Donor Exposure Research Articles

Donor Desmopressin Is Associated With Superior Graft Survival After Kidney Transplantation

A recent randomized trial showed that pretreatment of the brain-dead donor with low-dose dopamine improves immediate kidney graft function, by limiting injury from cold storage (ClinicalTrials.gov Identifier: NCT00115115). This study determines whether donor exposure to desmopressin (1-deamino-8-d-arginine-vasopressin [DDAVP]) before organ retrieval affects renal transplant outcome. This retrospective multicenter cohort study, nested in the database of the dopamine trial, includes 264 deceased heart-beating donors with confirmed brain death and corresponding 487 renal allograft recipients transplanted at 60 European centers between March 2004 and August 2007. We assessed differences in delayed graft function, biopsy-proven acute rejections, and 2-year kidney graft survival in recipients of a DDAVP-exposed versus unexposed graft. DDAVP was associated with improved graft survival (85.4% vs. 73.6%, P=0.003). This survival benefit persisted after censoring for death with functioning graft (91.1% vs. 82.0%, P=0.01) and after adjustment for confounders including covariate adjustment from propensity scoring (hazard ratio 0.40, 95% confidence interval [CI] 0.21-0.77; P=0.006). Delayed graft function (odds ratio 0.97, 95% CI 0.57-1.65; P=0.92) and biopsy-proven acute rejections (odds ratio 1.32, 95% CI 0.70-2.49; P=0.40) were unaffected. The survival effect was enhanced after a shorter cold ischemic time less than 14 hr (91.3% vs. 77.8%, P=0.008) and after dopamine pretreatment (92.7% vs. 78.6%, P=0.006). By contrast, prolonged cold ischemic time more than or equal to 14 hr (91.2% vs. 86.5%, P=0.39) and assignment to the nondopamine group (89.7% vs. 84.8%, P=0.37) abrogated the survival advantage. Donor DDAVP seems to improve renal allograft survival. Combined use of donor DDAVP and low-dose dopamine should receive further evaluation.

Transfusion medicine

ObjectiveCritically ill neonates frequently require multiple small volume red blood cell (RBC) transfusions. Red blood cell units assigned to individual infants, used sequentially in small aliquots until the original expiration date, can substantially reduce donor exposures. In 1993, adenine–saline solution (AS-3) was introduced by the Canadian Red Cross as the red cell storage medium to replace the citrate phosphate–dextrose–adenine anticoagulant preservative solution (CPDA-1). We surveyed the safety and efficacy of using AS-3 split packs, stored up to 35 days, for premature infants. Study designUnits of packed cells were aseptically welded to three satellite bags using a sterile connecting device. When blood was requested for a small volume transfusion, the first satellite bag was used and the others were set aside for the same baby, for use till their expiration date of 35 days. ResultsOver a 1-year period, 56 infants received a total of 263 AS-3 transfusions from 97 donors with a mean of 4.7 transfusions and 1.7 donor exposures per infant. Following a 7-mL/Kg RBC transfusion, the mean rise in hematocrit (HCT) was 0.04, regardless of the age of the unit, mean change in serum potassium was −0.16 mmol/L and the mean change in total bilirubin was +1.86 μmol/L. The post-transfusion HCT was not reduced with the use of the older red cell packs. ConclusionDesignated AS-3-preserved split RBC packs effectively limit donor exposures, can safely be used for neonatal small volume transfusions and give a constant transfusion effect after up to 35 days of storage.

Stage 1 Palliation for Hypoplastic Left Heart Syndrome Without the Use of Allogeneic Tissue, with Reduced Allogeneic Blood Product Exposure: A Case Report

In the 30 years since Norwood described the palliative procedure for hypoplastic left heart syndrome (HLHS), many modifications have been described which have increased the survival rate of children born with this lesion. We describe further modifications which result in reduced cardiopulmonary bypass time, no cooling or circulatory arrest time, and decreased banked blood exposure. A 16-day-old infant with HLHS undiagnosed during pregnancy presented for stage 1 palliation incorporating the Mee modification, Sano right ventricle to pulmonary artery conduit, dual arterial cannulation of the innominate artery and descending aorta, single venous cannulation of the right atrium, and a bypass prime volume of 130 mL. Anticoagulation and hemostasis were monitored with the Hepcon HMS Plus Hemostasis Management System (Medtronic USA, Minneapolis, MN). Bypass commenced at normothermia. A 5.0 Gore-Tex shunt was placed for the Sano Shunt, and the aortic arch was repaired without use of homologous tissue or synthetic material using a modification of the Mee technique. Bypass time was 92 minutes with a 10 minutes cardiac ischemic time. Modified ultrafiltration (MUF) was performed for 12 minutes and heparinization was reversed with protamine. There was no significant bleeding and no indication to transfuse clotting factors. The patient’s only allogeneic donor exposure was 350 mL of red blood cells during bypass necessary to achieve a post MUF hematocrit of 50% per our current institution policy for cyanotic infants. Using modified surgical and perfusion techniques along with low prime bypass circuits can result in reduced cross clamp and bypass times as well as a decrease in blood donor exposure. Hypothetical benefits include reduced operating room, ventilation, intensive care unit, and hospital times, improved neurodevelopmental outcomes, and an overall reduction in the cost of care for infants with HLHS.

Reconstituted Blood Reduces Blood Donor Exposure in Children Undergoing Craniofacial Reconstruction Surgery

Survey of Anesthesiology: October 2011 - Volume 55 - Issue 5 - p 237-238 doi: 10.1097/01.SA.0000399999.32373.94

Red blood cell alloimmunization in transfusion‐dependent Egyptian patients with thalassemia in a limited donor exposure program

Thalassemia is considered the most common hemoglobinopathy in Egypt and is one of its major health problems. Lifelong red blood cell (RBC) transfusion remains the main treatment for severe forms; however, RBC alloimmunization results as a complication of regular transfusions due to repeated exposure to foreign antigens. The objective was to compare the frequency of alloantibodies in a group of patients in a limited donor exposure program (LDEP) with those receiving RBCs from multiple donors in Egyptian transfusion-dependent patients with thalassemia. A total of 235 regularly transfused patients with thalassemia were studied, 36 of which were on LDEP. All patients were investigated for the presence of RBC autoantibodies and alloantibodies, followed by antibody identification for positive patients. Forty-six (19.5%) patients developed RBC alloantibodies. The most common clinically significant alloantibodies were directed against antigens in the Kell and Rh systems. Development of alloantibodies was associated with older age, higher transfusion frequency, and splenectomy. A trend toward lower alloimmunization was elicited in the LDEP group, where 8.3% (3/36) patients were alloimmunized compared to 21.6% (43/199) in the non-LDEP one (p=0.057). Examination of donor RBCs for presence of Kell and Rh(E) antigens before transfusion can help decrease RBC alloimmunization. Further larger studies are required to assess the frequency of alloantibody production in patients on LDEP.

Cesium cessation? An advantage of pathogen reduction treatments

Cesium cessation? An advantage of pathogen reduction treatments

Transmission of cytomegalovirus (CMV) infection by leukoreduced blood products not tested for CMV antibodies: a single‐center prospective study in high‐risk patients undergoing allogeneic hematopoietic stem cell transplantation (CME)

Measures to prevent transfusion-transmitted cytomegalovirus (TT-CMV) infection after hematopoietic stem cell transplantation (HSCT) include transfusion of CMV antibody-negative blood units and/or transfusion of leukoreduced cellular blood products. We assessed the incidence of TT-CMV in CMV-seronegative patients receiving CMV-seronegative HSC transplants, who were transfused with leukoreduced cellular blood products not tested for anti-CMV. In a prospective observational study between 1999 and 2009, all HSCT patients received leukoreduced cellular blood products not tested for anti-CMV. Patients were screened for CMV serostatus and CMV-negative recipients of CMV-negative transplants were systematically monitored for TT-CMV clinically and by CMV nucleic acid testing. Anti-CMV antibodies (immunoglobulin [Ig]G and IgM) were assessed after three time intervals (Interval 1, study inclusion to Day +30 after HSCT; Interval 2, Day +30-Day +100; Interval 3, after Day +100). Among 142 patients treated with allogeneic HSCT, 23 CMV-negative donor-patient pairs were identified. These 23 patients received 1847 blood products from 3180 donors. All patients remained negative for CMV DNA and none developed CMV-associated clinical complications. This results in a risk for TT-CMV per donor exposure of 0% (95% confidence interval, 0.0%-0.12%). However, 17 of 23 patients seroconverted for anti-CMV IgG, but none for anti-CMV IgM. CMV IgG seroconverters received significantly more transfusions per week than nonconverters. The risk of TT-CMV is low in high-risk CMV(neg/neg) HSCT patients transfused with leukoreduced blood products not tested for anti-CMV. The cause of anti-CMV IgG seroconversion is most likely passive antibody transmission by blood products.

Long-term outcome in relationship to neonatal transfusion volume in extremely premature infants: a comparative cohort study

BackgroundIn premature born infants red blood cell (RBC) transfusions have been associated with both beneficial and detrimental sequels. Upon RBC transfusion, improvement in cerebral blood flow and oxygenation have been observed, while a more liberal transfusion policy may be associated with a better developmental outcome. The effect of the transfusion volume on long-term outcome is not known.MethodsObservational follow-up study of a cohort of extremely premature born infants, treated in 2 neonatal intensive care units using a different transfusion volume (15 ml/kg in Unit A and 20 ml/kg in Unit B). The primary outcome was a composite of post discharge mortality, neuromotor developmental delay, blindness or deafness, evaluated at a mean corrected age (CA) of 24 months related to the transfusion volume/kg bodyweight administered during the postnatal hospital stay.ResultsDespite the difference in transfusion volume in clinically comparable groups of infants, they received a similar number of transfusions (5.5 ± 3.2 versus 5.5 ± 2.3 respectively in Unit A and B). The total transfused volume in unit A was 79 ± 47 ml/kg and 108 ± 47 ml/kg in unit B (p = 0.02). Total transfused RBC volume per kg bodyweight was not an independent predictor of the composite outcome (p = 0.96, OR 1.0 (CI 0.9-1.1).ConclusionThere was no relationship between the composite outcome at 24 months CA and transfusion volume received during the post natal hospital stay. As there was no clinical advantage of the higher transfusion volume, a more restrictive volume will reduce total transfusion volume and donor exposure. Future research on the optimal transfusion volume per event to extreme preterm infants should include larger, prospective studies with a longer follow-up period through to childhood or even adolescence.

Reduction in donor exposure with use of reconstituted blood in craniofacial patients – an alternative explanation

Reduction in donor exposure with use of reconstituted blood in craniofacial patients – an alternative explanation

Children with single-ventricle physiology do not benefit from higher hemoglobin levels post cavopulmonary connection: Results of a prospective, randomized, controlled trial of a restrictive versus liberal red-cell transfusion strategy*

To examine the impact of a restrictive vs. liberal transfusion strategy on arterial lactate and oxygen content differences in children with single-ventricle physiology post cavopulmonary connection. Children with single-ventricle physiology are routinely transfused postoperatively to increase systemic oxygen delivery, and transfusion thresholds in this population have not been studied. Prospective, randomized, controlled, clinical trial. Pediatric cardiac intensive care unit in a teaching hospital. Infants and children (n = 60) with variations of single-ventricle physiology presenting for cavopulmonary connection. Subjects were randomized to a restrictive (hemoglobin of < 9.0 g/dL), or liberal (hemoglobin of ≥ 13.0 g/dL) transfusion strategy for 48 hrs post operation. Primary outcome measures were mean and peak arterial lactate. Secondary end points were arteriovenous (C(a-v)o2) and arteriocerebral oxygen content (C(a-c)o2) differences and clinical outcomes. A total of 30 children were in each group. There were no significant preoperative differences. Mean hemoglobin in the restrictive and liberal groups were 11 ± 1.3 g/dL and 13.9 ± 0.5 g/dL, respectively (p < .01). No differences in mean (1.4 ± 0.5 mmol/L [Restrictive] vs. 1.4 ± 0.4 mmol/L [Liberal]) or peak (3.1 ± 1.5 mmol/L [Restrictive] vs. 3.2 ± 1.3 mmol/L [Liberal]) lactate between groups were found. Mean number of red blood cell transfusions were 0.43 ± 0.6 and 2.1 ± 1.2 (p < .01), and donor exposure was 1.2 ± 0.7 and 2.4 ± 1.1 to (p < .01), for each group, respectively. No differences were found in C(a-v)o2, C(a-c)o2, or clinical outcome measures. Children with single-ventricle physiology do not benefit from a liberal transfusion strategy after cavopulmonary connection. A restrictive red blood cell transfusion strategy decreases the number of transfusions, donor exposures, and potential risks in these children. Larger studies with clinical outcome measures are needed to determine the transfusion threshold for children post cardiac repair or palliation for congenital heart disease.

Toward a definition of “fresh” whole blood: an in vitro characterization of coagulation properties in refrigerated whole blood for transfusion

The hemostatic property of "fresh" whole blood (WB) has been observed in military application and cardiac surgery and is associated with reduced blood loss, transfusion requirements, and donor exposures. The time from donation to transfusion defining "fresh" has not been systematically studied. We undertook an in vitro study of coagulation properties of refrigerated WB stored for 31 days. Twenty-one WB units were obtained from healthy volunteer donors and stored under standard AABB refrigerated conditions. Samples were obtained on the day after donation and again on Days 2, 4, 7, 11, 14, 17, 21, 24, and 31. Tests included complete blood count, pH, pO2, pCO2, glucose, lactate, thromboelastography (TEG), and platelet function by light transmission aggregometry (LTA). There was progressive decline in pH, pO2, glucose, and sodium, but progressive increase in potassium, pCO2, and lactate. TEG variables in all units were normal through Day 11; abnormal values in some variables in some units began on Day 14. Final aggregation levels exhibited no change from Day 1 to Day 21 with adenosine diphosphate and epinephrine, but a decline with collagen (Day 7) and ristocetin (Day 17). This in vitro study of coagulation properties demonstrates preservation of normal integrated coagulation function to a minimum of 11 days under standard conditions of refrigerated storage of WB for transfusion. These observations strongly suggest that the hemostatic quality of WB may extend beyond current transfusion practices. If confirmed clinically, this would increase availability and extend benefits of reduced donor exposure and transfusion requirements.

Risk-Reduction Strategies for Platelet Transfusion in the United States

Despite bacterial culture of platelets, transfusion-associated bacteremia/sepsis (TABS) may occur with a frequency of approximately 1/60,000 platelet transfusions, while an emerging transfusion-transmitted infection (TTI) could reproduce the epidemic of transfusion-transmitted human immunodeficiency virus (HIV) in the future. As platelet pathogen-reduction (PR) systems licensed in Europe may eventually become licensed in the U.S., three alternative strategies for reducing the residual risks of TTIs and TABS may become available in the U.S. in the future: (1) transfusion of (already-available) non–pathogen-reduced single-donor (as opposed to pooled whole-blood-derived [PWBD]) platelets, (2) transfusion of pathogen-reduced single-donor platelets, or (3) transfusion of pathogen-reduced PWBD platelets (if trials of this component are conducted in the U.S. in the future). PR of platelets will increase the risk of mild and moderate (albeit perhaps not severe) bleeding complications and it cannot protect from all pathogens. Compared to PWBD platelets, single-donor platelets can reduce, by at least twofold, the risk of all known and emerging TTIs, as well as the risk of TABS, without incurring any risk. The fewer donor exposures secured by the use of single-donor platelets – especially if combined with collection of red blood cells and/or plasma from the same donation for transfusion to the same recipient through the use of multicomponent apheresis – may also reduce the risk of transfusion-related acute lung injury. To choose between pathogen-reduced and non–pathogen-reduced single-donor platelets, the increased risks of bleeding complications as well as other possible adverse events secondary to PR need to be quantified precisely and weighed against the competing risks of TABS and emerging TTIs.

Reconstituted blood reduces blood donor exposures in children undergoing craniofacial reconstruction surgery

To assess the effect of prophylactic administration of fresh-frozen plasma (FFP) in the form of reconstituted blood in children undergoing craniofacial reconstruction. The outcomes of interest included immediate postoperative coagulation laboratory test results, postoperative surgical drain output, and the number of unique blood donor exposures incurred. We recently changed our intraoperative transfusion strategy in children undergoing craniofacial reconstruction surgery to one in which blood loss is replaced with donor-matched reconstituted blood rather than traditional blood component therapy. We performed a query of our prospective craniofacial surgery perioperative registry for children who underwent fronto-orbital advancement or posterior cranial vault reconstruction. Registry data from this query were compared to data from a historical cohort. Data for 46 registry cases were compared to 150 historical cohort cases. The median number of unique donor exposures for the reconstituted blood group was 2 vs 3 in the historical cohort (P=0.004). The reconstituted blood group had a decreased incidence of postoperative derangements in soluble clotting factor tests (fibrinogen, PT, or aPTT; 2% vs 24%, P=0.001), while there was no evidence for a difference in the incidence of thrombocytopenia. There was no evidence for differences in postoperative surgical drain output in the reconstituted blood group and historical cohort over the first 12, 24, and 48 h. Prophylactic administration of FFP in the form of donor-matched reconstituted blood in children undergoing craniofacial reconstruction was associated with improved postoperative coagulation parameters, reduced blood donor exposures, and unchanged postoperative surgical drain output.

Transfusion Requirements and Outcomes In the Cohort of Patients Undergoing Isolated CABG Treated with Prasugrel or Clopidogrel: TRITON-TIMI 38 Data Analysis.

AbstractAbstract 1108▪Coronary artery bypass grafting (CABG)-related bleeding and associated transfusion support are concerns with dual antiplatelet therapy. The amount and the type of blood products transfused may be influenced by patient characteristics, procedural characteristics, acquired hemostatic defects, regional standard of care, and the amount of perioperative blood loss. Withdrawal of clopidogrel 5 days prior or prasugrel 7 days prior to CABG is suggested by the respective product labels to reduce the potential for CABG-related bleeding. Accordingly, a cohort of 422 patients undergoing isolated CABG in TRITON-TIMI 38 (PRASugrel n=208; CLOPidogrel n=214) was analyzed retrospectively to characterize the risk adjusted (using predicted risk of transfusion - Magovern, et al. Ann Thorac Surg 1996;61:27-32) difference in transfusion requirements between prasugrel and clopidogrel. Seventy-six patients who never received study drug or who received open label thienopyridine treatment prior to CABG were excluded. Packed red blood cells (PRBC) were the most frequently used blood product while platelet transfusions were relatively infrequent and regionally specific. No difference was noted in mean predicted transfusion risk score (TRS) between cohorts (PRAS 2.13 vs. CLOP 2.31; p=0.53; two-sided p value per ANOVA). TRS was associated with the number of units of PRBC transfused (p < 0.0001). Overall, there were significantly higher mean 12 hour chest tube loss (655 ±580 ml vs. 503± 378 ml; Kruskal-Wallis p=0.050) and platelet transfusion rates (18% vs. 9.8%; Pearson's chi-square p=.033) with PRAS. However, there were no statistically significant differences in PRBC transfusion units (mean 2.1±3.0 PRAS vs. 1.7±2.2 CLOP; Kruskal-Wallis p=0.44) or total donor exposure units (PRBC + whole blood + platelets + cryoprecipitate + fresh frozen plasma) (4.4±7.6 PRAS vs. 3.0±4.5 CLOP; Kruskal-Wallis p=0.46), although all of the analyses presented are underpowered. Total donor exposures were correlated with chest tube blood loss at 12 hours and the correlations were similar for both cohorts (PRAS, r=0.42; CLOP, r=0.45) (Figure). Transfusion requirements and blood loss by days from last dose categories are presented in the Table. Fifty-four (54)%, 22%, and 24% of patients went to CABG surgery ≤5 days, 6–7 days, and >7 days from the last dose of study drug, respectively (days from last dose to CABG unknown for 0.6% of patients). A significantly higher number of platelet units were used postoperatively in the PRAS patients going to surgery ≤5 days after withdrawal of drug. There is no suggestion of excess blood loss or excess of total units of blood transfusions after 7 days for PRAS or CLOP. In an analysis adjusted for the predicted risk of mortality (using Society of Thoracic Surgeons mortality score), total donor exposures were not associated with increased mortality risk [all-cause death within 30 days following CABG (odds ratio, 1.05 (0.97- 1.13) p=0.25; logistic regression analysis]. In addition, PRAS was independently associated with a reduction in mortality (PRAS, 1.2%; CLOP, 6.9%; p=0.027). In summary, the amount of blood products transfused is significantly influenced by patient and surgical characteristics, as well as by agents that can inhibit the hemostatic system. However, despite increased blood loss and use of greater numbers of platelets in a higher percentage of patients within the PRAS cohort, use of PRAS was associated with improved outcomes in the isolated CABG cohort of TRITON-TIMI 38. [Display omitted] Disclosures:Goodnough:Eli Lilly and Company: Consultancy. Despotis:Eli Lilly Company: Consultancy. Levy:Eli Lilly Company: Consultancy, Research Funding. Short:Eli Lilly & Company: Employment, Equity Ownership. Weerakkody:Eli Lilly & Company: Employment, Equity Ownership. Lenarz:Eli Lilly & Company: Employment, Equity Ownership.

Current debate on pathogen inactivation of platelet concentrates – To use or not to use?

It is an important goal in transfusion practice to improve the quality and safety of platelet transfusions. Accordingly, blood services have implemented several complimentary measures such as continual improvement in donor selection, donor testing, newer development in collection/processing, including the diversion of the first part of collection to reduce the potential risk of bacterial contamination and the use of various platelet additive solutions and reduction in donor exposures through production multiple doses by apheresis procedures. Unfortunately despite considerable improvement in blood components safety bacterial transmission by platelet transfusion remains the major microbial cause of morbidity and mortality in transfusion medicine. Currently two major interventions are in practice, in some establishments, to reduce bacterial transfusion by platelets: selective/full bacterial screening and pathogen inactivation. The later is also effective against most known and unknown emerging nucleic acid containing viruses, as well as, parasites. In addition it also reduces the side effect associated with leucocytes, making its implementation highly appealing.In recent years, two methods for pathogen inactivation/reduction (abbreviation used later in this paper PI) of platelet concentrates have become available. Pathogen inactivation was the original term for the technology, but as it is argued that the inactivation may not be complete, some authors prefer the term “pathogen reduction”. Although PI of cellular blood components is considered to be a “dream solution” to the problem of transfusion-related transmission of infectious diseases, the implementation of these precautionary interventional methods is not yet universally approved. The aim of this paper is to discuss some of the key issues in the debate on implementation of PI methods for platelet concentrates.

836 Audit of Neonatal Blood Transfusions

Introduction: Blood transfusions are very common on a neonatal unit. Patients often need a large number of blood transfusions but each may be as little as 8mls. To reduce donor exposure and wastage of blood each standard unit is split into 6 parts or a Pedipack which may be all or partly allocated to 1 infant. Our guideline was developed in 2007 and a prospective audit showed good compliance with no unnecessary donor exposure, but wastage due to inappropriate allocation of a full pedipack. Aims: This was a retrospective re-audit of all babies who had received a blood transfusion to ensure continued compliance with the protocol and to monitor donor exposure and the wastage of blood units. Results: Babies received between 1 and 17 blood transfusions. For babies ≤28 weeks gestation who did not receive pedipacks as per protocol they were exposed to up to 6 unnecessary donors. For babies >28 weeks 15% were allocated an inappropriate full pedipack resulting in wastage. Conclusions: There was very poor adherence to the protocol resulting in unnecessary exposure to multiple donors and excessive wastage. This was felt to be due to poor compliance with the guideline, poor communication between the neonatal unit and blood bank staff and an increase in the need for blood transfusions resulting in a lack of availability of full pedipacks. Recommendations: To provide teaching sessions for all staff. To improve communication between the neonatal unit and blood transfusion. To re-audit to ensure that improvements have occurred.

317 The Effect of Human Red Cells Storage Time on the Microcirculation of Preterm Infants

Background: Red blood cell (RBC) transfusion practices for neonates are controversial, variable, and based on limited scientific information. To decrease donor exposure satellite packs are used leading to the transfusion of older RBCs. Transfusion of stored RBCs in a hemodiluted animal resulted in significant malperfused and underoxygenated microvasculature that was not detected at the systemic level. Objective: Does the age of transfused erythrocytes influence functional vessel density (FVD) in the skin in premature infants?. Design Methods: 17 preterm infants with birth weight < 1500g received RBC transfusion, 11 infants repeatedly from the same donor. The age of RBCs at repeated transfusions was significant higher than at the first transfusion. Using Sidestream Dark Field Imaging all preterm infants were examined before and 2, 24 and 48 hours after transfusion. Images were blinded and analyzed with Microvision Analysis Software. Results: FVD before first and repeated transfusion did not differ. In the 2nd, 24th and 48th hour after the treatment the Functional Vessel Density (FVD) was significantly lower after the repeated transfusion with longer storage time (2nd: 250 vs. 238 cm/cm2, p=0.045; 24th: 259 vs. 231 cm/cm2, p=0.001; 48th: 234 vs. 220 cm/cm2, p=0.035). The proportion of vessels with altered sluggish blood flow was also significantly higher when older RBCs were transfused (24h: 0.3% vs 2.5%, p=0.017; 48h: 1% vs. 3.3%, p=0.013). Conclusions: Similar to the animal model longer storage of the red blood cells reduces functional vessel density in the skin of premature infants and more vessels display sluggish blood flow.

HBV reactivation after fludarabine chemotherapy identified on investigation of suspected transfusion-transmitted Hepatitis B virus

Multi-transfused patients often receive treatments inducing various levels of immunodeficiency. Acute viral infections may then be attributed either to transfusion-transmitted infection (TTI) or reactivation of a past infection. A patient with chronic lymphocytic leukemia (CLL) who had >250 blood donor exposures developed acute Hepatitis B virus (HBV) infection. Routine donor testing for HB core antibodies (anti-HBc) was in place in the relevant period and investigations undertaken on the blood donors were negative. Review of historical, molecular, and antigenic evidence demonstrated reactivation of a recovered HBV infection dating >30 years and the selection of a rare escape mutant that briefly replicated and caused acute liver disease. This mutant was unreactive with several HBsAg assays and poorly reactive with an HBV vaccine plasma. Correcting the C139Y substitution by site directed mutagenesis of recombinant surface proteins re-established assay reactivity. Fludarabine, but not Chlorambucil, appeared sufficiently immunosuppressive to trigger reactivation despite low levels of neutralizing antibodies. Differentiating between TTI and reactivation of HBV becomes more challenging with the increasing frequency of immunocompromised blood recipients. Chemotherapy with Fludarabine alone should be considered as carrying high risk of viral reactivation. Pre-treatment testing and peripheral blood sample archiving may be indicated in HBsAg negative patients.

Response to Zimmermann et al

Dear Editor, We appreciate the opportunity to respond to Zimmermann et al. They refer to publications by Vamvakas [1] and Heuft et al. [2]. Both base their conclusion on mathematical models. Vamvakas presents calculations for additional transfusion transmitted infections (TTI) contracted through platelet transfusions in the United States (US) if pooled platelet concentrate (PPC) would completely replace singledonor apheresis platelet concentrates (APC)[1]. These calculations are based on assumptions which do not all apply for Europe. The calculation is based on the risk of TTI in the US today (1 per 2 135 000 donations for HIV, 1 per 1 935 000 for HCV and 1 per 280 000 for HBV [1]). For the German Red Cross Blood Donor Services, the residual risk for TTI is substantially lower (data 1997–2005): 1 per 4 300 000 donations for HIV, 1 per 10 880 000 for HCV and 1 per 360 000 for HBV [3]. This analysis does not account the effect of anti-HBc testing, which became mandatory in Germany since 2006 and will most likely reduce the risk for HBV. The ‘worst-case scenario’ of Vamvakas who carefully confines the conclusions to the United States assumes that a PPC contains platelets from six whole blood (WB) donations [1]. In many European countries, PPC is pooled from five or four donations. The risk calculation is substantially different if assuming six or four donor exposures per PPC [1]. A significant proportion of APC represents split products so that an infected donor can infect two or even three recipients by one donation and in addition further recipients by subsequent donations during the ‘window period’ because of the potentially short interval of APC donations [4]. A model on GBV-C virus infections takes into account that pooling of a GBV-C RNA positive buffy coat (BC) with a BC containing a GBV-C neutralizing antibody could lead to a non-infectious PPC. A careful sensitivity analysis demonstrates that the number of theoretical GBV-C transmissions depends on the assumed frequency of neutralizing antibodies in the donor population [2]. Many assumptions affect the results of mathematical models and delimit their conclusions [4]. Zimmermann et al. argue that the preparation of PPC affects the quality of red blood cell concentrates (RCC) resulting ‘in a remarkable proportion of underfilled RCC’. The binding German Haemotherapy Guidelines [5] and the ‘Guide to the preparation, use and quality assurance of blood components’ [6] stipulate that at least 95% of the leucocyte-depleted RCC must contain ‡ 40g haemoglobin ⁄unit. The mean haemoglobin of RCC produced by our Blood Service using RCC filtration after BC-removal is 56AE4 g, and only 0AE2% of RCC had haemoglobin content below 40 g ⁄unit, and there is no difference when comparing haemoglobin content in RCC produced from donations without or with concomitant preparation of a PPC. For our Blood Service, we can decline that preparation of PPC by the BC method results in a remarkable proportion of underfilled RCC – and this applies also to other blood services obliged to meet regulatory requirements. Zimmermann et al. refer to the loss of 2,3-DPG during overnight storage at 22 C [7]. Several aspects need to be considered in interpretation of this surrogate parameter: Rapid cooling slowed the loss of 2,3-DPG levels but 2,3DPG levels were undetectable by day 21 irrespective of the initial storage temperature [7]. Wilsher et al. [7] compared processing within 8h versus storage for 24 h at 22 C. In practice, the actual interval between donation and start of processing in most institutions is shorter than 24 h even if overnight storage at 22 C is involved. It has been shown that 2,3-DPG levels return to near normal levels after transfusion [8]. The clinical significance of the observed difference needs to be studied further. Overnight storage at 22 C can increase the efficiency of separation of platelets from WB donations and can reduce bacterial contamination. Zimmermann et al. argue that the processing method affects the levels of platelet-derived cytokines in RCC [9]. It is important to take into account all details of the processing. A high concentration of platelet-derived cytokines was measured in PC prepared with the dock-in Sepacell RBC filter or with platelet-saving WB filters before removing plasma or platelet-rich plasma. In this study, the plasmareduced RCC (still containing platelets) were held overnight at 4 C. Neither a storage at 4 C nor a storage overnight after removal of plasma nor the use of platelet-saving WB filters can be considered as standard procedure for PPC Vox Sanguinis (2010)

Disparate risks and effects of pooled whole blood-derived vs. apheresis platelet production require an integral view on the blood supply

Dear Editor, Recently, Schrezenmeier and Seifried [1] presented a review on the question whether pooled buffy-coat-derived platelet concentrates (PPCs) or apheresis PCs (APCs) should be preferred. They claimed that PPCs and APCs have comparable content of platelets (PLTs), purity, safety, and efficacy. They argued that almost all APCs could be replaced by PPCs and that PLT apheresis donations should be restricted to PLT recipients with anti-HLA and ⁄ or anti-HPA antibodies from the donor¢s perspective to drop the apheresis procedure-related donor risks to a ‘zero’ value and to optimize the use of the whole blood (WB) donation. Some weeks ago, Vamvakas [2] gave a systematic review of disparate risks of PPCs vs. APCs. He calculated an annual increase of 1AE2 (best case) to 3AE5 (worst case) additional cases for HIV, 1AE3 to 3AE9 for HCV, and 9AE0 to 27AE1 for HBV transmission, if PPCs would completely replace APCs. For a novel ‘HIV like’ infectious agent with a prevalence of 1:10 000 donations (for comparison, the incidence of HIV in the last year before testing was ten times higher), he predicted 252AE6 to 757AE7 additional transmissions. From our group, a recent risk calculation was performed by Heuft et al. [3], Hannover Medical School. They found that an unrecognized infection with a prevalence of 1% in the donor population would result in three to four times higher infection rates for PPC recipients compared to pure APC supply. Both Vamvakas and Heuft considered shorter donation intervals, the influence of splitting apheresis donations and low numbers WB donations per PPC for their calculations. Schrezenmeier and Seifried [1] cited both studies but voted to ignore their results because ‘so far, no epidemiological study or clinical trial have demonstrated different risk of viral infections transmitted by pooled PCs compared to apheresis PCs.’ This argumentation is on absolutely no account acceptable. Of course, the effects of a novel HIV-like virus cannot be proven epidemiologically or clinically before it has emerged. However, over the past decades, many previously unknown infectious agents have emerged. Recent work on the genetic distance of the two oldest currently known specimens of HIV-1 demonstrated that the first infections of humans by HIV-1 have occurred more than 100 years ago, at least two decades earlier than previously believed [4]. This clearly demonstrates that a dangerous infectious agent, which can be transmitted via transfusion and which kills recipients some years or even decades after transmission, may spread over many decades until becoming uncovered. The only way to meet this typical risk of blood transfusion is to strictly limit the donor exposure for the transfusion recipient and to replace a pooled component by a nonpooled alternative whenever possible. On the strength of past experience with the transmission of HIV and hepatitis viruses by blood and blood products, the consideration of very small and even of fictitious and yet unproven risks is common practice as well in transfusion medicine as in the legislation and the jurisdiction in all developed countries. In addition, we want to point out another relevant, but currently neglected issue: the production of PPCs has negative effects on the overall quality of the red cell supply. WB for PPC production is often held overnight at room temperature. However, at this temperature, red cells lose 2,3diphosphoglycerate (2,3-DPG) extremely rapidly [5]. Red cell concentrates (RCCs) from WB leukoreduced by a PLTsaving filter and stored overnight at room temperature contain remarkable levels of PLT-derived cytokines [6]. Finally, if PCs are produced by the BC method, a relevant proportion of red cells, at least ten per cent, is removed from the WB. This may result in a remarkable proportion of underfilled RCCs [7]. In summary, the production of PPCs impairs the quality of the red cell supply by red cell loss, by the rapid loss of 2,3-DPG, and by the accumulation of PLT-derived cytokines. Therefore, we strongly argue for an integral view on the blood supply that notes and considers the negative effects of PPC production from WB on the red cell supply. In conclusion, we fully agree with Vamvakas and disagree with Schrezenmeier and Seifried. Not APCs should be replaced by PPCs, but PPCs should be replaced by APCs. The most important factor determining the PLT product choice must be the difference of the risk of transfusiontransmitted infections, particularly of the transmission of a new HIV-like agent. In addition, there is sufficient evidence Vox Sanguinis (2010)