Incorporation of low-density lipoprotein apheresis into the treatment program of patients with severe hypercholesterolemia

Treatment to low-density lipoprotein (LDL) cholesterol targets has become a focus in the management of patients with coronary heart disease (CHD). Many patients with familial hypercholesterolemia (FH) are unable to reach targets because of drug intolerance or extremely high baseline LDL cholesterol levels. Consequently, LDL apheresis has become a useful modality for the treatment of patients with severe hypercholesterolemia. Commonly used LDL apheresis systems utilize immunoadsorption columns, dextran sulfate cellulose columns, or heparin precipitation. A new and simpler treatment modality is emerging which uses whole blood compatible columns. All systems require systemic anticoagulation, extracorporeal processing of blood, and venous vascular access. Acute LDL lowering is 70% to 80% and time-averaged LDL lowering is 40% to 50%. Lipoprotein(a) is also substantially lowered. Clinical efficacy has been shown in several studies. Mechanisms for clinical improvement in addition to regression of atherosclerotic plaque have been suggested by recent research.     

Lp(a) apheresis for the treatment of severe CHD patients with Lp(a) hyperlipidemia

Objectives. To demonstrate the effectiveness of the specific lipoprotein(a)[Lp(a)] removal with immunosorption columns for treatment of severe CHD patients with elevated (more than 30 mg/dL) Lp(a) level. Methods. The following inclusion criteria were used for the recruitment of patients: age – under 55; coronary atherosclerosis documented by angiography; Lp(a) greater than 60 mg/dl; normal total and LDL cholesterol; clinically apparent progression of the CHD. Specific removal of Lp(a) from plasma was carried out with immunosorbtion columns ‘Lp(a) Lipopak’ contained specific antibodies against human Lp(a). Results. During last 10 years more than 1200 Lp(a) apheresis procedures have been carried out for ten severe CHD patients with 2–3 vessels disease in Moscow, Russia and Ludenscheid, Germany with Lp(a) Lipopak columns (POCARD Ltd, Russia). The Lp(a) level was reduced on the average on 75–85%, other parameters are practically constant during one procedure and duting all period of treatment. Our experience with Lp(a) Lipopak columns has shown that the specific removal of Lp(a) from the patient's plasma to 30 mg/dL or lower by weekly Lp(a) apheresis resulted in a significant improvement in the patient's health status and quality of life. After numerous Lp(a) apheresis procedures the progression of atherosclerosis was stopped in all cases, while some segments of coronary arteries showed regression of atherosclerotic plaques. Conclusion. We conclude that Lp(a) apheresis could be a very effective therapy for severe CHD patients with elevated Lp(a), and/or Lp(a) and LDL but for whom LDL level could be effectively corrected by lipids lowering drugs.     

Selective leukocyte apheresis for the treatment of inflammatory bowel disease

The etiology of inflammatory bowel disease (IBD) is not completely understood, thus current therapies have been empirical and directed at treating symptoms rather than addressing the cause. In IBD, the overexpression of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, leads to a persistent intestinal inflammatory response that damages the intestinal mucosa. Recent advances in pharmacologic therapies that target specific cytokines, chemokines, and adhesion molecules have proved successful in alleviating symptoms for some patients. There are 2 selective adsorption apheresis devices that remove leukocytes from whole blood, which are currently available in Japan and Europe-the Cellsorba leukocytapheresis column and the Adacolumn adsorptive extracorporeal granulocyte/monocyte apheresis device. The purported mechanisms of action of these devices have been extensively reviewed and are believed to exert an immunomodulatory and/or anti-inflammatory effect on patients with systemic inflammatory disease. The clinical trials presented here indicate that selective leukocyte apheresis effectively removes activated granulocytes and monocytes/macrophages from peripheral blood while maintaining an excellent safety profile. Despite these findings, large controlled trials of selective leukocyte apheresis in the treatment of IBD are needed to determine the true efficacy of this approach.     

Developments in the apheresis procedure for the treatment of inflammatory bowel disease

Initially used to treat rheumatoid arthritis, nonselective therapeutic leukocytapheresis was applied to the treatment of inflammatory bowel disease (IBD) as early as the 1980s. Since then, the process has been further refined and 2 blood perfusion systems using membrane filtration are presently employed in Japan and Europe for the selective removal of leukocytes in patients with IBD: Cellsorba is a column of polyethylenephtarate fibers that captures lymphocytes and granulocytes, and Adacolumn is a column of cellulose acetate beads that selectively adsorb granulocytes and monocytes. These systems overcome the limitations of centrifugation. Leukocytapheresis has been shown to exert an overall anti-inflammatory effect, as peripheral leukocytes demonstrated a diminished capacity to produce inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1, IL-6, IL-8, and IL-1beta. In addition, down-regulation in the expression of adhesion molecule L-selectin and a shift toward a more immature granulocyte phenotype were observed in the peripheral blood. The safety and beneficial therapeutic effect of leukocytapheresis in IBD are being investigated further.     

Vascular access for apheresis in intensive care patients

In the intensive care unit, apheresis therapy (including plasma exchange, selective immunoadsorption and -affinity and detoxification by hemoperfusion) is limited to certain disease entities. Temporary insertion of large-bore central venous catheters is necessary for efficient performance of apheresis therapy. The choice of the optimal catheter insertion site (femoral, subclavian or internal jugular vein route) depends on the individual situation, the experience of the operator and the anticipated treatment period. Morbidity and mortality of the patients concerned can be substantially increased by insertion and use of central venous catheters. Early and delayed complications are briefly discussed. Appropriate selection of the catheter insertion site, the catheter type, strictly aseptic insertion procedures and optimal care of catheter and insertion site are essential to avoid complications.     

Atorvastatin compared with simvastatin in patients with severe LDL hypercholesterolaemia treated by regular LDL apheresis

OBJECTIVES: Atorvastatin is a new potent HMG-CoA reductase inhibitor. We evaluated whether patients with coronary heart disease and severe hypercholesterolaemia showing insufficient LDL (low-density lipoprotein) cholesterol reduction despite combined therapy with simvastatin and regular LDL apheresis will benefit from atorvastatin therapy. SETTING: Tertiary care centre, university hospital. METHODS: In 21 patients treated by LDL apheresis, concomitant simvastatin therapy (40 mg day-1) was replaced by atorvastatin (40 mg day-1) and increased to 60 and 80 mg day-1 (each for 3 months) if no side-effects were reported and NCEP treatment goals were not reached. RESULTS: In 20 of 21 patients (95%), atorvastatin resulted in significant reduction of LDL cholesterol compared with simvastatin (by 10%, additional 8% and additional 1%, with 40, 60 and 80 mg day-1, respectively). In four patients, NCEP treatment goals were reached (in three by atorvastatin alone, and in one by atorvastatin and apheresis). Patients with little reduction in LDL cholesterol to 40 mg day-1 atorvastatin benefited most by increasing the dose to 60 mg day-1 (additional 13% reduction), whilst those responding to atorvastatin 40 mg day-1 benefited less (additional 1.9% reduction). During atorvastatin therapy, significantly less plasma had to be treated during apheresis resulting in shorter apheresis time. Eight patients (38%) reported side-effects, resulting in discontinuation of atorvastatin in three (14%) and dose reduction in five patients (24%), whilst no elevation of biochemical markers was observed. CONCLUSION: Concomitant atorvastatin therapy is superior to simvastatin therapy in patients with severe hypercholesterolaemia treated with regular LDL apheresis, but is associated with a high rate of subjective side-effects.     

Adsorptive granulocyte and monocyte apheresis versus prednisolone in patients with corticosteroid-dependent moderately severe ulcerative colitis

BACKGROUND/AIM: Active ulcerative colitis (UC) is often associated with increased peripheral granulocytes and monocytes/macrophages which show activation behavior and prolonged survival time. Further, mucosal granulocyte level parallels intestinal inflammation and can predict UC relapse. Accordingly, our aim was to see if adsorptive granulocyte/monocyte apheresis (GMA) can promote remission and spare steroid in patients with steroid-dependent (SD) UC. METHODS: 69 SD patients, at the time of relapse, were randomly assigned to groups I (n = 46) and II (n = 23). The mean dose of prednisolone (PSL) was 12 mg/day/patient, CAI (clinical activity index) 9.2 in both groups. Group I patients were given up to 11 GMA sessions over 10 weeks with Adacolumn; in group II, the mean dose of PSL was increased to 30 mg/day/patient. RESULTS: At week 12, 83% of group I and 65% of group II patients were in remission, CAI in group I was 1.7 (p < 0.001) and in group II, 2.5 (p < 0.001). Further, during the 12 weeks of treatment, the cumulative amount of PSL received per patient was 1,157 mg in group I and 1,938 mg in group II (p = 0.001). CONCLUSIONS: GMA appeared to be an effective adjunct to standard drug therapy of moderately severe UC by promoting remission and sparing steroids.     

Low-density lipoprotein apheresis as a treatment option for hyperlipidemia

Opinion statement  Data support the relevance of blood cholesterol levels, particularly high levels of low-density lipoprotein (LDL), in the pathogenesis and progression of atherosclerosis. A strong and continuous relationship between dyslipidemia and vascular morbidity and mortality has been established. The initial approach to treating dyslipidemia consists of lifestyle modifications followed by pharmacologic therapy, usually beginning with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Some patients with familial hypercholesterolemia (FH) fail to achieve their LDL goal despite aggressive pharmacologic therapy. In certain cases, LDL apheresis may be an effective therapeutic option. In the United States, LDL apheresis is approved for homozygous FH patients with an LDL cholesterol level ≥ 500 mg/dL. For patients with heterozygous FH, LDL apheresis may be offered if their LDL is ≥ 300 mg/dL, or ≥ 200 mg/dL with known coronary artery disease, despite maximum medical treatment. This review focuses on the principles and methods of LDL apheresis, its potential benefit in clinical care, and its current indications.     

Immunomodulatory effects of granulocyte and monocyte adsorption apheresis as a treatment for patients with ulcerative colitis

Our aim was to understand the mechanism of immunological changes associated with the use of an adsorptive-type extracorporeal device (Adacolumn) that has been developed for selective adsorption of granulocytes and monocytes/macrophages from peripheral blood of patients with active ulcerative colitis. The column is filled with carriers (G-1 beads) that have a diameter of 2 mm and are made of cellulose diacetate. In peripheral blood treated with the G-1 beads or peripheral blood from patients with active ulcerative colitis following granulocyte and monocyte adsorption apheresis, a significant suppression of proinflammatory cytokines (tissue necrosis factor-, interleukin-1, interleukin-6, and interleukin-8) production by leukocytes, neutrophil chemotaxis, down-regulation of leukocyte adhesion molecule (L-selectin) and neutrophil adhesion to interleukin-1-activated endothelial cells were observed. Furthermore, after granulocyte adsorption therapy, the number of CD10-negative premature granulocytes increased, indicating increased turnover of these cells in the circulation. Our observations suggest that selective granulocyte and monocyte adsorption is associated with modified peripheral blood leukocyte function favorable to patients with ulcerative colitis and possibly other autoimmune disorders which reflect leukocyte hyperactivity.     

老年重型颅脑损伤患者的围手术期治疗

目的 总结６７例格拉斯哥昏迷量表（Ｇｌａｓｇｏｗ ｃｏｍａ ｓｃａｌｅ,ＧＣＳ）３～８分老年重型颅脑损伤患者的围手术期治疗经验。方法 对我科１９９２年２月至１９９８年１０月收入院行手术治疗的６７例老年重型颅脑损伤患者进行回顾性分析。结果 ６７例老年重型颅脑损伤患者中存活４５例（６７．２％）,其中恢复良好和中残３４例（５０．７％）,重残１１例（１６．５％）,死亡２２例（３２．８％）。结论 积极的围手术期治疗,包括院前急救、颅内血肿的早诊早治、骨瓣减压、颅压监护、亚低温治疗、脑血管痉挛的治疗、各种并发症的防治及全身支持治疗等措施。可改善老年重型颅脑损伤患者的预后。     

Granulocyte adsorptive apheresis for pediatric patients with ulcerative colitis

Granulocytapheresis (GCAP) has produced efficacy in adult patients with ulcerative colitis (UC) by adsorbing activated granulocytes and monocytes/macrophages. We retrospectively investigated efficacy and safety of GCAP in pediatric patients with active UC. Twelve steroid-refractory children (12.2±3.1 years old) were treated with GCAP, one session/week for 5–10 consecutive weeks. In 8 patients, clinical symptoms improved after two GCAP sessions. Normal body temperature, stool frequency, and disappearance of blood in stool were seen after 24.3±11.5 days. The endoscopic grade improved from 2.6±0.3 to 0.4±0.2. One patient who initially responded, developed bloody diarrhea later and 2 cases remained unchanged. The dose of steroid was tapered during GCAP therapy by 50%. No serious adverse effects were noted. Four of 8 cases relapsed 3.5 ± 2.2 months after the last GCAP while on maintenance therapy, the other 4 were in remission up to 22.8±18.1 months. In conclusion, GCAP appears to be effective and well tolerated in children with steroid-refractory UC.     

Clinical effect of buffy-coat vs. apheresis platelet concentrates in patients with severe thrombocytopenia after intensive chemotherapy

BACKGROUND AND OBJECTIVES: Therapeutic or prophylactic use of platelet concentrates (PC) is essential for patients with thrombocytopenia due to intensive chemotherapy for various malignancies. PC quality has been improved after introduction of storage containers that are more oxygen permeable than the second-generation PC containers. Consequently, shelf life of PCs at our blood bank has been extended to 6.5 days after monitoring each PC for bacterial contamination. In this prospective observational study, we compared apheresis PCs harvested by Amicus cell separator with buffy-coat (BC) PCs during storage for up to 6.5 days. MATERIALS AND METHODS: All PCs were collected from healthy volunteer donors and were prepared for routine clinical use. A total of 446 transfusion episodes with 688 PCs for 77 adult patients with oncological and haematological diseases were registered during a 13-month period. Outcome measures were corrected count increment after 1 h (CCI-1), after 18-24 h (CCI-2), and transfusion intervals. Transfusions were carried out after storage from 1.5 to 6.5 days. RESULTS: Both CCI and the transfusion intervals decreased statistically significantly by increasing storage time after transfusions with apheresis PCs or BC PCs. However, less than 4% of the variation in CCI and transfusion interval could be explained by platelet storage time. There were no significant differences between BC PCs and apheresis PCs, regarding CCI and transfusion intervals. CONCLUSION: We can conclude that BC PCs are not inferior to apheresis PCs, and may serve the clinical purposes as well as apheresis PCs harvested by Amicus.     

Misoprostol is effective treatment for patients with severe chronic constipation

To assess the efficacy of misoprostol in the treatment of patients with severe chronic constipation, nine such patients were enrolled in a double-blind, randomized, crossover study of misoprostol (1200 µg/day) or placebo, that lasted three weeks. During this period each patient received the drug for one week and placebo for another with a week washout period in between. A colonic transit study, using radiopaque markers, was performed during each of the treatment weeks, while the number of stools and their total weight was recorded by each patient for the appropriate periods. Colonic transit time was significantly and consistently decreased by misoprostal compared to placebo [66 hr±10.2 vs 109.4 hr±8.1 (P=0.0005)]. Misoprostrol significantly increased the total stool weight per week [976.5 g±288.8 vs 434.6 g±190.5 (P=0.001)] and also significantly increased the number of stools per week compared to placebo [6.5±1.3 vs 2.5±0.11 (P=0.01)]. The incidence of abdominal pain was similar in both groups. We concluded that misoprostol, during a short trial period, proved effective in increasing the frequency and weight of bowel movements and decreasing colonic transit time in patients with severe chronic constipation. It may be used as a therapeutic measure to treat such patients.This study was supported by a grant from Searle, Chicago, Illinois, and presented at the annual meeting of the American Gastroenterological Association, Boston, Massachusetts, 1993.