Therapeutic plasma exchange for neuromyelitis optica spectrum disorder: A multicenter retrospective study by the ASFA neurologic diseases subcommittee.

IMPORTANCE: Neuromyelitis optica/neuromyelitis optica spectrum disorder patients' response to therapeutic plasma exchange (TPE) is currently incompletely characterized. OBJECTIVE: Our study aims to understand the clinical status improvement of neuromyelitis optica/neuromyelitis optica spectrum disorder patients treated with TPE. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective study conducted between 1 January 2003 and 31 July 2017 at 13 US hospitals performing apheresis procedures. Subjects studied were diagnosed with neuromyelitis optica/neuromyelitis optica spectrum disorder who received TPE during presentation with acute disease. MAIN OUTCOMES AND MEASURES: The primary outcome was clinical status improvement in patients treated with TPE. Secondary measures were procedural and patient characteristics associated with response to treatment. RESULTS: We evaluated 114 patients from 13 institutions. There was a female predilection. The largest ethnic group affected was non-Hispanic Caucasian. The average age of diagnosis was 43.1 years. The average time to diagnosis was 3.1 years. On average, five procedures were performed during each treatment series. The most commonly performed plasma volume exchange was 1.0 to 1.25 using 5% albumin as replacement fluid. Most patients (52%) did not require an additional course of TPE and noted "mild" to "moderate" clinical status improvement. Maximal symptom improvement appeared by the fourth or fifth TPE treatment. CONCLUSION AND RELEVANCE: TPE improved the clinical status of patients. Adults responded more favorably than children. Procedural characteristics, including number of TPEs, plasma volume exchanged, and replacement fluid used, were similar between institutions. TPE was well-tolerated and had a low severe adverse event profile.

Report of the ASFA apheresis registry on muscle specific kinase antibody positive myasthenia gravis.

BACKGROUND: Anti-muscle specific kinase antibody positive (MuSK Ab) myasthenia gravis (MG) patients are known to have different clinical course compared to anti-acetylcholine receptor Ab positive MG patients. Therapeutic plasma exchange (TPE) has been reported to be effective; however, little is known of the response and of TPE procedural information. An ASFA Apheresis Registry was developed to analyze those data. METHODS: The study collected detailed de-identified patient data, TPE procedures, and treatment outcome/complications. Collected data was described in aggregate. RESULTS: A total of 15 MuSK Ab MG patients with exacerbation of MG symptoms, 13 females/2 males, median age 44, were investigated. Thirty TPE courses (median 5 procedures/course, total 145 procedures) were evaluated. All TPE procedures were performed with citrate anticoagulation, 1 - 1.25 plasma volume exchange in 100% fluid balance, and 90% of courses used only albumin as replacement. Calcium was added to albumin or given orally as needed. TPE was performed every other day in 55% of courses. Adverse events occurred in 3.4% of procedures. Ten patients (67%) experienced relapses within a median of 7 weeks. Objective symptoms were resolved in more than 75% of courses. Overall subjective improvement rates were 94.1%/93.3% after 3/4 TPE procedures, respectively. Thirty-one percent of patients responded poorly with minimal recovery. CONCLUSION: Overall subjective improvement was seen up to 94% of patients after one course of TPE. Some patients were poor-responders. Five TPE may be adequate for initial course with additional TPE as needed. Based upon this preliminary data, we will modify our future data collection. J. Clin. Apheresis 32:5-11, 2017. © 2016 Wiley Periodicals, Inc.

Extracorporeal photopheresis practice patterns: An international survey by the ASFA ECP subcommittee.

BACKGROUND: Although many apheresis centers offer extracorporeal photopheresis (ECP), little is known about current treatment practices. METHODS: An electronic survey was distributed to assess ECP practice internationally. RESULTS: Of 251 responses, 137 met criteria for analysis. Most respondents were from North America (80%). Nurses perform ECP at most centers (84%) and the majority of centers treat adults only (52%). Most centers treat fewer than 50 patients/year (83%) and perform fewer than 300 procedures/year (70%). Closed system devices (XTS and/or Cellex) are used to perform ECP at most centers (96%). The most common indications for ECP are acute/chronic skin graft versus host disease (89%) and cutaneous T-cell lymphoma (63%). The typical wait time for ECP treatment is less than 2 weeks (91%). Most centers do not routinely perform quality control assessment of the collected product (66%). There are device-specific differences in treatment parameters. For example, XTS users more frequently have a minimum weight limit (P = 0.003) and use laboratory parameters to determine eligibility for treatment (P = 0.03). Regardless of device used, the majority of centers assess the clinical status of the patient before each procedure. Greater than 50% of respondents would defer treatment for hemodynamic instability due to active sepsis or heart failure, positive blood culture in the past 24 h or current fever. CONCLUSION: This survey based study describes current ECP practices. Further research to provide evidence for optimal standardization of patient qualifications, procedure parameters and product quality assessment is recommended.

Blood transfusions and pulmonary complications after hematopoietic cell transplantation.

BACKGROUND: Transfusion of blood products is an essential component of the hematopoietic cell transplantation (HCT) process. Blood transfusion carries several risks including, but not limited to, lung injury. The effect of transfusions on lung complications after HCT has not been previously investigated. STUDY DESIGN AND METHODS: We retrospectively studied 215 adult allogeneic HCT recipients at the University of Minnesota and examined the association between transfusion of blood components and development of lung complications after HCT. Patients without lung complications were used as the control group. RESULTS: A total of 113 (58%) of the patients developed lung injury events before Day 180 after HCT. Six-month survival was significantly lower in the lung event group (52%) versus the controls (78%; p = 0.01). Patients who eventually developed lung events received more transfusion episodes per week in the first month after HCT (median, 4.3 vs. 2.7 for controls), platelet units per week (3.5 vs. 2.0), and RBC units per week (1.8 vs. 1.4; p < 0.01) for all. In a multivariable analysis, each additional transfusion before Day +30 was associated with a 2.7% higher risk of lung complication (95% confidence interval, 0.8-4.8; p = 0.01), adjusting for time to engraftment, conditioning intensity, and donor type. Blood utilization increased after the lung event and remained high for several months relative to controls. CONCLUSION: Our data suggest that transfusion of blood products is associated with and may further complicate lung complications after HCT. Cautious use of blood components in the post HCT period is recommended.

Management of systemic unfractionated heparin anticoagulation during therapeutic plasma exchange.

BACKGROUND: Therapeutic plasma exchange (TPE) may remove medications from the patient's plasma. Data is limited on the effect of TPE on unfractionated heparin (UFH). STUDY DESIGN AND METHODS: A retrospective review was performed of patients receiving TPE and continuous IV infusion UFH from 1/1/2008 to 6/30/2010. TPE with plasma or 5% albumin for replacement fluid and pre and post anti-Xa levels within approximately six hours were analyzed. RESULTS: Three patients had 15 TPE with plasma replacement. Anti-Xa levels decreased 47% (mean, -0.25 IU/mL) for two TPE when UFH was not changed, 78% (-0.35 IU/mL) for one TPE when the UFH rate was decreased 25%; and 61% (mean -0.72 IU/mL) for two single volume TPE and 87% (-0.65 IU/mL) for one 1.5 plasma volume TPE when UFH was stopped. During nine TPE, the UFH rate was increased by 65% resulting in a mean increase in the anti-Xa level (mean 0.06 IU/mL, 30%). One patient had five single plasma volume TPE with 5% albumin. Anti-Xa levels decreased when the UFH was not changed (-0.06 IU/mL, 38%) and increased when UFH was increased by 30% (0.19 IU/mL, 61%) and 69% (mean 0.04 IU/mL, 15% in three TPE). The PTT increased with all albumin procedures, with more marked increases observed when the UFH rate was increased, while the antithrombin level decreased (mean 65%). CONCLUSION: Heparin was removed from the patient's plasma during TPE. Adjustment of the dose during TPE may be necessary to maintain therapeutic drug levels. Methods for monitoring UFH therapy may not agree. J. Clin. Apheresis 31:507-515, 2016. © 2016 Wiley Periodicals, Inc.

Report of the ASFA apheresis registry study on Wilson's disease.

PURPOSE: Wilson's disease is a rare autosomal recessive genetic disorder that results in accumulation of copper in the liver, brain, cornea and kidney. Therapeutic plasma exchange (TPE) has been used to remove copper and provide a bridge to liver transplantation. We report here the collective experiences through the ASFA apheresis registry on Wilson's disease. METHODS: The ASFA apheresis registry is a multi-center registry study. Both prospective and retrospective data, with the latter involving data collection back to January 2000 are entered in the registry. The registry includes patient demographics, apheresis procedural information, treatment schedules, and treatment outcomes and complications. RESULTS: A total of 10 patients (3 males and 7 females) with Wilson's disease treated between 2005 and 2013 were included. Median age of first diagnosis and first TPE were 16 and 17 years, respectively. Via central venous access, these patients underwent a total of 43 TPEs; the median number of TPE procedures per patient was 3.5. All of the TPEs used ACD-A as anticoagulation, 42/43 TPEs targeted 1-1.25 plasma volumes, and 41/43 TPEs were performed with 100% fluid balance. Post TPE procedures, 9 patients underwent liver transplantation; all 10 patients had at least a 6-month survival. CONCLUSIONS: All 10 patients with Wilson's disease who underwent TPE had a positive outcome in terms of 6-month survival. In this first report of the ASFA apheresis registry study, we have demonstrated the value of using this registry to collect apheresis-related patient outcomes from multiple centers.

Simulation-based education for transfusion medicine.

BACKGROUND: The administration of blood products is frequently determined by physicians without subspecialty training in transfusion medicine (TM). Education in TM is necessary for appropriate utilization of resources and maintaining patient safety. Our institution developed an efficient simulation-based TM course with the goal of identifying key topics that could be individualized to learners of all levels in various environments while also allowing for practice in an environment where the patient is not placed at risk. STUDY DESIGN AND METHODS: A 2.5-hour simulation-based educational activity was designed and taught to undergraduate medical students rotating through anesthesiology and TM elective rotations and to all Clinical Anesthesia Year 1 (CA-1) residents. Content and process evaluation of the activity consisted of multiple-choice tests and course evaluations. RESULTS: Seventy medical students and seven CA-1 residents were enrolled in the course. There was no significant difference on pretest results between medical students and CA-1 residents. The posttest results for both medical students and CA-1 residents were significantly higher than pretest results. The results of the posttest between medical students and CA-1 residents were not significantly different. CONCLUSION: The TM knowledge gap is not a trivial problem as transfusion of blood products is associated with significant risks. Innovative educational techniques are needed to address the ongoing challenges with knowledge acquisition and retention in already full curricula. Our institution developed a feasible and effective way to integrate TM into the curriculum. Educational activities, such as this, might be a way to improve the safety of transfusions.

Therapeutic plasma exchange in neuromyelitis optica: a case series.

Neuromyelitis optica (NMO) is a relapsing inflammatory disease of the central nervous system that predominantly affects the spinal cord and optic nerves. The clinical hallmark of the disease is a step-wise deterioration of visual and spinal cord function. This study reviews patients with steroid resistant relapsing NMO presenting for therapeutic plasma exchange (TPE) at our institution from December 2005 to December 2012. A total of five patients were treated with single volume TPE. Both subjective and objective clinical response to TPE was estimated by three different sources (the patient, a Transfusion Medicine physician, and the treating Neurologist) with the patient and Transfusion Medicine physician's final assessment of response made at the time of the last TPE in the series and the treating neurologist's assessment of response made at the time of the next neurological exam after the last TPE. A total of 17 TPE series were performed with the average course of therapy being three series (ranged 1-5) with five TPE (ranged 3-7) per series. All patients demonstrated improvement with each series of TPE and all procedures were well tolerated with only transient and well-described reactions all of which were successfully resolved with minor or no sequelae.

Effect of therapeutic plasma exchange on coagulation parameters in patients on warfarin.

Therapeutic plasma exchange (TPE) without plasma replacement results in coagulation factor removal. Warfarin decreases the activity of vitamin K dependent coagulation factors. The combined effect of TPE and warfarin on the coagulation system has not been studied. A prospective, observational study was conducted in patients undergoing TPE while on warfarin. One plasma volume TPEs were performed on the COBE Spectra Apheresis System (Terumo BCT, Lakewood, CO) with 5% albumin. International normalized ratio (INR), fibrinogen, and factor II activity were obtained pre and post procedure. Eight patients underwent 121 TPEs that met study criteria with pre and post data. The average pre values were INR 2.09 ± 0.58, fibrinogen 263 ± 76 mg/dl, and factor II 29 ± 16% and the average post values were INR 4.12 ± 1.44, fibrinogen 105 ± 31 mg/dl, and factor II 13 ± 7%. The pre-INR was ≥2.00 for 55% of TPEs. The pre value (Y0 ) predicts the post value (Y) by the following equations Y = -0.54 + 2.21Y0 , Y =12.10 + 0.35Y0, and Y =1.83 + 0.39Y0 for INR, fibrinogen, and factor II respectively. In conclusion, pre procedure laboratory values can predict the post laboratory values for patients on warfarin receiving single plasma volume TPE with albumin replacement. The post-INR is approximately twice the pre-INR. At normal and mildly elevated pre-INR, the effect of TPE on the INR is less marked. A single plasma volume TPE decreases the plasma level by ∼65% for fibrinogen and 60% for factor II.

The top clinical trial opportunities in therapeutic apheresis and neurology.

OBJECTIVE: The National Heart, Lung, and Blood Institute, of The National Institutes of Health, convened the 2012 State-of-the-Science Symposium in therapeutic apheresis (TA) with the goals of identifying and prioritizing future research concept proposals to optimize the use of TA over the next decade. METHODS: Six subcommittees, including neurology, were formed based on organ system, pathophysiology, and technology/special considerations. The subcommittees consisted of physicians, clinical subject matter experts, and basic scientists. Each subcommittee developed concept proposals that were presented, evaluated, and prioritized based on scientific importance, clinical significance, and feasibility. RESULTS: The neurology subcommittee developed eight concept proposals. The proposals include therapeutic plasma exchange (TPE) in neuromyelitis optica; TPE versus intravenous immunoglobulin (IVIG) in anti-muscle specific kinase associated myasthenia gravis, severe acute disseminated encephalomyelitis, and anti-NMDA encephalitis; extracorporeal photopheresis in relapsing remitting multiple sclerosis and polymyositis; fibrinogen/low-density lipoprotein apheresis in idiopathic sudden sensorineural hearing loss; and creation of a rare neurologic disease registry and biorepository. CONCLUSIONS: Key clinical research priorities to evaluate and optimize the use of TA on selected neurologic disorders exist. The research opportunities if addressed would provide evidence-based data to inform the care of patients with these selected neurologic diseases.

Therapeutic plasma exchange for fulminant hepatic failure secondary to Wilson's disease.

Wilson's disease (WD) is an autosomal-recessive disorder of impaired copper metabolism resulting in accumulation of copper primarily in the liver but ultimately in many organs and tissues. A small number of patients with WD initially present with fulminant hepatic failure (FHF), hypercupremia, and intravascular hemolysis. The therapeutic goals for these patients include quickly removing the copper and preparing the patient for liver transplantation. Here, we report on a 6-year-old male with WD in FHF with anemia, renal insufficiency, and coagulopathy. The patient received a series of therapeutic plasma exchanges (TPE) as adjunctive therapy to remove copper and stabilize his coagulopathy and anemia until a transplant was possible. A total of five single plasma volume (1500 mL) TPE were performed over the course of 11 days with plasma as the replacement fluid. Laboratory results demonstrated temporary improvement after each procedure. Liver transplantation was performed 12 days after beginning TPE and 35 days after admission to the hospital. TPE was a successful adjunctive therapy to bridge this patient with WD to transplantation.

Platelet and red blood cell utilization and transfusion independence in umbilical cord blood and allogeneic peripheral blood hematopoietic cell transplants.

Allogeneic hematopoietic cell transplantation (HCT) recipients have substantial transfusion requirements. Factors associated with increased transfusions and the extent of blood product use in umbilical cord blood (UCB) recipients are uncertain. We reviewed blood product use in 229 consecutive adult recipients of allogeneic HCT at the University of Minnesota: 147 with leukemia, 82 lymphoma or myeloma; 58% received unrelated UCB and 43% sibling donor peripheral blood stem cell (PBSC) grafts. Although neutrophil recovery was prompt (UCB median 17, range: 2-45 days, and PBSC 14, range: 3-34 days), only 135 of 229 (59% cumulative incidence) achieved red blood cell (RBC) independence and 157 (69%) achieved platelet independence by 6 months. Time to platelet independence was prolonged in UCB recipients (median UCB 41 versus PBSC 14 days) and in patients who had received a prior transplant (median 48 versus 32 days). Patients who received UCB grafts required more RBC through day 60 post-HCT (mean UCB 7.8 (95% confidence interval [CI] 6.7-8.9) versus PBSC 5.2 (3.7-6.7) transfusions, P = .04), and more platelet transfusions (mean 25.2 (95% CI 22.1-28.2) versus 12.9 (9.4-16.4), P < .01) compared to PBSC recipients. Patients receiving myeloablative (MA) conditioning required more RBC and platelet transfusions during the first 2 months post-HCT compared to reduced-intensity conditioning (RIC) (7.4 versus 6.2, P = .30 for RBC; 23.2 versus 17.5, P = .07 for platelets). Despite prompt neutrophil engraftment, UCB recipients had delayed platelet recovery as well as more prolonged and costly blood product requirements. Enhanced approaches to accelerate multilineage engraftment could limit the transfusion-associated morbidity and costs accompanying UCB allotransplantation.

An Observational Study of 3 Different Transfusion Medicine Teaching Methods for Medical Students.

Knowledge deficits of transfusion medicine are prevalent among learners and practicing physicians. In the past, the transfusion medicine community has thoughtfully defined the content of transfusion medicine curriculums through Transfusion Medicine Academic Award Group and The Academy of Clinical Laboratory Physicians and Scientists. The manner in which the curriculum should be delivered has been less carefully examined and defined. We completed an observational study in which we analyzed 3 different teaching techniques: in-person faculty-led simulation curriculum consisting of didactic session and simulation ("Simulation group"); hybrid education with a combination of online materials and short in-person simulation ("Hybrid group"); and online-only education module, which delivered the whole curricular content through a variety of online materials and videos ("Online-only group"). Knowledge acquisition was assessed with a 10-question multiple-choice questionnaire, and satisfaction was assessed by a 9-question online student satisfaction survey. A total of 276second-year medical students participated in the study. There was statistically significant difference between pre- and posttest results and in knowledge gain favoring the Simulation group as compared with the Online-only group (P=.03, P<.0001) and favoring the Simulation group as compared with the Hybrid group (P=.004, P<.0001). The Simulation group and Hybrid group medical students were also more satisfied with the education activity as compared with the Online-only group (P<.0001, P<.001). Our study demonstrated that a faculty-run transfusion medicine simulation curriculum consisting of an in-person didactic session and simulation session for the second-year medical students produced greater immediate knowledge acquisition compared with an online only or a hybrid curriculum. Furthermore, any curriculum that contained in-person teaching by faculty was preferred over the online only education.

National Institutes of Health State of the Science Symposium in Therapeutic Apheresis: scientific opportunities in extracorporeal photopheresis.

The clinical use of extracorporeal photopheresis (ECP) for accepted indications such as graft-versus-host disease, transplant rejection, and cutaneous T-cell lymphoma continues to increase. Expanded applications for ECP, such as the treatment of select autoimmune diseases, are being explored. Extracorporeal photopheresis's capacity to both immunotolerize in the autoreactive setting, while immunizing against a lymphoma is unusual and suggestive of a unique mechanism. It is likely that ECP's induction of dendritic cells is key to its efficacy in both of these settings, but exactly how ECP impacts other immune components and their interactions is not fully understood. Further basic science research is necessary to elucidate how these dissimilar cellular activities are functionally integrated. On the clinical side, collaborative multicenter trials designed to recognize the principal variables controlling therapeutic responses and improve prognostic indicators may enable tailoring devices, treatment schedules, and doses to the needs of the individual patients or diseases. This review describes our current understanding of how ECP influences the immune system, reviews the existing clinical applications of ECP, and explores areas for future basic science and clinical research as presented at the National Institutes of Health State of the Science Symposium in Therapeutic Apheresis in November 2012.