, due to the contents of apoprotein B Lp(a)-apheresis also eliminates LDL-cholesterol to some extent.
  2. LDL - apheresis (immune apheresis) and Liposorption appear to have a capacity of lowering about 76 % of the initial value in patients with both FH and elevated Lp (a).
  3. Filtration using the Kuraray LA 4 filter (in combination with centrifugal primary separation) allows for a decrease of 70 % whereas whole blood adsorption is limited to a decrease of only 65 %. However, it has to be taken into consideration, that plasma differential filtration is only semiselective, removing other high molecular plasma components (e.g. fibrinogen about 65% and total protein about 20 % of the pre-treatment value) together with Lp (a) and that the extent of treatment is limited from the loss of fibrinogen.
  4. The decrease of Lp (a) correlates with the plasma volume processed.
  5. As Lp (a) immune - apheresis uses repetitive cycling it allows for processing virtually indefinite volumes and due to the reuse it is most economic. Thus, it can be recommended for the treatment of Lp (a) values exceeding 80 mg/dl.
  6. A controlled trial applying Lp (a) apheresis to patients with Lp (a) values of more than 80 mg /dl is most desirable, as the data available so far strongly support the usefulness of extracorporeal Lp (a) lowering therapy in patients with selectively elevated Lp (a), whereas an improvement of the currently available technologies appears to be necessary for patients with familial hypercholesterolaemia (especially homozygous patients) and simultaneous Lp (a) levels beyond 100 mg/dl.


  1. Utermann G, Haibach C, Trommsdorff M, Kochl S, Lingenhel A, Abe A, Kraft HG
    Genetic architecture of the atherogenic lipoprotein(a).
    Ann N Y Acad Sci. 1995; 748: 301 - 312
  2. Kostner GM, Wo X, Frank S, Kostner K, Zimmermann R, Steyrer E
    Metabolism of Lp(a): assembly and excretion.
    Clin Genet. 1997; 52 (5): 347 - 354
  3. Ogorelkova M, Kraft HG, Ehnholm C, Utermann G
    Single nucleotide polymorphisms in exons of the apo(a) kringles IV types 6 to 10 domain affect Lp(a) plasma concentrations and have different patterns in Africans and Caucasians.
    Hum Mol Genet. 2001; 10 (8): 815 - 824.
  4. Kronenberg F, Steinmetz A, Kostner GM, Dieplinger H
    Lipoprotein(a) in health and disease.
    Crit Rev Clin Lab Sci. 1996; 33 (6): 495 - 543
  5. Kronenberg F, Kronenberg MF, Kiechl S, Trenkwalder E, Santer P, Oberhollenzer F, Egger G, Utermann G, Willeit J
    Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study.
    Circulation. 1999; 100 (11): 1154 - 1160
  6. Kraft HG, Lingenhel A, Raal FJ, Hohenegger M, Utermann G
    Lipoprotein(a) in homozygous familial hypercholesterolemia.
    Arterioscler Thromb Vasc Biol. 2000; 20 (2): 522 - 528
  7. Kostner KM, Kostner GM
    The Physiological Role of Lipoprotein (a).
    Drug News Perspect. 2002 Mar;15(2):69-77
  8. Kostner KM, Kostner GM
    Lipoprotein(a): still an enigma?
    Curr Opin Lipidol. 2002 Aug;13(4):391-6. Review
  9. Ignatescu M, Kostner K, Zorn G, Kneussl M, Maurer G, Lang IM, Huber K
    Plasma Lp(a) levels are increased in patients with chronic thromboembolic pulmonary hypertension.
    Thromb Haemost. 1998; 80 (2): 231 -232
  10. Christ G, Kostner K, Zehetgruber M, Binder BR, Gulba D, Huber K
    Plasmin activation system in restenosis: role in pathogenesis and clinical prediction?
    J Thromb Thrombolysis. 1999; 7 (3): 277 - 285
  11. Caplice NM, Panetta C, Peterson TE, Kleppe LS, Mueske CS, Kostner GM, Broze GJ Jr, Simari RD
    Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: A novel link between lipoproteins and thrombosis.
    Blood. 2001; 98 (10) : 2980 - 2987
  12. Buechler C, Ullrich H, Ritter M, Porsch-Oezcueruemez M, Lackner KJ, Barlage S, Friedrich SO, Kostner GM, Schmitz G
    Lipoprotein (a) up-regulates the expression of the plasminogen activator inhibitor 2 in human blood monocytes.
    Blood. 2001; 97 (4): 981 - 986
  13. Milionis HJ, Elisaf MS, Mikhailidis DP
    The effects of lipid-regulating therapy on haemostatic parameters.
    Curr Pharm Des. 2003;9(29):2425-43
  14. Marcucci R, Liotta AA, Cellai AP, Rogolino A, Gori AM, Giusti B, Poli D, Fedi S, Abbate R, Prisco D
    Increased plasma levels of lipoprotein(a) and the risk of idiopathic and recurrent venous thromboembolism.
    Am J Med. 2003 Dec 1;115(8):601-5
  15. Hoefler G, Harnoncourt F, Paschke E, Mirtl W, Pfeiffer H, Kostner GM
    Lipoprotein Lp(a). A rsik factor for myocardial infarction.
    Arteriosclerosis 1988; 8 ( 4 ): 398 - 401
  16. Sandkamp M, Funke H, Schulte H, Kohler E, Assmann G
    Lipoprotein (a) is an independent risk factor for myocardial infarction at a young age.
    Clin Chem 1990; 36 (1): 20 - 23
  17. Watts GF, Kearney EM, Taub NA Slavin BM
    Lipoprotein (a) as an independent risk factor for myocardial infarction in patients with common hypercholesteroaemia
    J. Clin Pathol. 1993; 46 (3): 267 - 70
  18. Cantin B, Gagnon F, Moorjani S, Despres JP, Lamarche B, Lupien PJ, Dagenais DR
    Is lipoprotein (a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study.
    J Am Coll Cardiool 1998; 32 (4): 1132 - 1134
  19. Dahlen GH, Stenlund H
    Lp(a) lipoprotein is a major risk factor for cardiovascular disease:Pathogenic mechanisms and clinical significance.
    Clin Genet 1997; 562 ( 5 ): 272 - 280
  20. Bostom AG, Cupples LA, Jenner JL, Ordovas JM, Seman LJ, Wilson PW, Schaefer EJ, Castelli WP
    Elevated plasma lipoprotein (a) and coronary heart disease in men aged 55 years and younger. A prospective study.
    JAMA 1996; 276 ( 7 ):544 - 548
  21. Fujino A, Watanabe T, Kunii H, Yamaguch N, Yoshinari K, Watanabe Y, Mutou M, Ishikawa S, Ogyuu A, Ashikawa K, Maruyama Y
    Lipoprotein (a) is a potential coronary risk factor
    Jpn Circ J 2000; 64 ( 1): 51 - 56
  22. Hopkins PN, Hunt SC, Sachreiner PJ, Eckfeldt JH, Borecki IB, Ellison CR, Williams RR, Siegmund KD
    Lipoprotein (a) interactions with lipid and non-lipid risk factors in patients with early onset coronary artery disease: Results from the NHLBI Family Heart Study.
    Atherosclerosis 1998; 141 ( 2 ): 333 - 345
  23. Lingenhel A, Kraft HG, Kotze M, Peeters AV, Kronenberg F, Kruse R,Utermann G
    Concentrations of the atherogenic Lp(a) are elevated in FH.
    Eur J Hum Genet. 1998 Jan;6(1):50-60
  24. Adlouni A, el Messal M, Ghalim N, Saile R
    Apolipoproteins and lipoprotein particles in Moroccan patients with previous myocardial infarction.
    Int J Clin Lab Res 1997; 27 ( 4 ): 247 -252
  25. Von Eckardstein A, Schulte H, Cullen P, Assmann G
    Lipoprotein (a) further increases the risk of coronary events in men with high global cardiovascular risk.
    J Am Coll Cardiol 2001; 37 ( 2 ):434 - 439
  26. Price JF, Lee AJ, Rumley A, Lowe DG, Fowkes FG
    Lipoprotein (a) and development of intermittent claudication and major cardiovascular events in men and Women: The Edinburgh Artery Study
    Atherosclerosis 2001; 157 (1): 241 - 249
  27. Cantin B, Despres JP, Lamarche B, Moorjani S, Lupien PJ, Bogaty P, Bergeron J, Dagenais GR
    Association of fibrinogen and lipoprotein (a) as a coronary heart disease risk factor in men (The Quebec Cardiovascular Study)
    Am J Cardiol 2002; 89 ( 6 ): 662 - 666
  28. Kronenberg F, Konig P, Neyer U, Auinger M, Pribasnig A, Lang U, Reitinger J, Pinter G, Utermann G, Dieplinger H
    Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
    J Am Soc Nephrol. 1995 Jul;6(1):110-20.
  29. Kronenberg F, Utermann G, Dieplinger H
    Lipoprotein (a) in renal disease.
    Am J Kidney Dis. 1996; 27 (1): 1 - 25
  30. Kronenberg F, Trenkwalder E, Lingenhel A, Friedrich G, Lhotta K, Schober M, Moes N, Konig P, Utermann G, Dieplinger H
    Renovascular arteriovenous differences in Lp[a] plasma concentrations suggest removal of Lp[a] from the renal circulation.
    J Lipid Res. 1997 Sep;38(9):1755-63
  31. Kronenberg F, Trenkwalder E, Sturm W, Kathrein H, Konig P, Neyer U, Grochenig E, Utermann G, Dieplinger H
    LDL-unbound apolipoprotein(a) and carotid atherosclerosis in hemodialysis patients.
    Clin Genet. 1997; 52 (5): 377 - 386
  32. Kostner, KM, Jansen M, Maurer G, Derfler K
    LDL-apheresis significantly reduces urinary apo(a) excretion.
    Eur J Clin Invest. 1997; 27 (1): 93 - 95.
  33. Kostner, KM, Clodi M, Bodlaj G, Watschinger B, Horl W, Derfler K, Huber K
    Decreased urinary apolipoprotein (a) excretion in patients with impaired renal function.
    Eur J Clin Invest. 1998 Jun;28(6):447-52
  34. Kerschdorfer L, Konig P, Neyer U, Bosmuller C, Lhotta K, Auinger M, Hohenegger M, Riegler P, Margreiter R, Utermann G, Dieplinger H, Kronenberg F
    Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.
    Atherosclerosis. 1999; 144 (2): 381 - 391
  35. Cauza E, Kletzmaier J, Bodlaj G, Dunky A, Herrmann W, Kostner K
    Relationship of non-LDL-bound apo(a), urinary apo(a) fragments and plasma Lp(a) in patients with impaired renal function.
    Nephrol Dial Transplant. 2003; 18 (8): 1568 - 1572
  36. Sechi LA, Kronenberg F, De Carli S, Falleti E, Zingaro L, Catena C, Utermann G, Bartoli E
    Association of serum lipoprotein(a) levels and apolipoprotein(a) size polymorphism with targetorgan damage in arterial hypertension.
    JAMA. 1997; 277 (21): 1689 -1695.
  37. Shi H, Fang J, Yang X, Shen Z, Zhu X
    Lipoprotein (a) concentration and apolipoprotein (a) phenotype in subjects with type 2 diabetes mellitus.
    Chin Med J 1998; 111 (11): 1013 - 1017
  38. Kronenberg F, Auinger M, Trenkwalder E, Irsigler K, Utermann G, Dieplinger H
    Is apolipoprotein(a) a susceptibility gene for type I diabetes mellitus and related to longterm survival?
    Diabetologia. 1999; 42 (8): 1021 - 1024
  39. Labudovic DD, Toseska KN, Alabakovska SB, Todorova, B
    Apoprotein(a) phenotypes and plasma lipoprotein(a) concentration in patients with diabetes mellitus.
    Clin Biochem. 2003 Oct;36(7):545-51
  40. Christopher R, Kailasanatha KM, Nagaraja D, Tripathi M
    Case-control study of serum lipoprotein (a) and apolipoproteins A-I and B in stroke in the young.
    Acta Neurol Scan 1996; 94 ( 2 ): 127 - 130
  41. Cao GF, Yang QD, Liu YH, Xu HW, Xia J
    Lipoprotein (a) and cerebral infarction in young adults
    Zhonghua Liu Xing Bing Xue Za Zhi 2003; 24 ( 5 ): 397 - 400
  42. Ignatescu M, Kostner K, Zorn G, Kneussl M, Maurer G, Lang IM, Huber K
    Plasma Lp(a) levels are increased in patients with chronic thromboembolic pulmonary hypertension.
    Thromb Haemost. 1998; 80 (2): 231 -232
  43. Schillinger M, Domanovits H, Ignatescu M, Exner M, Bayegan K, Sedivy R, Polterauer P, Laggner AN, Minar E, Kostner K
    Lipoprotein (a) in patients with aortic aneurysmal disease.
    J Vasc Surg. 2002; 36 (1): 25 - 30.
  44. Pokrovsky SN, Adamova IYu, Afanasieva OY, Benevolenskaya GF
    Immunosorbent for selective removal of lipoprotein (a) from human plasma: in vitro study.
    Artif Organs. 1991; 15 (2): 136 - 140
  45. Pokrovsky SN, Sussekov AV, Afanasieva OI, Adamova IY, Lyakishev AA, Kukharchuk VV
    Extracorporeal immunoadsorption for the specific removal of lipoprotein (a) (Lp(a) apheresis): preliminary clinical data.
    Chem Phys Lipids. 1994; 67 - 68: 323 - 330
  46. Pokrovsky SN, Ezhov MV, Il'ina LN, Afanasieva OI, Sinitsyn VY, Shiriaev AA, Akchurin RS
    Association of lipoprotein(a) excess with early vein graft occlusions in middle-aged men undergoing coronary artery bypass surgery.
    J Thorac Cardiovasc Surg. 2003; 126 (4): 1071 - 1075
  47. Luc G, Bard JM, Arveiler D, Ferrieres J, Evans A, Amouyel P, Fruchart JC, Ducimetiere, P
    PRIME Study Group Lipoprotein (a) as an predictor of coronary heart disease: The Prime Study
    Atherosclerosis 2002; 163 ( 2 ): 377 - 384
  48. Solfrizzi V, Panza F, Colacicco AM, Capurso D, D'Introno A, Torres F, Baldassare G, Capurso A
    Relation of lipoprotein (a) as coronary risk factor to type 2 diabetes mellitus and lowdensity lipoprotein cholesterol in patients > or = 65 years of age (The Italian Longitudinal Study on Aging, ILSA)
    Am J Cardiol 2002; 89 ( 7 ):825 - 829
  49. Kostner GM, Steinmetz A
    Standardization of Lp(a) measurements.
    Clin Genet. 1997; 52 (5): 393 - 397
  50. Kostner GM, Ibovnik A, Holzer H, Grillhofe H
    Preparation of a stable fresh frozen primary lipoprotein[a] (Lp[a]) standard.
    J Lipid Res. 1999; 40 (12): 2255 - 2263
  51. Tate JR, Rifai N, Berg K, Couderc R, Dati F, Kostner GM, Sakurabayashi I, Steinmetz A
    International Federation of Clinical Chemistry standardization project for the measurement of lipoprotein (a). Phase I. Evaluation of the analytical performance of lipoprotein (a) assay systems and commercial calibrators.
    Clin Chem. 1998 ; 44 (8 Pt 1):1629 - 1640
  52. Tate JR, Berg K, Couderc R, Dati F, Kostner GM, Marcovina SM, Rifai N, Sakurabayashi I, Steinmetz A
    International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Standardization Project for the Measurement of Lipoprotein(a). Phase 2: selection and properties of a proposed secondary reference material for lipoprotein (a).
    Clin Chem Lab Med. 1999; 37 (10): 949 - 958.
  53. Scholtz CL, Lingenhel A, Hillermann R, Stander IA, Kriek JA, Marais MP, Odendaal HJ, Kraft HG, Utermann G, Kotze MJ
    Lipoprotein (a) determination and risk of cardiovascular disease in South African patients with familial hypercholesterolaemia.
    S Afr Med J. 2000 Apr;90(4):374-8.
  54. Seed M, Ayres KL, Humphries SE, Miller GJ
    Lipoprotein (a) as a predictor of myocardial infarction in middle-aged men Am J Med 2001; 110 ( 1 ): 71 - 72

Table 1: Maximal decrease in patients with selectively elevated Lp (a) under apheresis therapy: Comparison of different technologies (Range of Lp (a) prior to treatment: 80 - 120 mg/dl; target value: 30 mg / dl)

Treatments Volume Decrease
  (N) processed mg/dl %
Lp (a) Apheresis
14 6 L 79 - 80 81 - 90
  60 5 L 73 - 83 79
  8 4 L 65 69
5 6 L 79 71
9 5 L 54 60
(Kuraray LA 4)
38 3,4 L 69 75

The rebound of these patients was in a range of 10 - 18 mg/dl per day

Table 2: Maximal Decrease of Lp(a) under apheresis therapy in patients with familial hypercholesterolaemia and elevated Lp(a): Comparison of different technologies (Range of Lp(a) before treatment: 80 - 120 mg/dl; target value: 30 mg / dl)

Maximal Decrease
Total Cholesterol
Maximal Decrease
8 6 72 82
(Immuneaph. P)
24 5 47 - 51 42 - 76
17 4 67 - 109 66 - 71
(Immuneaph. M)
6 5 51 56
6 6,5 120 72
5 6 77 63
21 5 65 77
14 4 54 69
Whole Blood
8 5 56 65
7 3,5 133 34
(Kuraray LA 5)
9 3,2 - 3,6 53 53
(Kuraray LA 4)
9 3,5 42 64

The rebound was figured to be in a range of 8 - 17 mg/dl per day

25 Years
LDL - Apheresis

Review of Experience


H. Borberg

German Haemapheresis Centre

Presentation of a Symposium
in honour of Prof. Kurt Oette

Cologne Germany

Correspondence to:
Prof. Dr. Dr. h.c. H. Borberg, Deutsches Hämapherese Zentrum
50825 KÖLN-Braunsfeld, Maarweg 165
Tel: +49-221-954235-0 Fax: +49-221-954235-95 E-Mail:


In 1981, when LDL (Low Density Lipoprotein)-Apheresis was introduced, it was already well established, that an eliminated LDL-cholesterol was a risk factor of the primary order for the development of atherosclerosis. It was thus obvious, that a decrease of the plasma cholesterol should also lead to a risk reduction for the corresponding patients. The efforts for a decrease of the eliminated plasma cholesterol and thus the reduction of risk developed into two directions, the decrease of LDL-cholesterol using diet and drugs and also the decrease using extracorporeal treatments. Both approaches were successful.

The first attempts to decrease plasma cholesterol applying extracorporeal procedures prior to the introduction of LDL-Apheresis were initiated from DeGennes in Paris (14) applying single plasma exchange therapies in 1996. Lupien was the first to use in 1976 therapeutic affinity chromatography applying Heparin as ligand (24). The first systematic investigation was applied from Thompson in England (36), who using regular plasma exchange therapy demonstrated, that the survival of the treated as compared to the untreated siblings with homozygous familiar hypercholesterolaemia (FH) was prolonged.

With the development of double filtration investigations were later on also applied in Japan to demonstrate, that this treatment approach would lead to a decrease of elevated LDL-cholesterol.

All unspecific or semi-selective extracorporeal procedures had in common, that they could decrease the LDL-cholesterol, however, the efficacy was limited. Thus the elevated LDL-cholesterol remained elevated after the treatment and a risk factor, which could not sufficiently be reduced.

Definition of LDL-Apheresis

LDL-Apheresis is defined as the immune specific extracorporeal LDL-Elimination using repetitive-cycling adsorption and deseorption applying continuous blood flow (therapeutic affinity chromatography).

The definition originated from Prof. Arens, Rockefeller University, New York, in 1982.

The technique of LDL-Apheresis consists of a centrifugal continuous flow separation of blood cells from the plasma and also with a simultaneous continuous flow secondary separation of plasma using adsorption columns (8,9,10). The systems are shown in figures 1 and 2.

Fig. 1 Fig. 2
Primary separation systemSecondary separation system

The principal of therapeutic infinity chromatography as applied for immune apheresis for the specific elimination of LDL-cholesterol (34,35) is shown in figure 3. Apolipoprotein B (Apo B) containing particles are independent from their size or consistency bound to polyclonal or monoclonal sheep antibody to an adsorber perfused from the separated plasma and sub-sequently eliminated. Repetetive-cycling adsorption and desorption permits to decrease at least 80 % of the initial pre-treatment value and thus differs from other technologies, which also may eliminate LDL-cholesterol among other plasma proteins.


Secondary Separation using therapeutic Affinity Chromatography

Carrier material + Ligand = Adsorption
(Sepharose) (Sheep antibody against
Apolipoprotein B)
(of Apo-B containing Particles
e.g. LDL-Cholesterol) *

* Other Apoprotein B containing particles: VLDL = Very low density lipoprotein,
IDL = Intermediate density lipoproteins, Lp(a) = Lipoprotein (a)
Fig. 3

The technique of LDL-Apheresis was often copied, modified and claimed to be optimised - without success. The name was and is permanently copied from so named "me-too-technolo-gies", the more frequently, the more disadvantages such "new" devices demonstrate. Thus, frequently blood purification procedures, which among other plasmatic substrates also eliminate cholesterol in a more or less moderate extent are nowadays incorrectly named "LDL-Apheresis" for economical reasons to imitate a none existent efficiency of LDL-cholesterol depletion. We left some of them already left in 1983 - 1984 during our own development, however, there are still sold as "modern" and "progressive" due to a skilled and aggressive marketing. The misuse of terminology leads to misunderstanding.

The following review of our own experience applies the term LDL-Apheresis exclusively to the original definition.

Summary of achievements during the period of 1981 - 2007

  • Up to 2007 more than 60.000 treatments were performed in Cologne, world-wide more than 400.000
  • the therapies were performed as outpatient treatments

  • so far no severe side effects were seen (at present approximately 4 % of minor undesired reactions) especially

    • no anaphylactic shocks
    • no transfer of any patient into a hospital as complication of any of the treatments
    • no artificial excess to the circulation necessary, even under long term therapy (according to our experience in apheresis an artificial excess to circulation is not necessary, thus avoiding the associated complications e.g. due to shunts which, under these circumstances, may well be considered as medical malpractice).
  • extension from originally 10 homozygous FH-patients to an increasing number of heterozygous patients without treatment alternative (more than 30 patients currently being treated in Cologne)
  • improvement or maintenance of the quality of life
  • (e.g. decrease of the number or severity of angina pectoris attacks up to their complete elimination
  • a prevention or delay of cardiological or cardiosurgical interventions (PTCA or bypass surgery) depending on the compliance of the patients or the existence of additional risk factors for instance LP(a)
    • positive influence on morphological - clinical parameters
    • in general complete regression of xanthomaes, xanthelasmae
    • regression (as shown by radiological procedures) of coronary heart disease in young patients of high risk (up to at least 18 years of age, probably up to a higher age)
    • secondary prevention (delay of progression and under optimal target values also a hold of progression) in the elderly
    • primary prevention up to 18 years of age possible
  • prolongation of life expectancy substantially in homozygous patients (so far no athero-sclerosis related death in 25 years)
  • corresponding experience also with heterozygous patients according to the current data and experience
  • impressive survival of patients with end-stage-disease
  • transfer of the technological principal of therapeutic affinity chromatography to other applications(e.g. Digoxin-, Ig-, Lp(a)-Apheresis).

Survival as proof of efficacy

Imaging morphology of atherosclerotic alterations in the vessel walls is mainly used to prove the efficacy of LDL-cholesterol lowering treatments. However, these diagnostic procedures are either of qualitative or if an appropriate standardisation is used, of semiquantitative nature only. Trials, especially with cholesterol decreasing medications, which demonstrate among others mainly the slow down of angiographical progression or the measurement of the carotis-media-intima-thickness may also support the value of other examinations, but suffer from disadvantages unless they do not include other parameters.

In contrast the prolongation of survival is the most efficient proof of the efficacy of LDL-Apheresis. Table 1 shows the total of the homozygous FH-patients treated in Cologne. It is obvious, that none of the patients died from premature atherosclerosis.

Table 1
in homozygous patients with familial hypercholesterolaemia

Age of death Period of
Result of
Total memeber of patients 10
Cause of death - after surgery 1 16 y 8 month ?
- suicide 1 30 y 18 years regression
- neoplasia 1 47 y 20 years 2 prevention
Removed 1 - 6 years 2 prevention
Currently under treatment 6 (s. Tab. 2)

NOTE: No death due to coronary heart disease in 25 years !

The patient who died after surgery was the first homozygous FH-patient treated with LDL-Apheresis in 1981. German surgeons rejected bypass-surgery in this patient due to his extremely progressed state of atherosclerosis. The subsequently performed bypass-surgery in the USA led to the predicted death after surgery. The surgical procedure was justified according to the state of the heart in 1981, however, being and according to our current experience LDL-Apheresis would have led most likely to a complete regression of his cholesterol deposits.

Another 30 years old homozygous patient suffered from severe social problems which finally lead him commit suicide. The initially existing coronary heart disease was be completely regressed.

Another 47 years old homozygous patient died from mammary carcinoma. The coronary status showed no progress of the cholesterol deposits and at death the patient was free from angina pectoris or other cardiac symptoms.

The last patient of table 1 could not be treated furthermore as she moved to a different location far from Cologne.

A total of 6 homozygous patients remain currently under treatment with LDL-Apheresis (Table 2).

Patient No.1 is homozygous. With a treatment period of 26 years she underwent the longest treatment period. The initial value of total cholesterol without treatment was 760 mg/dl combined with a low HDL-cholesterol of 30 mg/dl and a considerable elevation of LP(a) of 158 mg/dl. The first treatment began at an age of 13 years. In 2007 her age is now 39 years, which means, that if one refers to an approximate survival of these patients of 23 years according to Goldstein and Brown her prolongation of life is 16 years. The typical changes seen at the start of therapy such as coronary angiographic proven plaques, extreme xanthomas of the elbows and the Achilles tendons as well as smaller xanthomas of the tendons of both hands disappeared related to their size after 1 - 4 years. As the patient was free from symptoms and gave birth twice without complication her compliance decreased over time. In addition she started smoking and developed a diffuse coronary sclerosis, and extended sclerosis of both carotid arteries on either side though without stenosis yet. She finally developed coronary heart disease, which after 22 years was treated with a triple bypass surgery (triple bypass) including an aortic valve replacement. At present the patient is again without symptoms leading a normal life, however, her compliance is decreasing again. It is obvious that for this patient the additional risk factors such as decreasing compliance, cigarette smoking, low HDL-cholesterol, high LP(a), weight beyond a body mass index of 25 and lack of physical activity are at least as important as the suboptimal post-treatment LDL-cholesterol due to her limited compliance.

Patient No. 2 is treated for 23 years. Her initial total cholesterol without treatment was 758 mg/dl. The first treatment was initiation at an age of 20 years. At this age she had no morphological alterations of her coronaries, however, xanthomas in the Achilles' tendons, She was thus treated for primary prevention. After 12 years of LDL-Apheresis an replacement of the aortic valve was necessary. Her compliance is excellent and with an age of 44 years she survived 21 years longer than the reference mentioned before, has a normal quality of life and works full time as an interpreter. An LP(a) of 50 mg/dl is a moderate additional risk factor.

Patient No. 3 is treated for 22 years. The initiation total cholesterol without treatment was 960 mg/dl. At an age of 14 years, prior to the initiation of LDL-Apheresis, she had to undergo bypass surgery (triple bypass). The extended plaques shown prior to her first treatments in the coronaries (e.g. 50 % stenosis within the other RCA, 50 % RIVA)-stenosis could subsequently completely eliminated. However, over time this patient who emigrated from a different cultural area developed serious social problems, which could have caused serious depressions and made psychiatric treatment necessary. Her compliance thus decreased considerably. Also cigarette smoking played a temporary additional pathogenic role as well as difficulties in the treatment of her hypertonia. A rather low HDL-cholesterol of 30 mg/dl appears to be another risk factor. She thus needed aortic valve replacement at an age of 22 years combined with additional bypass surgery. At present the situation is stabile, however, due to the labile basic situation continuous stability cannot be guaranteed.

Patient No. 4 undergoes LDL-Apheresis for 22 years. The diagnosis originated in 1975 with a total cholesterol of more than 900 mg/dl. In 1983, prior to the apheresis therapy, bypass surgery and replacement of the aortic valve were performed. The treatment was not initiated in the German Haemapheresis Centre and initially performed without regular intervals. After the patient was transferred to the German Haemapheresis Centre in 1988 she is well under control, compliant and the average total cholesterol prior to apheresis is 304 mg/dl, the average values in between the therapies 206 mg/dl and the target values after LDL-Apheresis are at an average 102 mg/dl. The patient is now 60 years old, without progression, asymptomatic and works full time. Her heterozygous sister being 2 years younger living in another city was treated with cholesterol lowering medication, however, the necessary target values could not be obtained. She refused apheresis therapy and died recently from myocardial infarction.

Patient No. 5 is treated since 14 years. The initial value without treatment was 752 mg/dl total cholesterol. The first treatment began at an age of 22 years. The initial xanthomas at the elbows and knees disappeared after 1 year of treatment. The patient who suffered earlier from another disease has considerable social problems and in spite of extreme efforts of several physicians, the treating nurses and his family members to stimulate him to maintain a better compliance, he remained with a very limited compliance. Progression of his coronary heart disease can be anticipated. Already after one year of apheresis a PTCA was necessary. In 1998 the aortic valve in combination with bypass surgery had to be replaced. The unsatisfactory compliance is accompanied with a low HDL-cholesterol as an additional risk factor. Nevertheless, he survived so far for 13 years above the age of 23 years.

Patient No. 6 entered into the treatment at an age of 8 years with a total cholesterol of 1600 mg/dl prior to the initiation of the therapy. Xanthomas of the Achilles' tendons an the initial visible xanthomas of the knees and the elbows could be eliminated after regular treatment of several years. A 50 % stenosis of the right coronary artery shown to be present prior to the initiation of apheresis regressed completely. Due to a relative reliable compliance the prognosis appears to be good after she by now was treated for 14 years. She exceeded the reference age of 23 years already for one year. She is occasionally anaemic due to a lack of iron and the refusal of oral iron substitution and the intolerance of intra-venous iron substitution. A moderate stenosis of the aortic valve already prior to the first treatment is slowly progressing. The patient just married and is pregnant. So far the pregnancy is without any problems.

Table 2

Results of long-term - LDL - Apheresis
of homozygous Patients with Familial Hypercholesterolaemia

Patient Date of
Years under
Status of the coronary heart disease Age
1. 1968 26 Initial regression, now progression
(due to additional risk factors)
2. 1963 23 Primary prevention + 44
3. 1970 23 Partial regression, now progress ** 37
4. 1947 22 Secondary prevention* 60
5. 1971 14 Secondary prevention**(Progress expected) 36
6. 1983 14 Complete regression 24
Average age 40

Average age of death (according to Goldstein & Brown) for receptor negative 11, receptor defective 23 years + though with aortic valve replacement * according to clinical criteria ** under unsatisfactory cholesterol depletion

The prolongation of survival in heterozygous FH-patients under LDL-Apheresis therapy is more difficult to estimate as the initial diagnosis, the severity of the disease and the need for indication of LDL-Apheresis are by far more heterogeneous as compared to homozygous FH-patients. Also in at least some of the heterozygous FH-patients cholesterol lowering drugs or drug combinations can be applied though in relatively low dosages after individual dorsage testing.

Table 3

Average Age of heterozygous Patients
under longterm LDL - Immuneapheresis

Period of time* Age ( years) Number of patients
1981 - 1983* 33,3
( 11 - 57 )
2007 59,6
( 37 - 76 )

             * At start of apheresis
             The earlier treatments 1981 - 1982 were performed with suboptimal technology
as being still under deveolepment.

Table 4

Survival of heterozygous Patients with END-STAGE-DISEASE
Under long-termn LDL - APHERESIS
(with insuffizient response or side effects and cholesterol lowering drug therapy)
Gender Apheresis time Age Current status **
1.  ♀ 21 Years 66 At present normal quality of life
2.  ♂ 19 Years 69 Age related quality of life
3. ♀  * 9 Years 70 Quality of life still reduced
4. ♀ 8 Years 67 Quality of life still diminuished

* Type III with extremely elevated Lp(a)

_____** 1.5.2007 _____

The results of LDL-Apheresis for the treatment of patients with end-stage-disease may also be of considerable interest.

Patient No. 1 suffered 26 years ago from a first myocardial infarction which she survived.

A second infarction 20 years ago needed resuscitation. Due to the limited efficacy of cholesterol lowering therapy and also due to the high risk in a stage of progressed coronary 3 vessel disease LDL-Apheresis was initiated. The initial angina pectoris symptoms decreased over time and were finally completely eliminated. Xanthomas of the Achilles' tendons regressed completely. All her relatives suffering from familial hypercholesterolaemia died from myocardial infarction. The patient is fully compliant and is under regular treatment at weekly intervals. Our standard post-treatment target values are always obtained. Her quality of life is well and her exercise ECG is normal. However, a strongly elevated LP(a) of a maximal pretreatment value of 205 mg/dl provides for an additional risk factor. The HDL-cholesterol of the patient is at a low normal range. Cigarette smoking was decreased, another but is still another risk factor though at a lower level. In addition to her coronary heart disease the patient suffers from a peripheral arterial occlusion stadium with y-prothesis IIb and plaques in the aorta and the right lower limp. Atherosclerosis plaques in the carotid arteries are so far without clinical relevance.

Patient No 2 was according to cardiological judgement without treatment alternative suffering from several myocardial infarctions, quadruple bypass, occlusion of both carotis interna arteries, peripheral arterial occlusion disease, perfusion problems of the brain, ischaemic opticopathy, hearing loss, tinnitus and other signs of a diffuse progressed athero-sclerosis. He suffered from frequent angina pectoris at rest and could not perform any kind of physical exercise. An exercise ECG was impossible to perform. An increased LP(a) of 79 mg/dl and a low HDL-cholesterol of 32 mg/dl presented as additional risk factors. Following a period of continuous improvement which allowed a moderate physical challenge he suffers from moderate deterioration, which at an age of 69 years can also be interpreted as age dependent.

Patient No. 3 (Diagnosis Type III-IV according to Fredrickson with an apolipoprotein E2/E2 gene variant) suffers from an extended coronary 3 vessel disease. Several stents were applied as well as 2 bypass operations and an attempt of transmyocardial laser re-vascularisation. According to the treating cardiologist the patient was without treatment alternative. A cardiac transplantation was not accepted from the corresponding transplantation centre. The attempt of conventional haemorheotherapy performed at a department of cardiology at another university was without success. The patient is now for 9 years under aggressive and successful apheresis therapy. LP(a) was not determined in earlier years but turned out to be 238 mg/dl prior to the first LDL-Apheresis. Angina pectoris at rest disappeared and the patient can perform exercise at a low level. Nevertheless, the prognosis is critical as she suffers from a moderated depression leading to a limited compliance and the cardiological examination demonstrated a moderate progression.

Patient No. 4 suffers from a considerably advanced coronary 3 vessel disease after triple bypass surgery in addition to an also considerably advanced peripheral arterial occlusion disease (y-prothesis, femuro-popliteal bypass, iliaco-femural aneurysma, PTFE prothesis, femuro-popliteal bypass after several thrombectomies, femuro-fibular bypass, homologous vein transplantation) and stenosis (50 - 60 %) of both carotis internae arteries, mainly due to heavy smoking in earlier years and a low HDL-cholesterol (< 40 mg/dl), elevated LP(a), adipositas and lack of exercise as additional risk factors.

Alterations and change off paradigms of LDL-Apheresis during 25 years

1. Alteration of the treatment technology

The very first treatments were performed with single columns of a volume between 400 - 800 ml per column. The approach using a single column was not pleasing as the elimination capacity for LDL-cholesterol was unsatisfactory due to the limited column volume.

It is not surprising if the currently promoted whole blood adsorbers with their limited volumes suffer from the same problem. Also due to the simultaneous volume challenge for the patient the column volume was then decreased to 200 ml and divided into 4 adsorbers, which were loaded subsequently. This decreased the volume burden for the patient, who quite frequently suffered from symptoms of a progressed coronary heart disease associated with cardiac insufficiency, however, the problem of the limited capacity remained. The currently promoted whole blood columns are able to increase the elimination capacity, however, with the disadvantage of either increasing the costs or the volume problems. Especially if the LDL-cholesterol values prior to therapy are rather high, the capacity remains unsatisfactory. Thus, in analogy of the earlier promoted repetetive-cycling loading and desorption of granulocyte filters this principle was successfully transferred into LDL-Apheresis.

Further improvement of the adsorber capacity was reached in Moscow from Prof. Pokrovsky due to the application of monoclonal rather than the otherwise used polyclonal antibodies.

During the very early treatments the primary and the secondary separation systems had to be taken care of from one person each. Subsequently, the treatment procedure was developed towards automation and the most recent state of the technological art is represented in figures 4 and 5. Also it is essential for some patients that using centrifugal devices the single needle technique can be used if a patient presents with only one good cubital vein.

Fig. 4 Fig. 5
Primary separation system Secondary separation system

2. Extension of the indication for LDL-Apheresis
Since 1981 until today there is no pleasing drug therapy for homozygous patients with familial hypercholesterolaemia. Thus, the indication for LDL-Apheresis was originally restricted for homozygous patients.
However, it became soon obvious that heterozygous patients with a severe expression of their disease especially if side effects, incompatibilities and insufficient of lowering of the LDL-cholesterol with drug therapy should also be treated with apheresis therapy, as these patients were equally without treatment alternatives. Incompatibilities may be due to the drugs applied (e.g. severe constipation after applying bile acid binding drugs, so named "flush reactions" applying nicotinic acid) or may be due to a disease of the patient (e.g. chronic gastritis, oesophagitis with reflux).
Following the introduction of Statines and Ezetrol or the combination of both the frequency of drug induced incompatibilities is clearly reduced. It appears that the drug dependent incompa-tibilities may often being neglected from the pharmaceutical industry. Nevertheless, 5 - 8 % of the patients depending on an additional cholesterol lowering therapy remain especially if suffering from progressed coronary heart disease. If they cannot be sufficiently treated with cholesterol lowering drugs, they do need additional LP(a)-Apheresis therapy.
Another group of patients were those with a late stage of their atherosclerotic disease (end-stage-disease). This group of patients enclose those, who cannot be treated with cardiological therapies e.g. implantation of additional stents or further bypass surgery and those who for whatever reason have no further treatment alternative. Applying an especially aggressive diminuition of the LDL-cholesterol these patients frequently respond not only with an improvement of their quality of life but also with an extension of their life expectancy.
Other risk factors not taken into consideration in earlier years may also play a considerable role, e.g. a frequently elevated LP(a). It is elevated in approximately 60 % of our patients with familiar hypercholesterolaemia and may especially if considerably elevated (e.g. values of more than 100 mg/dl) reasonably decreased with repetetive cycling of loading and desorption of the columns. According to our experience an elevated LP(a) without clinical symptoms is no indication for LP(a)-Apheresis, however should be controlled with an annual check up. Alternatively, according to our experience LDL-Apheresis is indicated even when only LP(a) is elevated and no further risk factors are present if objectively proven progress of the clinical symptoms, premature atherosclerosis or an existent clinical pathology can be observed. As an example we can present a patient who after several myocardial infarctions at an age of less than 35 years without further risk factors who is now treated from us after a 10 years of treatment in another location and is without progress of the disease (Table 5). In contrast to the general experience this patient responds to high daily dosages of ascorbic acid, thus decreasing the number of treatments to an interval of 14 days.

Table 5

Efficacy of Lp(a) - Apheresis
(bi-weekly interval, 1-1,5 g ascorbic acid/day + Lipostabil)

Number of therapies
( N )
( % )
30 94 32 67

The treatment of patients with type III or type IV - V according to Frederickson characterised from an elevation of the IDL- and VLDL-cholesterol and thus the serum triglycerides, remain a rare exception. Theses patients cannot be controlled with an appropriate diet in combination with a corresponding lipid lowering therapy, the treatment can normally not be treated with LDL-Apheresis, but plasma exchange has to be used some times also allowing for secondary filtration as the elevated triglyceride depending on particle size and serum concentration remain in the adsorber or filter and lead to clogging. An analogues situation exists in patients with diabetes and hypertriglyceridemia. The indication in such diseases is normally only given if acute pancreatitis (type IV - V, sometimes also including diabetes mellitus). The efficacy of only a few plasma exchange therapies leads to dramatic improvement. As these complications are mainly due to deranged metabolic changes often following a dietary excess it must be pointed out that the control of the life style especially the maintenance of an appropriate diet is the therapy of choice. However, in some occasions this does not apply to patients in a sort of end-stage-disease where a control of the diet does not suffice any more. These patients cannot be judged with conventional standard, but need consideration of a special care.

3. Optimation of clinical target values

During the early years of development the clinical target values depended mainly on the limitations of technical efficacy. During the early 80th the unlimited efficacy of the repetetive-cyclic approach was basically known, however could not necessary always be used (18). However, over time and with increasing experience these technical chances were more precisely defined.

In the mid 80th we were not permitted to perform a controlled trial. However, we were however allowed to perform an open multicenter trial instead, which when performed did at that time not meet the present state of innovation, however the result of this trial demonstrated the value of LDL-Apheresis without any additional medication (39). Based on this trial and our additional now 25 years of experience and the overall available data we recommend already since many years the following clinical-chemical target values, which nowadays are also recommended for patients under drug therapy with severe coronary heart disease. We believe that if possible to eliminate a risk factor one should come as close to this aim as possible. This recommendation includes also the recommendation of such optimal target values for primary prevention.

The values after apheresis therapy should be lowered to the lowest possible LDL-cholesterol (e.g. lower than 50 mg/dl for heterozygous, in general also for homozygous FH-patients, whereas the rapid increase and the associated higher values in between the treatments have to be taken into consideration). In general however his recommended value should be reached after each single therapy independent from the initial values prior to apheresis.

Thus, it should be possible to obtain values in between two treatments (= pre-value + post-value /2) to be in the range of "normal" LDL-cholesterol (e.g. 100 mg/dl, in high risk patients accordingly lower).

LDL-cholesterol values prior to apheresis therapy should also include the HDL-cholesterol and lead to a assure a ratio of total cholesterol / HDL-cholesterol of 1 : 4 or as close as possible to that ratio.

In comparison to our own target values the German BUB guidelines from the 24.3.2004 deviate considerably, have to be criticised and need an urgent update:

  1. The nomenclature is incorrect. Specific, semi-selective and selective procedures are mixed up, though the efficacy of LDL-C elimination of different technologies is considerably divergent and may have clinical consequences. Though the clinical importance is often of limited value, however since they are considered to be guidelines they are generally used for formal judgement.
  2. The lowering of 60 % of the initial value of LDL-cholesterol is considered to be suffi-cient in these guidelines. Obviously a nomination of target values was not considered to be necessary.
  3. Quality control measures and thus the insurance of clinically relevant long term results was not being taken care of and should be included.
  4. It is assumed, that a certain group of physicians is automaticly qualified and thus permitted to treat such patients. However, their competence as related to apheresis technology or to the knowledge and the experience with the treatment of cholesterol lowering (and other metabolic diseases) may be doubtful.
  5. The same holds true for boards controlling the indication. This becomes obvious if the indications for the treatment of the patients with type III, IV and V according to Frederickson and the role of additional risk factors (e.g. low HDL-cholesterol, increased LP(a)) which must not necessarily be treated with LDL-Apheresis or some analogous procedures are to be decided. The specific competence especially of members of such public service should be transparent and thus available for the judgement of metabolic specialists especially in the field of cholesterol metabolism.

From our point of view the following aspects need to be corrected.
  1. The different procedures used to lower LDL-cholesterol should be evaluated and considered differently according to their specificity, their efficacy per single treatment and their economy.
  2. Target values should be introduced and replace the general recommendation of a decrease of 60 %.
  3. Quality control procedures are necessary to improve the safety and the clinically available aims, such as regression, decrease of progression or complete halt of progression. The establishment of individual risk profiles prior to the first therapy is according to our experience a must.
  4. According to the opinion of our patients a more detailed determination of the qualification of the treating physician is pre-requisite for the permission to perform LDL-cholesterol decreasing therapies. The establishment and promotion of centres of competence may well increase the efficacy and improve the cost-efficacy relation.
  5. The selection and the competence of the so named "competent commission" of the board of physicians deciding upon the indication for LDL-Apheresis should be transparent. A definition of the competence of the board members appears to be obligatory.
  6. In case treating physicians are supported from industry they should be obliged to reveal their relations to industrial sponsors.
  7. An individual judgement for the treatment indication should in special cases be possible.

4. Supportive cholesterol lowering therapy

Whereas in 1981 mainly fibrates, nicotinic acid, bile acid binding, drugs and Sitosterin were available as cholesterol lowering drugs, nowadays the generally well tolerable statines and the ezetimibe may be induced. However it has to be stated, that side effects even for these drugs may exist. Rosuvastatin is not admitted in Germany yet.

Positive effects of the additional cholesterol lowering drug therapy on LDL-Apheresis are possible if the medication and the dosage of all available drugs is tested in minimal compatible dosages. Due to the limited tolerance of cholesterol lowering drugs in FH-patients under LDL-Apheresis, especially of the statins, individual testing not only from single, but also from combinations of medications (see 5. Incompatibility of the drug therapy) is necessary. The following additional effects of an additive cholesterol lowering therapy can be expected:
  1. Reduction of the LDL-cholesterol increase after therapy.
  2. Optimation of the post-treatment values and values in between therapy.
  3. Abbreviation of the LDL-Apheresis procedure.
  4. Additional pleiotrophic effects, being under debate.

The rather limited additional effect (maximal additional decrease under apheresis up to 30 % of the initial value in patients in the metabolic equilibrium) should not be used to prolong the treatment intervals, as such procedure would automatically lead to a deterioration of the treatment basis and expand the total pool of cholesterol in the organism.

5. Optimation of the clinical targets
Apheresis therapies which use the term "LDL-Apheresis" though being semi-selective allow generally only for a slow down of the progression of the coronary heart disease. Applying a more potent decrease of the LDL-cholesterol by 70 to more than 80 % of the initial value and taking the above mentioned more stringent target values into account the elimination of an elevated cholesterol as risk factor may be possible and lead especially in the elderly heterozygous FH-patients to a hold rather than decrease of progression. This differs from a regression or primary prevention in young especially homozygous patients.

The following aspects speak in favour of a more aggressive decrease as compared to the earlier considerations which limited the decreased to 60 % of the initial value during extracorporal therapies:
  1. A diminuition of 60 % of the initial cholesterol does not represent the nowadays technical possibilities of a repetitive-cycling treatment procedure.
  2. The increase of the LDL-cholesterol after apheresis should be taken more into consideration and related to the technical procedure.
  3. End-stage-disease-patients can, if an aggressive lowering of the LDL-cholesterol is applied, experience an unexpected improvement of the quality of life and a remarkable prolongation.
  4. According to newer insights drug therapy alone already favours a more intensive treatment (1, 3, 16, 22).

An optimation of the clinical aims must include also the influence on and the treatment of the additional risk factors especially an improved consideration of the individually adapted life style strategy.

6. Pleiotropic mechanisms

The positive effects of LDL-Apheresis were mainly distributed in the past to the diminuition of the LDL-cholesterol. However, favoured from the discussion about the efficacy of statins additional mechanisms are taken into consideration. This includes among others:

  • The removal of modified LDL-cholesterol
  • The influence on the rheology
  • The influence on the membranes of blood cells mainly of erythrocytes and platelets
  • The influence on the endothelium (induction of blood vessel dilating factors and cytokines)
  • The anti-inflammatory effect.

The importance of modified LDL-cholesterol is for many years under debate as additional factor for the atherogenesis. According to the oxidation hypothesis oxidised LDL-cholesterol develops under the influence of free radicals mainly in the vessel wall, was shown to be present in the atheroclerotic plaques, is considered to alter the composition of LDL-particles and promotes under experimental conditions the foam cell formation due to an increased uptake via the "svavenger" receptor, inhibits the mobility of macrophages in the tissues, inhibits the endothelial mediated vessel dilatation, increases the expression of molecules on the endothelial surface and may lead to antibody formation. The LDL-cholesterol lowering effect of statins reduces the formation of modified LDL-cholesterol, thus permitting the assumption that potential atherogenic effects of the modified LDL-cholesterol in the plasma are increased binding the Apolipoprotein B of the modified LDL-cholesterol to the adsorber. It is debatable whether the favourable influences on the cell surface and on the mediators, already seen after a single apheresis treatment, leading to an improved myocardial perfusion are due to a decrease of the oxidative stress or an improvement of the equilibrium between atherogenic and atherogenesis inhibiting factors. This holds especially true for longterm apheresis applications.

Rheological alterations advantagous for the patients were first described from a procedure using heparin precipitation (32). However, it remains uncertain whether this is due to the decrease of the LDL-cholesterol and/or other plasmaproteins such as fibrinogen. Subsequently analogous effects were also described for the specific decrease of LDL-cholesterol using LDL-apheresis (31) from the plasma, but also for the reduction of the erythrocyte elevation (31) and the platelet aggregation (4, 27).

An endothelial independent vasodilatation is due to the stimulated release of NO. An improvement of the endothelial function could be described following cholesterol lowering therapy with statins (2, 25, 37) in an analogous system of selective LDL-decrease (38) and after LDL-Apheresis (5). The induction of other factors and cytokine types as well as adhesion molecules (e.g. E-Selectin, P-Selectin, MCP 1, Il-1, ICAM 1, VCAM 1 and Endoglin ) were also (6) described.

An anti-inflammatory effect can be recognised due to the diminuition of the C-reactive protein concentration among other factors (28). In our patients we could not observe impressive alterations, however this may be due to the already introduced longer therapies prior to the introduction of the high sensitive CRP-tests. The inhibition of pro-inflammatory cytokines, partially proven, partially speculative, may also especially refer to the behaviour of pro-inflammatory cells, the smooth vessel cells, and the maintenance or the recovery of plaque stability.

The question remains under debate which effects of LDL-Apheresis, accordingly to LDL-cholesterol lowering pharmaceutical treatments and other extracorporeal procedures, depend directly on the lowering of the LDL-cholesterol or the additional pleiotropic effects.

7. Quality control

An electronic data supported control of LDL-Apheresis able not only to control parameters of the treatment efficiency and economy, but also supports numerous otherwise rather complex functions, which are indirectly related to LDL-Apheresis. This includes:

  1. The control of the target values (laboratory data prior to and after each treatment)
  2. The documentation of the type and frequency of side effects as well due to the apheresis as the cholesterol lowering additional medication
  3. The technical documentation for instance of
    · the treatment technique (separation system, adsorbers, operators) and
    · the processed blood- /plasma-volume,
    · the flow rates, alarms etc.
  4. The detailed pre-treatment prescription of the responsible physician and the documenta-tion of the responsible operator
  5. The control of the patient data, interim history and all necessary forms
  6. Print outs of protocols and graphics of the treatment data
  7. Administration of safety certificates, validations and charges
  8. Statistical evaluations
  9. Support of the treatment reports
  10. Control of storage materials and purchasing
  11. Control of economy and accounting

An essential advantage of our quality control system was, that it enabled us to develop an individual, predictive decrease of the total-LDL-cholesterol. This is available prior to the treatment and thus enables the responsible physician and the operator to determine the variables of the treatments especially of the target values (7, 33).

8. Side effects of LDL-Apheresis (excluding "me - too" therapies)

The total number of side effects of the last 4000 performed treatments is summarised in tabl. 6

Table 6

Side effects of LDL - Apheresis *
Total number of treatments
from 2002 - 2006
Total number of side effects 189 ( 4,7 % )
Serious (e.g. leading to hospitalisation) 0
Moderate (e.g. prophylactic termination of treatment) 54 ( 1,3 % )
Low 135 ( 3,4 % )

*exclusive the "me - too " therapies

Complement activation, bradykinin activation and the activation of cellular systems were extensively investigated and published in several theses (15, 19, 21). The measurement of complement activation using standard diagnostic procedures shows no alteration. The application of more sensitive procedures showed a moderate activation of complement, when new adsorbers were applied for some early treatments, however, this was without clinical relevance and decreasing overtime with the number of treatments. This demonstrates that the reuse in the same patient is the safe procedure.

The formation of just demonstrable anti-sheep antibodies in approximately 50 % of the patients at low titers is without significance, except if a pre-existing incompatibility against sheep protein is demonstrable. Within 25 years we could never observe such incompatibility using immune-LDL-Apheresis. Also, overtime a reduction of the antibodies, which are bound to the adsorbers during therapy without influencing their capacity could be observed.

We repeatedly examined the particle release in the immune adsorbers applied. We used the limits as defined in the German and European pharmacopoeias for infusion solutions. The limits of 100 allowed for particles of up to 5 µm, 25 for particles of up to 10 µm and 3 for particles of up to 25 µm were never ever found to be extended. Analogous measurements with the same procedures in other systems, especially whole blood adsorbers, led at least in some instances to extensive deviations. Potential clinical consequences if considerable particle release occurs have to be discussed.

Based on our experience of 25 years we conclude that the reuse in the same patient is safe.

9. Economy of the repetitive - cycling technique and the reuse

After we could demonstrate that the safety of LDL-Apheresis no issue for discussion the question of the economy of the LDL-Apheresis arises. One major issue is the diversity of the application of the primary separation systems e.g. in transfusion medicine, haematology, oncology etc. The centrifugal primary separation system can be used for several different indications per day and enables a more economical use as compared to other technologies, which can be applied for one purpose only. The assumed high platelet content of the separated plasma is a fairy tale (unless one refers to the unsuitable centrifugal cytapheresis systems), if the separation systems are properly used until no platelets can be found in the plasma.

The adsorption columns can be reused between 50 - 200 times. Even if one takes the additional costs of the post-treatment handling e.g., the control of the sterility and other additional material costs, the total treatment costs decrease continuously after the 50th treatment. In contrast the treatment cost of disposable systems remain constant (fig. 6).

Re-use cost development of repetetive-cyclic adsorption columns:
Exponential decrease of material cost during re-use (yellow line)
as compared to constant costs of single use systems (red line).

An extended automation of the treatment process decreases the number of operators, increases the versatility of the secondary system leading to a more intensive use of the whole versatile technical system.

10. Limiting factors for a clinical effective LDL-decrease

According to our experience the clinical efficacy is decreased if the necessary target values are not reached. This refers mainly to inappropriate technical procedures such as disposable techniques which among other plasma components also decrease the LDL-cholesterol, however, without obtaining the optimal target values. This refers mainly to filtration procedures and whole blood adsorption.

So far quality control systems are not considered to be mandatory for extracorporeal LDL-Elimination procedures and if applied often unsatisfactory as the appropriate decrease of the LDL-cholesterol is not sufficiently taken into consideration. The quality control system we developed overtime does not only permit a retrospective data analysis but also the prospective determination of the efficiency criteria (7, 33).

Finally additional risk factors have to be taken into consideration. They may be of clinical-chemical nature (tab. 7), but also implies further atherosclerosis-inducing factors (tab. 8).

Table 7
Additional clinical-chemical Risk Factors in Patients under long-term
LDL - Immuneapheresis

Homozygotes Heterozygotes
Low HDL-C 4 / 6 16 / 25 = 64 %
Elevated Lp(a) > 40 mg/dl 3 / 6 16 / 25 = 64 %
Elevated Fibrinogen 4 / 6 19 / 25 = 76 %
Eleveted Homocystein* 1 / 6 19 / 25 = 76 %

* as atherogenic substrate under debate

Table 8

Additional Atherosclerosis inducing Risk Factors in Patients under long-term LDL - Immuneapheresis
Homozygote Heterozygote
Irregular treatments (Compliance) or
Abbreviated termination of treatment 2 / 6 5 / 25
Problems of nutrition 1 / 6 5 / 25
Overweight problems 1 / 6 6 / 25
Smoking 1 / 6 1 / 25
Lack of training 1 / 6 6 / 25
Additional diseases
  - Hypertonia 1 / 6
- Diabetes mellitus 3 / 25
- Small vessel disease 1 / 25
- Neoplasia* (1 / 7) (1 / 26)

* Patient decreased from neoplastic disease

The importance of a treatment of all risk factors beyond the elimination of the LDL-cholesterol does not represent a basically new recognition, however, as shown in the reduction of the rate of myocardial infarction demonstrated in Finland (22) and the USA it is of considerable importance (13, 23).

11. Side effects of supporting cholesterol lowering drug therapy

As compared to the nowadays available statins the LDL-cholesterol lowering medications available in 1981 were frequently difficult to tolerate for the patient (e.g. constipation after treatment with bile acid binding drugs for the so named "flush syndrome" of nicotine acid). The nowadays available statins are not only more efficient, but are accompanied with a lower rate of side effects, which allows to lower the LDL-cholesterol in patients with familial hypercholesterolaemia in more than 90 % of the patients excluding the homozygous. Whereas the target values even under cholesterol lowering drug therapy are nowadays much lower as compared to earlier years a considerable number of heterozygous patients tend to suffer from incompatibilities or a limited response to their medication, thus extending the indication for LDL-Apheresis.

The drug dependent incompatibilities in our patients are summarised in Table 9.

Table 9

Side Effects of Statins in 29 Patients with Familial Hypercholesterolaemia

N %
Muscle pain, weakness 14 48
Hairloss 4 14
Gastrointestinal discomfort 3 10
Arthralgies, bone pain 3 10
CPK increase 2 7
Increase of transaminases 1 3
Pseudoallergic reactions 1 3
Severe sleeping problems 1 3
Total: 29 98

12. End stage disease

According to the general cardiological and cardiosurgical criteria the assumption is justified that patients after exhaustive therapy and without treatment alternatives have limited chances for a treatment success with LDL-Apheresis. The following criteria may be valid for patients with advanced coronary heart disease and without treatment alternative or progressed atherosclerosis respectively.
  • Resuscitation after myocardial infarction due to progressed coronary sclerosis
  • No further therapeutic cardiological (e.g. stents) or cardiosurgery (e.g. 3 or 4 bypass surgeries) or analogous angiologic surgical procedures
  • Minimal working exercise (e.g. underneath 25 Watt)
  • More than 3 angina pectoris attacks per day at rest without physical challenge in spite of maximal antianginal therapy
  • Optimal treatment or exclusion of other risk factors
  • Proof of far advanced pathological coronary morphology
  • Exhaustive application of all maximal possible cholesterol lowering diet and drug therapy especially applying different drug combinations.

The experience with the 4 in table 4 presented patients with an end stage disease of their atherosclerosis and coronary heart respectively teaches that using an extreme aggressive lowering of the LDL-cholesterol leads overtime to a respectable improvement of the quality of life and a prolongation of the life expectancy over years is possible.

13. Subsequent developments of the principle of therapeutic affinity chromatography

The principle of therapeutic affinity chromatography as suggested from W. Stoffel in 1981 was subsequently extended to the elimination of other undesired or pathological components of the plasma.

At a time when intoxications with Digoxin could only be treated with plasma exchange our group showed, that Digoxin-Apheresis using adsorption columns was by far more effective. This treatment is nowadays replaced from the direct injection of the ligands coupled earlier to the adsorber.

The development of a C1q-adsorber initiated from our group could not be finished due to a lack of financial support. Though the clinical results were extraordinary. The major problem was the costly preparation of the C1q.

We could demonstrate that the replacement of the sheep antibody using a peptide construct for the specific elimination of LDL-cholesterol was basically possible, however, clinically less effective.

Immunoglobuline (Ig) - Apheresis was developed from our group at Cologne in analogy to LDL-Apheresis. In 1992 the doctoral fellow C. Jimenez-Klingberg was rewarded for his work "Selective Adsorption of Immunoglobulin G" with the young investigators research award on the WAA Congress in Sapporo. The procedure was successfully applied for several autoimmune diseases and subsequently copied from the Baxter Company, which used it mainly for the therapy of dilatative cardiomyopathy. The result of this development is presented in several theses of the University of Cologne and was subsequently improved in collaboration with the Russian National Academy of the Medical Sciences in Moscow.

LP(a) -Apheresis as developed from Pokrovski is based on the same principle and permitting a decrease of up to 85 % of the initial value represents the most efficient procedure for the treatment of isolated atherogenic LP(a) -elevation.


  1. The prolongation of patients survival mainly of those with homozygous familial hyper-cholesterolaemia without treatment alternative is among many other proofs of efficacy the strongest argument for the efficacy of LDL-Apheresis.

  2. Further optimation are possible such as improvement of the guidelines, definition of target values, consideration of sufficient competence for treating physicians and examination boards, quality control, mechanisms, development of industry competence centres etc. These improvements lead to an increase of the quality of life and a relativation of hypercholesterolaemia as risk factors and may also lead to increased consideration and treatment of other simultaneously present risk factors. This should lead to the need of an extensive maximal patient treatment, which can best be performed in industry independent competence centres.

  3. Further improvement of the economy is possible due to the use of optimal technical devices and the reuse of suitable absorbers and new technical development.

  4. If a medical and technical optimation is desired and an improvement organisation for the treatment of familial hypercholesterolaemia is desired, the discussion of the collected experience and results is an absolute necessity after we were prevented from performing a controlled trial 20 years ago (1).

References referring to LDL-Apheresis

  1. ANCEP Adult Treatment Panel III Guidelines
    Circulation 2004; 110: 227)

  2. Anderson, TJ, Meredith, IT, Yeung, AC, Frei, B, Selwyn, AP, Ganz, P
    The effect of cholesterol lowering and antioxidant therapy on endothelium-dependent coro-
  3. nary vasomotion
    N Engl J Med 1995, 332: 488 - 493

  4. Baigent,C et al.
    Metaanalyse 14 randomisierter Studien von 90.056 Pat.
    Lancet 2005;366:1267)

  5. Bláha M, Pecka M, Urbánková J, Bláha V, Malý J, Zadák Z, Blažek M.
    Activity of thrombocytes as a marker of sufficient intensity of LDL-apheresis in familial hypercholesterolaemia.
    Transfus Apheresis Sci. 2004 Apr;30(2):83-87

  6. Bláha M, Krejsek J, Bláha V, Andrýs J, Vokurková D, Malý J, Blažek M, Skorepová M.
    Selectins and monocyte chemotactic peptide as markers of atherosclerosis activity
    Physiol Res 2004;53:273-278.

  7. Bláha M, Cermanová M, Bláha V, Jarolím P, Andrýs C, Blažek M, Malý J, Smolej L, Zajíc
    J, Mašín V, Zimová R, Rehácek V.
    Changes in endoglin levels during extracorporeal elimination therapy for familial hyperli-
    poproteinemia. Atherosclerosis 2007, accepted

  8. Blaha M, Masin V, Stransky, P, Blaha, V, Cermanova, M, Maly J, Belada D
    Optimization of the therapeutic procedure during LDL-Apheresis - a computerized model
    Transfus Apher Sci 2005, 32 (2): 249 - 156

  9. Borberg.H., W.Stoffel, K.Oette:
    The development of specific plasmaimmunoadsorption.
    Plasma.Ther.Transfus.Technol. 1983; 4,4; 459 - 466

  10. Borberg,H.
    The development of an automated therapeutic immunoadsorption system using the LDL -
    apheresis model.
    Europ J Clin.Invest. 1983; 13 II; A 39

  11. Borberg,H, Gaczkowski, A, Hombach,V, Oette, K, Stoffel, W.
    Treatment of familial hypercholesterolaemia by means of specific immunoadsorption.
    J.Clin.Apheresis 1988; 4; 59 - 65

  12. Borberg, H., Oette, K
    Experience with and conclusions from three Trials on LDL-Apheresis in "Therapeutic
    Plasmapheresis (XII)", T. Agishi et al (Eds),
    VSP BV (Publ.), Utrecht (1993): 13 - 20

  13. Borberg, H, Oette, K
    Outlooks in LDL-Apheresis
    Blackwell Wissenschaft, Wien (Publ.) 1995: 306 - 318 (W. Koenig, V. Hombach, M.G.
    Bond, D.M. Kramsch eds. Progression and Regression of Atherosclerosis).

  14. Ford, ES, Ajani, UA, Croft, JB, Critchley, JA, DR Kottke, Th.E, Giles, WH Capewell S
    Explaining the decrease in US deaths from coronary disease 1980 - 2000
    N E J Med 2007, 356 (23): 2388 - 2398

  15. DeGennes JL, Maunand B, Maunand B
    Formes homozygotes cutaneo-tendineuses de xanthomatose hypercholesterolemique dans
    une observation familiale exemplaire-essai de plasmapherese a titre du traitement heroique
    Bulletins et Memoires de la Société Médicale des Hopitaux de Paris, 1967,118:1377-1387

  16. Freudenhammer, Ch.
    Untersuchungen zur Biokompatibilität der LDL-Apherese. Aktivierung von Monozyten
    und neutrophilen Granulozyten.
    Dissertation, Medizinische Fakultät der Universität Köln ,1995

  17. Genser, B, März, W,
    Low density lipoprotein cholesterol, statins and cardiovascular events: A meta-analysis.
    Clin Res Cardiol 2006, 95(8):393 -4 04.

  18. Hombach,V.,Borberg, H.,Gaczkowski,A.,Oette, K.,Stoffel, W.,
    Regression der Koronarsklerose bei familiärer Hyperchoelsterinämie Typ IIa durch
    spezifische LDL - Apherese
    Dtsch. Med. Wschr. 1986; 45; 1709 - 1715

  19. Hummelsheim,T., H.Borberg, R.Brunner, K.Oette
    Acute changes of haemorheological parameters by LDL-Apheresis:
    Specific immunoadsorption versus cascade filtration
    Infusionsther.Transfusionsmed. 1995; 22 (Suppl.1); 42 - 44

  20. Kadar,J.G.,Späth,P.J.,Gaczkowski,A.,Oette,K.,Stoffel,W.,Borberg,H.:
    Biocompatibility studies on a clinically well tolerated extracorporeal system.
    Plasma.Ther.Transfus.Technol. 1988; 8; 307 - 318

  21. Kadar,J.G.:
    Biocompatibility studies during specific immunoadsorption.
    2nd Int Congress World Aph Assoc, Ottawa, May 18th - 20th, 1988,
    Abstract vol. p.9

  22. Knisel, W, Di Nicuolo, A, Pfohl, M, Müller, H, Risler, H, Eggstein, M, Seifried, E
    Different effects of two methods of low-density lipoprotein apheresis on the coagulation
    and fibrinolytic system.
    J Intern Med 234 (1993), pp. 479-487. Abstract

  23. Laatikainen, T, Critchley, J, Vartiainen, E, Salomaa, V. Ketonen, M, Capewell, S
    Explaining the decline in coronary heart disease mortality in Finland between 1982 and
    Am J Epid 2005, 162: 764 - 773

  24. Law MR, Wald NJ, Rudnicka AR.
    Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart
    disease, and stroke: systematic review and meta-analysis.
    BMJ 2003; 326(7404): 1407 - 1423

  25. Lupien, PJ, Moorjani, S Awad, J
    A new approach to the management of familial hypercholesterolaemia : Removal of
    plasma-cholesterol based on the priciple of affinity chromatography
    Lancet 1976, 1 (7972): 1261 - 1265

  26. 0'Driscoll, G, Green, D, Taylor RR
    Simvastatin, a HMG-coenzyme A reductase inhibitor improves endothelial dependent
    vasodilatation in hypercholesteroaemic humans
    Circulation 1997, 95: 76 - 82

  27. Oette, K., Borberg, H.:
    Variables in Regression of atherosclerosis in familial hypercholesterolaemic patients
    under longterm LDL-apheresis.
    Plasma.Ther.Transfus.Technol. 1988; 9; 17-23

  28. Otto, C, Baumann, M, Schreiner, T, Bartsch, G, Borberg, H, Schwandt, P. Schmid -
    Schönbein, H
    Standardized ultrasound as a new method to induce platelet aggregation
    Eur J Ultrasound 2001, 14 (2-3): 157 - 166

  29. Otto, C, Geiss, HC, Empen, K, Parhofer, KG
    Longterm reduction of C-reactive protein concentration by regular LDL-apheresis
    Atherosclerosis 2004, 174: 151 - 156

  30. Parusel, M.:
    Untersuchungen zur Biokompatibilität der LDL-Apherese. Interaktionen zwischen der
    Anti-Apolioprotein-B IgG-Sepharose 4B cl, dem Komplementsystem und den Blutzellen
    Thesis, University of Köln 1994

  31. Richter, WO, Jacob, BG, Ritter, M, Sühler K, Sühler, K, Vierneisel, K, Schwandt, P
    3 year treatment of familial heterozygous hypercholesterolaemia by extracorporeal LDL-
    immunoadsorption with poly clonal apolipoprotein B antibodies
    Metabolism 1993, 42: 888 - 894

  32. Richter, W.0., Schwandt P in "Handbuch der Fettstoffwechselstörungen" Schwandt,
    Richter (Hrsg.), Schattauer Verlag 1995: 682 - 690

  33. Schuff-Werner, P, Schütz, E, Seyde, WC, Eisenhauer, T, Jannings G, Armstrong, W,
    Seidel D
    Improved haemorheologyassociated with a reduction in Plasma fibrinogen and LDL in
    patients being treated by heparin induced extracorporeal LDL-precipitation
    Eur J Invest 1989, 19: 30 - 37

  34. Stefanec GM
    Prädiktionsparameter extrakorporaler Eliminationstherapien am Modell der LDL-
    Apherese, Dissertation, Medizinische Fakultät der Universität Köln, 1999

  35. Stoffel,W., Demant, T
    Selective removal of apolipoprotein B-containing serum lipoproteins from blood plasma
    Proc. Nat. Acad. Sci. 1981; 78; 611 - 615

  36. Stoffel,W., Borberg, H., Greve, V.,
    Application of specific extracorporeal removal of low density lipoprotein in familial
    Lancet II 1981; 1005 - 1007

  37. Thompson, GR, Lowenthal, R, Myant, NB
    Plasma exchange in the management of homozygous familial hypercholesterolaemia
    Lancet 1975, 1(7918): 1208 - 1211

  38. Treasure, CB, Klein, JL, Weintraub, WS, Talley, JD, Stillabower, ME, Kosinski, AS,
    Zhang,J, Boccuzzi, SJ Cedarholm, JC, Alexander, RW
    Beneficial effects of cholesterol lowering therapy on the coronary endothelium in patients
    with coronary artery disease.
    N Engl J Med 1995, 332:481 - 487

  39. Tamai, O, Matsuoka, H, Itabe, H, Wada, Y, Kohno, K, Imaizumi, T
    Single LDL-apheresis improves endothelial dependent vasodilatation in hypercholesterol-
    aemic humans
    Circulation 1997, 95: 76 - 82

  40. Waidner,T., Franzen, D, Voelker, W, Ritter, M, Borberg, H, Hombach, V, Höpp, H.W.
    (for the LDL-Apheresis Study Group)
    The effect of LDL-apheresis on progression of coronary artery disease in patients with
    familial hypercholesterolaemia. Results of a multicenter LDL-apheresis study.
    Clin.Investig. 1994; 72; 858 - 863