Chairs: A. Kronbichler (Innsbruck, Austria), B. Hohenstein (Villingen-Schwenningen, Germany)
|P-01||EXPERIENCE FOR TREATMENT THROMBOTIC THROMBOCYTOPENIC PURPURA DISEASE WITH PLASMAPHERESIS USING NANOTECHNOLOGY MEMBRANE
1 University Hospital Queen Yoanna , Neurology ICU, Sofia, Bulgaria
2 Bulgarian Academy of Science, Institute of Biophysics and Biomedical Engineering, Sofia, Bulgaria
Abstract text :
Purpose: Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal disease. In 2013 in Bulgaria it has been introduced a new method of therapeutic apheresis (plasmapheresis), which uses a membrane created on the basis of nanotechnology. Here we present cases of patients with TTP disease who were admitted for the first time in Bulgaria for treatment with minimally invasive therapeutic nanomembrane-based plasmapheresis (EC Certificate № CQ102011-II).
Methods: Application of nanotechnology membrane which has been designed, manufactured and tested in the clinical practice, and in which the pores were obtained by acceleration in a collider and loaded with extra energy protons. The membrane thus produced provides a qualitatively new approach in the separation of plasma proteins and human blood. Its effective surface area is only 0.15 m² and the maximum working pressure can reach up to 40 kPa (300 mmHg). This membrane is produced by Trackpore technology (Russia) with the participation of the nuclear physicists in the Dubna collider under the name of "ROSA". This membrane filter may be used only with the "Hemofenix" apparatus. The whole therapeutic procedure is performed by catheterization of a single peripheral vein, which makes this approach low-invasive and safe for the patients.
Results: In the Clinic of Neurology, University Hospital "Queen Joanna-ISUL", Sofia, Bulgaria was performed nanotechnological membrane-based plasmapheresis to eighteen patients diagnosed with active TTP between November 2015 and July 2017. Thirteen of the patients were female and 5 were male. Plasmapheresis was performed every day and was based on the previously calculated volume of circulating blood of each patient. The total volume of exchanged plasma reached more than 40 liters in the course of 20 procedures. This resulted in termination of the coma state of the patients and improvement of the parameters of anemia and thrombocytopenia.
Conclusion: Early diagnosis and intensive treatment could be lifesaving. A reliable clinical indicator for successful treatment is the increase of the level of thrombocytes, erythrocytes and hemoglobin as well as the improvement of the consciousness disturbances – from coma to clear consciousness. Our experience support the idea that early treatment based on therapeutic apheresis is a first-choice approach in the therapy of TTP.
This research was supported by Grant №DH/03/1/2016 from the National Science Fund, Bulgaria.
|P-02||Extracorporeal IgE Immunoadsorption in Allergic Asthma - first centre experience
1 University Hospital, 4-th Internal Department - Hematology, Hradec Králové, Czech Republic
2 University Hospital, Institute of Clinical Immunology a Alergology, Hradec Králové, Czech Republic
Abstract text :
Background:IgE (immunoglobulin E)-associated allergies became an important health problem in industrialized countries affecting more than 25% of the population. One of the most severe manifestations is asthma with its strong impact on quality of life. Several therapeutic strategies targeting IgE are currently under clinical evaluation. Omalizumab, a therapeutic anti-IgE antibody is one of them but its using is limited by a maximum level of total IgE before administration (700 U/ml).Significant reduction can be reached by specific IgE immunoadsorption (IA). In 2016 Lupinek et al. published the results of the pilot trial with a single-use IgE immunoadsorber column. High selective depletion of IgE (86,2%) was acchieved in 9 patients (p.) after 9 cycles of IA. Data suggested the use of IA in allergic p. who are not eligible for omalizumab due to high IgE-levels. In such patients, IgE-levels could be reduced by IA in a first step, followed by administration of omalizumab.
Methods: In November 2016 we treated 41-year old man with severe asthma with very high IgE levels (1145 IU/ml) by IA. Plasma was separated by centrifugation (Spectra Optia,Terumo BCT, Lakewood, Co, USA) and then passed through a single-use IgE immunoadsorber column (IgEnio, Fresenius Medical Care, Bad Homburg, Germany).
Results: We provided 4 IA procedures in 8 days in this particular patient. Peripheral vein access was used, two plasma body volumes were washed, anticoagulation was maintained by continuous ACD-A and heparin. Plasma flow rate: 30 ml/min maximally. No side-effects were observed. IgE levels before and after last IA were 406 resp. 146 IU/ml. IgE levels decreased by 80%. Consecutive day the first dose of omalizumab was administered. The respiratory functions improved., The patient is in a very good clinical condition 14 months after last IA treatment without steroids and exacerbations. Omalizumab is administered monthly.
Conclusions: IgE immunoadsorption with IgEnio seems to be a promising treatment strategy for patients with severe allergic asthma attacks and for allergic patients with high serum total IgE-levels. Our experience shows successful and safe treatment approach, when IA is used before administration of omalizumab. Additional clinical investigations with a higher number of participants are needed to confirm these results.
Supported by AZV 16-30366A
|P-03||Comparative study of three systems for extracorporeal endotoxin removal by LPS adsorption (in vitro data).
1 National Medical Research Center of Cardiology Ministry of Health of Russian Federation, , Moscow, Russian Federation
2 M. V. Lomonosov Moscow State University, , Moscow, Russian Federation
Abstract text :
Question. Increased endotoxin (LPS) in patient blood may cause sepsis. Mortality from sepsis is 35-37% at pronounced sepsis and 52-56% in case of concealed sepsis. Using of extracorporeal LPS elimination can improve the survival of patients with sepsis and septic shock. Currently different systems for LPS adsorption are available. It is difficult to compare these systems in real clinical practice, but it is possible to compare them in the in vitro study in conditions simulating of LPS apheresis procedure.
Methods. Three commercial systems for LPS adsorption were included in the in vitro comparison study: column TOXIPAK® («POCARD» Ltd, Russia), cartridge TORAYMYXIN® PMX-20R («Toray Medical Co.», Japan), column LPS Adsorber® («Alteco Medical», Sweden). Plasma pool was prepared from plasma samples of 18 donors. «Pirogenal» («Medgamal», National Medical Research Center of immunology and microbiology, Moscow, Russia) was added to plasma pool to obtain model solution containing endotoxin in final concentration 50 ng/mL. Then 1,5 L of model solution containing endotoxin was passed throughout each of sorption columns, at the RT. Perfusion flow rate was 50 mL/min, perfusion time – 2 hours in recirculation mode. Sample selection was done before perfusion and after: 15, 30, 60, 120 minutes from used plasma pool. Endotoxin activity was measured by LAL Chromogenic test («Hycult biotech», Netherlands).
Results. As experiment has shown within first 30 minutes maximum endotoxin adsorption occurs if used TORAYMYXIN® PMX-20R – 52% from baseline level, but further no more reduction occurs and the total reduction of endotoxin is 53% at the end of plasma recycling. If used TOXIPAK® adsorber endotoxin reduction is 45% within first 30 minutes and 58% after 120 minutes perfusion. In case of LPS Adsorber® endotoxin reduction is 24% within first 30 minutes and 31% at the end of plasma recycling.
Conclusion. All tested systems for LPS adsorption remove endotoxin, but cartridge TORAYMYXIN® PMX-20R and column TOXIPAK® have higher LPS binding capacity than LPS Adsorber®.
|P-04|| Sorbents for selective removal of sFlt-1 to treat preeclampsia.
1 National Medical Research Center of Cardiology, Ministry of Health of Russian Federation, Moscow, Russia, Institute of Experimental Cardiology, Moscow, Russian Federation
2 Moscow State University, , Moscow , Russian Federation
Abstract text :
Question. The soluble sVEGFR-1 receptor (sFlt-1) is not only one of the most sensitive markers of preeclampsia, but also the probable target for the therapy of this disease. It is shown that the use of systems for LDL apheresis for the treatment of preeclampsia allows to extend the gestation period from 7 to 40 days (Ying Wang, 2006). Current knowledge about the role of sFlt-1 in the development of preeclampsia suggests that this positive clinical effect is associated with the co- elimination of sFlt-1 together with LDL during LDL apheresis (Thadhani R., 2011). But this hypothesis requires confirmation because the specificity of different currently existing systems for LDL apheresis does not allow to assert that the removal of this particular substance leads to the positive clinical effect.
The aim of our study was to design the line of sorbents with different selectivity for sFlt-1 and apoB100 containing lipoproteins suitable to investigate the role of sFlt-1 in preeclampsia by apheresis techniques.
Methods. The plasma samples from pregnant woman with preeclampsia were used for the testing of synthesized sorbents. The efficacy of sFlt-1 and lipids removing was evaluated by the difference in the concentrations before and after batch affinity chromatography. Incubation of plasma samples was carried out during 1 hour, at the RT. sFlt-1 and PlGF plasma concentrations were determined by ELISA kits («R&D systems», USA), the lipid profile – with Biocon/Analyticon reagent kit (Germany).
Results. The derivative of mucopolysaccharide and polyclonal antibodies against human LDL were immobilized on agarose matrixes with different pore sizes (the partition coefficient Kav for thyroglobulin (669 кDа) was 0.19 for small pores and 0.53 for large ones). It was shown that the sorbent for the specific elimination of LDL does not remove sFlt-1. Both sorbents with immobilized mucopolysaccharide were able to remove up to 98% of sFlt-1 and decreased the ratio of sVEGF-R1/PlGF in plasma after the chromatography up to 20 times. At the same time the sorbent with large pore size remove the LDL with high efficacy, but the sorbent with smaller pore size have low capacity for LDL binding.
Conclusion. Synthesized sorbents could be used to further study of sFlt-1, its pathogenic role in the development of preeclampsia and possible treatment of preeclampsia by selective sFlt-1 apheresis.
|P-05||Antibodies and synthetic ligands containing sorbents for Ig apheresis (in vitro comparison study)
1 National Medical Research Center of Cardiology, Ministry of Health of Russian Federation, Institute of Experimental Cardiology, Moscow, Russian Federation
2 Moscow State University, , Moscow, Russian Federation
Abstract text :
Question. The aim is to compare the efficacy of two sorbents for immunoglobulin (Ig) removal, suitable for plasma and whole blood perfusion in vitro under the same conditions.
Methods. Sorbents based on agarose matrixes with immobilized: polyclonal antibodies against human IgG (Ig-plasmasorbent-Sorbent 1) and synthetic ligand (Ig-hemosorbent - Sorbent 2), for Ig binding from human plasma and whole blood, respectively were examined. Chromatography was performed with three plasma samples of patients with antiphospholipid syndrome with the following sorbent/plasma volume of ratio of 1/5. Concentrations of IgG, IgA, IgM, specific antiphospholipid autoantibodies, as well as autoantibodies to DNA and atherogenic lipoproteins, C-reactive protein (CRP) were measured before and after affinity chromatography.
Results. The total IgG pool as well as pathogenic autoantibodies were removed by both sorbents with the same efficacy (data are present in the table). The sorbent with a synthetic ligand also was able to bind CRP with high efficacy.
Conclusion. Both tested sorbents are equally effective for the removal of IgG. The ability of a sorbent 2 to bind CRP can be an additional advantage in the treatment of patients with antiphospholipid syndrome and some other autoimmune diseases.
|P-06||Caplacizumab for acquired thrombotic thrombocytopenic purpura - results of the phase 3 HERCULES study
1 University College London Hospitals NHS Trust, Department of Haematology, London, United Kingdom
2 The Ohio State University, Department of Internal Medicine, Columbus, United States
3 University of Milan, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy
4 Saint-Antoine University Hospital, Department of Hematology, Paris, France
5 Medical University of Vienna, Department of Medicine 1, Vienna, Austria
6 Bern University Hospital, University Clinic of Hematology and Central Hematology Laboratory, Bern, Switzerland
7 Duke University School of Medicine, Division of Hematology, Durham, United States
8 Universidad Católica de Valencia Hospital Dr. Peset, Hematology Department, Valencia, Spain
9 St. Michael's Hospital/Research Institute, Department of Laboratory Medicine and Pathobiology, Toronto, Canada
10 Ablynx, Clinical Operations, Ghent, Belgium
Abstract text :
Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening autoimmune thrombotic microangiopathy. Episodes of aTTP are currently treated with plasma exchange (PE) to eliminate autoantibodies and to replenish ADAMTS13, and immunosuppression to address autoantibody formation.
We report the results of a randomised, double blind, placebo controlled study of caplacizumab, a bivalent Nanobody,targeting the A1 domain of vWF, in addition to standard of care.
Methods: Patients with an acute episode of aTTP who had received one PE treatment were randomized 1:1 to placebo or 10 mg caplacizumab (daily), in addition to daily PE and corticosteroids. The study drug was given during the PE period and 30 days thereafter. If at the end of this period there was evidence of ongoing disease, such as suppressed ADAMTS13 activity, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks together with optimization of immunosuppression. All patients entered a 28-day treatment-free follow up period after the last dose of study drug.
Results: 145 patients were randomized (73 placebo, 72 caplacizumab). Compared to placebo, caplacizumab-treated patients were >50% more likely to achieve a platelet count response (platelet count normalization rate 1.55, 95% CI 1.10 â€" 2.20, p<0.01). During the study drug treatment period, treatment with caplacizumab resulted in a 74% reduction in TTP-related death, recurrence of TTP, or a major thromboembolic event (p<0.0001). During the overall study period, patients administered caplacizumab had a 67% reduction in disease recurrence (p<0.001). No caplacizumab-treated patients were refractory to therapy versus 3 on placebo (p=0.057). The most common caplacizumab-related TEAEs were epistaxis, gingival bleeding, and bruising.
Conclusions: Treatment with caplacizumab reduced the time to platelet count response and resulted in a clinically meaningful reduction in aTTP-related death, recurrence of aTTP, or a major thromboembolic event during study drug treatment, as well as recurrences during the overall study period. The safety profile was favorable, with mucocutaneous bleeding the most frequently reported AE. Caplacizumab represents a novel treatment for patients with aTTP. (clinicaltrials.gov: NCT02553317).
|P-07||Immunoadsorption in Dilated Cardiomyopathy – what the literature tells us
1 Fresenius SE & Co. KGaA, , Bad Homburg, Germany
2 Fresenius Medical Care Deutschland GmbH, , Bad Homburg, Germany
Abstract text :
Dilated cardiomyopathy (DCM) is the most common form of heart muscle disease and one of the main reasons for heart failure (HF). Approximately 30% of all cases of HF can be attributed to DCM. Antibodies such as β1 receptor autoantibodies and immunoglobulins have been identified as pathogens in DCM. Clinical and experimental investigations have demonstrated removal of circulating cardiac autoantibodies by immunoadsorption (IA).
In order to evaluate the benefit of IA in DCM-patients a systematic literature review was conducted resulting in an evidence report. Searches were carried out using databases MEDLINE and EMBASE, complemented by hand-search. Relevant endpoints defining the medical benefit of IA and comparator interventions were derived from literature and expert interviews. Outcome parameters included: Left Ventricular Ejection Fraction (LVEF), New York Heart Association (NYHA) classification, mortality, cardiopulmonary performance, hemodynamics, biomarkers, time toheart transplantation, hospitalization (length of stay & re-hospitalization rate), treatment-related adverse events and Quality of Life. Included were all patients with DCM, excluding those with known alcohol-induced or genetically caused cardiomyopathy.
A total of 37 publications meeting the search criteria were identified. 11 of these were controlled or case-control trials, 26 were case series. LVEF and NYHA class were the most often assessed outcome parameters showing statistically significant effects. Improvement of the LVEF was observed after IA treatment independent of study type. This effect was not visible in control groups. In addition, an alleviation of symptoms of DCM was evident after treatment when assessed by the NYHA classification
There is a consistent direction reporting positive effects of IA treatment in DCM patients. In conjunction with the very low number of adverse events reported, it can be concluded that patients with DCM may benefit from IA.
|P-08||EFFECTS OF TERAPEUTIC APHERESIS METHODS IN TREATMENT OF STIFF-PERSON SYNDROM
1 S.M. Kirov Military Medical Academy, Department of Nephrology and Blood Purification, Saint Petersburg, Russian Federation
2 Pavlov First Saint-Petersburg State Medical University, Laboratory of Autoimmune Diagnostics, Saint Petersburg, Russian Federation
Abstract text :
Stiff-person syndrome (SPS) is a rare autoimmune disease with a paraneoplastic or unknown trigger caused by autoantibodies to glutamic acid decarboxylase (anti-GAD) and characterized by trunk and / or limb muscle spasticity.
Purpose: to evaluate the possibilities of therapeutic apheresis methods in the treatment of SPS.
Objects and methods. Two patients aged 37 and 50 with an idiopathic form of SPS were examined and treated. All patients were dynamically examined for the level of anti-GAD. Medication included immunosuppressive therapy (glucocorticosteroids 1 g / kg, cyclophosphamide 1000 mg) and symptomatic agents. In the first SPS case, two operations of double filtration plasmapheresis (DFPP) were used on the devices OctaNova with plasma fractionator «Cascadeflo EC20» («Asahi», Japan), with exfusion of 80% of circulating plasma volume (CPV) in combination with pulse therapy with methylprednisolone (PTM) (1 g; № 2); in the second case, two sessions of 5 plasmapheresis (PP) (30–40% of the CPV) in combination with PTM. Clinical and immunological effects of TA was assessed.
Results. In the first SPS case, immunosuppressive immunodeficiency therapy reduced the multiplicity and severity of painful muscle spasms, while the level of anti-GAD decreased from 242 433 to 190 434 U / ml. (-24%). Two subsequent operations of the DFPP significantly reduced the spasticity index (IS) from 5 to 3 and the sensitivity index (IS) from 4 to 1, while the anti-GAD level was 74 340 U / ml (-61%). The subsequent course of PP allowed to achieve a stable remission and to reduce the level of anti-GAD by 24% (to 65 307 U / ml). In the second SPS case, treatment by methylprednisolone (1 g / kg), levetiracetam (1000 mg / day), baclofen oral (75 mg / day) reduced only the incidence of painful spasms. After the first session of PP painful spasms disappeared and background spasticity decreased to 4 points, clear consciousness was restored. The level of anti-GAD decreased by 26% (from 640 850 to 474 230 U / ml) for the first session of PP and 24% for the second session of PP (up to 360 414 U / ml). After the courses of TA an asymmetric increase muscular hypertonus in the limbs was preserved.
Conclusions. Methods of TA in patients with SPS enhance the effectiveness of pathogenetic therapy and accelerate the achievement of persistent remission by reducing the level of anti-GAD.
|P-09||Outcomes following living donor kidney transplantation in patients with donor-specific HLA antibodies after desensitization with immunoadsorption
1 Nephrology Unit, University Hospital Heidelberg, Heidelberg, Germany
2 Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
3 Department of Transplantation Immunology, University Hospital Heidelberg, Heidelberg, Germany
Abstract text :
INTRODUCTION AND AIMS
Due to the current organ shortage, living donor kidney transplantation is increasingly performed over human leukocyte antigen (HLA) or ABO antibody barriers. Uncertainty still exists concerning the risk for antibody-mediated rejection episodes, possibly limiting long-term graft survival. The present study aimed to evaluate the outcomes of kidney transplantations performed after desensitization in patients with donor-specific HLA antibodies compared to standard risk recipients.
Thirty-seven sensitized patients were included in the study. Sixteen patients had a positive CDC and/or ELISA crossmatch result with their prospective living donor and 31 patients had Luminex-detected donor-specific HLA antibodies (DSA). Patients were successfully desensitized by immunoadsorption treatment (median of 8 treatments) and anti-CD20 antibody rituximab (N=32) combined with antithymocyte globulin (N=19) or anti-IL2 receptor antibody therapy (N=18). Eleven patients were additionally treated by plasmapheresis. All patients received a kidney transplant from a living donor. Postoperative apheresis was performed in 35 patients. The outcomes of the 37 patients were retrospectively compared to outcomes of 74 standard risk recipients (2:1 matching).
During a median of 8 pretransplant immunoadsorption treatments, IgG was reduced by 98% and IgM by 78% in sensitized patients. After transplantation, sensitized patients showed comparable death-censored graft survival and patient survival compared to standard risk recipients. Infectious complications, surgical complications and rejection rates (19% in both groups) were not significantly different between groups. Median 1-year serum creatinine was with 1.31 mg/dL in sensitized recipients not significantly different to the 1.38 mg/dL in standard risk recipients. One-year urinary protein excretion was also not significantly different with a low 10.8 and 10.5 g/mol creatinine, respectively.
Our desensitization protocol for sensitized living donor kidney transplant recipients results in good graft outcomes with comparable side effects and rejections rates to standard risk recipients.
|P-10||A Novel Smart Adsorbent For Extracorporeal Blood Purification Therapy
1 ImmutriX Therapeutics, Inc., , Rapid City, SD, United States
Abstract text :
Therapeutic apheresis has become a useful modality in the treatment for many autoimmune, inflammatory and metabolic disorders. Apheresis and plasmapheresis require a complex separation of plasma from cellular components of blood, thus there is much promise in extracorporeal whole blood cleansing procedures. To date many adsorbent and/or affinity materials have been developed for whole blood hemoadsorption. Despite their numerous potentials, these products have historically been challenged in the areas of molecular selectivity, surface area, particulate release and hemocompatibility that reduce their therapeutic efficacy.