T. Bosch

Efficacy of lipid apheresis: definitions and influencing factors.

The comparison of efficiency of currently available lipid apheresis systems has been hampered by different definitions of efficacy and poorly controlled apheresis conditions. This paper suggests definitions of efficacy and standardization of its determinants. The acute efficacy of risk factor reduction reflects the relative decrease of pathogen by a single treatment session compared to preapheresis levels. Standardization of treated plasma volume in relation to the patients plasma volume and correction of changes in plasma volume during the procedure are mandatory. Its determination is most useful in the technical evaluation of new systems. The long-term efficacy of risk factor reduction as compared to baseline is determined by mean interapheresis levels of e.g. LDL-C in the pseudo-steady-state after about 3 months of regular treatment. It is the major criterion for potential regression of coronary artery disease and absolute average plasma levels of 120 ≤ mg/dl LDL-C should be attained. It is influenced by the acute efficacy of the system, apheresis frequency and rebound kinetics. The clinical efficacy is defined by apheresis induced reduction of coronary morbidity and mortality. It is influenced by long-term risk factor reduction, the selectivity of the system as well as the control of non-lipid risk factors. Apheresis related effects on coronary artery disease comprise functional improvements of hemorheology and vasomotion as well as morphological benefits like regression of luminal narrowing and plaque stabilization. In conclusion, the acute efficacy of apheresis systems should be determined under strictly controlled conditions; however, as apheresis independent factors influence long-term efficacy and, even more so, clinical efficacy of the treatment, differences between the available systems are blurred so that factors like costs and ease of handling may eventually significantly influence the choice of procedure.

Heparin-free DALI LDL-apheresis in hyperlipidemic patients: efficacy, safety and biocompatibility.

Background and Aim of Study In routine DALI apheresis - the first technique for direct adsorption of lipoproteins from whole blood - heparin plus citrate (ACD-A) is used as anticoagulation regimen. However, recently several publications have warned of heparin-induced thrombocytopenia as a rare but potentially life-threatening complication of heparin administration (HIT type 2). The aim of the present study was therefore to test the efficacy and biocompatibility of DALI using a heparin-free anticoagulation regimen consisting exclusively of citrate. Methods Four symptomatic hypercholesterolemic patients on regular DALI apheresis were switched to the heparin-free protocol for two sessions each. Two of the patients were on oral anticoagulation using phenprocoumon. In the weekly sessions, 1.3 patient blood volumes were processed at a blood flow rate of 60 ml/min using ACD-A at a ratio of 1:20 (v/v) during adsorber priming and the session. Results Clinically, all sessions were essentially uneventful. Uncorrected lipoprotein reductions amounted to 65% for LDL-C, 62% for Lp(a), 53% for VLDL-C, 24% for HDL-C, 17% for triglycerides and 19% for fibrinogen. Cell counts remained virtually constant. No signs of hemolysis or clotting could be detected. Thromboplastin time (Quick) was slightly prolonged and partial thromboplastin time (PTT) moderately elevated in all patients. In constrast, whole blood coagulation time acc. to Lee-White and activated clotting times were increased only in orally anticoagulated patients. Biocompatibility in terms of complement, leukocyte and thrombocyte activation was excellent. Bradykinin activation was moderate peaking at 3038 pg/ml in the efferent line. Systemic thrombin-antithrombin complex (TAT) reflected perfect anticoagulation in orally anticoagulated patients and adequate anticoagulation in the patients without phenprocoumon. Conclusion In this pilot study, heparin-free DALI apheresis was safe and effective and may thus be performed in LDL-apheresis dependent patients who suffer from heparin intolerance.

Reverse Flux Filtration: A New Mode of Therapy Improving the Efficacy of Heparin - Induced Extracorporeal Ldl Precipitation in Hyperlipidemic Hemodialysis Patients

In the steady state after a run-in phase of 3 months, the acute effects of 3 modifications of weekly heparin-induced extracorporeal LDL precipitation (HELP) were studied in 5 ESRD and 2 non-uremic hypercholesterolemic coronary patients. In ESRD patients (n=29 sessions), HELP reduced LDL-cholesterol (LDL-C) (56 ± 7%) and fibrinogen (FIB) (54 ± 10%) by a similar percentage as compared to non-uremic controls (60 ± 4% and 61 ± 3%, resp.; n=5). In order to eliminate the need for extra HELP sessions in addition to the normal dialysis regimen, newly developed hardware was then used to perform combined synchronous HELP/HD (n=12). However, premature precipitate filter plugging probably due to hyperfibrinogenemia in ESRD patients, accentuated by ultrafiltration (UF), decreased the corresponding reductions to 26 ± 9% (LDL-C) and 34 ± 11% (FIB). Therefore, the procedure was modified by reversing the filtrate flux through the precipitate filter membrane after 900 ml of treated plasma (“reverse flux filtration”, RFF; n=11). Thus, in RFF-HELP/HD the LDL/FIB/heparin coprecipitate was deposited on both filter membrane sides which caused a significant enhancement of the filter capacity and improved reductions to 46 ± 14% for LDL-C and 51 ± 15% for FIB. Elution of the precipitate from the precipitate filter after the sessions showed that RFF-HELP/HD had trapped 1733 ± 238 mg LDL-C and 8108 ± 1876 mg FIB in ESRD patients, while HELP eliminated 1890 ± 333 mg LDL-C and only 3663 ± 369 mg FIB in non-uremics. Filter precipitate recoveries (relative to the mass removed from the patient plasma pool) amounted to 97 ± 18% for LDL-C and 158 ± 67% for FIB in the ESRD group treated by RFF-HELP/HD vs. 70 and 76% in the non-uremic HELP group. Probably, passive transport of lipoproteins and FIB from the interstitium into the vascular space caused repletion of this compartment during HELP/HD where an UF induced solvent drag is effective. In summary, the new RFF-HELP/HD procedure effectively reduced LDL-C and FIB in ESRD patients who could not be adequately treated by the conventional HELP/HD system.

Evaluation of microparticle leakage during DALI LDL adsorption in a simulated clinical setting.

The aim of the present study was to investigate microparticle (Mp) leakage during simulated LDL-hemoperfusion using 12 DALI 750 adsorbers and the original DALI hardware under conditions strictly comparable to the clinical situation. Thus, the sessions were divided into 4 sections, i.e. priming and preparation of the adsorber followed by treatment (6–7 L at a flow rate of 60 ml/min) and reinfusion. As Mp counts can be performed only in clear, cell-free media, blood was replaced by normal saline in sections 2–4 of the simulated sessions. Mp counts were analysed for ≥ 2, ≥ 5, ≥ 10 and ≥ 25 μm particle sizes in the efferent line post adsorber using a standard light blockage method. As there are no official thresholds for particle release in extracorporeal circuits, the limits for infusion of large fluid volumes of 500, 100 (80), 25 and 5 (3) Mp/ml according to the Europäische Arzneimittelbuch, the British and American Pharmacopoeias were used. Mean particle counts for the sections 3 and 4 in which the patient is connected to the efferent line were 19, 7, 2 and 0 Mp/ml and amounted to < 10% of the above mentioned limits. Modifications of the standard simulation procedure by inserting additional pump stops or using different flow rates during the treatment phase slightly increased Mp leakage, but never exceeded the prescribed limits. In summary, no undue particle release could be detected during simulations of the clinical DALI LDL-adsorption procedure.

Adsorption Treatment in Hyperlipidemia

Clinical LDL- adsorption has made overwhelming progress in recent years. Thus, immunoadsorption with polyclonal anti-LDL-antibodies and chemoadsorption using the dextransulfate system have been applied successfully for selective LDL-removal in routine clinical plasma treatment of hypercholesterolemic patients suffering from coronary artery disease. Clinical pilot studies showed good results using immunoadsorption with anti-LDL-F(ab)-columns. Promising laboratory results have been achieved using immunoadsorption with monoclonal LDL-antibodies, polyacrylate/fractogel and macroporous cellulose. While these systems need a primary separation step for cells and plasma, the integrated plasma separation/adsorption device and the LDL-hemoperfusion module using E 280590 can even treat whole blood. Thus, these systems hold a great promise for the future.

Klinische LDL-Adsorption an Dextransulfat mit automatischer On-line-Adsorberregeneration bei Hyperlipoproteinämie

Mit der Publikation der sog. Framingham-Studie [3] erfolgte die Dokumentation der Hypercholesterinamie als primarem Risikofaktor in der Pathogenese der Atherosklerose. Wegen der epidemiologischen Bedeutung dieses Befundes ruckte in der Folge die Behandlung der Hyperlipidamie in den Mittelpunkt des medizinischen Interesses. Wahrend die meisten Patienten mit Diat und Lipidsenkern adaquat behandelt werden konnen, hat sich die Lipidapherese in den letzten Jahren bei Patienten mit trotz oben genannter Masnahmen persistierender Hyperlipoproteinamie bewahrt. Neben unspezifischer Plasmapherese wurden z.B. Doppelfiltration [4], LDL-Fallung mit Heparin [5] oder LDL-Adsorption an Anti-LDL-Antikorper [1] und Dextransulfat [6] erfolgreich eingesetzt.