Journal of Clinical Apheresis (J Clin Apher )

Publisher: American Society for Apheresis, John Wiley and Sons

Description

The Journal of Clinical Apheresis publishes articles dealing with all aspects of hemapheresis. Articles welcomed for review include those reporting basic research and clinical applications of therapeutic plasma exchange therapeutic cytapheresis therapeutic absorption blood component collection and transfusion donor recruitment and safety administration of hemapheresis centers and innovative applications of hemapheresis technology. Experimental studies clinical trials case reports and concise reviews will be welcomed.

Impact factor 2.27

  • 5-year impact
    1.78
  • Cited half-life
    6.00
  • Immediacy index
    0.18
  • Eigenfactor
    0.00
  • Article influence
    0.42
  • Website
    Journal of Clinical Apheresis website
  • Other titles
    Journal of clinical apheresis (Online), Journal of clinical apheresis
  • ISSN
    1098-1101
  • OCLC
    38866660
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

John Wiley and Sons

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • See Wiley-Blackwell entry for articles after February 2007
    • On personal web site or secure external website at authors institution
    • Deposit in institutional repositories is not allowed
    • JASIST authors may deposit in an institutional repository
    • Non-commercial
    • Pre-print must be accompanied with set phrase (see individual journal copyright transfer agreements)
    • Published source must be acknowledged with set phrase (see individual journal copyright transfer agreements)
    • Publisher's version/PDF cannot be used
    • Articles in some journals can be made Open Access on payment of additional charge
    • 'John Wiley and Sons' is an imprint of 'Wiley'
  • Classification
    ​ green

Publications in this journal

  • Pallavi Galera, Hannah C. Martin, Linda Welch, Paula Sulmasy, Jan Cerny, Mindy Greene, Michelle Vauthrin, Jeffrey A. Bailey, Robert Weinstein
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    ABSTRACT: Sirolimus is an immunosuppressant used to prevent graft versus host disease in allogeneic hematopoietic stem cell transplant recipients. It has a large volume of distribution (12 ± 7.5 l/kg) and within the intravascular space ∼95% of it is bound to red blood cells. Because of potential toxic effects at high trough levels, therapeutic drug monitoring is recommended for sirolimus. We present a case of severe hepatic dysfunction due to Hepatitis B and sirolimus toxicity, in a 51-year-old male stem cell transplant recipient. An automated red cell exchange decreased his blood sirolimus level from 22.6 to 10.3 ng/ml (55% reduction) and improved his liver enzymes. Re-equilibration of sirolimus from other compartments to the blood necessitated a series of four red cell exchanges, after which the sirolimus level was 4.7 ng/ml. Although the patient ultimately succumbed to multiorgan failure, red cell exchange may be considered for acute removal of sirolimus in selected patients. J. Clin. Apheresis, 2015. © 2015 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 01/2015;
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    ABSTRACT: It has been shown that it is possible to predict the CD 34+ hematopoietic progenitor cell dose from collection procedures on TerumoBCT COBE Spectra® cell separator platform using simple variables available at the start of the procedure. In this article, we demonstrate that this can be done simply and reliably using TerumoBCT Spectra Optia® (“Optia”) cell separator platform with a very close correlation between predicted and actual results (correlation coefficient 0.956). This knowledge can be used to optimize apheresis sessions and to minimize harmful effects and costs. In addition, we have shown differences in collection efficiency between healthy donors and cancer patients undergoing autologous donation. Finally, we have shown a small but significant improvement in collection efficiency for the Optia platform compared with the COBE Spectra platform. J. Clin. Apheresis, 2015. © 2015 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 01/2015;
  • Marta Tremolada, Simone Schiavo, Tiziana Tison, Emilia Sormano, Giustina De Silvestro, Piero Marson, Luca Pierelli
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    ABSTRACT: Aims: In Italian and international background, there are no studies focusing on stress, burnout indicators, and job satisfaction in health professionals working in the apheresis units. This study aims to fill this void both for scientific and clinical reasons. Methods: The participants were 470 health professionals (220 physicians, 250 nurses), mostly female (73.4%), with an average age of 48.09 (with the 5° percentile under 32 years and the 95° percentile over 60), working in the Apheresis Units in the North (228), in the Center (131) and in the Southern-islands of Italy (111). The health professionals' years on the job were principally between one and 10 years (40.2%) or from 11 to 20 years (33.2%). The prevalent activity was therapeutic apheresis (48.5%). The self-report questionnaires were proposed electronically by a protected online site. Results: Important stress levels were identified in the health professionals. Physicians principally showed medium (47.5%) and high (35.8%) stress levels. Stress levels of nurses were mostly low (57.7%) or medium (25.7%). Female gender in nurses [t(268) = −3.29; P = 0.001] and in physician professions [t(217) = −3.01; P = 0.03] was a risk factor for stress. Both job categories were placed at a high risk level for burnout syndrome comparing with normative scales, especially the health professionals working in the center of Italy for the scales “Emotional exhaustion” [F(2) = 4.39; P = 0.013] and “Professional inefficacy” [F(2) = 4.38; P = 0.013]. Conclusions: Health professionals working in the apheresis unit show high stress levels and burnout risk. New preventive programs and specific clinical interventions should be constructed. J. Clin. Apheresis, 2015. © 2015 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 01/2015;
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    ABSTRACT: Propofol infusion syndrome (PRIS), a rare complication of propofol sedation, is associated with high mortality. There is no specific therapy. A 16-year-old with head injury and status epilepticus is described. Three days after seizure resolution, whilst receiving propofol, he developed severe lactic acidosis, rhabdomyolysis, and hemodynamic instability. Suspected PRIS was treated with a single session of therapeutic plasma exchange (TPE). This was associated with immediate improvement in hemodynamic status, resolution of lactic acidosis within 24 h, normalization of CPK over 10 days, and a subsequent full recovery. TPE is suggested as a novel therapy for PRIS. J. Clin. Apheresis, 2015. © 2015 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 01/2015;
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    ABSTRACT: Systemic autoimmune diseases (AID) have multiorgan, heterogeneous clinical presentations and are characterized by dysregulation of the immune system, immunodeficiency, irreversible organ damage and increased morbidity and mortality. Preventing or decreasing flares of AID correlate with durable disease control, significant reduction of inflammation and prevention of disability or therapy-related toxicity. There is an urgent need for better treatment of severe, therapy-refractory AID. Extracorporeal photopheresis (ECP) is a cell-based immunomodulatory treatment which has been extensively used in variety of autoimmune disorders for the last two decades. ECP treatment is FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL) with particularly promising results seen in graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Prolonged therapy is safe, well tolerated and allows reduction of systemic immunosuppression in therapy-refractory patients. Both clinical and experimental evidence suggest that ECP mechanism of action is characterized by apoptosis and phagocytosis of activated cells by antigen-presenting cells (APC), secretion of anti-inflammatory cytokines and stimulation of regulatory T cells (Tregs). The focus of this paper is to review the current evidence of ECP use in the treatment of AID. Here, we summarize the experience of nine major AID from 65 published reports. The key findings demonstrate substantial evidence of ECP feasibility, safety and in some AID also promising efficacy. However, the role of ECP in AID therapy is not established as most published studies are retrospective with limited number of patients and the trials are small or poorly standardized. The available data support future investigations of ECP as a therapeutic modality for the treatment of AID in well-designed prospective clinical studies. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 12/2014;
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    ABSTRACT: Introduction: Peripheral blood stem cell (PBSC) transplantation has become a routine procedure in pediatric oncology. A special group of PBSC donors are children weighing 20 kg or less. Limited vascular access and low blood volume puts them at a higher risk. Central line placement and a priming apheresis machine are recommended to avoid these complications. Patients and Methods: PBSC collections performed from July 2006 to May 2013 in children weighing less than 20 kg were included. All donors had a central venous catheter (CVC). An apheresis machine was primed with packet red blood cells. Results: Twenty-seven PBSC collections were performed in 22 children weighing 20 kg or less, 14 for allogeneic and 8 for autologous transplantation, in order to collect at least 2 × 106 CD34+ cells/kg. In the allogeneic group, median age and weight were 3 years (0.8–7) and 15.5 kg (8–20). In the autologous group, median age and weight were 3 years (2–7) and 15.35 kg (12.5–19.5). A single large-volume apheresis was sufficient to obtain the CD34+ cells needed in 78.5% and 75% of the allogeneic and autologous groups, respectively, with a median 11.84 × 106 and 5.79 × 106 CD34+ cells collected per kilogram of weight of the recipient. No serious complications related to the apheresis procedure or CVC placement occurred. Conclusion: PBSC collection in a single large-volume apheresis for allogeneic and autologous transplants in children weighing 20 kg or less is a safe and effective procedure when based on standardized protocols. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 12/2014;
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    ABSTRACT: BackgroundABO-incompatible organ transplantation requires pre-transplant conditioning to reduce ABO antibody levels in the recipients. With respect to replacement fluids used in plasma exchange, we intended to verify whether fresh-frozen plasma (FFP) containing soluble ABO substance (SAS) is more effective than albumin solution in reducing ABO IgG antibody levels.Methods Apheresis data were retrospectively studied for in vivo effects, and in vitro plasma mixing studies were prospectively performed. The amount of ABO IgG antibodies bound to red cells was measured as the mean fluorescence intensity (MFI) using flow cytometry. Neutralization of ABO antibodies in the recipientst plasma by an ABO-incompatible donornc plasma was measured using the inhibition assay principle. The MFI value of the unneutralized control tube was divided by that of the neutralized test tube (neutralizing-capacity index, NCI).ResultsThe plasma exchange procedures replaced with group AB FFP showed a significantly greater decreased titer than those replaced with albumin (P = 0.010). The in vitro plasma mixing study simulating plasma exchange also produced consistent results. When the pooled group O plasma was neutralized for anti-A by individual group AB plasmas (AB-to-O, N = 30), the NCI was 12.8 ± 5.4 (6.5–29.5). When this group O plasma was neutralized by pooled group AB or A plasma, the repeatedly measured NCI (N = 5) of A-to-O (11.4 ± 1.4) was not significantly different from that of AB-to-O (9.7 ± 1.3, P = 0.074).ConclusionsABO antibody levels are reduced more effectively by group AB FFP than by albumin. Either group AB or donor type (group A or B) FFP can be infused to group O recipients. FFP units with higher SAS levels can be selected from multiple available candidate units using our protocol for measuring the neutralizing-capacity. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 12/2014;
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    ABSTRACT: Background: Granulocyte transfusions are given to patients with life-threatening infections, refractory to treatment. The donors are stimulated with corticosteroids ± granulocyte colony stimulating factor (G-CSF). However, data regarding the donors' safety is sparse. The objective was therefore to evaluate short- and long-term adverse events (AE) in G-CSF stimulated donors. Study design and methods: All consecutive granulocyte donors from 1994 to 2012 were identified through our registry. From the donation records, the number of aphereses, stimulation therapy, AE, blood values post donation, and recent status were evaluated. Results: One hundred fifty-four volunteer donors were mobilized for 359 collections. Age at first granulocyte donation was 43 years (median; range 19–64 years). Follow-up was 60 months (median; range 0–229 months). The dose of G-CSF per collection was 3.8 ug/kg body weight (median; range 1.6–6.0 ug/kg). Sedimentation agent was HES. Short-term AE were mild. Blood values 4 weeks post donation with minor reductions/elevations mostly resolved in later donations. Fourteen donors were excluded from the registry due to hypertension (4), diabetes (2), atrial flutter (1), breast carcinoma (1), urethral carcinoma in situ (1), MGUS (1), thrombosis (1), anaphylaxis (1), primary biliary cirrhosis (1), and unknown (1). Three donors are deceased due to diabetes, acute myocardial infarction, and unknown cause. All excluded/deceased donors except one were excluded/died at least 6 months after first granulocyte donation. Conclusion: No serious short-term AE were observed. Due to the variability of diagnoses among excluded/deceased donors, we propose that it is less likely that granulocyte donations have a causative impact on these donors' exclusion or death. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 12/2014;
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    ABSTRACT: Background:Anti-muscle specific kinase antibody positive myasthenia gravis (MuSK MG) is often characterized by a relatively severe and progressive course, refractoriness to standard myasthenia gravis (MG) medications, and an increased risk of myasthenic crisis. We report here successful management of three MuSK MG patients using maintenance therapeutic plasma exchange (TPE) treatment for up to 4.5 years. Materials: The study was a 5-year retrospective review of all MG patients treated with TPE between 2008 and 2013 at University of Michigan. Inclusion criteria of MuSK MG were positive for anti-MuSK antibodies and a diagnosis of MuSK MG by staff neurologists. Patient data included age, gender, diagnostic testing results, medications, and the dates and response to TPE treatments. Results: A total of 153 MG patients underwent at least one course of TPE between 2008 and 2013. A total of 12 patients (7.8%) were positive for anti-MuSK antibodies. Patients were predominantly female (83.3%) and a median age of onset was 46-years old. Three MuSK MG patients were successfully managed with maintenance TPE. Conclusion: Maintenance TPE may be an effective option for MuSK MG patients. The key of successful maintenance treatment at our institution has been to tailor the TPE frequency for each individual, and to modify the treatment interval in conjunction with medical management. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 12/2014;
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    ABSTRACT: Fetal anemia is caused by Rhesus (RhD) sensitization as a result of RhD incompatibility during pregnancy. The severe form of this disease can cause hydrops fetalis leading to intrauterine death. We experienced a highly sensitized 39-year-old woman with B Rh-negative blood. She had a history of three induced abortions and experienced perinatal death associated with hydrops fetalis. During the pregnancy prior to her most recent one, she was treated with double-filtration plasmapheresis (DFPP), high dose γ-globulin and intrauterine fetal blood transfusion (IUT). For her most recent pregnancy, we performed only weekly or fortnightly DFPP from 13 weeks until delivery. Anti-D antibody titer was maintained between 32 and 256 without any signs of fetal anemia. IUT was not required at any stage of the pregnancy. No adverse events were observed. She successfully delivered a healthy male infant weighing 2,289 g by Cesarean section at 35 weeks. Repeated DFPP may be an effective and safe strategy to reduce antibody titers in highly sensitized women with RhD-incompatible pregnancy, avoiding the need for IUT. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 11/2014;
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    ABSTRACT: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening microangiopathy with a heterogeneous and largely unpredictable course. It is caused by ADAMTS13 deficiency, that can be either congenital or due to anti-ADAMTS13 autoantibodies development. ADAMTS13 deficiency is necessary but not always sufficient to cause acute clinical manifestations and trigger factors may be needed. We report the case of a woman diagnosed with congenital TTP in her adulthood, presenting with anti-ADAMTS13 autoantibodies in acute phase during ticlopidine consumption. Noteworthy, the two ADAMTS13 mutations identified in this patient are novel: one is a splice-site mutation located in intron 11 (c.1308+2_5delTAGG) and the other is a point missense mutation in exon 29 (c.4184T>C leading to p.Leu1395Pro substitution). Since congenital TTP is an extremely rare disease and drug-induced TTP is an uncommon side effect of treatment with ticlopidine, the simultaneous occurrence of both mechanisms of disease in one patient is exceptional. This case represents TTP as a multifactorial disease, with ADAMTS13 genetic abnormality and environmental exposures acting together in determining individual clinical phenotype. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 11/2014;
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    ABSTRACT: Drug associated thrombotic microangiopathy (TMA) is a rare event causing thrombocytopenia, microangiopathic anemia, renal failure, and neurologic abnormalities. Here, we present a case of TMA that occurred during the first cycle of treatment with carfilzomib for relapsed multiple myeloma. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 11/2014;
  • Journal of Clinical Apheresis 10/2014;
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    ABSTRACT: The bone marrow niche functions are modulated by complicated cytokines network. The aim of our study was to evaluate the levels of VCAM-1, VEGF, MMP-9 and SDF during mobilization of CD34+ cells in patients with hematological malignancies. Thirty four patients were enrolled to the study (19F, 15 M) at median age of 57 years. The group consisted of patients with multiple myeloma (26) and lymphoma (8). The mobilization procedures comprised chemotherapy and then G-CSF. Blood samples were collected before chemotherapy (N = 34) and on the day of the first apheresis (N = 26). Cytokines were evaluated with ELISA assay. We observed significant increase in VCAM-1 levels during mobilization. On contrary, VEGF and SDF levels decreased during mobilization procedure. The levels of MMP-9 were stable during mobilization. We divided patients according to baseline cytokines levels below and above median into “low” and “high” expressors. The group of VEGF “low” expressors had longer median time of G-CSF treatment before first apheresis than ‘high’ expressors. Baseline VEGF levels correlated adversely with duration of G-CSF treatment before first apheresis. Patients were also divided according to median cytokines levels at apheresis into “low” and “high” expressors. “High” VCAM-1 expressors had higher CD34+in peripheral blood as well as higher CD34+numbers collected during first apheresis than “low” expressors. In conclusion, the levels of niche cytokines change significantly during mobilization in patients with hematopoietic malignancies. Baseline VEGF can influence timing of mobilization. Higher VCAM-1 corresponds with higher mobilization efficacy. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 10/2014;
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    ABSTRACT: Apheresis can remove pathogens and mediators that contribute to pathogenic inflammatory responses in diseases not generally considered to be “Hematologic.” Erythrocytapheresis can remove intracellular pathogens such as Babesiosis. Plasmapheresis can remove mediators of the inflammatory response in conditions such as sepsis, chronic autoimmune urticaria and malignant pertussis. Leukapheresis can remove potentially harmful leukocytes in Crohn's Disease and malignant pertussis. While apheresis can remove all of these substances, the clinical efficacy and pathophysiologic changes that occur during apheresis in these conditions are largely unknown. Hence, the clinical utility of apheresis in these conditions is largely unknown and research in these areas has the potential to benefit many patients with a variety of diseases. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 10/2014;
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    ABSTRACT: Background:In patients suffering from dilated cardiomyopathy (DCM), immunoadsorption with subsequent IgG substitution (IA/IgG) leads to an acute and prolonged improvement of hemodynamics and heart failure symptoms. However, some patients receiving IA/IgG experience recurrence of heart failure after an initial benefit. The aim of this study was to investigate whether a second IA/IgG treatment episode improves left ventricular systolic function and further mitigates heart failure symptoms in these patients.Methods:We retrospectively analyzed 15 DCM patients who experienced a significant improvement of LVEF (≥ 5% absolute or ≥ 20% relative) and heart failure symptoms (≥ 1 NYHA functional class) but a subsequent deterioration (decline in LVEF ≥ 5% absolute or ≥ 20% relative and NYHA worsening ≥1 class) after the first IA/IgG. These patients underwent a second IA/IgG treatment 41.7 ± 27.4 months after the first cycle. Follow up data were acquired 3–6 months after both IA/IgG treatments.Results:The first IA/IgG induced an improvement of LVEF from 33 ± 6.4% to 43.2 ± 7.9% (P < 0.001) and of mean NYHA functional class from 2.9 ± 0.26 to 1.8 ± 0.56 (P < 0.001). The second treatment was associated with a significant improvement in LVEF (from 29.7 ± 4.6% to 34.9 ± 8.3%, P = 0.013) and NYHA functional class (2.87 ± 0.64 to 2.33 ± 0.72; P = 0.02). This improvement was less pronounced compared to the first treatment with respect to both, LVEF (P = 0.09) and NYHA improvement (P = 0.04).Conclusion:In DCM patients, who experience a significant improvement of LVEF and heart failure symptoms after IA/IgG but a subsequent relapse during follow up, repeated IA/IgG may be considered. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 10/2014;
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    ABSTRACT: High-dose cyclophosphamide (Cy) is frequently employed for peripheral blood mobilization of hematopoietic stem cells before high-dose chemotherapy with autologous stem cell transplantation (ASCT) in multiple myeloma (MM). The benefit of mobilization with Cy over filgrastim (granulocyte colony-stimulating factor; G-CSF) alone is unclear. Between 2000 and 2008, 167 patients with newly diagnosed MM underwent single ASCT after melphalan conditioning at our institution. Seventy-three patients were mobilized with G-CSF alone, and 94 patients with Cy plus G-CSF (Cy+G-CSF). We retrospectively analyzed Cy's impact on both toxicity and efficacy. Mobilization efficiency was augmented by Cy; a mean total of 12 versus 5.8 × 106 CD34+ cells/kg were collected from patients mobilized with Cy+G-CSF versus G-CSF, respectively, (P < 0.01), over a mean of 1.6 versus 2.2 days of peripheral blood apheresis (p = 0.001). Mobilization-related toxicity was also, however, augmented by Cy; 14% of Cy+G-CSF patients were hospitalized because of complications versus none receiving G-CSF (P < 0.0001). Toxicity, including death, related to ASCT was similar between cohorts. Regarding long-term outcomes, multivariate analysis revealed no difference for Cy+G-CSF versus G-CSF (hazard ratio 0.8 for event-free survival [95% confidence interval {CI} 0.57–1.25] and 0.96 for overall survival [95% CI 0.61–1.54]). In summary, we show that mobilization with Cy increases toxicity without positively impacting long-term outcomes in MM. Our findings place into question Cy's benefit as a routine component of stem cell mobilization regimens in MM. Randomized trials are needed to elucidate the risks and benefits of Cy more definitively. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 10/2014;
  • Journal of Clinical Apheresis 09/2014;
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    ABSTRACT: Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare clinical syndrome associated with significant mortality. Although the use of plasma exchange (PE) in TA-TMA continues to be explored, evidence for its efficacy is debated. We performed a single institution, retrospective study to evaluate the efficacy of PE in treating TA-TMA patients. Special attention was given to efficacy in relation to the timing of presentation with TA-TMA since transplant. Thirty-three patients diagnosed with TA-TMA and treated with PE between January 1999 and December 2010 were included in the study. Clinical improvement was seen in eight patients (24%); four patients achieved complete resolution while the remaining four achieved partial resolution. All-cause day-30 and day-100 mortality was 33 and 55%, respectively. There was a trend toward a better outcome (complete/partial) for those presenting ≥ 100 days after transplantation (42%) vs. < 100 days after transplantation (14%; P-value = 0.15). Similarly, those presenting at ≥ 100 days had better, but not significantly, 30-day and 100-day all-cause mortality rates (17 and 33%, respectively) than those presenting at < 100 days (43 and 67%, respectively) (P-value = 0.25 and 0.08, for 30- and 100-day all-cause mortality, respectively). This is the first study looking at the efficacy of PE while considering the time of presentation since transplantation and is one of the largest single institution series of TA-TMA. The overall efficacy of PE is poor; however, patients who present with TA-TMA ≥100 days after transplant may have better outcome and lower mortality. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Clinical Apheresis 09/2014;