[Lymphadenopathy and constitutional symptoms. Progress of a low-grade follicular lymphoma?]. / Generalisierte Lymphadenopathie und B-Symptomatik. Progression eines indolenten Non-Hodgkin-Lymphoms?

Atypical presentation of Churg-Strauss syndrome includes lymph-node and parenchymatous organ involvement which mimics the clinical presentation of lymphoproliferative disorders.A 54-year old man with a history of a low-grade follicular lymphoma presented with rapidly growing abdominal lymph-nodes and hepatic, renal and pulmonary infiltrations. CT guided biopsies to verify either lymphoma or infections showed eosinophilic, necrotizing, granulomatous vasculitis leading to the diagnosis of atypical Churg-Strauss syndrome. Within a few days of cyclophosphamide and prednisone treatment the clinical presentation improved and imaging studies detected regression of all manifestations during follow-up.

Efficacy and safety of DALI LDL-apheresis at high blood flow rates: a prospective multicenter study.

Direct adsorption of lipids (DALI) is the first LDL-apheresis method compatible with whole blood. Usually, the blood flow rate is adjusted at 60-80 ml/min, which results in session times of about 2 hr. The present study was performed to test the safety and efficacy of low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] removal by DALI at high blood flow rates in order to reduce treatment time. Thirteen chronic DALI patients in seven centers suffering from hypercholesterolemia (LDL-C 162 +/- 42 mg/dl at baseline) and coronary artery disease were treated on a weekly or biweekly basis by DALI apheresis. The blood flow rate QB was held constant for at least two sessions, respectively, and was increased from 60 to 80, 120, 160, 200, and 240 ml/min. All patients had pre-existing av-fistulas. The anticoagulation was performed by a heparin bolus plus ACD-A at a ratio of citrate:blood ranging from 1:20 to 1:90. Clinically, the sessions were well tolerated and only 26/201 sessions (12%) of the treatments were fraught with minor adverse events. Acute LDL-C reductions (derived from LDL-C levels determined by lipoprotein electrophoresis) averaged 72/66/60/53/50/48% for QB=60/80/120/160/200/240 ml/min. Lp(a) reductions were 68/67/62/60/58/56%, whereas HDL-C losses were < or =10%. Routine blood chemistries and blood cell counts remained in the normal range. Treatment times averaged 142/83/45 min at Qb=60/120/240 ml/min. On average, DALI LDL-apheresis could be performed safely and effectively at high blood flow rates up to at least 120 ml/min in patients with good blood access, which significantly reduced treatment time from 142 to 83 min (-42%).

Direct adsorption of low-density lipoprotein and lipoprotein(a) from whole blood: results of the first clinical long-term multicenter study using DALI apheresis.

Direct adsorption of lipoproteins (DALI) is the first low-density lipoprotein (LDL)-apheresis technique by which atherogenic LDL and lipoprotein(a) (Lp(a)) can be selectively removed from whole blood without plasma separation. The present study was performed to evaluate the efficacy, selectivity and safety of long-term DALI apheresis. Sixty-three hypercholesterolemic coronary patients were treated by weekly DALI sessions. Initial LDL-cholesterol (C) plasma levels averaged 238 +/- 87 mg/dl (range 130-681 mg/dl). On average, 34 sessions (1-45) were performed processing 1.5 patient blood volumes. The primary aim was to acutely reduce LDL-C by >or=60% per session. To this end, three different adsorber sizes could be employed, i.e., DALI 500, 750, and 1000, which were used in 4, 73, and 23% of the 2156 sessions, respectively. On average, 7387 ml of blood were processed in 116 min per session. This resulted in the following mean acute changes: LDL-C 198 --> 63 mg/dl (-69%), Lp(a) 86 --> 32 mg/dl (-64%), triglycerides 185 --> 136 mg/dl (-27%). HDL-C (-11%) and fibrinogen (-15%) were not significantly influenced. The mean long-term reduction of LDL-C was 42% compared to baseline while HDL-C slightly increased in the long run (+4%). The selectivity of LDL removal was good as recoveries of albumin, immunoglobulins, and other proteins exceeded 85%. Ninety-five percent of 2156 sessions were completely uneventful. The most frequent adverse effects were hypotension (1.2% of sessions) and paresthesia (1.1%), which were probably due to citrate anticoagulation. Access problems had to be overcome in 1.5%, adsorber and hardware problems in 0.5% of the sessions. In this multicenter long-term study, DALI apheresis proved to be an efficient, safe, and easy procedure for extracorporeal LDL and Lp(a) elimination.

Therapeutic plasma exchange in the intensive care setting.

The potential to treat life-threatening conditions with therapeutic plasma exchange (TPE) is limited to a few situations. In severe pulmonary hemorrhage as a complication of several immune disorders (e.g., antiglomerular basement membrane antibody disease, Wegener's granulomatosus, lupus erythematosus), TPE should only be considered after conventional measures (mostly pulses of methylprednisolone) have been applied. Idiopathic familial and nonfamilial thrombotic thrombocytopenic purpura as well as the subset of the hemolytic uremic syndrome not associated with diarrhea are clear indications for TPE using fresh frozen plasma as replacement fluid. Patients with myasthenic crisis will also benefit from TPE and will improve within 1 day. Acute pancreatitis as a complication of the chylomicronemia syndrome has a poor prognosis and should be treated with TPE without any delay. In the case of drug overdose or intoxication, the efficiency of TPE to remove the offending drug is usually overestimated. In this situation, TPE is useful only when the plasma protein binding of the substance is high (>80%) and the volume of distribution is low (<0.2 L/kg body weight). TPE is not without risks and hazards (e.g., vascular access, bleeding, allergy), which should also be considered when discussing this extracorporeal therapy in otherwise refractory clinical conditions.

High-efficiency DALI apheresis using 1,250 ml adsorbers in a hypercholesterolemic obese patient: a case report.

Direct adsorption of lipoproteins (DALI) apheresis is the first method for direct adsorption of lipoproteins from whole blood and is therefore an easy and rapid procedure. The majority of patients reaches >60% acute low-density lipoprotein cholesterol (LDL-C) reduction using either the DALI 750 or 1000 configuration. However, in patients with extremely high LDL-C levels or very large blood volumes, these configurations may lead to suboptimal results. The current study was performed to test the safety and efficacy of DALI 1250. In a severely obese patient (185 cm, 133 kg, blood volume 7.2 L, LDL-C 239 mg/dl), 11 L of blood (1.53-fold patient blood volume) was processed at a flow rate of 80 ml/min in 2.5 h; a combined heparin-plus-citrate anticoagulation regimen was used. Commercially available DALI 1250 and DALI hardware and disposables were manufactured by Fresenius HemoCare Adsorber Technology, St. Wendel, Germany. Twenty weekly sessions were performed. Clinically and technically, the apheresis sessions were completely uneventful. As compared to DALI 1000 (n = 4 sessions), the reduction rates by DALI 1250 (n = 20) improved for LDL-C (from 52% to 66%), lipoprotein (a) (Lp[a]) (53% vs. 66%), and fibrinogen (11% vs. 16%). There was a slight increase in high-density lipoprotein cholesterol (HDL-C) loss (20% vs. 24%). Moreover, the absolute amount of LDL-C removed per session increased from 5.06 g to 5.94 g. Laboratory safety parameters remained within the normal range, the anticoagulation was well controlled, and the pressure gradients over the adsorber remained constant. In this case report, DALI 1250 was perfectly safe and significantly increased the efficacy of LDL-C and Lp(a) elimination compared to standard DALI. Thus, this high-efficiency version of DALI may be used in patients with extremely high LDL-C levels and/or large blood volumes.

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 contrast, 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.

Ex vivo biocompatibility of avidin-agarose: a new device for direct adsorption of biotinylated antibodies from human whole blood.

Radioimmunotherapy using radiolabeled antitumor antibodies (RAA) is limited by the toxicity of unbound antibodies in the circulation. Removal of excessive antibodies by affinity-adsorption could therefore allow the administration of increased dosages of RAA while decreasing their adverse effects. Recently, avidin-agarose (AA) minicolumns were used in animal experiments for the removal of biotinylated antibodies from whole blood exploiting the high affinity binding of biotin to avidin (pK 1015 M-1). This study was performed to evaluate the ex vivo biocompatibility of AA minicolumns with human blood. Ten ml AA minicolumns were perfused online ex vivo in the single pass mode with fresh blood from 8 healthy donors at a flow rate of 6.25 ml/min. The anticoagulation consisted of 0.5 IU heparin plus 0.0-2.1 mg citrate per ml of blood. In Part 1 of the study (40 min perfusion, n = 4), the optimal anticoagulation was found to be 0.5 IU heparin plus about 1 mg citrate per ml of blood. In Part 2 of the study, four 80 min test-runs were performed. No signs of hemolysis were found, and the thrombogenicity of the AA gel was negligible. Cell counts and column inlet pressures remained constant; toward the end of the 80 min test-runs, some activation of blood cells (elastase, beta-thromboglobulin), the complement system (C3a, C5a) and the plasmatic coagulation (thrombin-antithrombin complex) was detectable. A moderate initial bradykinin release rapidly subsided to very low levels. In summary, AA minicolumns showed good biocompatibility upon contact with human whole blood and merit further investigation in a closed-loop system for a potential application of direct tumor antibody removal by hemoperfusion.

DALI apheresis in hyperlipidemic patients: biocompatibility, efficacy, and selectivity of direct adsorption of lipoproteins from whole blood.

Recently, the first apheresis technique for direct adsorption of low-density lipoprotein (LDL) and lipoprotein(a) [Lp(a)] from whole blood (DALI) was developed that does not require a prior plasma separation. That markedly simplifies the extracorporeal circuit. The aim of the present study was to test the acute biocompatibility, efficacy, and selectivity of DALI apheresis. In a prospective clinical study, 6 hypercholesterolemic patients suffering from angiographically proven atherosclerosis were treated 4 times each by DALI. 1.3 patient blood volumes were treated per session at blood flow rates of 60-80 ml/min using 750 or 1,000 ml of polyacrylate/polyacrylamide adsorber gel. The anticoagulation consisted of an initial heparin bolus followed by a citrate infusion. The sessions were clinically essentially uneventful. Mean corrected reductions of lipoproteins amounted to 65% for LDL-cholesterol, 54% for Lp(a), 28% for triglycerides, 1% for HDL-cholesterol, and 8% for fibrinogen. The selectivity of lipoprotein removal was high. Cell counts remained virtually unchanged and no signs of hemolysis or clotting were detected. Cell activation parameters elastase, beta-thromboglobulin, interleukin-1beta, and IL-6 showed no significant increase. Complement activation was negligible. There was significant, but clinically asymptomatic, bradykinin activation in the adsorber with mean maxima of 12,000 pg/ml in the efferent line at 1,000 ml of treated blood volume. In conclusion, DALI proved to be safe, selective, and efficient for the adsorption of LDL-C and Lp(a), which simplifies substantially the extracorporeal therapy in hypercholesterolemic patients.

Low density lipoprotein hemoperfusion by direct adsorption of lipoproteins from whole blood (DALI apheresis): clinical experience from a single center.

The elimination of low density lipoprotein (LDL) and lipoprotein (a) (Lp[a]) by conventional LDL apheresis techniques can only be achieved in a cell-free medium and thus requires the initial separation of plasma from the blood cells. The present paper describes the first LDL hemoperfusion system which is able to adsorb LDL and Lp(a) directly from whole blood. This simplifies the procedure substantially. The adsorber consists of polyacrylate ligands linked to a modified polyacrylamide matrix. These negatively charged polyacrylate ligands interact with the positively charged apoprotein B moiety of LDL and Lp(a), which results in selective adsorption of these lipoproteins onto the column. Three hypercholesterolemic patients suffering from overt atherosclerotic complications were treated weekly by direct adsorption of lipoproteins (DALI) (n = 20 sessions each). All patients were on the highest tolerated dose of cholesterol synthesis enzyme (CSE) inhibitors. About 1.3 patient blood volumes were treated per session. The anticoagulation was performed with acid citrate dextrose (ACD-A). The following acute reductions were achieved: LDL: 66%; Lp(a): 63%; and triglycerides: 29%. High density lipoprotein (HDL) (-13%) and fibrinogen (-16%) were not substantially reduced. The sessions were essentially uneventful. Due to a low ACD-A infusion rate, no hypocalcemic episodes were registered. One patient on enalapril was treated without complications when this angiotensin converting enzyme (ACE) inhibitor was withdrawn 2 days prior to apheresis. In summary, in our hands, DALI apheresis proved to be a simple, safe, and efficient method of lipid apheresis in hypercholesterolemic patients refractory to conservative lipid lowering therapy.

Therapeutic plasma exchange in patients with chylomicronemia syndrome complicated by acute pancreatitis.

Chylomicronemia syndrome (CMS) is a rare disorder characterized by the presence of chylomicrons in the fasting state causing a milky appearance of plasma, eruptive xanthomas, and hepatosplenomegaly; an acute and potentially life threatening complication is severe acute pancreatitis. The underlying defects are inborn errors of metabolism such as deficiencies of lipoprotein lipase (LPL) or apoprotein C-II (apo C-II) as well as familial hypertriglyceridemia. Moreover, CMS can be precipitated when mild hypertriglyceridemia is exacerbated by additional factors such diabetes mellitus, ethanol abuse, or pregnancy. The purpose of the present study was to retrospectively analyze the results of therapeutic plasma exchange (TPE) in 5 patients transferred to our hospital for severe acute pancreatitis due to chylomicronemia syndrome. In a total of 7 TPE sessions, on average 3,286 +/- 247 ml of plasma (i.e., about 1 patient plasma volume) were treated per session. Triglyceride (TG) levels were decreased from 4,972 +/- 2,469 mg/dl on admission to 1,614 +/- 1,276 mg/dl (-70%) after the TPE sessions, and a further decrease was achieved by conservative treatment. Part of the TG reducing effect of the treatment was probably due to heparin induced lipolysis. Acute pancreatitis was resolved in all cases, and 1 pregnant patient delivered without problems at term. In summary, 1 or 2 TPE sessions sufficed to substantially decrease the bulk of triglycerides in acutely exacerbated chylomicronemia syndrome causing a rapid resolution of acute severe pancreatitis.

Therapeutic plasma exchange in patients suffering from thrombotic microangiopathy after allogeneic bone marrow transplantation.

Thrombotic microangiopathy (TM) is a potentially fatal complication of allogeneic bone marrow transplantation (BMT). The underlying pathophysiology is thought to be generalized endothelial cell damage caused by several factors including conditioning treatment, cyclosporin A (CsA), or graft versus host disease (GVHD). In the present retrospective study, 6 patients suffering from Grade 2 BMT-TM at a mean of 62 days post BMT were treated by 3-15 daily sessions of therapeutic plasma exchange (TPE). In most sessions, cryosupernatant (CSN) of plasma, in some fresh frozen plasma (FFP) was used as the substitution fluid. All patients suffered from acute graft versus host disease (aGVHD) of the skin, which was treated by CsA. CsA was withdrawn in all patients. TPE caused a response in 4 of 6 patients evidenced by a decrease to Grade 0 (n = 3) or 1 (n = 1) BMT-TM. Only 1 patient had mild renal insufficiency which did not improve during TPE. While all patients were dependent on platelet transfusions at baseline, the platelet counts improved in 2 of 6 patients after the TPE course. One patient did not show any response to TPE with FFP, and his disease improved only after CSN was introduced as substitution fluid (Grade 0). Four patients were still alive 175-495 days post BMT, and 2 patients died about 2-3 weeks after the end of the TPE course, 1 from cachexia and 1 from systemic aspergillosis. In summary, in this pilot study, TPE positively influenced BMT-TM, especially if CSN was used as the substitution fluid.