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2nd Congress of the European Group – International Society for Apheresis

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03/22/2018 - Pirouette | 9:05am - 10:45am 

Chair: H. Sinzinger (Vienna, Austria), B. Hohenstein (Villingen-Schwenningen, Germany)

Changing indications in Apheresis – a historical retrospect
*Horst Klinkmann1
1 Honorary Member ISFA, Former President WAA, Rostock, Germany
Abstract text :

The concept of removing pathogenic agents from the body by blood purification procedures is one of the oldest therapeutic approaches in the history of medicine, starting in ancient times with bloodletting. Also in the Middle Ages bloodletting was abundantly used in an almost unlimited range of indications. In the last century new technologies such as centrifugation and membrane diffusion allowed selective and specific removal of toxic substances from blood.
On December 8th 1914, John Abel performed the first apheresis of modern times, often wrongly cited as first hemodialysis. Whereas hemodialysis today is a well established, life saving procedure around the world, apheresis has remained a field where personal experience of the caring physician still collides with the requirements of evidence based medicine. The spectrum of indications in the last 30-40 years is almost as broad and sometimes as questionable as it was for bloodletting in the Middle Ages, ranging in both times from preventive to life saving measures. Despite a revolution in available technology and diagnostic possibilities the prevailing reports in more than 2500 publications on therapeutic successes remain mainly anecdotical, raising hope and creating disappointment. Typical examples are Rheumatoid Arthritis, Cardiomyopathy and a number of neurological diseases.
As caring physicians and based on personal experiences, we "know", that therapeutic apheresis works in the treatment of diseases – as scientific investigators, we know also, that this observations have to be tested in sound clinical trials. Unfortunately, the approach to collect worldwide data or to inaugurate large trials has had limited success during the last decades. The unsatisfactory result is a wide variety in the acceptance of clinical indications worldwide and conflicting interpretations regarding the benefits of apheresis procedures. International societies like ISFA do have a chance and an obligation to be instrumental for the correction of this situation in order to achieve the deserved scientific recognition of apheresis as a powerful therapeutic tool of modern medicine. 

Aging, Disease, and Therapeutic Apheresis
*Paul S. Malchesky1
1 ICAOT, , Painesville, OH, United States
Abstract text :

It has been stated that the greatest risk factor for nearly every major cause of mortality in developing nations is aging. Our major goal in improving our health is not extending life but combating diseases. Some notable ways are by reversing genome damage caused by aging, diet, and environmental factors; research new tissue and blood; restrict caloric intake; and reprogram senescent cells. Senescent cells are cells that no longer divide but continue to secrete singling molecules as inflammation causing factors. These cells accumulate abnormal or degraded proteins that impair cellular functions. Therapeutic approaches are developed by pharma to target and reprogram these cells and to deactivate them. Another approach by therapeutic apheresis is the removal of these "toxic compounds". In studies by parabiosis the circulation systems of old and young species have been studied to have the young molecules repaired and detoxified; however, the results have been difficult to interpret and the exchange involves other processes as oxygenation and filtration.  Studies have demonstrated that old blood in mice contains substances that can cause health decline. With age, protein accumulation results from impaired protein degradation as misfolding. Human cells intentionally collect aggregates to prevent other cellular damage and these aggregates can spill over into the plasma. What to do? Remove the "bad" and/or replace with the "good"? Two clinical trials (Stanford University and Grifols) in Alzheimer"s patients aimed to administer plasma from young donors or replace plasma with albumin, respectively. While some early success has been seen these trials are on-going. One particular group of proteins that aggregate and seen in various diseases are cryoglobulins, cold-precipitable proteins. These proteins can be found in the plasma as well as tissues and synovial fluid, can be immune complexes, and are frequently seen in older non-healthy persons. They have been shown to have disease prognostic significance. In a review of various immunologic and metabolic diseases (Malchesky, Therapeutic Apheresis-Why?, Ther Apher Dial 2015; 19:417-426) over 100 diseases of varying types affecting the major organ systems are identified as having associated with them abnormal or high concentrations of macromolecular proteins in plasma that would lend themselves removable by therapeutic apheresis. This Author"s Team has paid particular attention to their removal by plasma membrane filtration technologies as cryofiltration.  We have identified various diseases containing cryoprecipitable proteins and have successfully treated them including cryoglobulinemia, rheumatoid arthritis, etc. We have shown that cryoprecipitable proteins are suppressive to the immunological system such as inhibiting the blastogenesis of normal mononuclear cells and inhibit neutrophil phagocytosis in a concentration dependent manner. Lymphocytes showed increases in proliferation pre- to post cryofiltration to mitogens showing their prior suppression to both T and B cell and cryoprecipitable proteins had a suppressive effect on normal lymphocyte proliferation. Patients" plasmas studied with cryoglobulinemia were inhibitory to normal granulocyte chemotaxis. In cryoglobulinemia and rheumatoid arthritis patients treated with cryofiltration the removal of cryoprecipitable proteins improved cellular functions. In biliary cirrhosis patients treated with plasma perfusion over charcoal and an anion exchange resin improved cellular functions and in hypercholesterolemia patients treated by thermofiltration LDL removal remained lower of an extended period of time. Plasma treatment for the removal of plasma macromolecules can produce beneficial effects lasting longer than would be expected from their physical removal. The clearing of the "biological smoke" can activate the biological system to return to normalcy and allow pharma agents to work more effectively. The normal detoxification processes are lacking in disease states. "Factors" accumulate leading to pathologic processes, at times in response to the disease processes, and normal removal processes become deficient and eventually overwhelmed. The uptake of "factors" by cells leads to their impairment. Aggregation of proteins can occur. A therapeutic apheresis approach can remove the degraded and abnormal proteins and improve cellular functions and stimulate the biological processes to restore the norm.

Lipoprotein apheresis in Germany – still more commonly indicated than implemented. How can patients in need access therapy? A model-based answer from the apheresis competence center Kempten-Allgäu
*Franz Heigl1, Tobias Pflederer1
1 Medical Care Center Kempten-Allgäu, , Kempten, Germany
Abstract text :

Background: Although lipid-lowering drugs, especially statins, and recently also PCSK9 inhibitors can reduce LDL cholesterol (LDL-C) and decrease the risk for coronary heart disease (CHD) events most efficiently, only 5-10% of high-risk cardiovascular patients reach the target values recommended by the international guidelines. Even in patients who cannot be treated adequately by drugs it is still possible to reduce excessively high LDL-C and Lp(a) values by the use of lipoprotein apheresis (LA) with the potential to decrease severe CHD events by more than 80%. We estimate however that even in Germany, a country with well established reimbursement of LA, only 5-10% of patients in need have access to this life-serving therapy.

Objective: Starting in 1996 our aim was to offer LA treatment in as many patients as possible with a clear indication.

Methods: Based on the experience of our large apheresis competence center looking back to nearly 70.000 LA treatments in the last 20 years, we depict the necessary structure for identification of patients, defining indication, referral, implementation and standardisation of therapy and reimbursement. LA is unfamiliar for most patients and even for many practitioners and consultants. Therefore nephrologists performing more than 90% of LA in Germany have to form a network for referral and ongoing medical education, comprising all regional care-givers, general practitioners as well as the respective specialists and insurances or other cost bearing parties for offering a scientifically approved therapeutic regimen and comprehensive care. An ideal way to realize such a structure is the implementation of a lipidological competence center and network certified by the German Society of Lipidology.

Results: Working as a lipidologial competence center and network and apheresis competence center in a catchment area of about 450.000 inhabitants, today we treat more than 140 patients in the chronic LA program. In spite of the recent availability of PCSK9 inhibitors the number of LA patients is still growing. In an analysis of nearly 37.000 LA treatments in our own center we could find a 80-90% reduction of cardiovascular events in patients treated by regular LA.

Conclusion: We have implemented the concept of a high volume apheresis competence center characterised by ongoing medical education with a focus on lipidological and cardiological aspects, interdisciplinary networking and referral. By this way we have been able to guide about ten times more patients in need to LA therapy compared to the average number of LA treatments in Germany and contribute to an extraordinary reduction of cardiovascular events.

Italian multicentre study on Hyper Lp(a)-lipoproteinaemia
*Claudia  Stefanutti1
1 Sapienza University of Rome, Molecular Medicine, ROMA, Italy
Abstract text :

Lipoprotein(a) (Lp(a)) is a complex of a low-density lipoprotein (LDL)-like particle and apolipoprotein-(B-100) covalently bound to apolipoprotein (a). Several  studies confirmed that Lp(a) plays a role in the pathogenesis of atherosclerosis. Lp(a) is thought to be an independent predictive risk factor for intima-media carotid thickening in individuals without cardiovascular disease, and for premature peripheral vascular disease. High  Lp(a)  levels and corresponding genotypes, were associated with increased risk of aortic valve stenosis in the general population, with levels > 90 mg/dL predicting a threefold increased risk. In the light of available evidence, therapeutic approaches are targeting at lowering Lp(a) levels. Current developments of novel pharmaceutical agents like Mipomersen (apolipoprotein-B100 synthesis inhibitor), Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors (Alirocumab, Evolocumab, Bococizumab) and Anacetrapib (a Cholesteryl Ester Transfer Protein - CETP inhibitor) showed interesting outcomes, albeit these novel drugs were not enough effective in lowering Lp(a) to desirable values. At present, the only suggested effective treatment for HyperLp(a)lipoproteinaemia is extracorporeal Lipoprotein Apheresis. Lipoprotein Apheresis treatment should be frequent (better QW) and continuous. Following previous Italian multicentre clinical experience and under the aegis of the MIGHTY MEDIC Group (www.mightymedic.org) a novel Italian multicentre study has designed in 2016 and launched in 2017. Rome, Genova, Parma, Verona and Pistoia centres have been involved in the study. Next-generation sequencing (NGS) based on a custom AmpliSeq™ panel designed for sequencing of human genes related to the lipoprotein metabolism have been performed with Ion PGM™ Sequencer. Liquid chromatography/mass spectrometry capable of measuring apolipoprotein(a) concentration while simultaneously determining the number of kringles present per protein has been set up. Cholesterol Loading Capacity (CLC) of sera containing Lp(a) was performed in order to evaluate possible correlation to number/size of kringles determined by chromatography/mass spectrometry. The above advanced genetic and lipid metabolism analysis methods have been performed for now, on sera from 18 patients with HyperLp(a)lipidaemia and Coronary Artery Disease and /or extracoronary atherosclerotic vascular complications, before and after treatment with Lipoprotein Apheresis. A control group, of 11 subjects with the same lipid disorders and cardiovascular complications, not treated with LA has also been set. Preliminary data confirmed that LPA gene is extremely polymorphic. The study on the correlation between genotype and phenotype will confirm the predictive role of genetic variant of LPA gene on cardiovascular risk. Moreover, the analysis of serum Cholesterol Loading Capacity in relation to the number of kringles repeat and LA will allow to discover new mechanisms for increasing cardiovascular risk and highlight the effect of therapeutic apheresis (LA) on HyperLp(a)lipidaemia.

Claudia Stefanutti and the MIGHTY MEDIC Group – Italian Section

Treatment and health related Quality of Life in Lipoprotein Apheresis Patients
*Anja Vogt1, Véronique De Gucht2, Krister Cromm3, Ulrich Julius4, Bernd Hohenstein5, Ralf Spitthöver6, Wolfgang Ramlow7, Volker Schettler8, Stan Maes2
1 Klinikum der Universität München, Stoffwechselambulanz, München, Germany
2 Leiden University, Psychology, Leiden, Netherlands
3 Fresenius Medical Care Deutschland GmbH, , Bad Homburg, Germany
4 University Hospital, Technische Universität Dresden, Department of Internal Medicine III, Dresden, Germany
5 Nephrological Center, , Villingen-Schwenningen, Germany
6 Dialyse- und Lipid-Zentrum Nordrhein, , Essen, Germany
7 Nephrocare Rostock GmbH, , Rostock, Germany
8 Nephrologisches Zentrum Göttingen GbR, , Göttingen, Germany
Abstract text :

Purpose: Research on quality of life (QOL) in lipoprotein apheresis (LA) patients is scarce. The present study aimed to advance knowledge about QOL in LA patients. Specifically, purposes of the study were: (1) to validate a new questionnaire measuring treatment specific QOL in LA patients (Apheresis-quality of life-form: A-QOL-F). (2) To explore whether age, gender, and duration of treatment are related to QOL in LA patients. (3) To compare QOL and physical complaints in a large sample of LA patients with normative data.

Methods: 206 LA patients from three sites in Germany completed a questionnaire composed of four instruments: two established health-related QOL (HRQOL) questionnaires (SF-12, EQ-5D-5L), a physical symptoms questionnaire (PHQ-15), and the recently developed A-QOL-F. We constructed the A-QOL-F by reducing 104 items of an initial questionnaire to 38 items according to psychometric guidelines. Furthermore, it was tested whether QOL depends on age, gender, and duration of LA. Additionally, patients` scores on SF-12 (physical and mental component summary: PCS and MCS), EQ-5D-5L, and PHQ-15 were compared to normative data.

Results: A-QOL-F was found to consist of seven factors: a) burden of apheresis, b) competence of the care team, c) mutual patient support, d) information provision on lifestyle consequences, e) trust in the care team, f) positive effects of the treatment, and g) importance of feedback. The A-QOL-F has good psychometric properties. Age, gender, and duration of LA do not correlate with QOL in LA patients. LA patients rate HRQOL lower than the general population (for SF-12 mean population = 50, SD = 10; PCS: mean LA = 39.85, SD =10.79, p< 0.0001; MCS: mean LA = 47.90, SD = 11.24, p< 0.0001; EQ-5D-5L: mean LA = 80.74, SD = 15.58, mean population = 91.50, SD = 13.00, p< 0.0001). LA patients indicate more physical symptoms than the general population (LA = 7.96, SD = 5.33, mean population = 5.50, SD = 3.93, p < 0.0001).

Conclusion: Expectedly, HRQOL is rated lower by LA patients than by the general population and does not correlate with age, gender, or length of treatment. A-QOL-F assesses treatment related QOL in LA patients but not the burden of cardiovascular disease. Next, we will develop a measure to discriminate disease severity to compare treatments. A-QOL-F may also be used in other diseases.