Therapeutic plasma exchange for steroid refractory idiopathic inflammatory myopathies with interstitial lung disease.

BACKGROUND: Idiopathic inflammatory myopathies (IIMs) encompass many rheumatologic diseases characterized by inflammatory muscle disease, typically unified by proximal muscle weakness. A subset of patients with IIM present with interstitial lung disease (ILD) with identifiable antibodies such as in anti-synthetase syndrome (AS) with antibodies to aminoacyl-tRNA synthetases, and clinically amyopathic dermatomyositis (CADM) with anti-melanoma differentiation-associated protein 5 (MDA5). Recent case reports demonstrate response to therapeutic plasma exchange (TPE) or column filtration plasmapheresis in IIM with ILD resistant to medical management. We present our experience with eight patients with IIM with ILD undergoing TPE at a large US-based hospital system. PATIENT CHARACTERISTICS: Eight patients with IIM with ILD were treated with TPE over the last 10 years. The therapy consisted of 5-7 one plasma volume exchanges every other day to daily. Seven of eight patients had identifiable antibodies. RESULTS: Following completion of TPE, seven of eight demonstrated improvement in pulmonary function despite lack of improvement of pulmonary function with standard therapy. CONCLUSION: In antibody-mediated, treatment refractory IIM with ILD, TPE may be a viable intervention. This is a disease for which the role of apheresis is evolving. CLINICAL TRIAL REGISTRATION: Not application.

Lectin Affinity Plasmapheresis for Middle East Respiratory Syndrome-Coronavirus and Marburg Virus Glycoprotein Elimination.

BACKGROUND/AIMS: Middle East respiratory syndrome coronavirus (MERS-CoV) and Marburg virus (MARV) are among the World Health Organization's top 8 emerging pathogens. Both zoonoses share nonspecific early symptoms, a high lethality rate, and a reduced number of specific treatment options. Therefore, we evaluated extracorporeal virus and glycoprotein (GP) elimination by lectin affinity plasmapheresis (LAP). METHODS: For both MERS-CoV (pseudovirus) as well as MARV (GPs), 4 LAP devices (Mini Hemopurifiers, Aethlon Medical, San Diego, CA, USA) and 4 negative controls were tested. Samples were collected every 30 min and analyzed for reduction in virus infectivity by a flow cytometry-based infectivity assay (MERS-CoV) and in soluble GP content (MARV) by an immunoassay. RESULTS: The experiments show a time-dependent clearance of MERS-CoV of up to 80% within 3 h (pseudovirus). Up to 70% of MARV-soluble GPs were eliminated at the same time. Substantial saturation of the binding resins was detected within the first treatment hour. CONCLUSION: MERS-CoV (pseudovirus) and MARV soluble GPs are eliminated by LAP in vitro. Considering the high lethality and missing established treatment options, LAP should be evaluated in vivo. Especially early initiation, continuous therapy, and timed cartridge exchanges could be of importance.

Anticoagulation, bleeding, and clotting at donor plasmapheresis.

This article is based on a question of a colleague from North America how coagulation could be triggered between a donor's arm and a fistula needle during plasma donation (synonymous with donor plasmapheresis). The technique of venipuncture and citrate anticoagulation are described. Uncommon and rare problems such as prolonged bleeding, scarring, and thrombosis in plasma donors are discussed. If venous puncture and citrate: blood flow ratio at 1:16 are correctly performed, however, there will be no anticoagulation abnormalities due to plasma donation.

Moderator's view: High-volume plasma exchange: pro, con and consensus.

I have been asked to comment on the pro and con opinions regarding high-volume plasma exchange. The authors of both positions have provided cogent arguments and a reasonable approach to choosing the exchange volume for any given therapeutic plasma exchange. The major issue of relevance in this discussion is the nature of the toxins targeted for removal. These parameters include molecular weight, the apparent volume of distribution, the degree of protein binding, the biologic and chemical half-life, and the severity and rapidity of its toxicity.

Pro: High dose of therapeutic plasma exchange-mind the gap!

'Mind the gap' is a recorded warning phrase used in the London Tube since 1969. The following article is meant to be a warning of an increasing knowing-doing gap in routine practice of therapeutic plasma exchange (TPE), a treatment method that is used more and more throughout the world. The American Society of Apheresis recommendations, including the most recent ones from 2016, suggest using a TPE volume of 1.0-1.5 times the actual calculated plasma volume of the patient. There are only a few exceptions to that rule, such as the recommnded exchange volume in vasculitis or mushroom poisoning. The published literature suggests that in routine clinical practice in many institutions in several countries the exchanged volume might in fact be lower than recommended by the guidelines. In the following article we argue for a high dose of exchanged plasma volume, yet sketch different scenarios on how this time-averaged high dose can be delivered in various ways depending on the underlying disease, refuting a one-size-fits-all strategy that might facilitate the procedure but may result in 'underpheresis' in many patients. Further, the objectives underlying the use of smaller exchange volumes, especially the gap between the cost of blood products and the reimbursement of TPE are discussed. Lastly, the knowing-guiding gap is described, which can only be overcome by collecting high-quality data and conducting prospective clinical trials in the field of TPE.

Con: High-volume plasma exchange application in nephrology and beyond.

The rationale behind the use of plasma exchange (PE) includes the removal of autoantibodies and other plasma constituents, such as cytokines, complement components, neutrophil extracellular traps, and microparticles, and the substitution of missing plasma factors. The more established indications are associated with the beneficial effects of PE of reducing the plasma levels of pathogenic agents, although the efficiency of this process decreases during the course of the procedure as the substituted replacement fluid dilutes the patient's original plasma. Thus, removal can be more effective by repeating sessions rather than continuing so-called high-volume PE. The kinetics of PE efficiency have been extensively investigated and exchange between body compartments of substances to be removed is of considerable importance.

[The indices of quality of the donor's plasma, obtained by the methods of plasmapheresis and primary fractionation, using various hemopreservatives and leukocytic filters].

There was estimated quality of the plasm indices; so in comparison with the fractioning methods, using two regimens of the donor's blood centifugating, harvested with the help of various conservants, the most secure and functionally adequate plasm preparation was determined such, which is obtained with the help of plasmapheresis procedures. The expediency of application and introduction of the differentiated centrifugation technology, providing rational usage of a donor's blood, was determined. After conduction of leukofiltration of the conserved blood and plasm the residual cells content is reducing significantly, while preserving activity of the blood coagulation factors.

Comparison of double filtration plasmapheresis with immunoadsorption therapy in patients with anti-glomerular basement membrane nephritis.

BACKGROUND: Double filtration plasmapheresis (DFPP) and (IA) are both used to clear antibody. However, the clinical efficacy and safety of DFPP in patients with anti-glomerular basement membrane (anti-GBM) disease are unclear. METHODS: The 28 enrolled patients diagnosed serologically and pathologically with anti-GBM disease from 2003 to 2013 included 16 treated with DFPP and 12 with IA, with all patients administered immunosuppressive agents. DFPP consisted of an EC50W filter for plasma separation and an EC20W filter for plasma fractionation. A double volume of plasma was processed, and each patient received a 30-40 g human albumin supplement during each session. IA consisted of 10 cycles per session, with 8-10 sessions performed daily or every other day and each session regenerating 30-60 L of plasma. Serum anti-GBM antibodies and IgG were measured, and urinary and blood tests were performed, before and after each procedure. Renal function and outcome were determined. RESULTS: The 28 patients consisted of 13 males and 15 females, of median age 44.5 years (range, 22.5-57 years). Six patients had pulmonary hemorrhage and 18 had serum creatinine concentrations >500 umol/L. The average serum creatinine concentration at early onset of disease was 525 umol/L while the peak concentration was 813 umol/L. All patients showed progressive increases in serum creatinine and required CRRT during the course of disease. Pathological examination showed an average 73.9% of crescents (range, 54.6-95.4%).The clinical and pathological features of the DPPP and IA groups were similar. Efficacy of clearing anti-GBM antibody was similar in the two groups (59.0 vs. 71.2%, P = 1.00), although fewer patients in the DFPP group experienced reduced IgG (62.7 vs. 83.5%, p = 0.002). One patient each had a pulmonary hemorrhage and a subcutaneous hemorrhage during treatment, but there were no other serious complications. At the end of follow-up, patient survival and renal survival were similar in the DFPP and IA groups. CONCLUSION: DPPP plus immunosuppressive therapy efficiently and safely removed anti-GBM antibodies. The fewer plasma-associated side effects and reduced loss of IgG suggest that DFPP may be a better treatment choice for anti-GBM disease, especially in patients with insufficient plasma.

Residual plasma in red blood cells and transfusion-related acute lung injury.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is the most common cause of death from blood transfusion and red blood cells (RBCs) now account for approximately 50% of these fatalities. RBCs from female donors have been implicated in large series and HLA Class II antibodies to cognate recipient antigens identified in small series and case reports. The absolute volume of residual plasma in these RBCs is unknown. STUDY DESIGN AND METHODS: Two confirmed cases of RBC-associated TRALI in which the implicated donors had Class II antibodies were investigated, and the antibody strength against recipient cognate antigens was assessed using a fluorescent bead assay. RBCs in additive solution (AS) were studied on Day 42 of liquid storage to calculate residual anticoagulated plasma. RESULTS: Both RBC units were stored in AS-1 and were from female donors who had anti-HLA Class II antibodies of high strength against cognate antigens in the recipients. Anti-DR4 was identified in both cases. Nineteen AS-1 RBC units manufactured from whole blood donations using a hard spin had a mean (±1SD) residual plasma content of 38 ± 8 mL, and 26 AS-3 RBC units manufactured using a soft spin had 66 ± 13 mL (p < 0.01). CONCLUSION: RBCs continue to be manufactured from female donors of unknown or even known anti-HLA status. The residual plasma content of these RBCs may approach 100 mL. A combination of a high-strength antibody and large residual plasma volume could explain severe or even fatal RBC-associated TRALI.

Beyond Criteria and Definitions: Outcome of a Standardized Antibody-Mediated Rejection Protocol with a Diagnostic Schema Different from the Banff 2009 Criteria.

A new clinical diagnostic schema is needed for the diagnosis of antibody-mediated rejection (AMR) in kidney transplant recipients due to the limited utility of C4d staining, lack of standardized quantitative tests for donor specific antibodies, and potential new diagnostic markers. The treatment of AMR remains controversial because previous studies included heterogeneous treatment modalities, small sample sizes, and short follow-up time. At the University of Michigan Transplant Center, 26 patients were diagnosed with AMR based on our diagnostic protocol including C4d-negative AMR in thesetting of graft dysfunction and Banff tissue injury type II (capillaritis) or type III (arteritis). After diagnosis, these patients received six sessions of plasmapheresis (PP) and IVIG (100 mg/kg after the first to fifth PP and 500 mg/kg with the last PP). Our novel finding in this analysis was the association between persistent C1q detection and graft loss. We confirmed that C4d positivity at diagnosis is associated with worse outcomes. Also, we found that response to our treatment protocol is dependent on C4d staining and Banff tissue injury type.

Pediatric sepsis: challenges and adjunctive therapies.

Sepsis remains an important challenge in pediatric critical care medicine. This review provides an appraisal of adjunctive therapies for sepsis and highlights opportunities for meeting selected challenges in the field. Future clinical studies should address long-term and functional outcomes as well as acute outcomes. Potential adjunctive therapies such as corticosteroids, hemofiltration, hemoadsorption, and plasmapheresis may have important roles, but still require formal and more rigorous testing by way of clinical trials. Finally, the design of future clinical trials should consider novel approaches for stratifying outcome risks as a means of improving the risk-to-benefit ratio of experimental therapies.

Therapeutic plasma exchange in neurology: 2012.

In treating neuroimmunological diseases, neurologists have a number of different drugs to choose from ranging from corticosteroids to IVIg to more specific cell based therapies, the latter most frequently from the world of oncology. In some diseases, therapeutic plasma exchange, a procedure rather than a drug, is used. The most obvious advantage of therapeutic plasma exchange is the usually rapid onset of action presumably due to removal of pathogenic auto-antibodies. In some diseases, a single course of therapeutic plasma exchange is used while in others prolonged treatment with therapeutic plasma exchange is used. This article will review the use of therapeutic plasma exchange in neurology and will draw heavily upon recent consensus statements from the American Society for Apheresis and the American Academy of Neurology and by Cochrane reviews.

Development of an automated plasmapheresis procedure for the harvest of equine plasma in accordance with current good manufacturing practice.

OBJECTIVE: To develop a high-speed, continuous-flow, automated plasmapheresis procedure for the high-volume harvest of equine plasma in accordance with current good manufacturing practice. ANIMALS: 143 horses (predominantly draft breeds) between 3 and 10 years of age at the time of purchase. PROCEDURES: Adaptations were made to automated plasmapheresis instruments and sterile disposable collection sets, which allowed for dual-instrument, continuous-flow operation. Donor horses were connected to the apparatus via 2 catheters (1 inserted in each jugular vein). The instruments removed whole blood from donors, fractionated the blood, diverted plasma to collection bags, and simultaneously returned concentrated cells to the donors. Plasmapheresis was performed on donor horses at 14-day intervals with a maximum of 22 mL of plasma/kg of donor body weight harvested during each plasmapheresis procedure. RESULTS: During a 5-year period, 3,240 plasmapheresis procedures were performed and > 50,000 L of sterile equine plasma was harvested in accordance with current good manufacturing practice. Donors typically remained calm during the plasmapheresis procedures and tolerated the procedures well. The high-volume and frequent plasma harvest did not result in sustained hypoproteinemia in donor horses. Adverse events associated with the automated plasmapheresis technique were infrequent, and the recurrence of adverse events was minimized by making minor adjustments to the procedure. CONCLUSIONS AND CLINICAL RELEVANCE: The automated plasmapheresis procedure described in this report can be used to safely harvest equine plasma or to perform therapeutic plasmapheresis in horses.

A prospective trial assessing the safety and efficacy of collecting up to 840 mL of plasma in conjunction with saline infusion during plasmapheresis.

BACKGROUND: The demand for plasma for manufacturing intravenous immunoglobulin and other plasma derivatives is increasing. A prospective study was conducted to determine whether up to 840 mL of plasma could be safely and effectively collected in conjunction with saline infusion during plasmapheresis. STUDY DESIGN AND METHODS: Ninety-one plasma donors were enrolled in a modified 3 × 3 crossover study to assess the equivalence of three plasma collection methods: 750 mL of plasma with no saline (control, Method 1), 840 mL of plasma with a 250-mL saline infusion during and at the end of the donation (Method 2), and 800 mL of plasma with a 500-mL saline infusion at the end of the donation (Method 3). The primary efficacy endpoint was the total protein concentration of the collected plasma. Secondary efficacy endpoints were immunoglobulin (Ig)G and Factor (F)VIII plasma concentration and donors' acceptance of the new procedures. Safety was determined from the adverse event (AE) rate. RESULTS: The total protein, IgG, and FVIII concentrations in plasma collected under Methods 2 and 3 were significantly lower than those in plasma collected under Method 1 (p < 0.0001). These variables were also significantly lower in plasma collected under Method 2 compared to Method 3. During the study, 75 AEs were recorded, 73 of which were mild to moderate. Significantly more donors (31%) preferred Method 2 compared to Method 3 (p = 0.006). CONCLUSIONS: Saline infusion during plasmapheresis led to hemodilution of plasma proteins. However, the benefits to donor safety and satisfaction are compelling reasons to implement saline infusion during plasmapheresis.

Allogeneic single-donor cryoseal produced from fresh-frozen quarantine apheresis plasma as alternative for multidonor or autologous fibrin sealants.

BACKGROUND: Fibrin sealant is a human blood product consisting of two components: cryoprecipitate and thrombin. Commercial fibrin sealants are produced from multidonors, increasing the viral risk, and contain fibrinolytic inhibitors such as tranexamic acid or bovine aprotinin. Autologous fibrin sealants reduce the viral risk and are mostly produced during a surgical procedure or well in advance. Alternatively, the allogeneic single-donor fibrin sealant cryoseal can be used. In this study cryoseal was characterized and the manufacturing consistency of the production process was investigated. STUDY DESIGN AND METHODS: Cryoseal was produced from plasma collected on apheresis machines using a commercial device. In a research setting the protein composition and recovery were determined. Also, the manufacturing consistency of the production process was tested in a research setting as well as in a routine setting. RESULTS: In the research setting all produced cryoseal met the quality control requirements of a clotting time of less than 10 seconds and the presence of Factor (F)XIII (qualitative). In the routine setting, one procedure per year did not meet these requirements. The protein composition showed the following mean ± standard deviation (%recovery) results: thrombin 25.7 ± 11.1 IU/mL, fibrinogen 19.9 ± 4.6 (15%) mg/mL, FVIII 15.6 ± 5.4 (44%) IU/mL, FXIII 2.7 ± 0.7 (6%) IU/mL, and plasminogen 1.8 ± 0.2 (4%) U/mL. In both research and routine settings the production process resulted in a consistent product. CONCLUSION: The cryoseal manufacturing process resulted in a consistent product, which meets the predetermined specifications. The single-donor origin and the absence of fibrinolytic inhibitors make cryoseal a good alternative for multidonor and autologous fibrin sealants.

Outcome of plasmapheresis in myasthenia gravis: delayed therapy is not favorable.

INTRODUCTION: The purpose of this study was to compare the in-hospital mortality and complication rates after early and delayed initiation of plasma exchange (PLEX) in patients with myasthenia gravis (MG). METHODS: Our cohort was identified from the Nationwide Inpatient Sample database for the years 2000 through 2005. Early treatment was defined as therapy with PLEX administered within the first 2 days from hospital admission. Univariate and multivariate analyses were employed. RESULTS: One thousand fifty-three patients were treated and included in the analysis. A delay in receiving PLEX was associated with higher mortality (6.56% vs. 1.15%, P < 0.001) and increased complications (29.51% vs. 15.29%, P < 0.001). Adjusted analysis showed increased mortality [odds ratio (OR) 2.812; 95% confidence interval (CI) 1.119-7.069] and complications (OR 1.672; 95% CI 1.118-2.501) with delayed PLEX therapy. CONCLUSIONS: Delaying PLEX therapy for MG by more than 2 days after admission may lead to higher mortality and complication rates, and thus prompt therapy is warranted.