Donor safety in an individualized plasmapheresis program - Results of an interim analysis.

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.

Impact of saline infusion and citrate infusion rate during donor plasmapheresis.

The purpose of our research was to evaluate the effects of saline infusion to counteract incidents of severe hypotension during donor plasmapheresis (DP; synonym with plasma donation), and on immunoglobulin G (IgG) content in collected plasma, and on donor hematological values. It examines the clearance (Cl) of IgG during DP without saline to calculate the distribution of citrate and citrate infusion rate (CIR) during DP. It is based on three studies: an observation of saline infusion in donors with severe drops in blood pressure at DP, and two crossover trials of 32 repeat plasma donors each on saline infusion during DP. We observed 50 cases with a significant drop of mean systolic blood pressure ≤90 mm Hg in 1 year, predominantly in young, female first-time donors. In trial 1, there was a reduction of IgG concentration in collected plasma related to the average IgG serum concentration without saline to 85.5% vs to 80.5% with saline (P < .001). In trial 2, there was an important 11%-12% increase of the donor hematological values without saline during DP. An average of 84.6% of citrate was removed in retained plasma; our calculated minimal CIR of 0.16 ± 0.17 mg/kg/min was confirmed by other empirical studies. Our research has led to significant improvements in the practice of DP: (a) Saline should be infused at DP as clinically indicated in agreement with the donor. (b) Young, female first-time donors require special care. (c) The long-time effects of minimal amounts of citrate on bone metabolism are improbable.

Safety of Plasmapheresis in Donors with Low IgG Levels: Results of a Prospective, Controlled Multicentre Study.

Background and Objectives: Although plasmapheresis is generally considered safe, there are still concerns about the long-term effects of plasma donation on immunoglobulin G (IgG) levels. The aim of the present study was to investigate if there is a need to permanently defer donors who donated three times with an IgG level below 6.0 g/L. Study Design and Methods: From September 2007 to December 2017, adverse events (AEs) including infections were analysed from data of a prospective, controlled multicentre study of healthy volunteer donors, participating in an individualized plasmapheresis programme stratified by initial IgG level and body weight (individualized arm) or in standard plasmapheresis according to national guidelines (control arm). IgG was monitored at every fifth donation, and donors with IgG levels below the threshold were identified and followed up for possible AEs. Results: In total, 97,540 donations in 1,462 donors in the control arm and 1,491,223 donations in 14,281 donors in the individualized arm were included. Donation-based incidences of at least severe AEs and any infections were 0.019% and 0.192% in the control arm, and 0.014% and 0.153% in the individualized arm. Three or more IgG-measurements below the threshold occurred in 38.2% of control arm donors and 20.9% of individualized arm donors. There were no increased incidence rates of at least severe AEs or any infections in donors with ≥3 IgG-measurements below the threshold in either donor's arm. Conclusions: Our data show no signs of compromised donor safety in donors with ≥3 IgG-measurements below the threshold, indicating that plasmapheresis is feasible and safe in these donors.

Anticoagulation, bleeding, and clotting at donor plasmapheresis.

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

Distribution of citrate and citrate infusion rate during donor plasmaphereses.

BACKGROUND: The purpose of this study was to describe the distribution of trisodium-citrate 4% (TSC) anticoagulant (AC) between the product and the donors undergoing plasma donation. SUBJECTS AND METHODS: Data of 32 regular donors of plasma initially collected for a study published in 2010 were re-analyzed to determine the amount of citrate received by the donor and the citrate infusion rate (CIR) in mg/kg/min to the donor. Donor plasmaphereses (DP) were performed with the automated Haemonetics plasma collecting system 2 (PCS2). Plasma volume was programmed at 760 ml including AC. CIR was calculated from citrate received by the donors divided by the body weight over time. RESULTS: 130 ± 12 ml TSC was used for 760 ml plasma. An average of 110 ml TSC or 84.6% of citrate load was in collected plasma and not given to the donor. From the difference of 20 ml or 514 mg citrate an average CIR of 0.16 mg/kg/min was calculated. CONCLUSION: The total amount of citrate received by the donor is minimal and the average CIR is below the critical level of 1 mg/kg/min.

Course of Hemoglobin and Hematocrit during and after Preparatory Plasmaphereses without and with Infusion of NaCl 0.9% 500 ml.

BACKGROUND: The aim of this study was to evaluate the course of hemoglobin (HGB) concentration and hematocrit (HCT) in donor blood during and after preparatory plasmaphereses (PP) without NaCl and with an infusion of 500 ml 0.9% NaCl during PP. METHODS: After informed consent 32 plasma donors were studied in a crossover design. They underwent PP once without NaCl infusion and once, on a different day, with infusion of 500 ml 0.9% NaCl. HGB concentration and HCT values in donor blood were analyzed using a Sysmex KX-21N analyzer. The values of HGB concentration and HCT before PP were set to 100%. Changes in HGB concentration and HCT were calculated in percent directly after PP, and after 24 and 72 h. RESULTS: During PP, there was a notable change in HGB concentration (11.2 ± 4.0%) and HCT (11.6 ± 3.9%) in donor blood. The difference between the 2 samples without and with NaCl was highly significant (p < 0.001). After 24 and 72 h, all differences were reduced. CONCLUSION: We observed significant changes in HGB concentration and HCT in donor blood during PP. We recommend a concomitant infusion of 500 ml 0.9% NaCl during PP to all donors.

Loss of red cell mass in a plasmapheresis machine: effect of rinsing the disposable tubing with normal saline and reinfusion.

The aim of this study was to determine the loss of red cell mass during a plasma donation. If the donor undergoes plasmapheresis 45 times within one year without rinsing the tubing system and reinfusing this normal saline into the donor at the end of the donation, the result is a loss of red cell mass of 11.01 ml per donation. This result translates into an accumulated loss of red cell mass of up to 495.63 ml per year. The loss of blood induced by plasma donations can be reduced to 58.01 ml per year, if the disposable tubing is rinsed with normal saline and reinfused into the donor at the end of each plasma donation.

Influence of NaCl 0.9% Infusion during Plasmapheresis on IgG Content in Plasma.

BACKGROUND: The aim of this study was to evaluate the influence of an infusion of NaCl 0.9% 500 ml during preparatory plasmapheresis or apheresis on the immunoglobulin G (IgG) content in separated plasma. METHODS: 32 donors of plasma were studied in a crossover design after informed consent on one day without NaCl 0.9% 500 ml during apheresis and on another day with infusion of NaCl 0.9% 500 ml during apheresis. Infusion of NaCl 0.9% 500 ml was given step by step in divided doses after each cycle through the harness set of the Haemonetics® plasma collecting system 2 (PCS2). Concentrations of IgG in serum and in plasma were measured by an immunoturbidimetric assay. Percentages of IgG concentrations in plasma were calculated by dividing the IgG concentration in plasma by the mean serum IgG concentrations (x 100). RESULTS: Without infusion of NaCl 0.9% 500 ml, the mean percentage of IgG in separated plasma was 85.5 ± 2.3% while it was 80.5 ± 3.4% when NaCl 0.9% 500 ml was given. The difference between the two samples was statistically highly significant (p < 0.001). CONCLUSIONS: We conclude that the gradual infusion of NaCl 0.9% 500 ml during apheresis causes a statistically highly significant difference of IgG content in separated plasma.

Enzyme linked immunosorbent assay (ELISA) as screening method for anti-paternal allo-antibodies in patients with recurrent pregnancy loss (RPL).

OBJECTIVES: Non-HLA-specific anti-paternal antibodies (APA) have been associated with immune responses against HLA-negative trophoblast. As screening for APA by using the flow cytometric cross match (FCXM) is complicated, we evaluated the One Lambda Antigen Tray Test (OLATT) an easy screening method for antibodies in organ transplant recipients. STUDY DESIGN: We randomly selected 92 patients of our recurrent pregnancy loss (RPL)-clinic merely on the basis of having had at least two consecutive miscarriages at <20 weeks representing positive and negative FCXM results. Stored sera were thawed and tested by OLATT. Concordance (Kappa statistic) and conformance (Chi-square test to McNemar) of FCXM and OLATT results were analysed. RESULTS: Of 48 FCXM-positive patients, 38 (79.2%) were positive and 10 (20.8%) negative by OLATT. Out of 44 FCXM negative patients, 37 (84.1%) were negative and 7 (15.9%) positive by OLATT. This resulted in a positive prediction value of 84.4%, a negative prediction value of 78.7% and a highly significant concordance (kappa=0.631 (p<0.0001; 81.5% versus 50%)) and conformance (p=0.23) between FCXM and OLATT in RPL patients. CONCLUSION: Using the OLATT could substitute the FCXM in screening RPL patients for APA and this might help to more closely study the role of APA in human gestation.

ProTime self-management yielding improvement of fluency and quality of life.

Patient self-management (PSM), as the standard of care for vitamin K-antagonist therapy management in Germany requires a detailed, point-of-care (POC) device-specific training program to ensure quality patient care. In a multi-center trial using the ProTime System (Training program plus POC device), 105 patients were enrolled to evaluate efficacy of training, knowledge retention, patient satisfaction and quality of life (QoL). Patients returned to the centers 1, 3 and 6 months after training to complete questionnaires and demonstrate INR test proficiency. Training assessment employed self-evaluation and comparison of POC results between PSM and professional operators. Patient satisfaction and QoL were assessed using a modification of the questionnaire described by Sawicki and the SF12v2 QoL Survey, respectively. Patients demonstrated statistically significant improvements in knowledge post training (p < 0.001) and retained the acquired information (p = NS vs. post-training; N = 45) after 6 months. Trained patients yielded equivalent INR results to professional operators (r = 0.92) with little or no bias across all clinic visits. Compliance with weekly testing improved from 1 to 3 months (p = 0.03), remaining at the required weekly frequency through 6 months. Average patient satisfaction improved significantly during the first month and remained constant thereafter. There was a statistically significant improvement in the Physical Component Summary of SF12 between baseline and 3/6 month assessments in all centers. In conclusion, PSM requires a comprehensive system including appropriate disease and POC device training. Such a system fosters compliance, improved knowledge about underlying disease, patient satisfaction and QoL.

Report on 50 cases of severe acute hypotension at donor plasmaphereses: treatment and course.

INTRODUCTION: This paper reports our experience in 50 cases with severe hypotensive reactions at plasma donations (synonymous with donor plasmaphereses). METHODS: Plasma donors who developed a severe acute hypotensive reaction at donor plasmapheresis, and were treated by placing the donor in the Trendelenburg position and rapid infusion of 1,000 mL saline were investigated. Plasmaphereses were performed with the Haemonetics® plasma collecting system 2 (PCS2). The results were analyzed using Excel. RESULTS: We observed 50 severe hypotensive reactions in plasma donors. The average systolic and diastolic blood pressures (SBP, DBP) were 128/75 mmHg - and heart rates were 78 beats/min (B/M) before plasmaphereses, 83/56 mmHg - 60 B/M at the event, and after treatment 119/71 mmHg - 69 B/M at the time of discharge. The volume of collected plasma was 602 ± 240 mL including anticoagulant (AC). The time until the event was 45 ± 20 minutes. With treatment 49 ± 18 minutes after the event all plasma donors had normal blood pressures and heart rates and could safely leave the center. CONCLUSIONS: Treatment by placing the donor in the Trendelenburg position and rapid infusion of 1,000 mL saline appears to be an effective procedure for resolving severe acute hypotension associated with donor plasmaphereses.

Post-operative course of coronary artery bypass surgery patients who pre-donate autologous blood.

BACKGROUND: Pre-operative autologous blood donation is used to reduce the need of allogeneic blood in patients undergoing coronary bypass surgery operations, but it is not clear what impact the blood donation has on the post-operative course of these patients. METHODS: We studied the post-operative course of 210 patients who pre-donated autologous blood before their coronary bypass operation (donors) and of 67 patients who were eligible to pre-donate but did not (controls). RESULTS: The clinical variables and the technical operative parameters of the patients in the two groups were similar. There was no significant difference between the duration of assisted ventilation post-operatively (756 +/- 197 vs. 802 +/- 395 min; P=0.54) or length of stay in the intensive care unit (1.8 +/- 1.1 vs. 1.7 +/- 0.9 days; P=0.52) of the two groups. The number of autologous units of packed red cells and of fresh frozen plasma (FFP) received by the donors was significantly higher than the number of units of allogeneic packed red cells (1.5 +/- 0.9 vs. 0.3 +/- 0.9; P=0.001) and the units of homologous FFP received by the controls (2.3 +/- 0.8 vs. 0.6 +/- 1; P=0.001). CONCLUSIONS: We found no evidence that autologous blood donation exerted a negative influence on the post-operative course of patients undergoing coronary bypass surgery. Patients who pre-donated blood received no allogeneic blood products, but the number of autologous blood products received by donors was higher than the number of blood products received by patients who did not pre-donate.

Low-dose oral anticoagulation in patients with mechanical heart valve prostheses: final report from the early self-management anticoagulation trial II.

AIMS: In mechanical heart valve recipients, low-dose international normalized ratio (INR) self-management of oral anticoagulants can reduce the risk of developing thrombo-embolic events and improve long-term survival compared with INR control by a general practitioner. Here, we present data on the safety of low-dose INR self-management. METHODS AND RESULTS: In a prospective, randomized multi-centre trial, 1346 patients with a target INR range of 2.5-4.5 and 1327 patients with a target INR range of 1.8-2.8 for aortic valve recipients and an INR range of 2.5-3.5 for mitral or double valve recipients were followed up for 24 months. The incidence of thrombo-embolic events that required hospital admission was 0.37 and 0.19% per patient year in the conventional and low-dose groups, respectively (P = 0.79). No thrombo-embolic events occurred in the subgroups of patients with mitral or double valve replacement. The incidence of bleeding events that required hospital admission was 1.52 and 1.42%, respectively (P = 0.69). In the majority of patients with bleeding events, INR values were < 3.0. Mortality rate did not differ between the study groups. CONCLUSION: Data demonstrate that low-dose INR self-management does not increase the risk of thrombo-embolic events compared with conventional dose INR self-management. Even in patients with low INR target range, the risk of bleeding events is still higher than the risk of thrombo-embolism.

Low-dose international normalized ratio self-management: a promising tool to achieve low complication rates after mechanical heart valve replacement.

BACKGROUND: International normalized ratio (INR) self-management can significantly reduce INR fluctuations, bleeding, and thromboembolic events compared with INR control managed by general practitioners. However, even patients with INR self-management may have an increased risk of bleeding if their INR value is above 3.5. This study evaluated the compliance, clinical complications, and survival of patients after mechanical heart valve replacement with low-dose INR self-management compared with conventional-dose anticoagulation. METHODS: Group 1 (n = 908) received low-dose anticoagulation with a target INR range of 1.8 to 2.8 for aortic valve replacement and 2.5 to 3.5 for mitral or double valve replacement. Group 2 (n = 910) received conventional-dose anticoagulation with a target INR range of 2.5 to 4.5 for all heart valve prostheses. RESULTS: In groups 1 and 2, 76% and 75% of INR values, respectively, were in the target range. Results did not differ according to schooling and age. The rate of thromboembolic events per patient year was 0.18% in group 1 and 0.40% in group 2 (p = 0.210). The rate of bleeding complications was 0.74% for group 1 and 1.20% for group 2 (p = 0.502). In most patients with clinically relevant bleeding, these complications occurred although their measured INR values were below 3.5. The survival rate did not differ between the study groups (p = 0.495). CONCLUSIONS: Low-dose INR self-management is a promising tool to achieve low hemorrhagic complications without increasing the risk of thromboembolic complications. INR self-management is applicable for all patients in whom permanent anticoagulation therapy is indicated. Even INR values below 3.5 can bear the risk of bleeding complications.

Analytical performance of the new coagulation monitoring system INRatio for the determination of INR compared with the coagulation monitor Coaguchek S and an established laboratory method.

An evaluation of the INRatio Prothrombin Time Monitoring system for determination of INR was done in two centers with a total of 5 healthy subjects and 77 subjects on oral anticoagulation. The INRatio and the Coaguchek S were compared with an established laboratory method. The correlation coefficient of the comparison with the laboratory was r=0.954 for INRatio and r=0.937 for Coaguchek S. The mean relative deviation from the lab method calculated according to Hill was 6.87% for INRatio, which is rated "very goo", and 9.72% for Coaguchek S ("goo"). The imprecision in the normal range (INR=1.1) showed a coefficient of variation (CV) of 7.8% and a standard deviation (SD) of 0.09. In the therapeutic range (INR 3.9) the CV was 5.4%, the SD 0.21 and above therapeutic range (INR 5.3), the CV was 8.4% (SD 0.44), rated satisfactory. The concordances of the compared methods with the routine were 81% for INRatio and 79% for Coaguchek S, which is considered state-of-the-art. Most of the patients' perceptions of the INRatio were very positive. In the hands of professionals the INRatio demonstrated very good accuracy and precision and an excellent technical reliability. Further studies using INRatio for self testing by patients are warranted.

Self management of oral anticoagulation with the IN Ratio system: impact of a structured teaching program on patient's knowledge of medical background and procedures.

BACKGROUND: Self management of oral anticoagulation (OAC) decreases complication rates and improves quality of life. Manual and cognitive abilities of patients and patient training in a structured format are a precondition for this concept. Up to now, there is no evidence about knowledge increase from teaching programs. METHODS: Seventy-six patients (mean age, 57.4 years, 71% male) who started long-term OAC were included in the prospective multi-center study at three teaching centers representing different populations of anticoagulation patients: a department of cardiovascular surgery, an inpatient rehabilitation center and an anticoagulation clinic. The patients were trained in a structured education program for two days. For the evaluation, the patients performed standardized tests including 16 questions prior to start (T0), after each training unit (T1/T2) and 6 weeks later (T3). The primary endpoint was the percentage of > or =75% of patients who could answer > or =50% of questions correctly at T3. Secondary endpoints were the overall and item-specific percentages of correct answers at the end of each training unit (T1, T2) and at T3. In addition, the teaching program was rated by the patients on a six-point rating scale. RESULTS: Seventy-four out of 76 patients gave at least 50% correct answers at T3 (97.4%; 95% confidence interval, 90.8-99.7%). The average rates of correct answers developed from 40% (T0), 86% (T1), 94% (T2) to 96% (T3). The greatest increase of knowledge was observed with blood components, interpretation of International Normalized Ratio (INR) value, and the interaction of anticoagulation with other variables (e.g. drugs or infection). Patients rated the teaching program between 1 (best rating) and 2 at all time points. At T3, the patients reported less fear of complications and less limitations in their daily life than in earlier evaluations. CONCLUSION: The structured training program INRatio appears to be an appropriate instrument for instruction of INR self management. In comparison with baseline knowledge, the percentage of correctly answered questions was twice as high directly after the end of training and remained at a high level of >90% for at least 6 weeks.

In vitro biocompatibility evaluation of the dynamic bubble trap.

The goal of this study was to evaluate the biocompatibility of the dynamic bubble trap (DBT) prior to the clinical trial. It was set up as an in vitro model, which simulates physiological conditions. Twenty runs were performed (ten with the DBT, ten without the DBT) at a blood flow of 3 l/min, each lasting 180 min. Fifteen blood parameters (hemogram, hemostasis, complement system, and cytokines) were measured at five time intervals. None of the tested parameters showed a statistically significant difference between the DBT and control group. The data assessed in this in vitro model show that the DBT has no adverse influence on hemocompatibility. It may be concluded that the DBT is a safe tool to be used in vivo.

Low-density lipoproteins induce the polar secretion of PAI-1 by endothelial cells in culture.

Patients with hypercholesterolemia and with coronary atherosclerosis have increased plasma levels of plasminogen activator inhibitor (PAI)-1. PAI-1 and low-density lipoproteins (LDL) are also present in the walls of atherosclerotic vessels, where they participate in the development and remodeling of the atherosclerotic plaques. We investigated the influence of LDL on the apical (luminal) and basolateral (subendothelial) secretion of PAI-1 by human umbilical vein endothelial cells in a two-compartment cell-culture model. Confluent cells were incubated with LDL either in the apical compartment or in the basal compartment. Cells incubated with culture medium served as controls. A significantly higher concentration of PAI-1 was found in both the apical (P = 0.025) and the basal compartment (P = 0.025) if cells were incubated with LDL on the basolateral side. In contrast, incubation of the cells with LDL apically resulted in an increased PAI-1 concentration only in the apical compartment (P = 0.028) and not in the basal compartment. Our findings indicate that the LDL particles that reach the subendothelial space can induce an increased release of PAI-1 by endothelial cells into the vessel lumen and also contribute to the release of PAI-1 into the subendothelial space and thus to the process of atherosclerotic plaque remodeling.