Donor Exposure Research Articles

Donor exposure to the plasticizer di(2-ethylhexyl)phthalate during plateletpheresis.

Di(2-ethylhexyl)phthalate (DEHP) is a plasticizer that is contained in most PVC devices, including apheresis disposables. Because DEHP can be extracted from apheresis disposables as the blood passes through the apheresis device, DEHP exposure was determined in healthy donors undergoing plateletpheresis performed with commercially available apheresis systems. The study population consisted of 36 healthy PLT donors undergoing plateletpheresis with either continuous or discontinuous apheresis devices. Serum concentrations of DEHP were determined from peripheral blood obtained before and after plateletpheresis, with gas chromatography-mass spectroscopy. Plateletpheresis performed with standard collection disposables resulted in a median increase of 232 percent of serum DEHP compared to levels before apheresis, corresponding to a total amount of DEHP exposed during a single apheresis of a median of 6.46 (range, 1.8-20.3) microg per kg of body weight. Endogenous levels of triglycerides showed a positive correlation with the amount of DEHP released. Increase in serum DEHP was short-term as serum DEHP rapidly returned to levels obtained before apheresis within 3 hours after completion of the apheresis course. Donor exposure to DEHP led to no variation in liver cell function within 48 hours after plateletpheresis. Commercial plateletpheresis disposables release considerable amounts of DEHP during the apheresis procedure, but the total dose of DEHP retained by the donor is within the normal range of DEHP exposure of the general population.

Feasibility and success of a single-donor red cell program for pediatric elective surgery patients.

Although the risks of allogeneic blood transfusions are small, it is wise to limit donor exposure whenever possible. A program has been developed in which one donor provided all red cell (RBC) units for each patient awaiting elective surgery. Patients were mostly children who were ineligible for autologous blood donation. Seventy-three patients and 115 donors (mostly parents) entered the program. Of the 115 donors, 90 (78%) were eligible to participate and 25 (22%) were ineligible; 21 were ineligible because of RBC incompatibility. For each of the 73 patients, one eligible donor was selected to donate all RBC units. Preoperative RBC orders were 1 to 2 units for 41 patients and > or = 3 units for 32 patients. Of the 73 donors, 58 (79%) gave all RBC units ordered; 15 (21%) failed to complete all donations, but only 1 because of anemia (hematocrit < 33% [0.33]). Of 73 patients entered, 46 (63%) underwent transfusion, and 27 (37%) did not. Of 46 patients transfused, 38 (83%) received only single-donor RBCs. Thus, the RBC needs of nearly all pediatric elective surgery patients were provided by a single donor for each patient. Single-donor blood programs should be considered for elective surgery patients who are ineligible for autologous blood donation and who would otherwise be exposed to multiple donors.

Bacterial contamination of blood components: risks, strategies, and regulation: joint ASH and AABB educational session in transfusion medicine.

Bacterial contamination of transfusion products, especially platelets, is a longstanding problem that has been partially controlled through modern phlebotomy practices, refrigeration of red cells, freezing of plasma and improved materials for transfusion product collection and storage. Bacterial contamination of platelet products has been acknowledged as the most frequent infectious risk from transfusion occurring in approximately 1 of 2000-3000 whole-blood derived, random donor platelets, and apheresis-derived, single donor platelets. In the US, bacterial contamination is considered the second most common cause of death overall from transfusion (after clerical errors) with mortality rates ranging from 1:20000 to 1:85000 donor exposures. Estimates of severe morbidity and mortality range from 100 to 150 transfused individuals each year. Concern over the magnitude and clinical relevance of this issue culminated in an open letter calling for the "blood collection community to immediately initiate a program for detecting the presence of bacteria in units of platelets." Thereafter, the American Association of Blood Banks (AABB) proposed new standards to help mitigate transfusion of units that were contaminated with bacteria. Adopted with a final implementation date of March 1, 2004, the AABB Standard reads "The blood bank or transfusion service shall have methods to limit and detect bacterial contamination in all platelet components." This Joint ASH and AABB Educational Session reviews the risks, testing strategies, and regulatory approaches regarding bacterial contamination of blood components to aid in preparing practitioners of hematology and transfusion medicine in understanding the background and clinical relevance of this clinically important issue and in considering the approaches currently available for its mitigation, as well as their implementation. In this chapter, Drs. Hillyer and Josephson review the background and significance of bacterial contamination, as well as address the definitions, conceptions and limitations of the terms risk, safe and safety. They then describe current transfusion risks including non-infectious serious hazards of transfusion, and current and emerging viral risks. In the body of the text, Dr. Blajchman reviews the prevalence of bacterial contamination in cellular blood components in detail with current references to a variety of important studies. He then describes the signs and symptoms of transfusion-associated sepsis and the sources of the bacterial contamination for cellular blood products including donor bacteremia, and contamination during whole blood collection and of the collection pack. This is followed by strategies to decrease the transfusion-associated morbidity/mortality risk of contaminated cellular blood products including improving donor skin disinfection, removal of first aliquot of donor blood, pre-transfusion detection of bacteria, reducing recipient exposure, and pathogen reduction/inactivation. In the final sections, Drs. Vostal, Epstein and Goodman describe the regulations and regulatory approaches critical to the appropriate implementation of a bacterial contamination screening and limitation program including their and/or the FDA's input on prevention of bacterial contamination, bacterial proliferation, and detection of bacteria in transfusion products. This is followed by a discussion of sampling strategy for detection of bacteria in a transfusion product, as well as the current approval process for bacterial detection devices, trials recommended under "actual clinical use" conditions, pathogen reduction technologies, and bacterial detection and the extension of platelet storage.

Neonatal red blood cell transfusions.

Red blood cell and blood product transfusion in the fetus, neonate, and premature infant are often administered with poorly defined indications and unintentional adverse consequences. Products may be altered in an effort to limit potential adverse events or may be specially selected to meet the unique needs of a specific diagnosis. One area of particular concern to neonatologists is selection blood for small volume (5-15 mL/kg) transfusions in premature infants. For infants, use of red blood cells collected in anticoagulant-additive solutions and administered in small aliquots over the shelf life of the product to decrease donor exposure has supplanted the use of fresh red blood cells with each transfusion resulting in a donor exposure. The safety of this practice has been documented and procedures established to aid a transfusion service in making these products available. Less well established are the indications for transfusion in this population; hemoglobin or Hematocrit alone are likely insufficient unless clinical findings like oxygen desaturation, apnea, and bradycardia are part of the criteria used to define transfusion need. The comorbidities that increase oxygen demands in these infants, like bronchopulmonary dysplasia and increased oxygen consumption to accommodate growth, must be part of the decision to transfuse. Noninvasive methods or assays that will reflect the unique pathophysiology of oxygen delivery and peripheral oxygen offloading are needed.

Red blood cell transfusions in newborn infants: Revised guidelines

In general, health care professionals taking care of high risk infants in neonatal intensive care units have become more restrictive in their use of red blood cell transfusion over the past 10 years. The present statement is intended for those caring for high risk newborn infants (preterm to one month of age). The objectives of this statement are to provide guidelines to reduce the incidence of anemia in preterm and term infants, to identify strategies to decrease the need for red blood cell transfusions and to limit donor exposure in this population. Recommendations for red blood cell transfusions are included.

Storage of red blood cells: New approaches

Longer red blood cell (RBC) storage can improve blood logistics, increase the usefulness of autologous blood storage, and reduce donor exposure in neonatal intensive care. Better RBC storage can prevent membrane loss and preserve the secretion of adenosine 5'-triphosphate (ATP) in response to deformation. Better RBC storage may also reduce the formation of proinflammatory membrane breakdown products that lead to transfusion-related acute lung injury and the systemic inflammatory response syndrome. To improve RBC storage, the authors have attempted to maximize the production of ATP by the manipulation of pH and to minimize membrane loss through the use of membrane protectants and the manipulation of tonicity. Increasing the initial storage pH led to successively higher RBC ATP concentrations until pH 7.2 was reached, when the synthesis of 2,3-diphophoglycerate was initiated at the expense of ATP. Synthesis of ATP could be maintained by buffering the fall of pH with increased storage solution volume or the addition of bicarbonate. Maintaining RBC ATP turns out to be an important way of preventing membrane microvesiculation or blebbing, as does the manipulation of tonicity and the addition of mannitol. These experiments show that it is possible to store RBC in experimental additive solutions containing only saline, adenine, glucose, mannitol, sodium bicarbonate, and disodium phosphate for 11 weeks or longer with little loss of membrane and high in vivo recovery.

Evidence-based use of blood products

Clinical governance requires the introduction of evidence-based practice in all areas of medicine. Variations in transfusion practice in neonatal units in the UK and USA indicate that evidence-based paediatric transfusion practice is not currently practised in many units and, as a result, children are being exposed to transfusion risks without likelihood of clinical benefit. This also places excessive demands on the transfusion services which are faced with escalating costs of providing safe blood and difficulties in recruiting suitable donors. Introduction of restrictive transfusion policies in some neonatal units has been achieved without increase in morbidity and with significant reduction in donor exposure and indicates what can be achieved once the barriers to the introduction of evidence-based transfusion practice can be broken down. Communication, education and increased resources are required in order to change current practices but, more than anything else, paediatricians must be prepared to take the initiative in examining their current practices and modifying these appropriately.

Risk factors for cytomegalovirus reactivation after CD6+ T-cell-depleted allogeneic bone marrow transplantation.

Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Recipients of T-cell-depleted (TCD) transplants may be more susceptible to CMV infection as a result of the reduction in transferred T cell immunity. We sought to determine the effect of prior donor and patient CMV exposure on the incidence of CMV infection after TCD allogeneic HSCT. We retrospectively examined CMV antigen testing results in all patients who had undergone CD6+ TCD related and unrelated donor allogeneic HSCT at our institution from 1996 to 1999. All 124 patients who had documented donor and recipient CMV serologies pretransplant and had undergone CMV antigen testing before day +100 posttransplant were included in the analysis. Forty-one percent of seropositive recipients and 1% of seronegative recipients developed evidence of CMV reactivation (odds ratio 54.1, 95% confidence interval [CI] 6.9-424.1, P<0.001). Prior donor CMV exposure did not place seronegative recipients at increased risk of CMV conversion. Multivariable analysis indicated that prior donor CMV exposure significantly reduced the risk of CMV reactivation in seropositive recipients by 81% (odds ratio 0.19, 95% CI 0.04-0.91, P=0.04). Grades II to IV acute graft-versus-host disease (GVHD) was associated with CMV conversion (P=0.04) when seropositive recipients underwent HSCT from CMV-negative donors, but not when the donor was CMV-seropositive (P=0.54). The CMV serology status of the recipient, rather than the donor, was the primary determinant of risk for CMV conversion after TCD allogeneic HSCT. Despite CD6+ T-cell depletion, immunity against CMV seemed to be transferred with the donor graft and protected seropositive HSCT recipients from CMV reactivation.

Early treatment with erythropoietin β ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g

Objective: To investigate whether recombinant erythropoietin (rhEPO) reduces the need for transfusion in extremely low birth weight (ELBW) infants (birth weight 500-999 g) and to determine the optimal time for treatment. Methods: In a blinded multicenter trial, 219 ELBW infants were randomized on day 3 to one of 3 groups: early rhEPO group (rhEPO from the first week for 9 weeks, n = 74), late rhEPO group (rhEPO from the fourth week for 6 weeks, n = 74), or control group (no rhEPO, n = 71). All infants received enteral iron (3-9 mg/kg/day) from the first week. The rhEPO β dose was 750 IU/kg/week. Success was defined as no transfusion and hematocrit levels never below 30%. Results: Success rate was 13% in the early rhEPO group, 11% in the late rhEPO group, and 4% in the control group (P =.026 for early rhEPO versus control group). Median transfusion volume was 0.4 versus 0.5 versus 0.7 mL/kg/day (P =.02) and median donor exposure was 1.0 versus 1.0 versus 2.0 (P =.05) in the early rhEPO group, the late rhEPO group, and the control group, respectively. Infection risk was not increased and weight gain was not delayed with rhEPO β. Conclusion: Early rhEPO β treatment effectively reduces the need for transfusion in ELBW infants. (J Pediatr 2002;141:8-15)

Nitric Oxide Stimulates Adrenomedullin Secretion and Gene Expression in Endothelial Cells

Adrenomedullin, a peptide with vasorelaxant activity, stimulates nitric oxide (NO) synthesis. We tested whether or not NO regulates the function of the adrenomedullin system. Human umbilical vein endothelial cells (HUVEC) were incubated with the NO donors sodium nitroprusside (SNP), morpholinosydnonimine (SIN-1) and the phospodiesterase V inhibitor zaprinast. In HUVEC, adrenomedullin concentration in the supernatant was measured by radioimmunoassay and mRNA expression was studied by Northern blot and competitive quantitative PCR. SNP, SIN-1, and zaprinast (100 µmol/l each) significantly increased adrenomedullin concentration in the supernatant of HUVEC twofold. The same concentrations increased adrenomedullin mRNA expression four- to tenfold. Similar results were obtained by both quantitative PCR and Northern blot. Thus, NO donor exposure in vitro increases both adrenomedullin secretion and mRNA expression in a dose-dependent manner.

Blood Conservation During Pediatric Cardiac Surgery

SUMMARYEliminating blood product exposure in pediatric cardiac surgery is a challenging and difficult task. Avoidance of allogeneic blood products decreases the risk of a transfusion reaction and potential complications. Various strategies have been explored to decrease donor exposure from the preoperative through the postoperative period. In this paper, the authors review the current literature on blood conservation techniques and examine the changing practice of blood use and blood conservation in the field of pediatric cardiac surgery.

Red cell storage lesion assessed by the levels of potassium, haemoglobin and Annexin V in supernatants

The conventional and a new marker of global cellular lesion (Annexin V) are used to assess the processing/storage-induced changes in four types of RBC and filtered blood at 4° and 22°C, stored for a period of 35 days, in multi-satellite packs. It appears that mechanical trauma and presence of leucocytes and residual platelets have potential to increase levels of all markers of storage lesion, but to a variable extend. We have also provided new evidence that multi-satellite packs can be safely used for up to 35 days for small volume transfusion to sick premature infants, in a well-managed system by administering several transfusions from the same donation, hence reducing donor exposure.

Essential role of caspase‐11 in activation‐induced cell death of rat astrocytes

We have previously shown that rat astrocytes undergo apoptosis upon inflammatory activation. Nitric oxide (NO) produced by activated astrocytes was the major cytotoxic mediator in this type of autoregulatory apoptosis. However, an inhibitor of nitric oxide synthase did not completely block the apoptosis of activated astrocytes, suggesting the presence of other apoptotic pathways. Here, we present evidence that caspase-11 is an essential molecule in NO-independent apoptotic pathway of activated astrocytes. Inflammatory activation (lipopolysaccharide, interferon-gamma, and tumor necrosis factor-alpha treatment) of rat astrocyte cultures and C6 glioma cells led to the induction of caspase-11 followed by activation of caspases-11, -1, and -3. In contrast, NO donors induced activation of caspase-3 only. Inactivation of caspase-11 by the transfection of dominant negative mutant or treatment with the caspase inhibitors rendered the astrocytes partially resistant to the apoptosis following inflammatory activation, but not NO donor exposure. These results indicate that inflammatory stimuli not only induce the production of cytotoxic NO, but also initiate NO-independent apoptotic pathway through the induction of caspase-11 expression.

Significance of platelet-reactive antibody screening for patients facing frequent platelet transfusions

Abstract It is not clear whether platelet-reactive antibody screening is clinically significant for patients facing frequent platelet transfusions. On the basis of data from 96 patients who had been examined for platelet-reactive antibodies by the mixed passive hemagglutination method for a variety of reasons, we investigated the following three issues retrospectively: (1) the relationship between platelet-reactive antibodies and the occurrence of problems in platelet transfusions, such as refractoriness or nonhemolytic reactions;(2) the influence of a history of transfusion on the production of those antibodies; and (3) the effect of screening for those antibodies on the prompt administration of appropriate platelet components. More than half of the platelet transfusion-related problems were associated with platelet-reactive antibodies. For patients with a history of transfusion, the mean period before a clinical problem occurred with platelet transfusions was 9 days,compared with 66 days for those without such a history. Accordingly, during the period, patients with a history of transfusions received fewer units of platelets and had fewer donor exposures than did patients without such a history. On the other hand, most patients who had been screened in advance for those antibodies received appropriate platelet components without delay, whereas an average of 10 days was needed before those who had not been screened received compatible platelets. The patients who had not been screened were transfused with 68 units of random platelets on average during the period. When frequent platelet transfusions are anticipated, especially for patients with a history of transfusion, screening for platelet-reactive antibodies beforehand would be helpful for prompt administration of appropriate platelets, although problems, such as the cost of those platelets and the burden on donors, remain to be resolved. Immunohematology 2002;18:104–108

Advances in cardiac surgical transfusion practices during the 1990s in a Finnish university hospital.

Recent transfusion practices in coronary artery bypass (CABG) operations in a Finnish university hospital were evaluated, utilizing the data stored automatically in hospital registers. The register-based transfusion data on all 2363 CABG patients operated on during a 2.5-year period, from 1997 to 1999, were analysed and compared with a review of surgical transfusion practices in Finland from 1993 to 1994. The rate of allogeneic transfusion showed a decrease from 76% in 1993-94 to 48% in the time-period January to June 1999, and the mean number of donor exposures decreased from 3.3 to 2.0 units per patient. The mean blood product purchase costs per patient almost halved from 1993-94 to 1997-99. Hospital registers provide a good means for prompt evaluation and reporting of large-scale transfusion data. Since 1993, transfusion rates and costs in CABG operations have decreased markedly. Further development of transfusion registers is warranted.

Reduction of donor exposures in premature infants by the use of designated adenine-saline preserved split red blood cell packs.

Critically ill neonates frequently require multiple small volume red blood cell (RBC) transfusions. RBC 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 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. Units 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 up until their expiration date of 35 days. Over 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, 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 mean change in total bilirubin was +1.86 micromol/l. The posttransfusion hct was not reduced with the use of the older red cell packs. Designated 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.

Dual Role of Inflammatory Stimuli in Activation-induced Cell Death of Mouse Microglial Cells: INITIATION OF TWO SEPARATE APOPTOTIC PATHWAYS VIA INDUCTION OF INTERFERON REGULATORY FACTOR-1 AND CASPASE-11

We have previously shown that mouse microglial cells undergo apoptosis upon inflammatory activation and that nitric oxide (NO) is the major autocrine mediator in this process (Lee, P., Lee, J., Kim, S., Yagita, H., Lee, M. S., Kim, S. Y., Kim, H., and Suk, K. (2001) Brain Res. 892, 380-385). Here, we present evidence that interferon regulatory factor-1 (IRF-1) and caspase-11 are the essential molecules in activation-induced cell death of microglial cells. The apoptogenic action of inflammatory stimuli such as lipopolysaccharide (LPS) and interferon-gamma (IFNgamma) was mediated through the induction of IRF-1 and caspase-11 expression in two separate events. Although IRF-1 was required for NO synthesis, caspase-11 induction was necessary for NO-independent apoptotic pathway. Microglial cells from IRF-1-deficient mice showed markedly decreased NO production, and they were partially resistant to apoptosis in response to LPS/IFNgamma but were sensitive to NO donor exposure. LPS/IFNgamma treatment resulted in the induction of caspase-11 followed by activation of caspase-11, -1, and -3. Inactivation of caspase-11 by the transfection of dominant-negative mutant or treatment with the caspase inhibitors rendered microglial cells partially resistant to LPS/IFNgamma-induced apoptosis. Inhibition of both NO synthesis and caspase-11 completely blocked LPS/IFNgamma-induced cytotoxicity. These results indicated that LPS/IFNgamma not only induced the production of cytotoxic NO through IRF-1 but also initiated the NO-independent apoptotic pathway through the induction of caspase-11 expression.

Managing the anemia of prematurity: red blood cell transfusions versus recombinant erythropoietin.

Transfusion-dependent anemia remains a problem for preterm infants, particularly those with a birth weight less than 1.0 kg. Several studies have documented the efficacy and safety of transfusing red blood cells stored up to 42 days as a means to diminish donor exposures. Recombinant erythropoietin therapy has not been widely adopted because it does not consistently reduce the need for red blood cell transfusions in very low-birth weight preterm infants.

Directed blood donation in pediatric general surgery: Is it worth it?

Purpose: To date, there are no data to support the safety, efficacy, and cost-benefit ratio of donor-directed blood donation (DD). The objectives were to determine whether a DD program in pediatric general surgery practice is justified. Methods: A retrospective analysis was conducted of the transfusion practice and all DD requests received by transfusion services in a full calendar year (1997) at a tertiary care pediatric hospital. The authors examined the donations, utilization, and possible benefits for the recipients. Results: A total of 22,527 units of blood were transfused in 1997. General surgery used 471 (2%) of the total and 471 of 4,825 (10%) of all surgical transfusions. Total DD requests were 219 with only 11 of 219 (5%) originating from the general surgery department. After all the exclusions, 133 of 219 (61%) requests had DD blood available. DD blood had a higher true-positive rate for transmissible disease (1.1% v 0.10%), high-risk activity (2.5% v 1.2%), and malaria risk (3.1% v 0.31%). Total utilization of DD blood was 132 of 236 units (55.9%) and general surgery utilized 4 of 11 (36.4%) of their directed donations. Thirty-seven patients (27.8%) benefited from decreased donor exposure. No general surgery patient received more than 1 blood component to benefit from decreased donor exposure. Conclusion: DD deferral rates are higher than for volunteer donors for infectious disease markers, malaria, and high-risk activities. There is no evidence that DD is safer than volunteer donation. DD blood wastage of 63.6% is much higher than in volunteer donation (7%). Thirty-seven patients (28%) received multiple units from one donor suggesting a benefit from decreased donor exposure. Given the low frequency of transfusion and the poor utilization of DD in general surgical practice, a DD program is not justified. J Pediatr Surg 36:722-725. Copyright © 2001 by W.B. Saunders Company.

Safety and efficacy of AS-1 red blood cell use in neonates

Many Regional Blood Centers are providing AS-1(Adsol preservative) red blood cells (RBCs) as a standard product because of the extended shelf life (42 days). The use of AS-1 RBCs is concerning in neonates because of high exposure to dextrose, adenine and mannitol. We conducted this study to evaluate the safety and efficacy of AS-1 RBC use in neonates. We assigned one unit of AS-1 RBCs to each infant for small volume transfusions (15 ml/kg) for the life of the unit (42 days). The study was conducted for one year. The infants under 1500 g were included in the study. We measured the pre- and post-transfusion hematocrit, post-transfusion serum sodium, potassium, glucose, bilirubin and blood pH. We compared the average number of transfusions per patient and average blood donor exposure per patient using AS-1 RBC to CPDA-1 packed red blood cells (PRBC) use, data available for prior year. We monitored the blood transfusion reactions during the study period. The hematocrit increased significantly from 30.1±4.6 pre-transfusion to 38.3±4.9 post-transfusion. The post-transfusion serum bilirubin, blood pH, serum potassium, sodium and glucose remained within the normal range. In spite of an increase in the number of average transfusions per patient with AS-1 RBC (6.67±5.1), the average donor exposure (1.8±1.1) remained less than two donors. There were not any transfusion reactions reported during the study. In conclusion, the use of AS-1 red blood cells is safe for small volume transfusions in neonates.