Advertisement

Donor safety in an individualized plasmapheresis program – Results of an interim analysis

Open AccessPublished:April 08, 2022DOI:https://doi.org/10.1016/j.transci.2022.103446

      Highlights

      • Individualizing plasmapheresis based on IgG levels does not affect donor safety.
      • Slightly higher donation-based incidence of AEs/SAEs than in control donors.
      • There is an increase in mild and moderate events directly related to plasma donation.
      • Overall, donation-based incidences compare favorably with published values.
      • Higher donation frequencies appear feasible for donors with high IgG levels.

      Abstract

      Background and objectives

      Although plasma donation by plasmapheresis is generally considered to be safe, there are still concerns about the long-term effects of intensive plasma donation on the levels of certain blood components, such as immunoglobulin G (IgG). The IPS study aims to assess donor safety during individualized plasma donation according to pre-donation IgG levels and body weight compared with plasma donation under current German guidelines.

      Study design and methods

      This ongoing prospective multicenter study allows eligible donors to choose between an individualized plasma donation program or plasma donation according to current German guidelines. Adverse events (AEs), serious AEs (SAEs) and serum IgG levels are systematically documented for up to 12 years, with AE/SAE recording from study start until 8 months after the last donation on-study.

      Results

      At data cut-off (30 th June 2019), 1,919,334 donations in 20,598 donors were documented. The donation-based incidence for all AEs/SAEs was 2.07% in the control group (n = 2155) and 2.22% in the individualized program group (n = 18,443). For related AEs/SAEs, incidences were 1.23% and 1.62%, respectively. Most AEs/SAEs were of mild or moderate severity; events related to venepuncture were most frequent (46.8%). The majority of withdrawals with known causes were due to non-medical reasons. After an initial drop, IgG levels remained stable for up to 10 years.

      Conclusions

      The results of this interim analysis showed no critical difference in donor safety between donors in an individualized program and those who donated according to current guidelines, supporting the concept of donor stratification by pre-donation IgG levels

      Keywords

      1. Introduction

      Plasma donation by plasmapheresis is the key source for plasma as a starting material to produce immunoglobulins and clotting factor concentrates. Key parameters, such as the maximum plasma volume per donation and/or per year, maximum frequency of plasma donations, or a combination of these parameters, are usually defined in country-specific guidelines [

      U.S. Food and Drug Administration. Electronic Code of Federal Regulations, Title 21, Part 640—Additional standards for human blood and blood products, 〈https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=f09b5a7c4c544c8bd2089e8732599953&mc=true&r=PART&n=pt21.7.640〉; 2015 [accessed August 19, 2021].

      ,

      Bundesärztekammer, Germany. Richtlinie zur Gewinnung von Blut und Blutbestandteilen und zur Anwendung von Blutprodukten (Richtlinie Hämotherapie): Gesamtnovelle 2017 mit vom Vorstand der Bundesärztekammer auf Empfehlung seines Wissenschaftlichen Beirats am 18.01.2019 verabschiedeten Erratum/Anpassungen, 〈https://www.bundesaerztekammer.de/fileadmin/user_upload/downloads/pdf-Ordner/MuE/Richtlinie_Haemotherapie_2017.pdf〉; 2019 [accessed August 19, 2021].

      , ,

      Joint United Kingdom Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee. Red Book, Chapter 3: Care and selection of whole blood and component donors (including donors of pre-deposit autologous blood), 〈https://www.transfusionguidelines.org/red-book/chapter-3-care-and-selection-of-whole-blood-and-component-donors-including-donors-of-pre-deposit-autologous-blood〉; 2021 [accessed August 19, 2021].

      ,

      La ministre des solidarités et de la santé, France. Arrêté du 17 décembre 2019 fixant les critères de sélection des donneurs de sang, 〈https://www.legifrance.gouv.fr/loda/id/LEGIARTI000039704296/2020–04-02/〉; 2019 [accessed August 19, 2021].

      ,

      Ministerio de Sanidad y Consumo, Spain. Criterios básicos para la selección de donantes de sangre y componentes, 〈https://www.mscbs.gob.es/profesionales/saludPublica/medicinaTransfusional/publicaciones/docs/criteriosBasicosTomoII_2006_030907.pdf〉; 2006 [accessed August 19, 2021].

      ,

      Ministero Della Salute, Italy. Decreto 2 novembre 2015: Disposizioni relative ai requisiti di qualità e sicurezza del sangue e degli emocomponenti, 〈https://www.centronazionalesangue.it/wp-content/uploads/2017/07/GU-SG-n.300-del-28–12-2015_SO_069.pdf〉; 2015 [accessed August 19, 2021].

      ,

      Blutspende SRK Schweiz, Switzerland. Vorschriften, Kapitel 17C: Spezielle Bedingungen für unterschiedliche Spendearten, 〈https://dokuman.sbsc-bsd.ch/de-de/vorschriftenbsd/vorschriftenkapitelbeschl%C3%BCsse/kapitel.aspx〉; 2019 [accessed August 19, 2021].

      ,

      Bundesministerium für Arbeit, Soziales, Gesundheit und Konsumentenschutz, Austria. Verordnung der Bundesministerin für Arbeit, Gesundheit und Soziales betreffend den Gesundheitsschutz von Spendern und die Qualitätssicherung von Blut und Blutbestandteilen (Blutspenderverordnung – BSV), 〈https://www.ris.bka.gv.at/GeltendeFassung.wxe?Abfrage=Bundesnormen&Gesetzesnummer=10011170〉; 2019 [accessed August 19, 2021].

      ]. Of particular concern is maintaining appropriate total serum protein (TSP) and immunoglobulin G (IgG) levels in donor blood, and several guidelines offer guidance on qualitative or quantitative monitoring of these parameters [

      U.S. Food and Drug Administration. Electronic Code of Federal Regulations, Title 21, Part 640—Additional standards for human blood and blood products, 〈https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=f09b5a7c4c544c8bd2089e8732599953&mc=true&r=PART&n=pt21.7.640〉; 2015 [accessed August 19, 2021].

      ,

      Bundesärztekammer, Germany. Richtlinie zur Gewinnung von Blut und Blutbestandteilen und zur Anwendung von Blutprodukten (Richtlinie Hämotherapie): Gesamtnovelle 2017 mit vom Vorstand der Bundesärztekammer auf Empfehlung seines Wissenschaftlichen Beirats am 18.01.2019 verabschiedeten Erratum/Anpassungen, 〈https://www.bundesaerztekammer.de/fileadmin/user_upload/downloads/pdf-Ordner/MuE/Richtlinie_Haemotherapie_2017.pdf〉; 2019 [accessed August 19, 2021].

      , ,

      Bundesministerium für Arbeit, Soziales, Gesundheit und Konsumentenschutz, Austria. Verordnung der Bundesministerin für Arbeit, Gesundheit und Soziales betreffend den Gesundheitsschutz von Spendern und die Qualitätssicherung von Blut und Blutbestandteilen (Blutspenderverordnung – BSV), 〈https://www.ris.bka.gv.at/GeltendeFassung.wxe?Abfrage=Bundesnormen&Gesetzesnummer=10011170〉; 2019 [accessed August 19, 2021].

      ]. The maximum number of donations allowed is currently highest in the US, where donors can donate up to 104 times per year [

      U.S. Food and Drug Administration. Electronic Code of Federal Regulations, Title 21, Part 640—Additional standards for human blood and blood products, 〈https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=f09b5a7c4c544c8bd2089e8732599953&mc=true&r=PART&n=pt21.7.640〉; 2015 [accessed August 19, 2021].

      ]. Current German guidelines allow up to 60 donations per year and require measurement of IgG and TSP levels prior to first plasma donation and subsequently at every 5th donation. Donors with serum IgG levels below 6 g/L must be deferred for at least two weeks [

      Bundesärztekammer, Germany. Richtlinie zur Gewinnung von Blut und Blutbestandteilen und zur Anwendung von Blutprodukten (Richtlinie Hämotherapie): Gesamtnovelle 2017 mit vom Vorstand der Bundesärztekammer auf Empfehlung seines Wissenschaftlichen Beirats am 18.01.2019 verabschiedeten Erratum/Anpassungen, 〈https://www.bundesaerztekammer.de/fileadmin/user_upload/downloads/pdf-Ordner/MuE/Richtlinie_Haemotherapie_2017.pdf〉; 2019 [accessed August 19, 2021].

      ]. However, these regulations do not account for a donor's individual capacity for IgG regeneration.
      Other studies have investigated different approaches to intensify and/or individualize donation regimens. In SIPLA (Study on Intensified PLAsmapheresis), individualizing donation volumes based on donor body weight did not lead to an increased number of drop-outs, and a high IgG level at study start was protective against drop-out due to low IgG, TSP or hemoglobin [
      • Schulzki T.
      • Seidel K.
      • Storch H.
      • Karges H.
      • Kiessig S.
      • Schneider S.
      • et al.
      A parospective multicentre study on the safety of long-term intensive plasmapheresis in donors (SIPLA).
      ].
      In SIPLA donors with higher IgG levels at study start, IgG decreased over time but generally remained above the threshold, whereas donors with lower initial IgG levels tended to fall below the threshold (unpublished data). These findings corroborate published data on monthly plasmapheresis, which demonstrated that donors falling below the IgG threshold at least once during the study had significantly lower IgG levels pre-donation than donors who stayed above the threshold [
      • Burgin M.
      • Hopkins G.
      • Moore B.
      • Nasser J.
      • Richardson A.
      • Minchinton R.
      Serum IgG and IgM levels in new and regular long-term plasmapheresis donors.
      ]. An analysis of 1293 German plasma donors who were deferred at least once due to low IgG levels revealed a large inter-individual variation in the calculated regeneration rates for IgG post-donation, and a possible correlation of the regeneration rate with baseline IgG levels was shown [

      Möller A. Der Einfluss der präparativen Plasmapherese auf den Immunoglobulin G-, Gesamteiweiss- und Flüssigkeitshaushalt des Plasmaspenders. Dissertation, 〈https://d-nb.info/1070604445/34〉; 2014 [accessed August 19, 2021].

      ]. Therefore, it appears reasonable to use baseline IgG levels to estimate the individual IgG regeneration rate post-donation and to define appropriate donation frequencies, as donors who regenerate IgG more rapidly than others may be able to donate plasma more frequently. This approach has potential to help in optimizing donation frequency while ensuring donor safety.
      Here we report interim data from the ongoing IPS study, which aims to compare donor safety of plasmapheresis in an individualized program (Individualisiertes PlasmaSpendeprogramm, IPS) – according to donor body weight and IgG levels prior to the first donation – with that of donation according to current German haemotherapy guidelines. This is the only study worldwide that systematically captures adverse events (AEs) occurring between donations and after the final donation.

      2. Materials and methods

      2.1 Study design

      The ongoing IPS study is a prospective, multicenter, stratified, controlled study and was initiated by Octapharma Plasma GmbH (OPLG) in September 2007. As of 30th June 2019 (data cut-off), study participation was possible for all donors attending any of the 13 German plasmapheresis centers of OPLG (see Supplementary material). Approval was obtained from all relevant regional ethics committees.
      It is planned to observe 30,000 donors for at least 3 years up to maximum 12 years thereafter.

      2.2 Study participants

      Donors must be eligible for plasmapheresis according to current German guidelines. Donors who have donated plasma at least once before, and are expected to be available as donors for at least one year, are offered participation in the IPS study. Informed consent is required for enrollment; participation in any other clinical trial is not permitted.

      2.3 Plasmapheresis regimens and group allocation

      Eligible donors who accept to participate in the study may choose between plasmapheresis according to current German guidelines (control group) and participation in an individualized plasmapheresis program (individualized program group). Individualized program donors are assigned to a donation regimen according to their body weight, which determines the maximum volume per donation, and their serum IgG levels prior to the first plasma donation, which determine the maximum number of donations per year. In the individualized program, IgG in the low normal range is defined as ≥ 6 and < 8 g/L, the medium normal range is ≥ 8 and < 10 g/L and the high normal range is ≥ 10 g/L (Table 1). A change of regimen is only possible if there is a change of over 6 kg in body weight that causes the donor to cross the thresholds of 60 or 70 kg. If body weight falls below 50 kg, participants can no longer donate plasma, as stipulated by current German guidelines. Throughout the study, data were collected in the same way for both control and individualized program donors.
      Table 1Number of donations and volume per donation for plasmapheresis regimens in the study.
      Initial IgG levelsBody weight
      ≥ 50 and < 60 kg≥ 60 and < 70 kg≥ 70 kg
      ≥ 6 and < 8 g/L (IgG in the low normal range)≤ 26 donations per year 760 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      ≤ 26 donations per year 820 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      ≤ 26 donations per year 860 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      ≥ 8 and < 10 g/L (IgG in the medium normal range)≤ 52 donations per year 760 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      ≤ 52 donations per year 820 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      ≤ 52 donations per year 860 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      ≥ 10 g/L (IgG in the high normal range)≤ 104 donations per year 760 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      ≤ 104 donations per year 820 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      ≤ 104 donations per year 860 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      Control group
      Information for the control group is current as of 30th June 2019 but has changed over the years, e.g. there were only two body weight categories before 2010, and the maximum number of donations was 45 until 2017.
      ≤ 60 donations per year 660 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      ≤ 60 donations per year 760 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      ≤ 60 donations per year 860 mL
      Including anticoagulant and sample for analysis (approximately 10 mL).
      per donation
      IgG, immunoglobulin G.
      a Including anticoagulant and sample for analysis (approximately 10 mL).
      b Information for the control group is current as of 30th June 2019 but has changed over the years, e.g. there were only two body weight categories before 2010, and the maximum number of donations was 45 until 2017.

      2.4 Deferrals and study termination

      Participants can be deferred from donation for any of the reasons listed in the current German guidelines (see Supplementary Methods).
      Participants may withdraw from the study at any time and without justification. Participants excluded by the investigator are classified as withdrawals but may continue to donate plasma outside of the study, provided they are still eligible to do so. Re-entry into the study is not possible.

      2.5 Study objective

      The primary objective of the study is to assess plasmapheresis in an individualized program compared with donation according to current German guidelines in terms of donor safety, defined as incidences of AEs and serious AEs (SAEs). A secondary objective is the description of IgG levels over time.

      2.6 Plasmapheresis procedure and routine monitoring

      All plasmapheresis procedures were performed with the PCS2 Plasma Collection System (Haemonetics) using software version G until 2016 and subsequently Express software. Sodium citrate anticoagulant (4% w/v, Haemonetics) was used at an anticoagulant-to-blood ratio of 1:16.
      Routine monitoring is described in the Supplementary Methods.

      2.7 AE/SAE monitoring

      To assess donor safety, all AEs and SAEs were documented, including events clearly unrelated to plasmapheresis, such as work accidents and diagnoses of malignant disease, as well as technical AEs, such as machine failures and repeat venepunctures. For all AEs/SAEs, severity and causal relationship to plasmapheresis were rated (see Supplementary methods). A possible causal relation was assumed if the AE/SAE was temporally related to plasmapheresis, or a causal relationship could not be excluded. For a probable causal relation, the AE/SAE had to be considered probably or definitely related to plasmapheresis. More detailed assessment of severe or life-threatening AEs/SAEs also included whether the AEs/SAEs occurred at the center. AEs/SAEs were recorded from study start until 8 months after the last donation. Donors were prompted at each donation for any AEs/SAEs that had occurred since the previous donation. Participants who had not informed the center of any longer-term absence, but did not return, were contacted for follow-up.
      Overall donor safety in the study was monitored by a safety committee consisting of independent experts in the field of plasmapheresis with experience in clinical trial conduct.

      2.8 Data analysis

      Details on data handling are available in the Supplementary methods. All donors with at least one donation during the study were included in the safety population. Donors considered valid for the analysis of IgG levels over time must have had ≥ 1 donation and ≥ 2 measurements of serum IgG levels over a period of ≥ 14 days.
      Starting from 2011, incidences of AEs/SAEs were calculated by category of causal relationship. Prior to 2011, these calculations are not meaningful due to low numbers of study participants. Frequencies of AEs/SAEs were calculated both as donation-based incidence (number of events per 100 study donations) and as the number of events per year at risk.
      Descriptive statistics (frequency and incidence for categorical parameters; arithmetic mean and standard deviation for continuous variables) were primarily used. Statistical hypothesis testing and confidence intervals to determine differences between donor groups or to detect associations are exploratory in nature. Estimation, confidence intervals and comparisons of binary variables (e.g. incidence rates) between donor groups were based on a logistic regression model. For all continuous baseline characteristics, ANOVA with subsequent pairwise comparisons of mean values was used, except for the proportion of male donors, which was again analysed using logistic regression.

      3. Results

      Of the two parameters used for stratification, IgG and body weight, IgG was deemed more relevant to categorize the data in terms of withdrawals and AEs/SAEs, as the SIPLA study showed that low IgG levels were associated with higher risk of withdrawal from study. Therefore, throughout the manuscript we present data stratified only according to pre-donation IgG levels.
      At the time of this interim analysis (data cut: 30th June 2019), 20,620 donors were registered. Of these, 20,598 had at least one donation (1,919,334 donations in total) and were included in the safety analysis; 19,051 donors (1,912,844 donations in total) were valid donors according to the analysis criteria. Median (range) time at risk for all valid donors and all donors in the safety population was 1.56 (0.0–11.7) and 1.39 (0.0–11.7) years, respectively.
      Fig. 1 shows the donor distribution across the IgG classes and study phases; donor characteristics for valid donors are summarized in Table 2.
      Fig. 1
      Fig. 1Donor disposition.
      IgG, immunoglobulin G.a Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).
      Table 2Demographic and clinical characteristics of donors included in the analysis population.
      ControlIndividualized program
      (N = 1950)IgG in the low normal range
      Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).
      (N = 317)
      IgG in the medium normal range
      Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).
      (N = 3091)
      IgG in the high normal range
      Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).
      (N = 13,693)
      Total (N = 17,101)
      Age
      At study start.
      (years) (median [range])
      33.9

      (18.2–71.0)
      36.9

      (18.3–74.1)
      32.2

      (18.1–74.7)*#
      28.2

      (18.0–71.2)*
      28.8

      (18.0–74.7)*
      Body weight
      At study start.
      (kg)
      83.8 ± 18.277.6 ± 17.2*83.5 ± 18.2#83.1 ± 18.2#83.1 ± 18.2
      Male sex (n [%])1128 (57.9)168 (53.0)1949 (63.1)7806 (57.0)§9923 (58.0)
      Initial serum IgG
      At study start.
      (g/L)
      7.27 ± 1.526.38 ± 0.92*7.15 ± 1.10#8.56 ± 1.82*8.27 ± 1.80 *
      Initial TSP
      At study start.
      (g/L)
      67.1 ± 4.1567.5 ± 3.8367.7 ± 4.11*67.8 ± 4.81*67.8 ± 4.68 *
      Initial hemoglobin
      At study start.
      (g/L) capillary blood
      Missing values for 29 donors in the control group.
      15.4 ± 1.4115.3 ± 1.3315.3 ± 1.37*15.2 ± 1.43*15.2 ± 1.42 *
      Initial hemoglobin
      At study start.
      (g/L) venous blood
      Missing values for 1 donor in the control group, 1 donor with IgG in the low normal range, 2 donors with IgG in the medium normal range and 31 donors with IgG in the high normal range.
      14.4 ± 1.2014.2 ± 1.2014.4 ± 1.2214.3 ± 1.26§14.3 ± 1.25
      Duration of plasma donation activity before study start (years) (median [range], n)0.97 (0.0–15.9), 19270.87 (0.1–13.7), 308*0.75 (0.0–15.6), 2959 *0.62 (0.0–16.1), 12,876 *0.65 (0.0–16.1), 16,143*
      Time at risk on study
      Up to 30th June 2019.
      (years) (median [range])
      1.47 (0.0–10.7)1.17 (0.0–10.1)1.63 (0.0–11.7)*#1.57 (0.0–11.7)*#1.57 (0.0–11.7)*
      Absolute number of valid donations
      Donations with a volume > 120 mL.
      (N)
      129,1658540235,7091,539,4301,783,679
      Actual donation frequency (valid donations
      Donations with a volume > 120 mL.
      /year)
      36.0 ± 16.417.6 ± 6.77 *32.2 ± 11.5*#46.7 ± 21.1*43.6 ± 20.6*
      IgG, immunoglobulin G; SD, standard deviation; TSP, total serum protein.
      Data are for all valid donors included in the IgG analysis and are presented as mean ± SD unless indicated otherwise.
      Statistical significance of differences was tested by ANOVA pairwise comparison of mean values for all parameters except for the proportion of male donors, for which odds ratios based on a Poisson regression model were calculated.
      * p < 0.0001 vs control
      # p < 0.0001 vs IgG in the low normal range
      § p < 0.0001 vs IgG in the medium normal range
      a Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).
      b At study start.
      c Missing values for 29 donors in the control group.
      d Missing values for 1 donor in the control group, 1 donor with IgG in the low normal range, 2 donors with IgG in the medium normal range and 31 donors with IgG in the high normal range.
      e Up to 30th June 2019.
      f Donations with a volume > 120 mL.

      3.1 Donor safety

      Up to 30th June 2019, 2692 AEs/SAEs during 129,900 donations in 2155 donors were recorded in the control group, translating into a donation-based incidence of 2.07% and a rate of AEs/SAEs per year at risk of 0.701. In the individualized program groups, 39,569 events occurred during 1,789,434 donations in 18,443 donors, with a donation-based incidence of 2.22% and rate of AEs/SAEs per year at risk of 0.997.
      Table 3 shows the donation-based incidence of different types of AEs/SAEs for all events and related events. Across all donors, events related to venepuncture (46.8%) and vasovagal reactions (11.3%) were among the most frequently recorded events. Supplementary Table 1 provides further information on the frequencies of individual AE/SAE categories in the group of AEs/SAEs classified as ‘other’.
      Table 3Donation-based incidence
      Donation-based incidence rate of AEs/SAEs in percent, calculated as (100∙number of AEs/SAEs / number of donations).
      (in %) of different types of AEs/SAEs.
      ControlIndividualized program
      Type of AE/SAE
      Donation-based incidence rate of AEs/SAEs in percent, calculated as (100∙number of AEs/SAEs / number of donations).
      (N = 129,900)IgG in the low normal range
      Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).
      (N = 8817)
      IgG in the medium normal range
      Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).
      (N = 236,875)
      IgG in the high normal range
      Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).
      (N = 1,543,742)
      Total (N = 1,789,434)
      All AEs/SAEs
      All AEs/SAEs2.074.50*2.44*#2.172.22
      Cardiac AEs/SAEs0.01850.04540.009290.00687*0.00738*
      Thrombosis0.004620.02270.008440.004730.00531
      Infection0.2510.3630.2200.175*0.182*
      Malignant disease0.007700.000.005910.003630.00391
      Vasovagal reactions0.2060.873*0.297*#0.2410.251
      Neurological/psychiatric diseases0.03540.07940.03040.02140.0229
      Machine/equipment failure0.1880.397*0.278*0.260*0.263*
      AEs/SAEs related to venepuncture0.8051.64*1.06*#1.04*#1.05*
      Abnormal laboratory values
      Most of these represent reactive test results for markers of (viral) infection and most of these cannot be confirmed in follow-up tests. Nevertheless, the plasma of these donors is not accepted for processing by fractionation companies and the corresponding donors are excluded from plasmapheresis.
      0.004620.01130.008020.008230.00821
      Behavior-related AE/SAE0.02930.05670.05360.03860.0407
      Possible citrate reaction0.005390.01130.005490.002720.00313
      Lipemic plasma0.02690.02270.03800.02860.0298
      Withdrawal from study due to other possibly related AE/SAE0.000.000.000.000390.00034
      Other AEs/SAEs
      See Supplementary Table 1 for details.
      0.4900.975*0.429#0.334*0.350*
      Related
      All AEs/SAEs which were considered possibly or probably related to donation. Categories in which no related AEs were recorded are not shown.
      AEs/SAEs
      All AEs/SAEs1.232.95*1.69*#1.60*#1.62*
      Cardiac AEs/SAEs0.001540.000.000420.000710.00067
      Thrombosis0.000.000.000420.001100.00101
      Infection0.003080.02270.003800.003040.00324
      Malignant disease0.000.000.000.000130.00011
      Vasovagal reactions0.1800.817*0.273*#0.2260.235*
      Neurological/psychiatric diseases0.000.000.000420.002070.00184
      Machine/equipment failure0.1880.397*0.278*0.260*0.263*
      AEs/SAEs related to venepuncture0.8051.64*1.06*#1.04*#1.05*
      Abnormal laboratory values
      Most of these represent reactive test results for markers of (viral) infection and most of these cannot be confirmed in follow-up tests. Nevertheless, the plasma of these donors is not accepted for processing by fractionation companies and the corresponding donors are excluded from plasmapheresis.
      0.001540.000.003380.003500.00346
      Behavior-related AE/SAE0.01310.02270.02740.02340.0239
      Possible citrate reaction0.005390.01130.005490.002660.00307
      Lipemic plasma0.02620.01130.03630.02720.0283
      Other AE/SAE
      See Supplementary Table 1 for details.
      0.009240.02270.008020.007320.00749
      AE, adverse event; IgG, immunoglobulin G; N, number of donations; SAE, serious adverse event.
      Statistical significance of differences was tested by calculating odds ratios based on a Poisson regression model.
      * p < 0.0001 vs control
      # p < 0.0001 vs IgG in the low normal range
      § p < 0.0001 vs IgG in the medium normal range
      a Donation-based incidence rate of AEs/SAEs in percent, calculated as (100∙number of AEs/SAEs / number of donations).
      b Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).
      c Most of these represent reactive test results for markers of (viral) infection and most of these cannot be confirmed in follow-up tests. Nevertheless, the plasma of these donors is not accepted for processing by fractionation companies and the corresponding donors are excluded from plasmapheresis.
      d See Supplementary Table 1 for details.
      e All AEs/SAEs which were considered possibly or probably related to donation. Categories in which no related AEs were recorded are not shown.
      The donation-based incidence of related, but not of all, AEs/SAEs was significantly higher in the individualized program group compared with the control group (1.62% vs 1.23% for related events), which was driven by significantly higher rates of vasovagal reactions, machine/equipment failure and venepuncture-related events. In donors with IgG in the low normal range, donation-based incidences of all AEs/SAEs and related AEs/SAEs were approximately twice as high as in the other groups (Table 3). In contrast, the incidence of unrelated AEs/SAEs, expressed as events per year at risk, was similar for all groups (Supplementary Table 2).
      The vast majority of AEs/SAEs in both the control group (2627; 97.6%) and the individualized program groups (39,046; 98.5%) were of mild or moderate severity. The number of AEs/SAEs classified as possibly or probably related to plasmapheresis was 1602 (59.5%) in the control group and 28,988 (73.1%) in the individualized program groups . Fig. 2 shows the frequencies of AEs/SAEs by severity and causal relationship. For mild or moderate AEs/SAEs with no causal relationship, donation-based frequency was highest in donors with IgG in the low normal range and lowest in those with IgG in the high normal range, whereas the numbers of such events per year at risk were comparable across all groups. For mild or moderate AEs/SAEs deemed possibly or probably related, donation-based frequency was approximately twice as high in donors with IgG in the low normal range as in other groups; the number of such events per year at risk was lowest in the control group and highest in donors with IgG in the high normal range. For severe, life-threatening and fatal AEs/SAEs deemed unrelated, donation-based frequency was again highest in donors with IgG in the low normal range and lowest in those with IgG in the high normal range; however, for these events, the rate per year at risk was also higher in those with IgG in the low normal range compared with the other groups. For related severe, life-threatening and fatal AEs/SAEs, no clear trends could be observed due to the low numbers. Overall, there appears to be a trend towards a comparable donation-based incidence for donation-related events and a comparable number of events per year at risk for non-related events. This was confirmed in an analysis of AE/SAE incidence by actual donation frequency (Supplementary Table 3).
      Fig. 2
      Fig. 2Frequency of AEs by severity and causal relationship. A) Donation-based incidencea of mild or moderate AEs/SAEs; B) Donation-based incidencea of severe, life-threatening or fatal AEs/SAEs; C) Number of mild or moderate AEs/SAEs per year at riskc; D) Number of severe, life-threatening or fatal AEs/SAEs per year at riskc.
      AE, adverse event; CI, confidence interval; IgG, immunoglobulin G; SAE, serious adverse event.
      a Donation-based incidence rate of AEs/SAEs in percent, calculated as (100∙number of AEs/SAEs / number of donations), and 95% Pearson-Clopper CI. b Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).c Estimated number of AEs/SAEs per year at risk and 95% CI, based on the total number of AEs/SAEs and the total number of years at risk based on a Poisson regression model.
      Statistical significance of differences was tested by calculating odds ratios based on a Poisson regression model.
      * p < 0.0001 vs control; # p < 0.0001 vs IgG in the low normal range; § p < 0.0001 vs IgG in the medium normal range.
      Supplementary Table 4 lists all 44 AEs/SAEs that were severe or life-threatening and possibly or probably related to plasmapheresis; of these, 40 events occurred in donors with IgG in the high normal range, 2 events in donors with IgG in the medium normal range and 2 events in donors in the control group. Ten deaths occurred during the study; of these, 7 were recorded in donors with IgG in the high normal range, 2 in donors with IgG in the medium normal range and 1 in a control group donor; none were judged to be related to plasmapheresis (Supplementary Table 5).
      The cumulative donation-based incidence of AEs/SAEs increased slightly over time in all groups, both for related and unrelated AEs/SAEs (Fig. 3). When comparing the periods ‘study start until December 2011’ and ‘study start until June 2019’, the relative increase in cumulative incidence of all AEs/SAEs was 31% in the control group and 15–19% in the individualized program groups.
      Fig. 3
      Fig. 3Donation-based incidencea of AEs/SAEs over time. A) All AEs/SAEs; B) Related AEs/SAEs; C) Unrelated AEs/SAEs.
      AE, adverse event; IgG, immunoglobulin G; SAE, serious adverse event.
      a Donation-based incidence rate of AEs/SAEs in percent, calculated as (100∙number of AEs/SAEs / number of donations).b Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).c The observation period comprises the time between study start and 31 December of the year indicated, except for 2019, where the observation period ends on 30th June.
      Statistical significance of differences was tested by calculating odds ratios based on a Poisson regression model.
      * p < 0.0001 vs control; # p < 0.0001 vs IgG in the low normal range; § p < 0.0001 vs IgG in the medium normal range.
      In the safety population, 1349 participants withdrew from the control group and 13,760 from the individualized program groups. For more than a third of donors, the reason for withdrawal was unknown. Overall, the majority of withdrawals with known reasons occurred for non-medical reasons, such as lack of time (27.7% of all withdrawals), socioeconomic reasons (7.78%) and no donations within the last 8 months (7.51%). A total of 79 (5.86%) and 766 (5.57%) withdrawals due to medical reasons were recorded in the control group and the individualized program groups, respectively (Supplementary Table 6).

      3.2 IgG levels over the course of the study and deferrals due to laboratory parameters

      Serum IgG levels at study entry were lower than those prior to the first donation in all groups, illustrating the IgG-depleting effect of regular plasma donation. The absolute drop was higher in donors with high normal IgG levels pre-donation; however, the post-donation levels remained above those of the other groups. After this initial drop, IgG levels remained constant in all groups for up to 10 years, with lower steady-state levels in donors with lower initial levels (Fig. 4).
      Fig. 4
      Fig. 4IgG levels over the course of the study.
      IgG, immunoglobulin G; SD, standard deviation.
      Data are mean ± SD serum IgG levels.
      a Low normal range: ≥ 6 and < 8 g/L; medium normal range: ≥ 8 and < 10 g/L; high normal range: ≥ 10 g/L (all pre-donation).
      Across all donors, most temporary deferrals (54,260/60,290; 90.0%) were due to abnormal laboratory parameters. Of those, 41.5% were due to IgG, 33.4% to TSP, 22.5% to hemoglobin, and 2.62% to other parameters. IgG-related deferrals were most frequent in individualized program donors with IgG in the low normal range (donation-based incidence 5.35% vs 1.78%, 1.00% and 1.92% in individualized program donors with IgG in the medium and high normal range and control group donors, respectively).

      4. Discussion

      In an interim analysis of the IPS study, comprising 1,919,334 donations made by 20,598 donors, donation-based incidences of AEs/SAEs were 2.07% and 2.22% and rates of AEs/SAEs per year at risk were 0.701 and 0.997 for control and individualized program donors, respectively. For related events, donation-based incidences were 1.62% vs 1.23%. The most prominent events were AEs/SAEs related to venepuncture and vasovagal reactions. To our knowledge, this is the first study to systematically record AEs/SAEs in plasma donors participating in an individualized program based on body weight and initial IgG levels.
      A comparison of the incidence rates observed in this study to the literature is challenging because most published studies included other donation types besides plasmapheresis, frequently only recorded predefined types of AEs, and in most cases did not document AEs occurring between donations.
      A study evaluating 19,611 apheresis procedures (6.9% plasma donations) in 17 US centers between May and December 1995 reported a 3.06% donation-based incidence of immediate AEs [
      • McLeod B.C.
      • Price T.H.
      • Owen H.
      • Ciavarella D.
      • Sniecinski I.
      • Randels M.J.
      • et al.
      Frequency of immediate adverse effects associated with apheresis donation.
      ]. Notably, common responses to apheresis, such as light-headedness and paresthesias, were not considered AEs. Events related to venepuncture were the most frequently reported AEs (donation-based incidence 1.15%).
      In an Italian study including 240,596 donations (16.1% plasmapheresis procedures) in 2 centers between 2002 and 2006, the donation-based incidence of AEs was 0.285% [
      • Crocco I.
      • Franchini M.
      • Garozzo G.
      • Gandini A.R.
      • Gandini G.
      • Bonomo P.
      • et al.
      Adverse reactions in blood and apheresis donors: experience from two Italian transfusion centres.
      ]. Across all donation types, 71% of AEs were vasovagal reactions of mostly mild intensity; venepuncture-related events were not recorded as AEs. For plasmapheresis, the donation-based incidence of vasovagal reactions was 0.163% and no severe AEs were observed.
      The donation-based incidence of moderate to severe AEs was 0.374% in an analysis of 15,763 apheresis procedures in a single US center between 2006 and 2009 [
      • Yuan S.
      • Ziman A.
      • Smeltzer B.
      • Lu Q.
      • Goldfinger D.
      Moderate and severe adverse events associated with apheresis donations: incidences and risk factors.
      ].
      A large study assessed the safety of preparatory plasmapheresis, considering 1,107,846 donations made between 2008 and 2011 [
      • Diekamp U.
      • Gneißl J.
      • Rabe A.
      • Kießig S.T.
      Donor hemovigilance during preparatory plasmapheresis.
      ]. AEs were defined as local or systemic reactions or technical issues occurring during or within 24 h of donation (48–72 h for local reactions). The overall corrected donation-based incidence of AEs was 6.55%, with incidences of 1.4%, 0.55% and 4.6% for local, systemic and technical AEs, respectively. The most frequently observed AEs were repeat venepuncture and discontinued collection. Most systemic AEs were of mild or moderate intensity; donation-based incidence of severe systemic AEs was 0.036% [
      • Diekamp U.
      • Gneißl J.
      • Rabe A.
      • Kießig S.T.
      Donor hemovigilance during preparatory plasmapheresis.
      ].
      Overall, our results can therefore be considered in line with previously published data, particularly considering the differences in AE definitions and observation periods.
      In our study, the donation-based incidences of related AE/SAEs are significantly higher in the individualized program group compared with the control group, which is also reflected in the higher proportion of related AE/SAEs in this group. This is mostly driven by an increase in mild and moderate events, in particular events directly related to the donation, such as vasovagal reactions and venepuncture-related events, and may also to some extent be due to reporting bias in the individualized program group.
      The group with baseline IgG in the low normal range have approximately twofold higher incidences compared with the other groups. Since this is observed for practically all categories of AEs/SAEs, this may in part be a statistical artifact due to the small numbers of donors and donations in this group. Vasovagal reactions and venepuncture-related events may have been influenced by reduced experience with donation; the increase in vasovagal reactions may also be related to the lower body weight in this group.
      Of note, even in this group with the highest incidence, the overall incidence of AEs/SAEs is still lower than that reported by Diekamp et al. [
      • Diekamp U.
      • Gneißl J.
      • Rabe A.
      • Kießig S.T.
      Donor hemovigilance during preparatory plasmapheresis.
      ] despite the systematic documentation of all AEs/SAEs in our study, including unrelated events and AEs/SAEs occurring between donations. Moreover, there were no markedly higher proportions of AEs/SAEs graded at least as severe, or AEs/SAEs deemed related to plasmapheresis, in this donor group, and none of the severe AEs/SAEs were deemed donation-related.
      Our data highlight the importance of capturing AE/SAE incidence both as donation-based incidence and the number of events per year at risk when also documenting events which are unrelated to donation. Unlike venepuncture-related events or vasovagal reactions, the number of these events is expected to be unaffected by the number of donations made. Therefore, the donation-based incidence will appear lower in donors with a higher donation frequency, as observed in our study, whereas the number of events per year at risk will be similar across donor groups.
      In all groups, the cumulative incidence of both related and unrelated AEs/SAEs appeared to increase during the study. This was caused by an increase in non-severe AEs/SAEs, particularly events related to venepuncture and machine/equipment failure (data not shown), most likely due to an increase in staff turnover and the implementation of new materials, such as new plasmapheresis sets and needles. It is also possible that the quality of documentation improved over the course of the study, resulting in more events being captured.
      In terms of withdrawals, our results are in line with findings from other studies [
      • Schulzki T.
      • Seidel K.
      • Storch H.
      • Karges H.
      • Kiessig S.
      • Schneider S.
      • et al.
      A parospective multicentre study on the safety of long-term intensive plasmapheresis in donors (SIPLA).
      ,
      • Bechtloff S.
      • Tran-My B.
      • Haubelt H.
      • Stelzer G.
      • Anders C.
      • Hellstern P.
      A prospective trial on the safety of long-term intensive plasmapheresis in donors.
      ] in that the majority of withdrawals with known reasons were due to non-medical aspects. From a donor safety perspective, this is an encouraging finding considering that at the time of this interim analysis some donors had been participating in the study for over 10 years.
      Our findings parallel previous reports of an initial drop in IgG levels after starting plasmapheresis [
      • Burgin M.
      • Hopkins G.
      • Moore B.
      • Nasser J.
      • Richardson A.
      • Minchinton R.
      Serum IgG and IgM levels in new and regular long-term plasmapheresis donors.
      ,

      Möller A. Der Einfluss der präparativen Plasmapherese auf den Immunoglobulin G-, Gesamteiweiss- und Flüssigkeitshaushalt des Plasmaspenders. Dissertation, 〈https://d-nb.info/1070604445/34〉; 2014 [accessed August 19, 2021].

      ,
      • Ciszewski T.S.
      • Ralston S.
      • Acteson D.
      • Wasi S.
      • Strong S.J.
      Protein levels and plasmapheresis intensity.
      ] and subsequent maintenance of this level [
      • Bechtloff S.
      • Tran-My B.
      • Haubelt H.
      • Stelzer G.
      • Anders C.
      • Hellstern P.
      A prospective trial on the safety of long-term intensive plasmapheresis in donors.
      ,
      • Ciszewski T.S.
      • Ralston S.
      • Acteson D.
      • Wasi S.
      • Strong S.J.
      Protein levels and plasmapheresis intensity.
      ]. However, to our knowledge, this study is the first to demonstrate stable levels for up to 10 years, supporting the usefulness of a donation scheme taking IgG levels into account.
      Limitations of this study are the large difference in group size between the control and individualized program groups and the unequal distribution of donors between the IgG groups in the individualized program arm. These differences are inherent in the study design, which allows donors to choose between the two arms at study start, and therefore cannot be controlled. It is possible that particularly donors with IgG in the low normal range did not wish to enroll in the study due to previous IgG-related deferrals.

      5. Conclusion

      Interim results of this large, controlled, prospective study show that individualizing plasma donation frequency and volume according to pre-donation IgG levels and body weight does not result in obvious differences in donor safety compared with donation according to current German guidelines. Further data from this study will help to more fully assess the validity of our approach to individualize plasma donation.

      CRediT authorship contribution statement

      Uwe Taborski: Conceptualization, Methodology, Writing – Review & Editing, Supervision, Project administration Teija Laitinen: Conceptualization, Methodology, Writing – Review & Editing, Supervision, Project administration.

      Acknowledgments

      This ongoing study is sponsored by OPLG, Langenfeld, Germany, who thank all donors and study personnel for their participation, particularly the members of the safety committee (Roland Belzig, MD; Matthias Eberhardt, MD; Dr. rer. nat. Helmut Kamlah and Maria Westphal, MD).
      Medical writing support was provided by nspm ltd, Meggen, Switzerland, and funded by OPLG. Statistical analyses were performed by Ergomed CDS, Cologne, Germany.

      Conflicts of interest

      Both authors are employees of OPLG, Langenfeld, Germany.

      Appendix A. Supplementary material

      References

      1. U.S. Food and Drug Administration. Electronic Code of Federal Regulations, Title 21, Part 640—Additional standards for human blood and blood products, 〈https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=f09b5a7c4c544c8bd2089e8732599953&mc=true&r=PART&n=pt21.7.640〉; 2015 [accessed August 19, 2021].

      2. Bundesärztekammer, Germany. Richtlinie zur Gewinnung von Blut und Blutbestandteilen und zur Anwendung von Blutprodukten (Richtlinie Hämotherapie): Gesamtnovelle 2017 mit vom Vorstand der Bundesärztekammer auf Empfehlung seines Wissenschaftlichen Beirats am 18.01.2019 verabschiedeten Erratum/Anpassungen, 〈https://www.bundesaerztekammer.de/fileadmin/user_upload/downloads/pdf-Ordner/MuE/Richtlinie_Haemotherapie_2017.pdf〉; 2019 [accessed August 19, 2021].

      3. Health Canada. Guidance Document: Blood Regulations, 〈https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/pdf/brgtherap/applic-demande/guides/blood-reg-sang/blood-guid-sang-ligne-eng.pdf〉; 2014 [accessed August 19, 2021].

      4. Joint United Kingdom Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee. Red Book, Chapter 3: Care and selection of whole blood and component donors (including donors of pre-deposit autologous blood), 〈https://www.transfusionguidelines.org/red-book/chapter-3-care-and-selection-of-whole-blood-and-component-donors-including-donors-of-pre-deposit-autologous-blood〉; 2021 [accessed August 19, 2021].

      5. La ministre des solidarités et de la santé, France. Arrêté du 17 décembre 2019 fixant les critères de sélection des donneurs de sang, 〈https://www.legifrance.gouv.fr/loda/id/LEGIARTI000039704296/2020–04-02/〉; 2019 [accessed August 19, 2021].

      6. Ministerio de Sanidad y Consumo, Spain. Criterios básicos para la selección de donantes de sangre y componentes, 〈https://www.mscbs.gob.es/profesionales/saludPublica/medicinaTransfusional/publicaciones/docs/criteriosBasicosTomoII_2006_030907.pdf〉; 2006 [accessed August 19, 2021].

      7. Ministero Della Salute, Italy. Decreto 2 novembre 2015: Disposizioni relative ai requisiti di qualità e sicurezza del sangue e degli emocomponenti, 〈https://www.centronazionalesangue.it/wp-content/uploads/2017/07/GU-SG-n.300-del-28–12-2015_SO_069.pdf〉; 2015 [accessed August 19, 2021].

      8. Blutspende SRK Schweiz, Switzerland. Vorschriften, Kapitel 17C: Spezielle Bedingungen für unterschiedliche Spendearten, 〈https://dokuman.sbsc-bsd.ch/de-de/vorschriftenbsd/vorschriftenkapitelbeschl%C3%BCsse/kapitel.aspx〉; 2019 [accessed August 19, 2021].

      9. Bundesministerium für Arbeit, Soziales, Gesundheit und Konsumentenschutz, Austria. Verordnung der Bundesministerin für Arbeit, Gesundheit und Soziales betreffend den Gesundheitsschutz von Spendern und die Qualitätssicherung von Blut und Blutbestandteilen (Blutspenderverordnung – BSV), 〈https://www.ris.bka.gv.at/GeltendeFassung.wxe?Abfrage=Bundesnormen&Gesetzesnummer=10011170〉; 2019 [accessed August 19, 2021].

        • Schulzki T.
        • Seidel K.
        • Storch H.
        • Karges H.
        • Kiessig S.
        • Schneider S.
        • et al.
        A parospective multicentre study on the safety of long-term intensive plasmapheresis in donors (SIPLA).
        Vox Sang. 2006; 91: 162-173https://doi.org/10.1111/j.1423-0410.2006.00794.x
        • Burgin M.
        • Hopkins G.
        • Moore B.
        • Nasser J.
        • Richardson A.
        • Minchinton R.
        Serum IgG and IgM levels in new and regular long-term plasmapheresis donors.
        Med Lab Sci. 1992; 49: 265-270
      10. Möller A. Der Einfluss der präparativen Plasmapherese auf den Immunoglobulin G-, Gesamteiweiss- und Flüssigkeitshaushalt des Plasmaspenders. Dissertation, 〈https://d-nb.info/1070604445/34〉; 2014 [accessed August 19, 2021].

        • McLeod B.C.
        • Price T.H.
        • Owen H.
        • Ciavarella D.
        • Sniecinski I.
        • Randels M.J.
        • et al.
        Frequency of immediate adverse effects associated with apheresis donation.
        Transfusion. 1998; 38: 938-943https://doi.org/10.1046/j.1537-2995.1998.381098440858.x
        • Crocco I.
        • Franchini M.
        • Garozzo G.
        • Gandini A.R.
        • Gandini G.
        • Bonomo P.
        • et al.
        Adverse reactions in blood and apheresis donors: experience from two Italian transfusion centres.
        Blood Transfus. 2009; 7: 35-38https://doi.org/10.2450/2008.0018-08
        • Yuan S.
        • Ziman A.
        • Smeltzer B.
        • Lu Q.
        • Goldfinger D.
        Moderate and severe adverse events associated with apheresis donations: incidences and risk factors.
        Transfusion. 2010; 50https://doi.org/10.1111/j.1537-2995.2009.02443.x
        • Diekamp U.
        • Gneißl J.
        • Rabe A.
        • Kießig S.T.
        Donor hemovigilance during preparatory plasmapheresis.
        Transfus Med Hemother. 2014; 41: 123-133https://doi.org/10.1159/000357991
        • Bechtloff S.
        • Tran-My B.
        • Haubelt H.
        • Stelzer G.
        • Anders C.
        • Hellstern P.
        A prospective trial on the safety of long-term intensive plasmapheresis in donors.
        Vox Sang. 2005; 88: 189-195https://doi.org/10.1111/j.1423-0410.2005.00632.x
        • Ciszewski T.S.
        • Ralston S.
        • Acteson D.
        • Wasi S.
        • Strong S.J.
        Protein levels and plasmapheresis intensity.
        Transfus Med. 1993; 3: 59-65https://doi.org/10.1111/j.1365-3148.1993.tb00105.x