Blood donation for iron removal in individuals with HFE mutations: study of efficacy and safety and short review on hemochromatosis and blood donation.

Background: Elevated serum ferritin with/without HFE variants in asymptomatic persons leads frequently to referral for blood donation. Hemochromatosis (p.C282Y/p.C282Y) only requires treatment. We evaluated safety and feasibility of iron removal in healthy persons with elevated ferritin and HFE variants using blood donation procedures. Materials and methods: Thirty subjects with ferritin >200 ng/mL (women) or >300 ng/mL (men) with p.C282Y/p.C282Y, p.C282Y/p.H63D or p.H63D/p.H63D were randomized to weekly phlebotomy (removal of 450 mL whole blood) or erythrapheresis (removal of 360 mL red blood cells) every 14 days. The ferritin target was <100 ng/mL. A full blood count and ferritin were measured at each visit. Hemoglobin (Hb) ≥140 g/L was required at inclusion. If Hb dropped to <120 g/L (women) or <130 g/L (men), procedures were postponed (7 or 14 days). Primary endpoint was the number of procedures needed to the ferritin target; secondary objectives were duration of treatment and compliance. The treatment effect was tested with Poisson regression; number of procedures and treatment duration were compared between study arms with the Kruskal-Wallis test. Results: Twenty-five of 30 participants were men (83%); mean age was 47 years (SD 10.5), mean BMI 26.6 kg/m2 (SD 3.6); 17 had p.C282Y/p.C282Y, nine p.C282Y/p.H63D, four p.H63D/p.H63D. Median baseline Hb was 150 g/L (IQR 144, 1,559), median ferritin 504 ng/mL (IQR 406,620). Twenty-seven subjects completed the study. Treatment arm (p < 0.001) and HFE variant (p = 0.007) influenced the primary endpoint significantly. To ferritin levels <100 ng/mL, a median number of 7.5 (IQR 6.2, 9.8) phlebotomies and 4.0 (IQR 3.0, 5.8) erythraphereses (p = 0.001) was needed during a median of 66.5 days (IQR 49,103) and 78.5 days (IQR 46139), respectively (p = 0.448). Low Hb was the principal reason for protocol violation; anemia occurred in 13 participants (48%). Immediate complications were infrequent; fatigue was reported after 25% of phlebotomies and 45% of erythraphereses. Thirty-five procedures were postponed because of low Hb and 15 for non-medical reasons. The median interval was 7.0 (IQR 7.7) and 14.0 (IQR 14, 20) days between phlebotomies and erythraphereses, respectively. Conclusion: Blood donation procedures remove iron effectively in HC, but frequent treatments cause Hb decrease and fatigue that can impair feasibility.

Pathogen inactivation treatment of triple-dose apheresis platelets with amotosalen and ultraviolet a light.

BACKGROUND: A triple storage (TS) set allows for pathogen inactivation (PI) treatment of triple-dose apheresis platelet products with amotosalen + UVA. We evaluated the quality and metabolic parameters of platelet concentrates (PCs) pathogen inactivated and stored for 7 days. MATERIALS AND METHODS: Twelve triple-dose products collected with two different apheresis platforms were treated with amotosalen+UVA. Products were split into three single-dose units. Testing was made pretreatment, after splitting, at days 5 and 7 of storage. RESULTS: Single-dose PI PCs had a mean platelet content of 2.89 ± 0.35 x 1011 . From baseline to day 7, pH remained stable (7.1 ± 0.1 vs. 7.0 ± 0.1), pO2 increased (11.3 ± 2.4 vs. 18.3 ± 3.5 kPa) as did LDH (201 ± 119 vs. 324 ± 203 U/L) and lactate (3.6 ± 1.7 vs. 12.1 ± 1.5 mmol/L) (all p < 0.01); pCO2 decreased (4.1 ± 0.8 vs. 1.5 ± 0.7 mmHg; p < 0.01) and so did bicarbonate (6.6 ± 1.1 vs. 2.5 ± 1.4 mmol/L), glucose (5.6 ± 1.2 vs. 0.4 ± 0.4 mmol/L) and ATP (3.4 ± 0.9 vs. 2.5 ± 1.4 nmol/108 platelets) (all p < 0.05). CONCLUSION: Triple-dose PCs processed with the TS sets fulfilled the quality requirements and displayed metabolic changes of expected extent during 7-day storage.

Indices of iron homeostasis in asymptomatic subjects with HFE mutations and moderate ferritin elevation during iron removal treatment.

We analysed iron biomarkers and their relationships in 30 subjects with HFE mutations and moderate hyperferritinaemia undergoing iron removal at our blood donation centre. Body mass index (BMI) and liver enzymes were assessed. Serum iron (SI), ferritin, transferrin saturation (TSAT), hepcidin and non-transferrin bound iron (NTBI) were measured serially. Seventeen subjects had p.C282Y/p.C282Y, nine p.C282Y/p.H63D, four p.H63D/p.H63D. Median age (p = 0.582), BMI (p = 0.500) and ferritin (p = 0.089) were comparable. At baseline, 12/17 p.C282Y/p.C282Y and 2/9 p.C282Y/p.H63D had measurable NTBI (p = 0.003). The p.C282Y/p.C282Y had higher TSAT (p < 0.001), lower hepcidin (p = 0.031) and hepcidin/ferritin ratio (p = 0.073). After treatment, iron indices were similar among groups, except TSAT (higher in p.C282Y/p.C282Y; p = 0.06). Strong relationships were observed between ferritin and TSAT (R = 0.71), NTBI and TSAT (R = 0.61), NTBI and SI (R = 0.54) in p.C282Y/p.C282Y. Hepcidin correlated weakly with ferritin in p.C282Y/p.C282Y (R = 0.37) but strongly in p.C282Y/p.H63D (R = 0.66) and p.H63D/p.H63D (R = 0.72), while relationships with TSAT were weak (R = 0.27), moderate (R = 0.55) and strong (R = 0.61), respectively. Low penetrance p.C282Y/p.C282Y phenotype displays hepcidin dysregulation and biochemical risk for iron toxicity.

Long-Term Course of Haemoglobin and Ferritin Values in High-Frequency Donors of Whole Blood and Double Erythrocyte Apheresis.

BACKGROUND: High-intensity donation is a risk factor for iron deficiency in blood donors. Interdonation intervals for whole blood (WB) donation and double unit red blood cell apheresis (2RBC) vary among countries. We retrospectively evaluated the course of haemoglobin (Hb) and ferritin values in men regularly donating WB 4 times a year or 2RBC twice a year (i.e., maximal frequency) over a period of 48 months. METHODS: Data of male donors with 16 WB or 8 2RBC consecutive donations were analysed. The minimum Hb levels for WB donation and 2RBC apheresis (collection of 360 mL RBC) were 135 and 140 g/L, respectively. There was no lower limit set for ferritin, and no iron was substituted. RESULTS: We identified 294 WB (mean age 53 years, SD 11) and 151 2RBC donors (mean age 48 years, SD 9) who donated at a mean interval of 97 (SD 18) and 201 days (SD 32), respectively, between January 1, 2008, and December 31, 2013. At baseline, Hb and ferritin values were lower in WB donors compared to 2RBC donors, with a mean Hb of 153 g/L (SD 13) versus 159 g/L (SD 8) and a mean ferritin of 44 µg/L (SD 52) versus 73 µg/L (SD 56; p < 0.001 for both parameters), respectively. Ferritin was below 15 µg/L in 40 WB (14%) and in 4 (3%) 2RBC donors. In WB donors, the mean Hb levels at baseline versus last donation showed no significant difference (153 vs. 152 g/L, p = 0.068), whereas the mean ferritin levels decreased significantly (44 vs. 35 µg/L, p < 0.001). The 2RBC donor group displayed a statistically different decrease in both the mean Hb levels (158 vs. 157 g/L; p < 0.05) and the mean ferritin levels (73 vs. 66 µg/L; p = 0.052). The lowest Hb was measured at the 11th WB donation (152 g/L; p < 0.05) and at the 4th 2RBC apheresis (157 g/L; p < 0.05). There was no deferral due to low Hb at any time. The lowest ferritin was shown at the 4th WB (37 µg/L) and at the 3rd 2RBC donation (60 µg/L), respectively. At the last visit, ferritin was below 15 µg/L in 23 WB donors (8%) and in 2 2RBC donors (1%). CONCLUSIONS: High-intensity male donors with an interdonation interval of 12 weeks for WB donation and 24 weeks for 2RBC apheresis maintain acceptable Hb levels and, after an initial decline, stable ferritin levels despite ongoing blood donation.

Adverse events and retention of donors of double red cell units by apheresis.

BACKGROUND: Safety of double-erythrocyte (2RBC) collection and reasons for ceasing 2RBC donation were retrospectively analysed in the blood donor population of Basel, Switzerland. METHODS: Donors with at least 1 2RBC apheresis were included in the study. Minimal requirements were Hb ≥140 g/L and body weight ≥70 kg; serum ferritin (SF) values were measured routinely, but were not part of the selection criteria. 2RBC collections were performed with ALYX devices at 6-month intervals. Adverse events (AEs) were systematically recorded and classified according to the ISBT EHN 2008 criteria. Data of procedures were retrieved from the ALYX software. Demographics, apheresis data and AEs were analysed with descriptive statistics. RESULTS: Data of 4,377 2RBC aphereses performed in 793 donors (779 males) between 1(st) January 2003 and 31(st) May 2015 were evaluated. Mean donor age at first 2RBC donation was 44 years (standard deviation [SD] 21), median number of donations was 4 (interquartile range [IQR] 8); 32% of the donors underwent a single procedure. There were 161 AEs, mostly local haematomas (55%) and vasovagal reactions (20%); fatigue was reported in 6% of the cases and was more frequent than citrate toxicity. Two severe AEs were observed. The most frequent reasons for abandoning 2RBC donation were low SF levels and donor choice (both 11%), but most donors simply did not reply to invitations (16%). Overall, procedure-related causes (AEs, low SF levels, no time for apheresis, inadequate venous access) were observed in 14% of the cases. At the end of the observation period, 40% of the donors were still active blood donors, but only 20% were donating 2RBC. DISCUSSION: 2RBC donation is overall safe. Donor retention was low over a period of 11 years. An important reason for abandoning 2RBC was the detection of low SF levels. The impact of fatigue on donor retention and the course of iron stores after repeated 6-monthly 2RBC apheresis require further investigation.

Safety and immunogenicity of pneumococcal protein vaccine candidates: monovalent choline-binding protein A (PcpA) vaccine and bivalent PcpA-pneumococcal histidine triad protein D vaccine.

BACKGROUND: Pneumococcal vaccines based on protein antigens may provide expanded protection against Streptococcus pneumoniae. OBJECTIVE: To evaluate safety and immunogenicity in adults of pneumococcal vaccine candidates comprising S. pneumoniae pneumococcal histidine triad protein D (PhtD) and pneumococcal choline-binding protein A (PcpA) in monovalent and bivalent formulations. METHODS: This was a phase I, randomized, observer-blinded, placebo-controlled, step-wise dose-escalation study. Following a pilot safety study in which participants received one intramuscular injection of either aluminum hydroxide (AH)-adjuvanted PcpA (25 µg) or PhtD-PcpA (10 µg each), participants in the main study received AH-adjuvanted PcpA (25 µg), AH-adjuvanted PhtD-PcpA (10, 25, or 50 µg each), unadjuvanted PhtD-PcpA (25 µg each), or placebo as 2 injections 30 days apart. Assignment of successive dose cohorts was made after blinded safety reviews after each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD and anti-PcpA antibodies (ELISA). RESULTS: Six adults 18-50 years of age were included in the pilot study and 125 in the main study. No obvious increases in solicited reactions or unsolicited AEs were reported with escalating doses (adjuvanted vaccine) after either injection, or with repeated administration. Adjuvanted vaccine candidates were associated with a higher incidence of solicited reactions (particularly injection site reactions) than unadjuvanted vaccine candidates. However, no SAE or discontinuation due to an AE occurred. Geometric mean concentrations of anti-PhtD IgG and anti-PcpA IgG increased significantly after injection 2 compared with injection 1 at each dose level. No enhancement of immune responses was shown with adjuvanted vaccine candidates compared with the unadjuvanted vaccine candidate. In the dose-escalating comparison, a plateau effect at the 25 µg dose was observed as measured by geometric mean concentrations and by fold increases. CONCLUSIONS: Promising safety profiles and immunogenicity of these monovalent and bivalent protein vaccine candidates were demonstrated in an adult population (ClinicalTrials.gov registry no. NCT01444339).