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BACKGROUND Source plasma (SP) is the primary starting material for 87% of plasma-derived medicinal products globally. Plasmavigilance is a program designed to collect, analyze, and monitor donor adverse events (AEs) across the SP collection industry. Donor retention depends on donors having a safe and satisfactory experience. This study analyzes AE rates and SP donor characteristics that may be predictors of an AE. STUDY DESIGN AND METHODS Donation data for 1.1 million donors making 12,183,182 SP donations over a 4-month period were analyzed. This represented approximately 72% of the donations collected by the U.S. plasma industry. The Standard for Recording Donor Adverse Events was used for AE definitions and classifications. RESULTS The overall AE rate was 15.85/104 donations. The two AEs with the highest rates were Hypotensive and Phlebotomy events (8.32 and 5.91/104 donations, respectively). Females had higher overall AE rates than males (25.76 vs. 9.85/104 donations), and first-time donors had higher overall AE rates than repeat donors (136.66 vs. 12.37/104 donations). Weight, body mass index, age, and pre-donation estimated blood volume also were predictors of AE. DISCUSSION SP donors have low AE rates with 90% being events classified as Hypotensive or Phlebotomy. Special attention and mitigation strategies should be directed to donors who are young, lightweight (between 100 and 124 pounds), female, or first-time donors to further reduce the incidence of AE, continue to ensure the donor has a safe experience, and facilitate donor retention.

Background To ensure that immunoglobulin (Ig) products have adequate functional antibody, the US Food and Drug Administration (FDA) requires that Ig lots contain minimum levels of measles neutralizing antibody; the current minimum is 0.48 x US Reference Ig 176. Study design and methods In the first part of the study, measles antibody titers were measured in donor plasma samples collected in 2007, 2011, and 2017. In the second part, trough or steady-state serum levels of measles neutralizing antibody were measured in two studies of patients with primary immunodeficiency (PID) who were treated with intravenous (Study 1; N = 46) or subcutaneous (Study 2; N = 18) Ig replacement therapy, meeting previous requirements for lot potency (≥0.6 x US Reference Ig 176). Serum measles neutralizing antibody titers were then estimated for conditions in which the potency of the Ig replacement product was 0.48 or 0.30 x US Reference Ig 176. Results Measles antibody titers in donated plasma samples declined in donors born after 1963. In the two studies of patients with PID who were treated with intravenous or subcutaneous Ig replacement therapy, all patients exhibited trough (intravenous Ig) or steady-state (subcutaneous Ig) measles neutralizing antibody titers above 0.12 IU/mL, which has been shown to protect against clinical measles in the general population. Estimates suggest that all patients except one would have continued to meet this standard if the Ig lot potency had been 0.48 or 0.30 x US Reference Ig 176. Conclusion These studies provide supporting evidence that the lot release specification can be safely lowered from 0.48 to 0.30 x US Reference Ig 176, which will accommodate declining measles neutralizing antibody levels in donor plasma.

BACKGROUND Intravenous immunoglobulins (IVIG) are derived from large human plasma pools. IVIG‐associated hemolytic anemia (HA) is a known class effect, likely attributed to dose‐dependent passive transfer of anti‐A/B isoagglutinins. Two isoagglutinin reduction steps were implemented in the manufacturing process of Privigen (human 10% liquid IVIG): exclusion of high–anti‐A–titer donors in 2013, replaced by specific immunoaffinity chromatography in 2015. We aim to estimate the clinical effectiveness of both measures. STUDY DESIGN AND METHODS Using the US hospital‐based Premier Healthcare Database, three Privigen cohorts were generated based on calendar periods indicative of manufacturing changes: Period 1 (baseline) January 2008 to December 2012, Period 2 (high–anti‐A–titer donor exclusion) October 2013 to December 2015, and Period 3 (immunoaffinity chromatography) October 2016 to April 2019. HA within a 10‐day at‐risk period after Privigen administrations was identified from review of patient record summaries. Incidence rate ratios (IRRs) were estimated from Poisson regression (Period 1 reference) adjusting for hospital setting, sex, age, Privigen indication, dose, and first use. RESULTS Crude incidence rates of HA were 1.49 per 10,000 person‐days in Period 1 (38 HA, 9439 patients), 1.01 in Period 2 (20 HA, 7710 patients), and 0.14 in Period 3 (3 HA, 7759 patients). Adjusted IRR for HA in Period 2 was 0.71 (95% confidence interval [CI], 0.41‐1.23), and in Period 3 was 0.10 (0.03‐0.33) compared with Period 1. The IRR for HA in Period 3 compared with Period 2 was 0.14 (95% CI, 0.04‐0.47). CONCLUSION Implementation of immunoaffinity chromatography in Privigen manufacturing resulted in a significant 90% reduction of HA risk. HA has become a rare event in association with Privigen use., See editorial on page 1337–1339, in this issue

Background Whole blood and red blood cell (RBC) donors are at risk of iron deficiency. Since Source plasma (SP) donors have RBCs returned during apheresis, risk of iron depletion appears low. However, SP donors can donate frequently and assessment of frequent donor iron status is needed. Study design and methods A total of 1254 SP donors were enrolled in four frequency groups determined by donations in the prior 12 months: no donations and 1 to 24, 25 to 69, and 70 or more donations. Ferritin was determined for each donor. Donors with ferritin levels of less than 12 ng/mL were classified as having absent iron stores (AIS). Results Compared to new donors, ferritin for females was higher in each successive frequency group. For 70 or more donations, ferritin was 13 ng/mL higher than in new donors (p = 0.02). For males, 1 to 24 donations had the highest ferritin levels. Compared to new donors, highest-frequency donors had lower ferritin levels, 114 ng/mL versus 100 ng/mL (p = 0.14). Age for females and males increased with each successive frequency group. Age adjustment resulted in smaller ferritin differences for females and larger differences for males in the high-frequency groups; AIS for females was highest in new donors (7%) and lowest in the highest-frequency group (1%). In aggregate, AIS occurred in less than 1% of all male donors. Male new and highest-frequency donors had 1% AIS with none in the other groups. Conclusion Few SP donors have iron depletion and it is not higher in frequent donors. Frequent SP donation does not adversely impact iron stores. Thus, monitoring donor iron status or iron supplementation is not necessary.

BACKGROUND Haemate-P/Humate-P (Humate-P) is a pasteurized human plasma-derived concentrate containing both Factor VIII and von Willebrand factor for treatment of hemophilia A and von Willebrand disease (VWD). STUDY DESIGN AND METHODS We analyzed the safety of Humate-P based on more than 33 years of postmarketing pharmacovigilance data, representing an estimated exposure of approximately 25,000 patient-years. The analysis comprises reports of potential adverse drug reactions (ADRs) from all sources, reported as part of routine pharmacovigilance at CSL Behring. ADRs considered clinically relevant or potential risks of Humate-P were identified based on defined and standardized Medical Dictionary for Regulatory Activities queries. Recognizing the limitations of spontaneous reporting, we also reviewed the literature, including clinical trials with mandatory reporting. RESULTS From 1982 to 2015, a total of 670 postmarketing cases had been reported via pharmacovigilance, for an overall reporting rate of approximately one ADR per 3900 administered standard doses. Of these cases, 343 involved ADRs considered clinically relevant risks (33 thromboembolic complications, 97 inhibitor formation, 110 hypersensitivity or allergic reactions) or potential risks (103 suspected virus transmissions) for Humate-P. Most thromboembolic complications occurred in patients undergoing surgery or with other known risk factors. Inhibitor formation occurred mostly in patients with hemophilia A (24 cases were high titer). Most patients with hypersensitivity or allergic reactions had VWD. None of the reported suspected virus transmission cases were confirmed to be associated with Humate-P. Reported results of company-sponsored studies showed a low incidence of adverse events possibly or probably related to Humate-P. CONCLUSIONS More than 33 years of pharmacovigilance data continue to support the safety of Humate-P.

Use of nucleic acid testing (NAT) in donor infectious disease screening improves transfusion safety. Advances in NAT technology include improvements in assay sensitivity and system automation, and real-time viral target discrimination in multiplex assays. This article describes the sensitivity and specificity of cobas MPX, a multiplex assay for detection of human immunodeficiency virus (HIV)-1 Group M, HIV-2 and HIV-1 Group O RNA, HCV RNA, and HBV DNA, for use on the cobas 6800/8800 Systems.The specificity of cobas MPX was evaluated in samples from donors of blood and source plasma in the United States. Analytic sensitivity was determined with reference standards. Infectious window periods (WPs) before NAT detectability were calculated for current donor screening assays.The specificity of cobas MPX was 99.946% (99.883%-99.980%) in 11,203 blood donor samples tested individually (IDT), 100% (99.994%-100%) in 63,012 donor samples tested in pools of 6, and 99.994% (99.988%-99.998%) in 108,306 source plasma donations tested in pools of 96. Seven HCV NAT-yield donations and one seronegative occult HBV infection were detected. Ninety-five percent and 50% detection limits in plasma (IU/mL) were 25.7 and 3.8 for HIV-1M, 7.0 and 1.3 for HCV, and 1.4 and 0.3 for HBV. The HBV WP was 1 to 4 days shorter than other donor screening assays by IDT.cobas MPX demonstrated high specificity in blood and source plasma donations tested individually and in pools. High sensitivity, in particular for HBV, shortens the WP and may enhance detection of occult HBV.

Hepatitis E virus (HEV) is a small, nonenveloped, single-stranded, RNA virus of emerging concern in industrialized countries. HEV transmission through transfusion of blood components has been reported, but not via plasma-derived medicinal products (PDMPs) manufactured with virus inactivation and/or removal steps. This study aimed to determine the prevalence of HEV among US source plasma donors.Samples were collected from US source plasma donors at centers across the United States and were initially screened for HEV RNA in 96-sample minipools using the Roche cobas HEV test on the cobas 8800 system. Assuming a sensitivity of 18.6 IU/mL, the minipool screening strategy allowed for reliable detection of individual donations with HEV RNA titers of more than 2 × 10A total of 128,020 samples were collected from 96 CSL Plasma centers in the United States, representing 27 states. The prevalence of HEV RNA-positive samples was 0.002% with three unique HEV-positive donors identified, all HEV Subgenotype 3a. Virus titers of HEV-positive samples were relatively low (10Routine screening of US source plasma donations for HEV would not substantially improve the safety of most PDMPs. The low prevalence and potential viral load of HEV, together with effective virus reduction steps in manufacturing processes, results in a low residual risk and acceptable safety margins for PDMPs derived from US plasma donors.

Pathogen safety is crucial for plasma-derived clotting factor concentrates used in the treatment of bleeding disorders. Plasma, the starting material for these products, is collected by plasmapheresis (source plasma) or derived from whole blood donations (recovered plasma). The primary measures regarding pathogen safety are selection of healthy donors donating in centers with appropriate epidemiologic data for the main blood-transmissible viruses, screening donations for the absence of relevant infectious blood-borne viruses, and release of plasma pools for further processing only if they are nonreactive for serologic markers and nucleic acids for these viruses. Despite this testing, pathogen inactivation and/or removal during the manufacturing process of plasma-derived clotting factor concentrates is required to ensure prevention of transmission of infectious agents. Historically, hepatitis viruses and human immunodeficiency virus have posed the greatest threat to patients receiving plasma-derived therapy for treatment of hemophilia or von Willebrand disease. Over the past 30 years, dedicated virus inactivation and removal steps have been integrated into factor concentrate production processes, essentially eliminating transmission of these viruses. Manufacturing steps used in the purification of factor concentrates have also proved to be successful in reducing potential prion infectivity. In this review, current techniques for inactivation and removal of pathogens from factor concentrates are discussed. Ideally, production processes should involve a combination of complementary steps for pathogen inactivation and/or removal to ensure product safety. Finally, potential batch-to-batch contamination is avoided by stringent cleaning and sanitization methods as part of the manufacturing process.

NIH Public Access Author Manuscript Transfusion. Author manuscript; available in PMC 2014 November 01. NIH-PA Author Manuscript Published in final edited form as: Transfusion. 2013 November ; 53(11): 2766–2775. doi:10.1111/trf.12209. Laboratory variables for assessing iron deficiency in REDS-II Iron Status Evaluation (RISE) blood donors Joseph E. Kiss, Whitney R. Steele, David J. Wright, Alan E. Mast, Patricia M. Carey, Edward L. Murphy, Jerry L. Gottschall, Toby L. Simon, Ritchard G. Cable, and for the NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II) The Institute for Transfusion Medicine, Pittsburgh, Pennsylvania; Westat, Rockville, Maryland; the Blood Center of Wisconsin, Milwaukee, Wisconsin; the Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin; the Hoxworth Blood Center, University of Cincinnati Academic Health Center, Cincinnati, Ohio; the University of California at San Francisco and Blood Systems Research Institute, San Francisco, California; CSL Plasma, Boca Raton, Florida; and New England Region, American Red Cross Blood Services, Farmington, Connecticut. NIH-PA Author Manuscript Abstract BACKGROUND—Iron deficiency is common in regular blood donors. We evaluated the diagnostic sensitivity and specificity of red blood cell (RBC) hematology analyzer indices to assess iron status as a part of donor management. STUDY DESIGN AND METHODS—A total of 1659 male and female donors from the Retrovirus Epidemiology Donor Study-II (REDS-II) Donor Iron Status Evaluation (RISE) study who were either first-time/reactivated (FT/ RA; no donations for 2 years) or frequent donors were recruited into a longitudinal study of regular donation of RBCs. Of these, 1002 donors returned 15 to 24 months later for a final assessment. Absent iron stores (AIS) was defined as plasma ferritin level of less than 12 µ.g/L. Logarithm of the ratio of soluble transferrin receptor to ferritin of at least 2.07 (≥97.5% in FT/RA males) was used to define iron-deficient erythropoiesis (IDE). Receiver operating characteristics analysis was performed to assess selected RBC indices (e.g., percentage of hypochromic mature RBCs, proportion of hypochromic mature RBCs [HYPOm], and hemoglobin [Hb] content of reticulocytes [CHr]) in identifying AIS and IDE. NIH-PA Author Manuscript RESULTS—HYPOm and CHr detected IDE with comparable sensitivity, 72% versus 69%, but differed in specificity: HYPOm 68% and CHr 53%. For detecting AIS, sensitivity was improved to 85% for HYPOm and 81% for CHr but specificity was reduced for both. Venous Hb had high specificity but poor sensitivity for IDE and AIS. A plasma ferritin level of less than 26.7 u.g/L was a good surrogate for assessing IDE. CONCLUSION—RBC indices correlate with AIS and IDE and are more informative than Hb measurement, but lack sufficient sensitivity and specificity to be used as diagnostic tools in blood donors at risk for iron deficiency. Iron deficiency is a frequent condition that arises as a direct consequence of regular blood donation in both men and women, who lose approximately 230 mg of elemental iron with each whole blood donation. This amount represents approximately 25% of the average iron Address correspondence to: Joseph E. Kiss, MD, Hemapheresis and Blood Services, The Institute for Transfusion Medicine, University of Pittsburgh, 3636 Boulevard of the Allies, Pittsburgh, PA 15213; JKiss@itxm.org. CONFLICT OF INTEREST AEM has received payment for educational lectures from Siemens Corporation. The other authors declare that they have no conflicts of interest relevant to the manuscript.

Author(s): Cable, Ritchard G; Glynn, Simone A; Kiss, Joseph E; Mast, Alan E; Steele, Whitney R; Murphy, Edward L; Wright, David J; Sacher, Ronald A; Gottschall, Jerry L; Tobler, Leslie H; Simon, Toby L; NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II) | Abstract: BackgroundBlood donors are at risk of iron deficiency. We evaluated the effects of blood donation intensity on iron and hemoglobin (Hb) in a prospective study.Study design and methodsFour cohorts of frequent and first-time or reactivated (FT/RA) blood donors (no donation in 2 years), female and male, totaling 2425, were characterized and followed as they donated blood frequently. At enrollment and the final visit, ferritin, soluble transferrin receptor (sTfR), and Hb were determined. Models to predict iron deficiency and Hb deferral were developed. Iron depletion was defined at two levels: iron deficiency erythropoiesis (IDE) [log(sTfR/ferritin) ≥ 2.07] and absent iron stores (AIS; ferritin l 12 ng/mL).ResultsAmong returning female FT and RA donors, 20 and 51% had AIS and IDE at their final visit, respectively; corresponding proportions for males were 8 and 20%. Among female frequent donors who returned, 27 and 62% had AIS and IDE, respectively, while corresponding proportions for males were 18 and 47%. Predictors of IDE and/or AIS included a higher frequency of blood donation in the past 2 years, a shorter interdonation interval, and being female and young; conversely, taking iron supplements reduced the risk of iron depletion. Predictors of Hb deferral included female sex, black race, and a shorter interdonation interval.ConclusionsThere is a high prevalence of iron depletion in frequent blood donors. Increasing the interdonation interval would reduce the prevalence of iron depletion and Hb deferral. Alternatively, replacement with iron supplements may allow frequent donation without the adverse outcome of iron depletion.

BACKGROUND: Descriptions of donor demographics are of value in formulating recruitment and retention strategies. The demographics of successful (SV), unsuccessful (UV; meaning a nonuseable unit), and deferred (DV) donor visits over a 4-year period were investigated using Retrovirus Epidemiology Donor Study (REDS)-II databases. STUDY DESIGN AND METHODS: Fourteen deferral categories were created that included low hematocrit (Hct) or hemoglobin (Hb), feeling unwell, malaria travel, malaria other, couldn't wait, blood pressure or pulse, medical diagnosis, medication, test results, higher-risk behavior, variant Creutzfeldt-Jakob disease (CJD), CJD, needle exposure or tattoo, and other. Rates per 10,000 donor presentations were determined for each category globally and for six subcategorizations (first-time or repeat donor status, sex, race/ethnicity, age, education, and fixed or mobile donation location). Deferral rates were also calculated on simultaneous stratifications of donor status, sex, and race/ethnicity. RESULTS: Of 5,607,922 donor presentations there were 4,553,145 SVs (81.2%), 302,828 UVs (5.4%), and 751,381 DVs (13.4%). Overall rates of deferral ranged from 0.6 per 10,000 presentations for CJD, human growth hormone, or dura mater exposure to 777 per 10,000 presentations for low Hct or Hb. Deferral rates were remarkably different by first-time or repeat donor status, sex, race/ethnicity, and other demographics. The highest overall deferral rate was 3953 per 10,000 presentations, or nearly 40% in first-time, female, Asian donors, and the lowest rate was 5.6% in repeat, male, white donors. CONCLUSION: Successful donation visits according to demographic characteristics need to be placed within the context of all donor visits. Deferral rates indicate that the burden of donor deferral is high. Efforts to expand the diversity of the donor base through recruitment of minority donors may bring additional challenges because certain deferral reasons were proportionally much higher in these groups.

As the US population ages, and those over 65, who represent 53% of the red blood cell (RBC) transfusion recipients, grows from 40 to 72 million by 2030, it is assumed that there will be an increase in the transfusion needs of the US population. 1,2 As outlined by Riley and coworkers,3 approximately 37% of the US population is eligible to donate blood but only 5% actually participate in blood donor programs. This raises concern as to the viability of the blood donor pool, because the majority of current donors are older and may make fewer donations and become recipients as they age. Several studies have investigated the reasons first-time donors do not return for a subsequent donation. These studies have documented the results of age,4 sex,5,6 education,5,7 race/ethnicity,8–10 convenience,8,9,11 donor intention to return,4,8 and donor return patterns.7,8 In 2009, Notari and colleagues12 reported on donor age and its impact on return behavior in first-time donors over a 13-month period. Sixteen- and 17-year-old donors had the highest return rate with 62 and 52% returning, respectively, whereas donors 60 years and older had the next highest return rate at 48%. The frequencies of donations in the 13-month follow-up period were 2.61, 2.46, and 3.09 donations for 16-, 17-, and 60+-year-old donors, respectively, compared to 2.40 to 2.95 for donors aged 18 to 59 years. Others have summarized the issues related to the donation experience that, if addressed, may change blood donation behavior. These issues include: 1) understanding the motivations of first-time versus long-term donors and their differing responses to incentives;10 2) contacting first- and second-time donors in a timely fashion to schedule a repeat donation;5,7 and 3) deferral, reactions, pain, or anxiety during the first and second donation, all of which lead to lower return rates.4 Since donation frequency in the first year is correlated with an increased likelihood of returning during the next 6 years, encouraging first-time donors to make additional donations in the first year may produce more dedicated lifetime donors.7 This could be facilitated by providing these donors information on convenient donation locations for future donations, thereby potentially reducing blood donation barriers, especially among those who are interested and willing to become a regular donor.7 Convenience is important for donors. Bringing the donation site closer to the donor by conducting more mobile blood drives is one way to increase convenience, while at the same time contributing to blood center goals of increased numbers of donors and increased donation frequency. Of course, in this scenario, the number of donations is tied to the frequency the mobile site presents itself to the donor. With this in mind, the characteristics of donations at fixed versus mobile locations should be examined. Specifically, more information is needed about donors who visit fixed and mobile sites to better understand donation patterns and behavior for movement within and between these donation locations. This study investigates the demographic characteristics of donors by donation type (whole blood [WB], plateletpheresis [PP], and double RBC [R2]), the median number of donations (frequency), median interdonation interval, and the median return time (controlling for mandatory wait time).

BACKGROUND: The consequences of temporary predonation deferral are unsatisfactorily understood. Studies have found that deferral negatively impacts future donor return. However, the applicability of these findings across centers has not been established. STUDY DESIGN AND METHODS: Using a cohort design, presenting donors with a temporary deferral in 2006 to 2008 in one of six categories (low hematocrit [Hct], blood pressure or pulse, feeling unwell, malaria travel, tattoos or piercing and related exposures, or could not wait or second thoughts) were passively followed for up to a 3-year period for the time to first return after deferral expiration at six US blood centers. Time-to-event methods were used to assess return. We also analyzed which donor characteristics were associated with return using multivariable logistic regression. RESULTS: Of 3.9 million donor presentations, 505,623 resulted in deferral in the six categories. Low Hct was the most common deferral, had the shortest median time to return (time in days when 50% of deferred donors had returned), and had the largest cumulative proportion of donors returning. Deferrals of shorter duration had better return. Longer-term deferrals (up to 1 year in length) had the lowest cumulative return proportion, which did not exceed 50%. Return was associated with previously identified factors such as repeat donor status, older age, and higher educational attainment regardless of the type of deferral. In addition, return was associated with having been born in the United States and donation at fixed sites. CONCLUSION: The category of temporary deferral influences the likelihood of future return, but the demographic and donation factors associated with return are largely consistent regardless of the deferral.

Author(s): Cable, Ritchard G; Glynn, Simone A; Kiss, Joseph E; Mast, Alan E; Steele, Whitney R; Murphy, Edward L; Wright, David J; Sacher, Ronald A; Gottschall, Jerry L; Vij, Vibha; Simon, Toby L; NHLBI Retrovirus Epidemiology Donor Study-II | Abstract: BackgroundRegular blood donors are at risk of iron deficiency, but characteristics that predispose to this condition are poorly defined.Study design and methodsA total of 2425 red blood cell donors, either first-time (FT) or reactivated donors (no donations for 2 years) or frequent donors, were recruited for follow-up. At enrollment, ferritin, soluble transferrin receptor (sTfR), and hemoglobin were determined. Donor variables included demographics, smoking, dietary intake, use of iron supplements, and menstrual and/or pregnancy history. Models to predict two measures of iron deficiency were developed: Absent iron stores (AIS) were indicated by a ferritin level of less than 12 ng/mL and iron-deficient erythropoiesis (IDE) by a log(sTfR/ferritin) value of 2.07 or greater.ResultsA total of 15.0% of donors had AIS and 41.7% IDE. In frequent donors, 16.4 and 48.7% of males had AIS and IDE, respectively, with corresponding proportions of 27.1 and 66.1% for females. Donation intensity was most closely associated with AIS and/or IDE (odds ratios from 5.3 to 52.2 for different donation intensity compared to FT donors). Being female, younger, and/or menstruating also increased the likelihood of having AIS and/or IDE, as did having a lower weight. Marginally significant variables for AIS and/or IDE were being a nonsmoker, previous pregnancy, and not taking iron supplements. Dietary variables were in general unrelated to AIS and/or IDE, as was race and/or ethnicity.ConclusionA large proportion of both female and male frequent blood donors have iron depletion. Donation intensity, sex and/or menstrual status, weight, and age are important independent predictors of AIS and/or IDE. Reducing the frequency of blood donation is likely to reduce the prevalence of iron deficiency among blood donors, as might implementing routine iron supplementation.

Pathogen safety is crucial for plasma‐derived clotting factor concentrates used in the treatment of bleeding disorders. Plasma, the starting material for these products, is collected by plasmapheresis (source plasma) or derived from whole blood donations (recovered plasma). The primary measures regarding pathogen safety are selection of healthy donors donating in centers with appropriate epidemiologic data for the main blood‐transmissible viruses, screening donations for the absence of relevant infectious blood‐borne viruses, and release of plasma pools for further processing only if they are nonreactive for serologic markers and nucleic acids for these viruses. Despite this testing, pathogen inactivation and/or removal during the manufacturing process of plasma‐derived clotting factor concentrates is required to ensure prevention of transmission of infectious agents. Historically, hepatitis viruses and human immunodeficiency virus have posed the greatest threat to patients receiving plasma‐derived therapy for treatment of hemophilia or von Willebrand disease. Over the past 30 years, dedicated virus inactivation and removal steps have been integrated into factor concentrate production processes, essentially eliminating transmission of these viruses. Manufacturing steps used in the purification of factor concentrates have also proved to be successful in reducing potential prion infectivity. In this review, current techniques for inactivation and removal of pathogens from factor concentrates are discussed. Ideally, production processes should involve a combination of complementary steps for pathogen inactivation and/or removal to ensure product safety. Finally, potential batch‐to‐batch contamination is avoided by stringent cleaning and sanitization methods as part of the manufacturing process.

Blood donors are at risk of iron deficiency. We evaluated the effects of blood donation intensity on iron and hemoglobin (Hb) in a prospective study.Four cohorts of frequent and first-time or reactivated (FT/RA) blood donors (no donation in 2 years), female and male, totaling 2425, were characterized and followed as they donated blood frequently. At enrollment and the final visit, ferritin, soluble transferrin receptor (sTfR), and Hb were determined. Models to predict iron deficiency and Hb deferral were developed. Iron depletion was defined at two levels: iron deficiency erythropoiesis (IDE) [log(sTfR/ferritin) ≥ 2.07] and absent iron stores (AIS; ferritin12 ng/mL).Among returning female FT and RA donors, 20 and 51% had AIS and IDE at their final visit, respectively; corresponding proportions for males were 8 and 20%. Among female frequent donors who returned, 27 and 62% had AIS and IDE, respectively, while corresponding proportions for males were 18 and 47%. Predictors of IDE and/or AIS included a higher frequency of blood donation in the past 2 years, a shorter interdonation interval, and being female and young; conversely, taking iron supplements reduced the risk of iron depletion. Predictors of Hb deferral included female sex, black race, and a shorter interdonation interval.There is a high prevalence of iron depletion in frequent blood donors. Increasing the interdonation interval would reduce the prevalence of iron depletion and Hb deferral. Alternatively, replacement with iron supplements may allow frequent donation without the adverse outcome of iron depletion.

This study investigated the effect of blood donation environment, fixed or mobile with differing sponsor types, on donation return time.Data from 2006 through 2009 at six US blood centers participating in the Retrovirus Epidemiology Donor Study-II (REDS-II) were used for analysis. Descriptive statistics stratified by whole blood (WB), plateletpheresis (PP), and double red blood cell (R2) donations were obtained for fixed and mobile locations, including median number of donations and median interdonation interval. A survival analysis estimated median return time at fixed and mobile sites, while controlling for censored return times, demographics, blood center, and mandatory recovery times.Two-thirds (67.9%) of WB donations were made at mobile sites, 97.4% of PP donations were made at fixed sites, and R2 donations were equally distributed between fixed and mobile locations. For donations at fixed sites only or alternating between fixed and mobile sites, the highest median numbers of donations were nine and eight, respectively, and the shortest model-adjusted median return times (controlling for mandatory eligibility times of 56 and 112 days) were 36 and 30 days for WB and R2 donations, respectively. For PP donations, the shortest model-adjusted median return time was 23 days at a fixed location and the longest was 693 days at community locations.WB, PP, and R2 donors with the shortest time between donations were associated with fixed locations and those alternating between fixed and mobile locations, even after controlling for differing mandatory recovery times for the different blood donation procedures.

Platelets collected by using a two-stage automated blood cell separator were evaluated after 5 days of storage. The procedure caused no unanticipated physiologic changes in donors and produced greater than 3 x 10(11) intact platelets in 200 mL of plasma, plus an additional 400 mL of plasma with intact coagulation factors. Posttransfusion recovery of autologous radiolabeled platelets was comparable to that seen in platelets prepared by manual centrifugation techniques. Corrected count increments in 14 patients showed results similar to those with control transfusions. This device, which involves a collection time of less than 90 minutes, provides an option for platelet-pheresis in a variety of settings including blood mobiles.

Few studies addressing possible immune sequelae of long-term whole blood donation have been published. The purpose of this study was to determine if there were any differences in lymphocyte subsets, monocyte and neutrophil receptors, and antigens important to host defense in committed whole blood donors and in nondonor controls. Blood samples were obtained from 27 whole blood donors who had been donating on a regular basis for at least 4 years and from 21 nondonor controls. A panel of single- and dual-labeled monoclonal antibodies was used to characterize peripheral white cells, and then the cells were analyzed by flow cytometry. Lymphocyte subsets included T (CD3) cells, helper T (CD4) cells, suppressor T (CD8) cells, B (CD19) cells, natural killer (NK) (CD56) cells, and subpopulations of T cells defined by the coexpression of markers for CD3/HLA-DR, CD3/CD56, and CD8/CD11b. Monocyte and neutrophil analysis included quantitation of receptors for C5a, formyl-met-leu-phe, and C3bi (CR3). Monocytes were also analyzed for expression of HLA-DR and CD14 antigens. No significant differences were observed in the whole blood donors and nondonor controls for any of these factors used to assess immunologic status, except for an increase in C3bi receptors on both neutrophils and monocytes from whole blood donors. These findings indicate that the lymphocyte parameters analyzed in this study are unaltered by long-term whole blood donation. Further research is necessary to determine the significance of complement receptor upregulation in whole blood donors and to identify any changes in the functional characteristics of peripheral white cells from whole blood donors.

The aging of our society will result in an increased demand for blood components, but it also has the potential to produce a large group of blood donors, the elderly. To study the effects of regular donation by older persons, a randomized, controlled trial is being conducted among 244 healthy, elderly volunteers. This report focuses on the efficacy of the recruiting efforts for that study and describes the resultant population in terms of their demographics, medical status, and donation safety. Of 325 potential subjects, 18 percent were disqualified and 7 percent refused entry into the study. After medical evaluation, only 2 persons were disqualified for conditions not detected by the usual blood services screening protocols. The resultant elderly donor population (n = 244) was well-educated, middle-income, and, for the most part, married. The group reported more past and present medical conditions, past surgical procedures, and current medications than would be expected in a younger donor group. Reactions to donation were infrequent and mild. With current screening and donation procedures, blood donation by the elderly appears to be safe and practical.

From the Departments of Pathology and Pediatrics, University of New Mexico, United Blood Services of New Mexico, and TriCore Reference Laboratories, Albuquerque, New Mexico. Address reprint requests to: Toby L. Simon, MD, 5201 Congress Avenue, Suite 220, Boca Raton, FL 33487; e-mail: toby.simon@zlbplasma.com. Received for publication March 31, 2006; revision received August 17, 2006, and accepted August 30, 2006. doi: 10.1111/j.1537-2995.2007.01058.x TRANSFUSION 2007;47:8-14. H O W D O I . . . ?

BACKGROUND: The possible effects of long-term plasma donation remain unknown, but it is important to investigate them so that donor safety is ensured. The purpose of this study was to determine if long-term plasma donation alters plasma proteins or lymphocyte phenotypes. STUDY DESIGN AND METHODS: Two groups of long-term plasma donors, source plasma donors (n = 20) and Rh immune globulin plasma donors (n = 26), were compared with whole blood donors (n = 29) and nondonor controls (n = 30). Blood samples were obtained prior to donation. Serum protein, albumin, globulin, and immunoglobulin levels were determined. In an assay using whole blood, lymphocyte phenotypes were characterized with a panel of single- and dual-labeled monoclonal antibodies and subsequent analysis by flow cytometry. RESULTS: As compared to the nondonor controls and/or whole blood donors, the mean values for serum protein, globulin, and IgG levels were lower in both plasma donor groups, with a significant negative correlation between donation frequency and serum protein values for the source plasma donors. Albumin levels were within normal ranges for both groups of plasma donors. No significant differences existed among the donor groups in total white cell counts, the percentage or absolute number of lymphocytes, T (CD3) cells, or helper T (CD4) cells. However, there were increased percentages of B (CD19) cells and decreased percentages of suppressor T (CD8+/CD11b+) cells and natural killer cells in both groups of plasma donors as compared to nondonor controls. CONCLUSION: Many plasma donors have low levels of serum protein, globulin, and IgG. In addition, they have increased percentages of B cells and decreased percentages of suppressor T and natural killer cells. The clinical significance of these findings warrants further investigation.

A new apheresis device using microprocessor control for the collection of a high-purity single-donor platelet concentrate was evaluated, as was the storage of platelets for up to 5 days in a citrate-plasticized polyvinylchloride blood bag. The study was conducted in three phases: collection of platelets for in vitro studies and determination of donor safety; autologous transfusion of platelets in healthy volunteers; and transfusion of platelets in patients requiring platelet transfusion therapy. Donors had mild hypocalcemia and minimal changes in blood counts except for a platelet count reduction from 288 +/- 50 x 10(3) (288 +/- 50 x 10(9)/L) to 217 +/- 43 x 10(3) per microL (217 +/- 43 x 10(9)/L). A mean of 3.36 +/- 1.24 x 10(11) platelets was collected in the mean volume of 214 mL with red cell and white cell contamination in the range of 10(7). Morphology and aggregation were as described previously in stored platelets. Platelet survival data in eight subjects showed a mean recovery of 61 +/- 11 percent and mean survival of 5.03 +/- 1.07 days by a weighted-mean model. Patients transfused with platelets had mean increments of 23,000 immediately and of 8000 at 24 hours; corrected count increments were 6000 at 1 hour and 4000 at 24 hours. The platelets were successful in providing hemostasis to these patients. Clinically useful 5-day-stored platelets are obtained by using this apheresis technology with a functionally closed system and a citrate-plasticized blood bag.

Depletion of body iron stores is a major factor limiting regular blood donations by menstruating females. To determine if regular iron supplementation would solve this problem, we conducted a double-blind study in which menstruating female donors were randomly placed into one of three groups: one taking 39 mg elemental iron, a second taking 39 mg of iron plus 75 mg vitamin C, and a third taking 100 mg vitamin C daily. The women were requested to donate every 8 weeks for at least 1 year. Blood samples were taken on each donation for measurements of hemoglobin, total iron binding capacity (TIBC), and ferritin. In the two groups taking iron supplements hemoglobin and ferritin increased from baseline values and the TIBC decreased. The vitamin C control group showed decreases from baseline for hemoglobin and ferritin and increases in TIBC. Differences between groups taking iron supplements and the group not taking supplements were highly significant. Drop-out from the study was due to various causes; however, iron intolerance was uncommon. Minimal daily iron supplementation was beneficial in maintaining body iron stores and hemoglobin levels in menstruating females on a schedule of blood donation as often as every 8 weeks.

Red cells (RBCs) prepared by a new system using centrifugation to produce neocyte enrichment were studied in two laboratories. The system used a blood bag with a geometric configuration such that younger, less dense cells could be separated from older, denser cells. Phthalate ester density gradient curves determined that neocyte enrichment was 81.3 percent in one laboratory and 82 percent in the other. RBC viability was studied by 51Cr autologous transfusion in normal volunteer donors. A randomized, paired design was used in which each donor was transfused once each with neocytes and with RBCs of all ages. The mean control half-life was 34.8 +/- 5.4 days in one laboratory and 34.0 +/- 3.6 days in the other. The mean half-life of the neocyte-enriched RBCs was 45.2 +/- 8.2 days in one laboratory and 45.1 +/- 4.4 days in the other. This represented a more than 30 percent increase in half-life for the neocyte-enriched RBCs, a significant difference. This new system, a two-bag set that costs +15, allows the simple, efficient separation of neocyte-enriched RBCs that would have a longer half-life and could reduce the transfusion requirement in patients receiving chronic transfusion therapy.

To determine the best procedure for concentrating platelets in a smaller volume after storage, we studied platelet loss after concentration at various centrifugation g forces for various times. In vitro studies demonstrated the need to let platelets sit for 1 hour prior to resuspension by gentle kneading. 500 X g gave unacceptable results. Losses were minimal at 1500 X g for 7 minutes, 2000 X g for 10 minutes and 5000 X g for 6 minutes. Reinfusion of 51 Cr-labeled platelets into normal volunteers after concentration at both 2000 X g for 10 minutes and 5000 X g for 6 minutes showed normal viability. Numbers and viability of platelets stored up to 5 days in 50 ml plasma and then concentrated in 10 ml plasma after centrifugation at 1500 X g for 7 minutes, 2000 X g for 10 minutes or 5000 X g for 6 minutes should be clinically acceptable.

Platelet concentrates stored for 7 days in 50 ml of plasma in both thin film and enlarged variations of the standard 5-day CLX plastic bags were evaluated for pH maintenance and in vivo viability by two laboratories working independently. 51Cr-labeled platelets were reinfused into normal volunteers at the end of storage and recovery and half-life calculated. The pH was maintained well; less than 10 percent of units fell below 6.0 at 7 days. Mean 7-day recovery for both laboratories was 43.6 +/- 11.6 percent in the thin-film bag and 45.4 +/- 8.52 percent in the enlarged bag, compared with 43.6 +/- 8.8 percent at 5 days in the 5-day plastic licensed bag. After 7 days storage the half-life was 3.6 +/- 0.9 days in the thin-film bag and 3.7 +/- 0.6 days in the enlarged bag, compared with 3.6 +/- 0.5 days in the previously licensed CLX plastic bag after 5 days. Thus, platelet viability was maintained well at 7 days of storage in both of the container variations that allowed increased gas exchange.

The 2,3 diphosphoglycerate (2,3 DPG) content of red cells stored in current anticoagulant-preservative products decreases rapidly after the first few days of storage, and by 3 weeks the red cells are essentially depleted of 2,3 DPG. Because ascorbic acid and ascorbate-2-phosphate (A-2-P) are effective in maintaining erythrocyte 2,3 DPG during liquid preservation, ascorbate was stabilized through autoclaving and subsequent storage by adding it as the trisodium salt of A-2-P to a phosphate-adenine-saline solution at a pH of 8.5 to 9.0. Red cell concentrates prepared from blood drawn into citrate-phosphate-double-dextrose were supplemented with the A-2-P additive solution (AS-4) and studied in vitro and in vivo. Mean 2,3 DPG values for 22 units were 147.6, 113.5, and 82.3 percent of initial value after storage for 3, 4, and 5 weeks, respectively. Maintenance of 2,3 DPG was at the expense of adenosine triphosphate (ATP), which fell to as low as 22.2 percent of initial value after 5 weeks. Despite the low ATP values, the 24 hour 51Cr-labeled red cell recoveries averaged 80.8 and 74.1 percent after 4 and 5 weeks of storage, respectively. The AS-4 system provides a red cell product with acceptable viability and improved oxygen off-loading function.

Platelet concentrates stored in bags (made of a plastic film incorporating a new plasticizer) on flat-bed agitators for up to 5 days were found to have accelerated pH decline when the surface of the bag was obstructed with added labels and an invoice on the non-labeled side. Without the over-labeling and invoice, only one of 20 concentrates had a pH below 6.0, even at very high concentrations of platelets. Blood banks experiencing problems with pH decline in the platelet concentrates being stored up to 5 days should consider eliminating surface obstruction on the bag.