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Transfusion  2013;54(4):1015-1027.
Human red blood cells (RBCs) can be stored for up to 42 days under controlled conditions. Physical and chemical changes occur during RBC storage, altering their function. This study links stored cells mechanical changes with hemodynamic functional alterations upon transfusion.
Mechanical properties of fresh and stored RBCs were evaluated in vitro. Their transfusion effects were evaluated in vivo using intravital microscopy of the rat's cremaster muscle preparation. Rats were hemodiluted to 30% hematocrit, to mimic an anemic state pre-transfusion, then exchange transfused with fresh or stored cells.
In vitro studies on rheology and oxygen affinity of stored cells confirmed previously published results. Storage was found to modify static and dynamic red cell mechanic behavior. Post transfusion, systemic hemodynamics were similar for fresh and stored cells; however, microvascular hemodynamics were drastically affected by stored cells. Stored cells reduced blood flow and oxygen delivery. Additionally, the presence of stored cells in circulation affected cell-to-cell and cell-to-wall interactions, affected cell hydrodynamics. Stored cells disrupted the erythrocyte cell free layer (CFL) and wall shear stress (WSS) signals.
The reduced cell deformability due to RBC “storage lesions” caused pathological changes in microvascular hemodynamics, endothelial cell mechanotransduction, and RBC dynamics. Thus, the mechanical changes of blood banked cells can limit transfusion ability to achieve its intended goal.
PMCID: PMC4105299  PMID: 23901933
Oxygenation; blood flow; anemia; cell free layer; wall shear rate; wall shear stress; cell dynamics; erythrocyte deformability
2.  Analysis of the Recovery of Cryopreserved and Thawed CD34+ and CD3+ Cells Collected for Hematopoietic Transplantation 
Transfusion  2013;54(4):1088-1092.
Cryopreservation is often used to store cellular therapies, but little is known about how well CD3+ or CD34+ cells tolerate this process.
Study Design
Viable CD34+ cell recoveries were analyzed from related and unrelated donor G-CSF-mobilized peripheral blood stem cell (PBSC) products and viable CD3+ cell recoveries from G-CSF-mobilized and non-mobilized apheresis products from related and unrelated donors. All products were cryopreserved with 5% dimethyl sulfoxide and 6% pentastarch using a controlled-rate freezer and were stored in liquid nitrogen. Related donor products were cryopreserved immediately after collection and unrelated donor products greater than 12 hours post-collection.
The post-thaw recovery of CD34+ cells from related donor PBSCs was high (n=86; 97.5±23.1%) and there was no difference in post-thaw CD34+ cell recovery from unrelated donor PBSCs (n=14; 98.8±37.2%; p=0.863). In related donor lymphocyte products the post-thaw CD3+ cell recovery (n=48, 90.7±21.4%) was greater than that of unrelated donor products (n=14, 66.6±35.8%, p=0.00251). All unrelated donor lymphocyte products were from G-CSF mobilized products, while most related donor lymphocyte products were from non-mobilized products. A comparison of the CD3+ cell recovery from related donor G-CSF-mobilized products (n=19, 85.0±29.2%) with that of unrelated donor products found no significant difference (p=0.137).
The post-thaw recovery of CD34+ cells was high in both related and unrelated donor products, but the recovery of CD3+ cells in unrelated donor G-CSF-mobilized products was lower. G-CSF-mobilized unrelated donor products may contain less CD3+ cells than non-G-CSF exposed products upon thaw and, when indicated, cell doses should be monitored.
PMCID: PMC3983171  PMID: 24117879
T cells; cryopreservation; donor lymphocyte infusions; hematopoietic stem cell transplantation
3.  The association between red blood cell and platelet transfusion and subsequently developing idiopathic pneumonia syndrome after hematopoietic stem cell transplantation 
Transfusion  2013;54(4):1071-1080.
Blood transfusions are common during hematopoietic stem cell transplantation (HSCT) and may contribute to lung injury.
This study examined the associations between red blood cell (RBC) and platelet (PLT) transfusions and idiopathic pneumonia syndrome (IPS) among 914 individuals who underwent myeloablative allogeneic HSCT between 1997 and 2001. Patients received allogeneic blood transfusions at their physicians' discretion. RBCs, PLTs, and a composite of “other” transfusions were quantified as the sum of units received each 7-day period from 6 days before transplant until IPS onset, death, or Posttransplant Day 120. RBC and PLT transfusions were modeled as separate time-varying exposures in proportional hazards models adjusted for IPS risk factors (age, baseline disease, irradiation dose) and other transfusions. Timing of PLT transfusion relative to myeloid engraftment and PLT ABO blood group (match vs. mismatch) were included as potential interaction terms.
Patients received a median of 9 PLT and 10 RBC units. There were 77 IPS cases (8.4%). Each additional PLT unit transfused in the prior week was associated with 16% higher IPS risk (hazard ratio, 1.16; 95% confidence interval, 1.09–1.23; p < 0.001). Recent RBC and PLT transfusions were each significantly associated with greater risk of IPS when examined without the other; only PLT transfusions retained significance when both exposures were included in the model. The PLT association was not modified by engraftment or ABO mismatch.
PLT transfusions are associated with greater risk of IPS after myeloablative HSCT. RBCs may also contribute; however, these findings need confirmation.
PMCID: PMC4059041  PMID: 24033082
4.  Measuring the Processes of Change for Increasing Blood Donation in Black Adults 
Transfusion  2012;53(6):1280-1290.
Blacks have significantly lower blood donation (BD) rates than Whites. Many views, experiences, and behaviors associated with BD are unique to Black culture. Evidence suggests that culturally tailored health promotion programs help with increasing Black BD. To be effective, tailored interventions should be based on valid and reliable measures. The Transtheoretical Model's (TTM) Processes of Change (POC) construct provides an assessment of participants’ covert and overt activities and experiences in BD. This study describes development and validation of POC for increasing BD tailored to Blacks.
Cross-sectional measure development with online survey dissemination was used in 566 Blacks in Northeastern US. Factor analytic structural modeling procedures were used to examine validity of the POC measure. BD POC were examined in participants representing a range of BD history and intentions (non-donors, sometimes donors, regular donors) based on an established algorithm.
Confirmatory analyses replicated the theoretically expected structure of POC scales which is a ten-factor, fully correlated best fit model. Expected POC patterns by SOC based on theoretical and empirical predictions were confirmed. The range of effect sizes for 10 POC were η2= .04-.25; indicating that TTM POC are strong strategies in BD decision making for Blacks and can be applied to interventions to increase BD for a minority population.
POC measure was internally and externally valid in a sample of Blacks. Interventions can utilize the POC measure to guide stage matched interventions to encourage use of relevant experiential and behavioral strategies to increase blood donation.
PMCID: PMC3511599  PMID: 22928841
Blood donation; Black Adults; Transtheoretical Model; Processes of Change; Validation
5.  The Effect of salvaged blood on Coagulation Function as measured by Thromboelastography 
Transfusion  2012;53(6):1235-1239.
There is concern that salvaged blood has the potential to activate the coagulation system, which might place patients at risk of thrombotic complications. The aim of this study was to determine whether transfusion of salvaged blood after total knee arthroplasty (TKA) would lead to procoagulopathic changes as measured by thromboelastography (TEG), and furthermore if washing would reduce this risk.
Twenty two patients undergoing TKA were enrolled. Control samples were venous blood samples taken before surgery. Test samples were created by mixing the control samples with postoperatively salvaged blood, either washed or unwashed. TEG profiles were measured, noting the time to initiate clotting (R), the time of clot formation (K), the angle of clot formation (α-angle), and the maximum strength of clot (MA).
The changes in the coagulation profile from control samples to test samples were consistent for both the washed and unwashed groups: R time decreased, MA decreased, and K and alpha-angle remained the same. However, the changes were more pronounced in the unwashed group than the washed group, with a 61% decrease in R time as compared with 14%, and a 26% drop in MA as compared with 6%.
The addition of salvaged blood to the patient’s preoperative blood resulted in decreased clot strength as well as decreased time to initial clot formation. This suggests that the reinfusion of postoperatively salvaged washed or unwashed blood after TKA favors a change towards a more hypocoagulable state, and washing appears to reduce this effect.
PMCID: PMC3521840  PMID: 22934712
Autotransfusion; Blood transfusion; Coagulation; Salvaged blood; Thromboelastography; Total knee arthroplasty
6.  A mathematical modeling approach to quantify the role of phlebotomy losses and need for transfusions in neonatal anemia 
Transfusion  2012;53(6):1353-1360.
Very preterm infants commonly develop anemia requiring multiple red blood cell transfusions (RBCTx). This is in part attributable to heavy laboratory phlebotomy loss. Quantification of the extent to which laboratory blood loss contributes to anemia sufficient to prompt RBCTx has not been examined.
Twenty-six preterm infants weighing <1500 g at birth requiring ventilator support who received one or more RBCTx were intensively studied during the first month of life. Hemoglobin (Hb) loss via laboratory blood loss and RBC senescence, and Hb gain from RBCTx were precisely accounted for in a Hb mass balance mathematical model developed to assess the impact of phlebotomy on RBCTx when a restrictive RBCTx criteria were applied.
Study subjects had a birth weight 880±240 g (mean±SD), a Hb level of 14.4±2.4 g/dl at birth and received 3.81±2.15 RBCTx during the study period. Modeling indicated that even with the total elimination of laboratory phlebotomy loss, a reduction of 41–48% in RBCTx was achievable.
The present modeling results indicate that while phlebotomy reduction can significantly decrease the number of RBCTx administered to preterm infants, total elimination of all RBCTx will likely require other approaches, e.g., stimulation of erythropoiesis with erythropoiesis stimulating agents.
PMCID: PMC3546127  PMID: 23033916
Hematology–Red Cells; RBC Transfusion; Transfusion Practices (Neonatal, Pediatrics)
7.  Motivation and Social Capital among prospective blood donors in three large blood centers in Brazil 
Transfusion  2012;53(6):1291-1301.
Studies analyzing motivation factors that lead to blood donation have found altruism to be the primary motivation factor; however social capital has not been analyzed in this context. Our study examines the association between motivation factors (altruism, self-interest and response to direct appeal) and social capital (cognitive and structural) across three large blood centers in Brazil.
Study Design and Methods
We conducted a cross-sectional survey of 7,635 donor candidates from October 15 through November 20, 2009. Participants completed self-administered questionnaires on demographics, previous blood donation, HIV testing and knowledge, social capital and donor motivations. Enrollment was determined prior to the donor screening process.
Among participants, 43.5% and 41.7% expressed high levels of altruism and response to direct appeal respectively, while only 26.9% expressed high levels of self-interest. More high self-interest was observed at Hemope-Recife (41.7%). Of participants, 37.4% expressed high levels of cognitive social capital while 19.2% expressed high levels of structural social capital. More high cognitive and structural social capital was observed at Hemope-Recife (47.3% and 21.3%, respectively). High cognitive social capital was associated with high levels of altruism, self-interest and response to direct appeal. Philanthropic and high social altruism was associated with high levels of altruism and response to direct appeal.
Cognitive and structural social capital and social altruism are associated with altruism and response to direct appeal, while only cognitive social capital is associated with self-interest. Designing marketing campaigns with these aspects in mind may help blood banks attract potential blood donors more efficiently.
PMCID: PMC3542409  PMID: 22998740
blood donation; Brazil; social capital; motivation
8.  Measurement of the absolute immature platelet number reflects marrow production and is not impacted by platelet transfusion 
Transfusion  2012;53(6):1201-1204.
The ability to distinguish increased platelet destruction from platelet hypo-production is important in the care of patients with bone marrow failure syndromes and patients receiving high dose chemotherapy. The measurement of immature circulating platelets based on RNA content using an automated counter is now feasible. This study evaluated the impact of recent platelet transfusion on measurement of immature platelet parameters.
The immature platelet fraction (IPF) and absolute immature platelet number (AIPN) were measured using the Sysmex XE-5000 analyzer prior to and following platelet transfusion in 9 transfusion-dependent patients with marrow failure secondary to aplastic anemia, myelodysplasia or transplantation conditioning. IPF and AIPN were also measured serially over 5 days of storage in 3 plateletpheresis components collected from normal donors.
Platelet transfusion did not significantly change the mean AIPN in transfused patients. In contrast, IPF decreased significantly from 6.6 ±4.6% at day -1 to 2.3 ±1.4% at day 0 before returning to 4.3 ±2.3% at day +1. In the platelet component, AIPN and IPF% increased significantly over 5 days of storage, most likely due to an artifact of the staining and detection process for stored platelets, no longer detected in vivo once the platelets were transfused.
Platelet transfusion decreases the IPF due to the resultant increase in circulating platelet count. However, platelet transfusion does not change the circulating absolute immature platelet number (AIPN), validating this assay as a reflection of ongoing platelet production by the bone marrow in various clinical settings, regardless of proximity to platelet transfusion.
PMCID: PMC3543490  PMID: 23043309
9.  Prevalence, Incidence, and Residual Risks for Transfusion Transmitted HIV-1/2 Infection among Chinese Blood Donors 
Transfusion  2012;53(6):1240-1249.
There is little data on HIV prevalence, incidence or residual risks for transfusion transmitted HIV infection among Chinese blood donors.
Donations from five Chinese blood centers in 2008–2010 were screened using two rounds of ELISA testing for anti-HIV-1/2. A reactive result in either or both rounds led to Western Blot confirmatory testing. HIV prevalence and demographic correlates among first time donors, incidence rate and demographic correlates among repeat donors were examined. Weighted multivariable logistic regression analysis examined correlates of HIV confirmatory status among first time donors. Residual risks for transfusion transmitted HIV infection were evaluated based on incidence among repeat donors.
Among 821,320 donations, 40% came from repeat donors.1,837 (0.34%) first time and 577 (0.17%) repeat donations screened reactive for anti-HIV-1/2, among which 1,310 and 419 were tested by Western Blot. 233 (17.7%) first time and 44 (10.5%) repeat donations were confirmed positive. Estimated prevalence was 66 infections per 100,000 (95% CI: 59–74) first time donors. Estimated incidence was 9/100,000 (95% CI: 7–12) person-years among repeat donors. Weighted multivariable logistic regression analysis indicate that first time donors 26–45 years old were 1.6–1.8 times likely to be HIV positive than those 25 years and younger. Donors with some college or above education were less likely to be HIV positive than those with middle school education, ORs ranging from 0.35 to 0.60. Minority were 1.6 times likely to be HIV positive than Han majority donors (OR: 1.6; CI: 1.2–2.1). No difference in prevalence was found between gender. Current HIV TTI residual risk was 5.4 (1.2–12.5) infections per million whole blood donations.
Despite the declining HIV epidemic China, estimated residual risks for transfusion transmitted HIV infection are still high, highlighting the potential blood safety yield of NAT implementation in donation screening.
PMCID: PMC3586939  PMID: 23113801
HIV infection; blood donors; China; Prevalence; Incidence; Residual Risks
10.  Scratching the surface of allergic transfusion reactions 
Transfusion  2012;53(6):1361-1371.
Allergic transfusion reactions (ATRs) are a spectrum of hypersensitivity reactions that are the most common adverse reaction to platelets and plasma, occurring in up to 2% of transfusions. Despite the ubiquity of these reactions, little is known about their mechanism. In a small subset of severe reactions, specific antibody has been implicated as causal, although this mechanism does not explain all ATRs. Evidence suggests that donor, product, and recipient factors are involved, and it is possible that many ATRs are multi-factorial. Further understanding of the mechanisms of ATRs is necessary so that rationally designed and cost-effective prevention measures can be developed.
PMCID: PMC3711222  PMID: 22998777
allergy; transfusion reaction; platelets; plasma; red cell; hypersensitivity; urticaria; pruritus
11.  Antibody levels correlate with detection of Trypanosoma cruzi DNA by sensitive PCR assays in seropositive blood donors and possible resolution of infection over time 
Transfusion  2012;53(6):1257-1265.
The clinical significance of anti-T. cruzi low-level reactive samples is incompletely understood. PCR-positive rates and antibody levels among seropositive blood donors in three countries are described.
Follow-up whole blood and plasma samples were collected from T. cruzi-seropositive donors from 2008-2010 in the US (n=195) and Honduras (n=58). Also 143 samples from Brazil in 1996-2002, originally positive by three serological assays, were available and paired with contemporary follow-up samples from these donors. All samples were retested with the FDA-approved Ortho ELISA. PCR assays were performed on coded sample panels by two laboratories (BSRI and ARC) that amplified kinetoplast minicircle DNA sequences of T. cruzi.
PCR testing at BSRI yielded slightly higher overall sensitivity and specificity (33% and 98%) compared with the ARC lab (28% and 94%). Among seropositive donors, PCR-positive rates varied by country (p<0.0001) for the BSRI laboratory: Brazil (57%), Honduras (32%) and the US (14%). ELISA signal/cutoff (S/CO) ratios were significantly higher for PCR-positive compared to PCR-negative donors (p<0.05 for all comparisons). Additionally, PCR-negative Brazilian donors exhibited greater frequencies of antibody decline over time versus PCR-positive donors (p=0.003).
For all three countries, persistent DNA positivity correlated with higher ELISA S/CO values, suggesting that high-level seroreactivity reflects chronic parasitemia. The higher rate of PCR positivity for Brazilian donors was likely attributable to required reactivity on three assays available a decade ago. Significant S/CO declines in 10% of the PCR-negative Brazilian donors may indicate seroreversion following parasite clearance in the absence of treatment.
PMCID: PMC3940448  PMID: 23002996
T cruzi; Chagas disease; PCR; antibodies
12.  Cost-Effectiveness of Blood Donor Screening for Babesia microti in Endemic Regions of the United States 
Transfusion  2013;54(3 0 2):889-899.
Babesia microti is the leading reported cause of red blood cell (RBC) transfusion-transmitted infection in the United States (US). Donor screening assays are in development.
Study Design and Methods
A decision analytic model estimated the cost-effectiveness of screening strategies for preventing transfusion-transmitted babesiosis (TTB) in a hypothetical cohort of transfusion recipients in Babesia-endemic areas of the US. Strategies included: (1) No screening, (2) Uniform Donor Health History Questionnaire (UDHQ), “status quo”, (3) Recipient risk-targeting using donor antibody (Ab) and polymerase chain reaction (PCR) screening, (4) Universal endemic donor Ab screening, (5) Universal endemic donor Ab and PCR screening. Outcome measures were TTB cases averted, costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios ($/QALY). We assumed a societal willingness to pay of $1 million/QALY based on screening for other transfusion-transmitted infections.
Compared to no screening, the UDHQ avoids 0.02 TTB cases per 100,000 RBC transfusions at an incremental cost effectiveness ratio (ICER) of $160,000/QALY whereas recipient risk-targeted strategy using Ab/PCR avoids 1.62 TTB cases per 100,000 RBC transfusions at an ICER of $713,000/QALY compared to the UDHQ. Universal endemic Ab screening avoids 3.39 cases at an ICER of $760,000/QALY compared to the recipient-risk targeted strategy. Universal endemic Ab/PCR screening avoids 3.60 cases and has an ICER of $8.8 million/QALY compared to universal endemic Ab screening. Results are sensitive to blood donor Babesia prevalence, TTB transmission probability, screening test costs, risk and severity of TTB complications, and impact of babesiosis diagnosis on donor quality of life.
Antibody screening for Babesia in endemic regions is appropriate from an economic perspective based on the societal willingness to pay for preventing infectious threats to blood safety.
PMCID: PMC4039174  PMID: 24252132
Babesia microti; cost-effectiveness; transfusion; blood supply screening
13.  Patients with sickle cell anemia on simple chronic transfusion protocol show gender differences for hemodynamic and hematologic responses to transfusion 
Transfusion  2012;53(5):1059-1068.
Chronic transfusion therapy (CTT) is a mainstay for stroke prophylaxis in sickle cell anemia, but its effects on hemodynamics are poorly characterized. Transfusion improves oxygen carrying capacity, reducing demands for high cardiac output, while decreasing hemoglobin S%, reticulocyte count, and hemolysis. We hypothesized that transfusion would improve oxygen carrying capacity, but that would be counteracted by a decrease in cardiac output due to increased hematocrit and vascular resistance, leaving oxygen delivery unchanged.
Study Design and Methods
To test this hypothesis, we examined patients on CTT immediately pre transfusion and again 12–120 hours post transfusion, using echocardiography and near infrared spectroscopy.
Comparable increases in hemoglobin and hematocrit, and decreases in reticulocyte count and hemoglobin S with transfusion were observed in all patients; but males had a larger rebound of hemoglobin S%, reticulocyte count, and free hemoglobin levels between transfusions. In males, transfusion decreased heart rate by 12%, stroke volume by 15%, and cardiac index by 24% while estimates for pulmonary and systemic vascular resistance rose, culminating in 6% decrease in oxygen delivery. In contrast, stroke volume and cardiac index, systemic and pulmonary vascular resistance did not change in women following transfusion, such that oxygen delivery improved 17%.
In our sample population, males exhibit a paradoxical reduction in oxygen delivery in response to transfusion because the rise in vascular resistance is larger than the increase in oxygen capacity. This may result from an inability to adequately suppress their hemoglobin S% between transfusion cycles.
PMCID: PMC3957479  PMID: 23176402
Pulmonary Circulation; Vascular Resistance; Cardiopulmonary Interactions; Cardiovascular Performance
14.  RHCE*ceTI encodes partial c and partial e and is often in cis to RHD*DIVa 
Transfusion  2012;53(4):741-746.
In the Rh blood group system, variant RhD and RhCE express several partial antigens. We investigated RH in samples with partial DIVa that demonstrated weak and variable reactivity with anti-C.
Material and methods
Standard hemagglutination techniques, PCR-based assays, and RH sequencing were used.
DNA analysis showed that six RBC samples with weak and inconsistent reactivity with anti-C lacked RHCE*C, but all had RHD*DIVa, which encodes partial D and Goa. We then tested RBCs from 19 Go(a+) cryopreserved samples (confirmed to have RHD*DIVa) with four anti-C and observed weak variable reactions. RHCE genotyping found all but one of the samples with RHD*DIVa also had RHCE nt 48G>C and 1025C>T; named RHCE*ceTI. Look-back of samples referred for workup and found to have either allele revealed 47/55 had both RHD*DIVa and RHCE*ceTI; four had RHD*DIVa without RHCE*ceTI; four had RHCE*ceTI without RHD*DIVa. Alloanti-c was found in a patient with c+ RBCs and RHCE*ceTI in trans to RHCE*Ce, and alloanti-e was found in a patient with e+ RBC and RHCE*ceTI in trans to RHCE*cE. RHD*DIVa in trans to RHD erroneously tested as RHD hemizygous.
RHD*DIVa and RHCE*ceTI almost always, but not invariably, travel together. This haplotype is found in people of African ancestry and the RBCs can demonstrate aberrant reactivity with anti-C. RHCE*ceTI encodes partial c and e antigens. We confirm that RHD zygosity assays are unreliable in samples with RHD*DIVa.
PMCID: PMC3477252  PMID: 22804620
Blood groups; RH alleles; Rh blood group system; blood transfusion; partial antigen
15.  Prevalence of Serological Markers for Hepatitis B and C Viruses in Brazilian Blood Donors, and Incidence and Residual Risk of Transfusion-Transmission of Hepatitis C Virus 
Transfusion  2012;53(4):827-834.
We evaluate the current prevalence of serological markers for HBV and HCV in blood donors and estimated HCV incidence and residual transfusion-transmitted risk at three large Brazilian blood centers.
Material and Methods
Data on whole blood and platelet donations were collected from January through December 2007 and analyzed by center, donor type (replacement vs. community), age, sex, donation status (first-time vs. repeat), and serological results for HBsAg, anti-HBc and anti-HCV. HBV (HBsAg+/anti-HBc+) and HCV (anti-HCV) prevalence rates were calculated for all first time donations. HCV incidence was derived including inter-donation intervals that preceded first repeat donations given during the study and HCV residual risk was estimated for transfusions derived from repeat donors.
There were 307,354 donations from January through December 2007. Overall prevalence of concordant HBsAg and anti-HBc reactivity was 289 per 100,000 donations and of anti-HCV confirmed reactivity 191 per 100,000 donations. There were significant associations between older age and hepatitis markers, especially for HCV. HCV incidence was 3.11 (95% CI 0.77-7.03) per 100,000 person-years, and residual risk of HCV window-phase infections was estimated at 5.0 per million units transfused.
Improvement in blood donor selection, socioeconomic conditions and preventive measures, implemented over time, may have helped to decrease prevalence of hepatitis B and C viruses, relative to previous reports. Incidence and residual risk of HCV are also diminishing. Ongoing monitoring of hepatitis B and C viral markers among Brazilian blood donors should help guide improved recruitment procedures, donor selection, laboratory screening methods and counseling strategies.
PMCID: PMC3499633  PMID: 22882510
Blood donors; Brazil; Residual Risk; Hepatitis B; Hepatitis C; Prevalence; Incidence
16.  Loss of CD26 Protease Activity in Recipient Mice during Hematopoietic Stem Cell Transplantation Results in Improved Transplant Efficiency 
Transfusion  2012;53(4):878-887.
A firm understanding of the biology of hematopoietic stem and progenitor cell (HSC/HPC) trafficking is critical to improve transplant efficiency and immune reconstitution during hematopoietic stem cell transplantation (HSCT). Our earlier findings suggested that suppression of CD26/DPPIV (dipeptidylpeptidase IV) proteolytic activity in the donor cell population can be utilized as a method for increasing transplant efficiency. However, factors in the recipient should not be overlooked, given the potential for the bone marrow (BM) microenvironment to regulate HSCT.
We first evaluated CD26 expression and then investigated the effects of the CD26 inhibitor, Diprotin A, and the absence of CD26 (CD26−/−) in recipient mice on HSC/HPC homing and engraftment using an in vivo congenic mouse model of HSCT.
A significant increase in donor cell engraftment into the peripheral blood (PB), and to a lesser extent homing into the BM, was observed in CD26−/− mice or CD26 inhibitor-treated mice. Increased PB engraftment of CD26−/− mice was significant at 3 and 6, but not 1 month, post-transplant. It was noted that the increased homing was statistically greater with donor cell manipulation [CD26−/− donor cells] than with recipient manipulation [CD26−/− recipient mice]. Conversely, donor and recipient manipulation both worked well the increase PB engraftment at 6 months.
These results provide pre-clinical evidence of CD26, in the HSCT recipient, as a major regulator of HSC/HPC engraftment with minor effects on HSC/HPC homing and suggest the potential use of CD26 inhibitors in HSCT patients to improve transplant efficiency.
PMCID: PMC3499665  PMID: 22882234
Stem Cell Transplant; Engraftment; Trafficking; Protease; Chemokines; CXCL12
17.  Red blood cell microparticles show altered inflammatory chemokine binding and release ligand upon interaction with platelets 
Transfusion  2010;51(3):610-621.
Storage of red blood cells (RBCs) under standard blood bank conditions results in reduced structural integrity leading to membrane budding and release of microparticles. Microparticles express the blood group Duffy antigen known to bind multiple inflammatory chemokines, but the functional chemokine binding properties of microparticles are not known.
We determined whether storage-induced microparticles show inflammatory chemokine binding through the expression of the Duffy antigen, comparing the binding properties to intact RBCs, and assessed microparticle interactions with platelets (PLTs) that release chemokines upon activation.
Intact RBCs retained similar equilibrium dissociation constants for CCL2 (Kd = 7.4 ± 0.9 nmol/L), CXCL8 (Kd = 7.9 ± 1.0 nmol/L), and CXCL1 (Kd = 4.4 ± 1.0 nmol/L) throughout storage. In contrast, microparticles increased in relative counts with storage, showed higher percentages of surface phosphatidylserine, and demonstrated impaired Duffy-dependent chemokine binding affinity with wider variability in dissociation constant for CXCL1(Kd = 362 ± 328 nmol/L; range, 0.6–2000 nmol/L). The altered chemokine binding affinity of RBC microparticles was associated with a propensity to release ligand upon incubation with PLTs. Relative quantification of microparticles, based on criteria of glycophorin A expression and size, underestimated particle numbers with functional chemokine binding, suggesting that glycophorin A–negative particles and nanoparticles contribute to overall chemokine binding capacity.
Microparticle burden in transfusates, as determined by functional chemokine binding, is considerable. Altered membrane properties of RBC microparticles enhance PLT interactions to increase inflammatory chemokine bioavailability in vitro.
PMCID: PMC3963470  PMID: 20738825
18.  Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists 
Transfusion  2013;53(11):2807-2812.
Thrombopoietin receptor agonists (TRAs) are effective treatments for immune thrombocytopenia (ITP). However, continuous therapy is generally required to maintain platelet (PLT) count responses.
In this case series, we describe ITP patients from our practice who achieved durable responses to the TRAs romiplostim and eltrombopag. Patients were classified as having a definite TRA-induced remission if PLT counts increased above 100 × 109/L after TRA treatment and remained above 100 × 109/L even after the medication was discontinued; or a possible TRA-induced remission if PLT counts increased above 100 × 109/L, remained elevated for at least 3 months after the medication was discontinued, but a subsequent relapse occurred or the effect of other disease-modifying therapies could not be excluded.
Of 31 patients with chronic ITP treated with TRAs in our practice, nine patients achieved a PLT count response with either romiplostim (n = 6) or eltrombopag (n = 3) that was maintained even after the medications were discontinued. Three patients met criteria for a definite TRA-induced remission, each after exposure to romiplostim. Patients had ITP for a median of 7.8 years and had failed a median of four prior therapies including eight patients who had a splenectomy. We documented a progressive decline in anti-glycoprotein IIbIIIa PLT autoantibodies in one patient while on treatment.
Some patients with ITP can achieve sustained PLT count responses after the use of TRAs. This observation raises the possibility that these agents may restore immune tolerance to PLT antigens in some patients and supports the practice of down titrating the dose.
PMCID: PMC3938454  PMID: 23451917 CAMSID: cams4132
19.  The low prevalence Rh antigen STEM (RH49) is encoded by two different RHCE*ce818T alleles that are often in cis to RHD*DOL 
Transfusion  2012;53(3):539-544.
STEM (RH49) is a low prevalence antigen in the Rh blood group system. A scarcity of anti-STEM has precluded extensive study of this antigen. We report that two alleles with a RHCE*ce818C>T change encode a partial e, and a hrS−, hrB+, STEM+ phenotype and that both alleles are frequently in cis to RHD*DOL1 or RHD*DOL2.
Materials and methods
Blood samples were from donors and patients in our collections. Hemagglutination, DNA and RNA testing was performed by standard techniques.
Fourteen STEM+ samples were heterozygous RHCE*ce818C/T: six had RHCE*ceBI and eight had a novel allele, RHCE*ceSM. Eleven were heterozygous for RHD*DOL1 or RHD*DOL2. Eleven samples, previously typed STEM−, had RHCE*ce818C/C (consensus nucleotide). RBCs from informative STEM+ samples were e+/− hrS− hrB+. One person who was heterozygous RHCE*ceBI and RHCE*cE had an anti-e-like antibody in her plasma, and one person, who was hemizygous for RHD*DOL2 had anti-D in her plasma.
We show that two alleles with a RHCE*ce818C>T change (RHCE*ceBI and RHCE*ceSM) encode a hrS− hrB+ STEM+ phenotype. In addition, both alleles are frequently in cis to RHD*DOL1 or RHD*DOL2 and RHCE*ceBI encodes a partial e antigen. In the small cohort of samples tested, RHD*DOL invariably traveled with RHCE*ce818T. Our study also confirmed the presumption that RHD*DOL2, like RHD*DOL1, encodes a partial D antigen and the low prevalence antigen DAK.
PMCID: PMC3461235  PMID: 22738288
Rh blood group system; RHCE variant; partial D phenotype; low prevalence Rh antigen; STEM
20.  Frequency of glucose-6-phosphate dehydrogenase deficient packed red blood cell units in a metropolitan transfusion service 
Transfusion  2012;53(3):606-611.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is characterized by red blood cell (RBC) destruction in response to oxidative stress. Although blood donors are not routinely screened for G6PD deficiency, the transfusion of stored G6PD-deficient RBCs may have serious adverse outcomes. By measuring G6PD enzyme activity of RBC units from a large metropolitan hospital transfusion service we sought to determine 1) the prevalence of G6PD-deficient RBC units, 2) if G6PD activity changes during storage, and 3) if G6PD activity in segments correlates with its activity in the bags.
Study Design and Methods
Quantitative G6PD activity was measured in 301 randomly selected packed RBC (pRBC) units and 73 D+C-E- (i.e. R0r or R0R0) pRBC units, all stored in additive solutions. G6PD deficiency was defined as activity <60% of the normal mean.
The frequency of G6PD-deficient units in the general inventory was 0.3% (1/301) [95% CI <0.01%–2.1%]. In contrast, its frequency in D+C-E- pRBC units was 12.3% (9/73) [95% CI 6.4%–22.0%]. G6PD activity did not significantly change during the 42 day storage period, and G6PD activity measured in pRBC storage bags and attached segments correlated well (r=0.7–0.9, p≤0.001, Spearman rank correlation).
Although the frequency of G6PD-deficient pRBC units in the transfusion service general inventory was relatively low, it was significantly higher among a subset of R0r or R0R0 units. The latter are preferentially allocated for transfusion to patients with sickle cell disease to decrease the risk of RBC alloimmunization, possibly allowing more of these units to be inadvertently targeted to these patients.
PMCID: PMC3461237  PMID: 22738400
glucose-6-phosphate dehydrogenase deficiency; hemolysis; oxidative stress; sickle cell disease
21.  US Public Cord Blood Banking Practices: Recruitment, Donation, and the Timing of Consent 
Transfusion  2012;53(3):679-687.
Cord blood has moved rapidly from an experimental stem cell source to an accepted and important source of hematopoietic stem cells. There has been no comprehensive assessment of US public cord blood banking practices since the Institute of Medicine study in 2005.
Of 34 US public cord blood banks identified, 16 participated in our qualitative survey of public cord blood banking practices. Participants took part in in-depth telephone interviews in which they were asked structured and open-ended questions regarding recruitment, donation, and the informed consent process at these banks.
13 of 16 participants reported a variably high percentage of women who consented to public cord blood donation. 15 banks offered donor registration at the time of hospital admission for labor and delivery. 7 obtained full informed consent and medical history during early labor and 8 conducted some form of phased consent and/or phased medical screening and history. 9 participants identified initial selection of the collection site location as the chief mode by which they recruited minority donors.
Since 2005, more public banks offer cord blood donor registration at the time of admission for labor and delivery. That, and the targeted location of cord blood collection sites, are the main methods used to increase access to donation and HLA diversity of banked units. Currently, the ability to collect and process donations, rather than donor willingness, is the major barrier to public cord blood banking.
PMCID: PMC3477280  PMID: 22803637
22.  Effect of storage on levels of nitric oxide metabolites in platelet preparations 
Transfusion  2012;53(3):637-644.
Nitric oxide (NO), a potent signaling molecule, is known to inhibit platelet function in vivo. We investigated how the levels of NO and its metabolites change during routine platelet storage. We also tested whether the material of platelet storage containers affects nitrite content since many plastic materials are known to contain and release nitrite.
Study design and methods
For nitrite and nitrate measurement, leukoreduced apheresis platelets (PLT) and concurrent plasma (CP) were collected from healthy donors using the Trima Accel. Sixty mL aliquots of PLT or CP were stored in CLX or PL120 Teflon containers at 20–24°C with agitation and daily samples were processed to yield PLT pellet and supernatant. In a separate experiment, PLT was stored in PL120 Teflon to measure NO generation using electron paramagnetic resonance (EPR).
Nitrite level increased markedly in both PLT supernatant and CP stored in CLX containers at a rate of 58 nM/day and 31 nM/day respectively. However, there was a decrease in nitrite level in PLT stored in PL120 Teflon containers. Nitrite was found to leach from CLX containers and this appears to compensate for nitrite consumption in these preparations. Nitrate level did not significantly change during storage.
Platelets stored at 20–24°C maintain measurable levels of nitrite and nitrate. Nitrite decline in non-leachable Teflon containers in contrast to increases in CLX containers which leach nitrite, suggests that it is consumed by platelets, residual leukocytes or erythrocytes. These results suggest NO-related metabolic changes occur in platelet units during storage.
PMCID: PMC3548060  PMID: 22804724
nitric oxide; nitrite; platelet storage; transfusion
23.  Analysis of donor deferral at three blood centers in Brazil 
Transfusion  2012;53(3):531-538.
The safety of the blood supply is ensured through several procedures from donor selection to testing of donated units. Examination of the donor deferrals at different centers provides insights into the role that deferrals play in transfusion safety.
A cross-sectional descriptive study of prospective allogeneic blood donors at three large blood centers located in São Paulo, Belo Horizonte and Recife, Brazil from August 2007 to December 2009 was conducted. Deferrals were grouped into similar categories across the centers, and within each center frequencies out of all presentations were determined.
Of 963,519 prospective blood donors at the three centers, 746,653 (77.5%) were accepted and 216,866 (22.5%) were deferred. Belo Horizonte had the highest overall deferral proportion of 27%, followed by Recife (23%) and Sao Paulo (19%). Females were more likely to be deferred than males (30% versus 18%, respectively). The three most common deferral reasons were low hematocrit/hemoglobin (Ht/Hb), medical diagnoses and higher-risk behavior.
The types and frequencies of deferral vary substantially among the three blood centers. Factors that may explain the differences include demographic characteristics, the order in which health history and vital signs are taken, the staff training, an the way deferrals are coded by the centers among other policies. The results indicate that blood donor deferral in Brazil has regional aspects that should be considered when national policies are developed.
PMCID: PMC3595366  PMID: 22845775
blood donation; deferred donors; deferral reasons
24.  Receiver operating characteristic curve analysis of circulating blood dendritic cell precursors and T cells predicts response to extracorporeal photopheresis in patients with chronic graft-versus-host disease 
Transfusion  2010;50(11):2424-2431.
One proposed mechanism of extracorporeal photopheresis (ECP) in reducing chronic graft-versus-host disease (cGVHD) is alteration in numbers of circulating dendritic cells (DCs). This hypothesis was tested by correlating numbers of DC precursors and T cells in the blood before and during ECP therapy with response of cGVHD.
Twenty-five patients with cGVHD were treated with ECP. Data were collected with emphasis on blood cellular markers, clinical response to ECP, and overall survival.
Fourteen patients (56%) responded and had better 2-year survival than nonresponders (88% vs. 18%, p = 0.003). Responders had higher baseline circulating myeloid DC (mDC) and plasmacytoid DC precursors and CD4+ and CD8+ T cells compared with nonresponders. Receiver operating characteristic curve analyses showed that the best baseline cutoff values to predict response to ECP were mDC counts of 3.7 cells/µL (79% sensitivity, 82% specificity) and CD4+ T-cell counts of 104 cells/µL (71% sensitivity, 82% specificity). CD4+ T cells declined in responders over time, but not in nonresponders, and no significant changes were seen in CD8 T-cell or DC numbers over a 12-month period in responder or nonresponder groups.
Higher baseline numbers of circulating DCs and T cells may predict clinical response to ECP in patients with cGVHD.
PMCID: PMC3926317  PMID: 20529004
25.  Platelet count is a sensitive predictor of autologous peripheral blood progenitor cell collection yield in previously treated plasma cell disease patients 
Transfusion  2008;48(6):1106-1114.
It is often a clinical dilemma to determine when to collect autologous peripheral blood progenitor cells (PBPCs) in patients who received prior chemotherapy. It is also challenging to predict if the collected cells will be enough for one or two transplants.
A total of 103 PBPC donors were followed to evaluate factors that predict poor autologous PBPC collection. The donors were categorized into three groups: plasma cell disorders (PCDs), lymphomas, and normal allogeneic donors.
Our evaluation showed that platelet (PLT) count before growth factor administration significantly correlated with total CD34+ cell yield (Spearman r = 0.38, p < 0.001). Further analysis showed this correlation was only significant in plasma cell disease patients who received prior chemotherapy (Spearman r = 0.5, p = 0.008). Baseline PLT counts did not correlate with PBPC collection yield in untreated PCD, lymphoma, and normal allogeneic donors. In addition, daily PLT count during PBPC harvest correlated with CD34+ cell yield for that day (Spearman r = 0.41, p < 0.001). With a multiple linear regression model (adjusted R2 = 0.31, AIC = 63.1), it has been determined that the baseline PLT count significantly correlates with total CD34+ cell yield in treated PCD patients.
Baseline PLT count is a sensitive indicator of autologous PBPC mobilization in PCD patients who received prior chemotherapy. This finding may be considered before growth factor administration to determine the optimal period to mobilize treated PCD patients and to predict if enough cells can be collected for one or two transplants.
PMCID: PMC3919131  PMID: 18315528

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