[Blood safety in the Netherlands: prevention of blood-transmitted infections]. / De bloedveiligheid in Nederland.

Amongst the various blood-safety measures to prevent blood-transmitted infections in transfusion recipients, the most important are the selection of blood donors and the testing for infections of the donations. A look-back procedure aims to inform hospitals about potentially infected blood products and to trace the relevant recipients. The opposite, reverse look-back, can also occur: following a report that a patient has an infection of which blood transfusion may be the possible source, all possibly implicated donors will be screened for the particular agent. Over the period 2007-2017, 84 look-backs were carried out by the Dutch blood product organisation Sanquin. Transmission via blood products of the human immunodeficiency virus, hepatitis C virus, human T-cell Lymphotropic virus or Treponema pallidum were not found. Look-back identified four recipients with hepatitis-B virus infection. These recipients had received a blood product from donors with an occult chronic hepatitis-B virus infection. In the Netherlands, the risks associated with transmission of infection through blood products are minimal; however, transmission may still occur, despite extensive blood-safety measures.

Ensuring HLA-matched platelet support requires an ethnic diverse donor population.

BACKGROUND: Patients refractory for platelet transfusions benefit from human leukocyte antigen (HLA)-matched platelet transfusions. Differences in ethnic background of patients and donors could hamper the availability of sufficient numbers of HLA-matched donors for all patients. We evaluated our HLA-matched donor program and explored the role of ethnic background of patients related to the number of available donors. METHODS: We performed a cohort study among consecutive patients who received HLA-matched platelet concentrates in the Netherlands between 1994 and 2017. The number of available matched donors was determined per patient. Haplotypes were constructed from genotypes with computer software (PyPop). Based on haplotypes, HaploStats, an algorithm from the National Marrow Donor Program, was used to assess the most likely ethnic background for patients with 5 or fewer and 30 or more donors. RESULTS: HLA typing was available for 19,478 donors in September 2017. A total of 1206 patients received 12,350 HLA-matched transfusions. A median of 83 (interquartile range, 18-266) donors were available per patient. For 95 (10.3%) patients, 5 or fewer donors were available. These patients were more likely to have an African American background, whereas patients with 30 or more donors were more often from Caucasian origin, compared with Caucasian origin for patients with 30 donors. CONCLUSION: Adequate transfusion support could be guaranteed for most but not all refractory patients. More non-Caucasian donors are required to ensure the availability of HLA-matched donors for all patients in the Netherlands.

HLA-matched platelet transfusions are effective only in refractory patients with positive HLA antibody screening.

BACKGROUND: Recipients of platelet transfusions with 1-hour corrected count increments (1hCCIs) of 7.5 or less on two subsequent platelet transfusions with random platelets may benefit from human leukocyte antigen (HLA)-matched platelet concentrates. We aimed to quantify the efficacy of HLA-matched platelets concentrates expressed in 1hCCIs. METHODS: We performed a cohort study among consecutive refractory patients who received HLA-matched platelet concentrates in the Netherlands between 1994 and 2017. We performed mixed-model linear regression comparing 1hCCIs after HLA split-antigen-matched transfusions with 1hCCIs after HLA-mismatched transfusions, adjusted for within-patient correlations. A donor-to-patient match was categorized as a split-match if all donor HLA-A and -B antigens were present in the patient as well; that is, donor and patient were HLA identical or compatible. Subgroup analyses were performed for patients with positive or negative HLA antibody screens. Finally, the additional effect of ABO mismatches on 1hCCIs was investigated. RESULTS: The 1hCCI after an HLA-matched transfusion was 14.09 (95% reference interval, 1.13-29.89). This was 1.94 (95% confidence interval [CI], 0.74-3.15) higher than 1hCCI after HLA-mismatched transfusions. In patients with negative HLA antibody screening tests, HLA matching did not affect 1hCCIs. Conditional on HLA matching, 1hCCIs decreased by 3.70 (95% CI, -5.22 to -2.18) with major ABO mismatches. CONCLUSION: Matched platelet concentrates yielded maximal 1hCCIs, whereas mismatched transfusions still resulted in adequate increments. There is no indication for HLA-matched platelets in patients with negative antibody screens.

A Conceptual Framework for Optimizing Blood Matching Strategies: Balancing Patient Complications Against Total Costs Incurred.

Alloimmunization is currently the most frequent adverse blood transfusion event. Whilst completely matched donor blood would nullify the alloimmunization risk, this is practically infeasible. Current matching strategies therefore aim at matching a limited number of blood groups only, and have evolved over time by systematically including matching strategies for those blood groups for which (serious) alloimmunization complications most frequently occurred. An optimal matching strategy for controlling the risk of alloimmunization however, would balance alloimmunization complications and costs within the entire blood supply chain, whilst fulfilling all practical requirements and limitations. In this article the outline of an integrated blood management model is described and various potential challenges and prospects foreseen with the development of such a model are discussed.

Utility of zinc protoporphyrin in management of whole blood donors.

BACKGROUND: Deferral for low hemoglobin (Hb) increases the likelihood that donors do not return for future donations. Zinc protoporphyrin (ZPP) has been described as a sensitive marker of iron-deficient erythropoiesis, before Hb decreases. It is a relatively cheap, rapid, and easy-to-perform measurement in a drop of whole blood. To assess the utility of ZPP measurement in donor management we examined whether ZPP and Hb levels among first-time donors differ from repeat donors. We further explored whether ZPP increases over subsequent donations at a donor population level and whether increasing ZPP levels coincide with decreasing Hb levels and donor deferral. STUDY DESIGN AND METHODS: We included first-time (n = 4983) and repeat (n = 3533) whole blood donors from the ZPP and Iron in the Netherlands Cohort (ZINC) study. ZPP and Hb were measured at each subsequent donation during a 4-year period after inclusion in the study. RESULTS: Median ZPP levels were higher in repeat than in first-time donors. In first-time donors, especially women, ZPP levels were increased with a corresponding decline in Hb levels over subsequent donations. ZPP levels were increased among first-time donors deferred for low Hb. CONCLUSION: Our results suggest that adding ZPP to Hb measurements in the daily blood collection setting, especially for first-time donors and first-time female donors may add to the identification of a donor subpopulation with low functional iron stores.

Reporting transfusion-related acute lung injury by clinical and preclinical disciplines.

BACKGROUND: Disciplines involved in diagnosing transfusion-related acute lung injury (TRALI) report according to a "one-hit" theory. However, studies showed that patients with an underlying condition are at increased risk of the development of TRALI. We investigated whether accumulating evidence on the "two-hit" theory has changed the practice of reporting TRALI. MATERIALS AND METHODS: Departments of haematology, haemovigilance, transfusion medicine, intensive care and anaesthesiology from all Dutch hospitals with at least five beds equipped for mechanical ventilation were invited to participate in an online survey. Using clinical vignettes with conjoint analysis we investigated the effect of patients' age, admission diagnosis, type and number of transfusions and presence of risk factors for acute lung injury on TRALI reporting. A positive ß-coefficient indicated a higher likelihood of reporting TRALI. RESULTS: We received 129 questionnaires (response rate 74%). Respondents were more likely to report TRALI in younger patients, if symptoms developed within 2 hours of transfusion and if patients had received multiple transfusions. Sepsis and the presence of a risk factor for acute lung injury reduced the inclination to report. Transfusion medicine physicians and haemovigilance staff no longer took the age of transfusion products into account in their diagnostic considerations on TRALI. DISCUSSION: We conclude that the multidisciplinary team involved in TRALI reporting, still considers TRALI a "one-hit" event, despite accumulating evidence that supports the "two-hit" theory. These results suggest that the patients most at risk of developing TRALI are not reported to the blood bank.

The effect of World Blood Donor Day on digital information seeking and donor recruitment.

BACKGROUND: The purpose of World Blood Donor Day (WBDD) is to raise awareness for the importance of blood donation. The aim of this study was to quantify the impact of WBDD on digital information seeking and donor recruitment. STUDY DESIGN AND METHODS: Google Trends data were used to quantify seeking behavior on "blood donation" and "blood donor." Differences in relative search volume (RSV) between the 3 weeks surrounding WBDD and the rest of the year were calculated. Second, mean differences in RSV were compared to assess the additional effect of hosting using translated search terms. Third, we compared the period around WBDD with the control period regarding page views of the Sanquin website and Facebook likes and number of newly registered donors in 2016. RESULTS: The mean RSV for "blood donation" in the period of interest was 78.6, compared to 72.1 in the control period (difference, 6.5; 95% confidence interval [95% CI], 1.2-11.8). For "blood donor" this was 78.9 compared to 65.9 (difference, 12.9; 95% CI, 8.1-17.8). We found no additional effect of hosting. In the period of interest, the website of Sanquin was visited 6862 times a day and 4293 times in the control period (difference, 2569; 95% CI, 1687-3451). In June 2016, 54.6% (95% CI, 53.0-56.2) more new donors were registered compared to the control period. CONCLUSION: An international campaign like WBDD raises the awareness of blood donation and is effective in convincing people to register as blood donors.

Impact of red blood cell transfusion strategies in haemato-oncological patients: a systematic review and meta-analysis.

Haemato-oncological patients receive many red blood cell (RBC) transfusions, however evidence-based guidelines are lacking. Our aim is to quantify the effect of restrictive and liberal RBC transfusion strategies on clinical outcomes and blood use in haemato-oncological patients. A literature search, last updated on 11 August 2016, was performed in PubMed, EMBASE (Excerpta Medica Database), Web of Science, Cochrane, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Academic Search Premier without restrictions on language and year of publication. Randomized controlled trials and observational studies that compared different RBC transfusion strategies in haemato-oncological patients were eligible for inclusion. Risk of bias assessment according to the Cochrane collaboration's tool and Newcastle-Ottawa scale was performed. After removing duplicates, 1142 publications were identified. Eventually, 15 studies were included, reporting on 2636 patients. The pooled relative risk for mortality was 0·68 [95% confidence interval (CI) 0·46-1·01] in favour of the restrictive strategy. The mean RBC use was reduced with 1·40 units (95% CI 0·70-2·09) per transfused patient per therapy cycle in the restrictive strategy group. There were no differences in safety outcomes. All currently available evidence suggests that restrictive strategies do not have a negative impact regarding clinical outcomes in haemato-oncological patients, while it reduces RBC use and associated costs.

How we manage patients with hereditary haemochromatosis.

A number of disorders cause iron overload: some are of genetic origin, such as hereditary haemochromatosis, while others are acquired, for instance due to repeated transfusions. This article reviews the treatment options for hereditary haemochromatosis, with special attention to the use of erythrocytapheresis. In general, therapy is based on the removal of excess body iron, for which ferritin levels are used to monitor the effectiveness of treatment. For many decades phlebotomy has been widely accepted as the standard treatment. Recent publications suggest that erythrocytapheresis, as a more individualized treatment, can provide a good balance between effectiveness, tolerability and costs. Other treatments like oral chelators and proton pomp inhibitors, which are used in selected patients, create the possibility to further individualize treatment of hereditary haemochromatosis. In the future, hepcidin-targeted therapy could provide a more fundamental approach to treatment.

Rare transmission of hepatitis B virus by Dutch donors with occult infection.

BACKGROUND: To reduce the rate of transfusion-transmitted hepatitis B virus (HBV), HBV DNA testing was introduced for all Dutch blood donations in 2008, in addition to the existing screening for HBV surface antigen (HBsAg). This study describes the lookback results for repeat donors with an "HBV DNA-only" test result (HBV DNA-positive and HBsAg-negative). STUDY DESIGN AND METHODS: From November 2008 until June 2011, a total of 2.3 million blood donations were tested for HBV DNA and 22 donors showed the HBV DNA-only profile. Four donors had early preseroconversion HBV infection, two showed suppressed infection after vaccination, and 16 donors had occult chronic HBV infection (OBI). Potentially infectious donations were traced back as far as 1992. If possible the recipients were tested for current and past HBV infection. RESULTS: A total of 416 implicated donations could be traced in blood bank records, involving 448 issued blood products. For 170 (38%) of the recipients no information was obtained from the hospitals; 196 (44%) recipients had died, and 82 (18%) were tested for HBV. Six recipients tested positive for current (n = 4) or past (n = 2) HBV infection. For two recipients transfusion was ruled out as the source of infection. Three patients showed HBV DNA sequences matching with the HBV in one common OBI donor. Overall, in four of 82 tested recipients (5%) HBV transmission was likely. CONCLUSION: In our lookback study HBV testing was possible in only a minority (18%) of potentially exposed recipients. A low transmission rate (5%) was observed in recipients of blood components from donors with OBI.

Phosphatidylserine exposure on stored red blood cells as a parameter for donor-dependent variation in product quality.

BACKGROUND: Exposure of phosphatidylserine on the outside of red blood cells contributes to recognition and removal of old and damaged cells. The fraction of phosphatidylserine-exposing red blood cells varies between donors, and increases in red blood cell concentrates during storage. The susceptibility of red blood cells to stress-induced phosphatidylserine exposure increases with storage. Phosphatidylserine exposure may, therefore, constitute a link between donor variation and the quality of red blood cell concentrates. MATERIALS AND METHODS: In order to examine the relationship between storage parameters and donor characteristics, the percentage of phosphatidylserine-exposing red blood cells was measured in red blood cell concentrates during storage and in fresh red blood cells from blood bank donors. The percentage of phosphatidylserine-exposing red blood cells was compared with red blood cell susceptibility to osmotic stress-induced phosphatidylserine exposure in vitro, with the regular red blood cell concentrate quality parameters, and with the donor characteristics age, body mass index, haemoglobin level, gender and blood group. RESULTS: Phosphatidylserine exposure varies between donors, both on red blood cells freshly isolated from the blood, and on red blood cells in red blood cell concentrates. Phosphatidylserine exposure increases with storage time, and is correlated with stress-induced phosphatidylserine exposure. Increased phosphatidylserine exposure during storage was found to be associated with haemolysis and vesicle concentration in red blood cell concentrates. The percentage of phosphatidylserine-exposing red blood cells showed a positive correlation with the plasma haemoglobin concentration of the donor. DISCUSSION: The fraction of phosphatidylserine-exposing red blood cells is a parameter of red blood cell integrity in red blood cell concentrates and may be an indicator of red blood cell survival after transfusion. Measurement of phosphatidylserine exposure may be useful in the selection of donors and red blood cell concentrates for specific groups of patients.

Increased volume of distribution for recombinant activated factor VII and longer plasma-derived factor VII half-life may explain their long lasting prophylactic effect.

INTRODUCTION: Prophylaxis with plasma-derived or recombinant activated factor VII is beneficial in severe factor VII deficiency. To understand why prophylactic treatment with both products is efficacious, we conducted a pharmacokinetic study. MATERIALS AND METHODS: Ten factor VII deficient patients were treated with either recombinant activated (20 µg/kg) or plasma-derived (25 IU/kg) factor VII in a cross-over design. Pharmacokinetic parameters were analyzed through activated factor VII activity, factor VII clotting activity, and factor VII antigen levels on depicted time points. RESULTS: Factor VII activity half-lifes, determined by non-compartmental and one-compartmental analysis (results in brackets), were shorter for recombinant activated (1.4h; 0.7h) than for plasma-derived factor VII (6.8h; 3.2h); both recombinant activated (5.1h; 2.1h and plasma-derived factor VII (5.8h; 3.2h) resulted in longer half-lives of factor VII antigen. Activated factor VII half-lives (based on activated factor VII activity levels) were significantly higher compared to factor VII clotting activity (1.6h; 0.9h). Volumes of distribution were significantly higher for activated factor VII (236 ml/kg; 175 ml/kg, measured by activated factor VII) as compared to plasma-derived factor VII (206 ml/kg; 64 ml/kg, measured by factor FVII activity), suggesting a plasma- and extracellular fluid distribution for recombinant activated factor VII. CONCLUSIONS: Recombinant activated factor VII showed significantly shorter half-lifes than plasma-derived factor VII. Volumes of distribution were significantly higher for treatment with recombinant activated factor VII. The longer half-life for plasma-derived factor VII, compared to recombinant activated factor VII, and the increased volume of distribution for recombinant activated factor VII, compared to plasma-derived factor VII may further elucidate the beneficial effect of prophylactic treatment of both products.

Pharmacodynamics of recombinant activated factor VII and plasma-derived factor VII in a cohort of severe FVII deficient patients.

Recombinant activated factor VII (rFVIIa) and plasma-derived factor VII (pdFVII) are used to prevent bleedings in severe FVII deficient patients, despite their short half-lifes. It is suggested that FVII levels of 15-20 IU/dL are sufficient to maintain hemostasis. We analyzed the pharmacodynamic effects of FVII substitution therapy in the Nijmegen Hemostasis Assay (NHA) that simultaneously measures thrombin and plasmin generation. Ten severe FVII deficient patients were treated with 20 µg/kg rFVIIa or 25 IU/kg pdFVII in a cross-over design. Thrombin generation lag-time (TG-LT) was identified as an effect-response parameter. Pharmacodynamic analysis using a maximum effect model showed 50% reduction of the TG-LT effect at ~2 IU/dL FVII activity for both rFVIIa and pdFVII. The FVII activity to obtain TG-LT comparable to the upper limit of normal range in healthy controls (4 min) was given by the effective concentration (ECnormal), showing sufficient hemostasis at 3-4 IU/dL FVII activity. No association was seen between FVII activity and other thrombin or plasmin generation parameters as measured by NHA. In conclusion, 3-4 IU/dL FVII activity seems sufficient to maintain hemostasis in patients with severe FVII deficiency during prophylaxis. These data may suggest a potential value for measurement of TG-LT in the monitoring of FVII(a) therapy.

Lookback procedures after postdonation notifications during a Q fever outbreak in the Netherlands.

BACKGROUND: Since 2007, large outbreaks of Q fever occurred in the Netherlands. The unprecedented number of Q fever infections resulted in the need for the Dutch blood transfusion service to evaluate the risk of transmission of Coxiella burnetii via blood. STUDY DESIGN AND METHODS: A lookback procedure (recipient tracing) was performed for transfused blood products of whole blood donors with confirmed C. burnetii infection within 3 weeks before to 3 weeks after blood donation. Repository samples of index donations were tested with real-time polymerase chain reaction (PCR) for C. burnetii DNA. Hospitals were asked to review the medical records of recipients and-if considered necessary-to test the recipients for infection with C. burnetii. RESULTS: From 2007 through 2011, a total of 33 blood donors notified the blood bank of infection with C. burnetii. Thirteen donations fulfilled the criteria for a lookback procedure (18 blood products). C. burnetii PCR was positive in 1 of 13 repository samples of index donations. Blood products were transfused to 18 recipients. Information was retrieved from 12 of them; seven were tested for C. burnetii. Two recipients showed positive serology. However, transmission of C. burnetii via transfusion was unlikely, especially since most recipients lived in the same Q fever-affected area as the donors. CONCLUSION: Blood donors who have clinical Q fever around the time of blood donation are unlikely to test positive for C. burnetii by PCR in repository samples. Transmission of C. burnetii via transfusion of blood products could not be demonstrated in a lookback exercise.