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1.  RHCE*ceTI encodes partial c and partial e and is often in cis to RHD*DIVa 
Transfusion  2012;53(4):741-746.
Background
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1537-2995.2012.03800.x
PMCID: PMC3477252  PMID: 22804620
Blood groups; RH alleles; Rh blood group system; blood transfusion; partial antigen
2.  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.
Background
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.
Results
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.
Conclusion
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.
doi:10.1111/j.1537-2995.2012.03840.x
PMCID: PMC3499633  PMID: 22882510
Blood donors; Brazil; Residual Risk; Hepatitis B; Hepatitis C; Prevalence; Incidence
3.  Loss of CD26 Protease Activity in Recipient Mice during Hematopoietic Stem Cell Transplantation Results in Improved Transplant Efficiency 
Transfusion  2012;53(4):878-887.
BACKGROUND
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.
STUDY DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
doi:10.1111/j.1537-2995.2012.03826.x
PMCID: PMC3499665  PMID: 22882234
Stem Cell Transplant; Engraftment; Trafficking; Protease; Chemokines; CXCL12
4.  Red blood cell microparticles show altered inflammatory chemokine binding and release ligand upon interaction with platelets 
Transfusion  2010;51(3):610-621.
BACKGROUND
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.
STUDY DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
doi:10.1111/j.1537-2995.2010.02861.x
PMCID: PMC3963470  PMID: 20738825
5.  Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists 
Transfusion  2013;53(11):2807-2812.
BACKGROUND
Thrombopoietin receptor agonists (TRAs) are effective treatments for immune thrombocytopenia (ITP). However, continuous therapy is generally required to maintain platelet (PLT) count responses.
STUDY DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
doi:10.1111/trf.12139
PMCID: PMC3938454  PMID: 23451917 CAMSID: cams4132
6.  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.
Background
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1537-2995.2012.03754.x
PMCID: PMC3461235  PMID: 22738288
Rh blood group system; RHCE variant; partial D phenotype; low prevalence Rh antigen; STEM
7.  Frequency of glucose-6-phosphate dehydrogenase deficient packed red blood cell units in a metropolitan transfusion service 
Transfusion  2012;53(3):606-611.
Background
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.
Results
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).
Conclusions
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.
doi:10.1111/j.1537-2995.2012.03765.x
PMCID: PMC3461237  PMID: 22738400
glucose-6-phosphate dehydrogenase deficiency; hemolysis; oxidative stress; sickle cell disease
8.  US Public Cord Blood Banking Practices: Recruitment, Donation, and the Timing of Consent 
Transfusion  2012;53(3):679-687.
BACKGROUND
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.
STUDY DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
doi:10.1111/j.1537-2995.2012.03785.x
PMCID: PMC3477280  PMID: 22803637
9.  Effect of storage on levels of nitric oxide metabolites in platelet preparations 
Transfusion  2012;53(3):637-644.
Background
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).
Results
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.
Conclusion
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.
doi:10.1111/j.1537-2995.2012.03777.x
PMCID: PMC3548060  PMID: 22804724
nitric oxide; nitrite; platelet storage; transfusion
10.  Analysis of donor deferral at three blood centers in Brazil 
Transfusion  2012;53(3):531-538.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1111/j.1537-2995.2012.03820.x
PMCID: PMC3595366  PMID: 22845775
blood donation; deferred donors; deferral reasons
11.  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.
BACKGROUND
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.
STUDY DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
Higher baseline numbers of circulating DCs and T cells may predict clinical response to ECP in patients with cGVHD.
doi:10.1111/j.1537-2995.2010.02712.x
PMCID: PMC3926317  PMID: 20529004
12.  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.
BACKGROUND
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.
STUDY DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
doi:10.1111/j.1537-2995.2008.01651.x
PMCID: PMC3919131  PMID: 18315528
13.  Low shear red cell oxygen transport effectiveness is adversely affected by transfusion and further worsened by deoxygenation in sickle cell disease patients on chronic transfusion therapy 
Transfusion  2012;53(2):297-305.
BACKGROUND
Simple 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 transfusion decreases factors associated with vaso-occlusion, including percent HbS, reticulocyte count and circulating cell-free hemoglobin, it increases blood viscosity, which reduces microvascular flow. The hematocrit to viscosity ratio (HVR) is an index of red cell oxygen transport effectiveness that varies with shear stress and balances the benefits of improved oxygen capacity to viscosity-mediated impairment of microvascular flow. We hypothesized that transfusion would improve HVR at high shear despite increased blood viscosity, but would decrease HVR at low shear.
STUDY DESIGN AND METHODS
To test this hypothesis, we examined oxygenated and deoxygenated blood samples from 15 sickle cell patients on CTT immediately pre-transfusion and again 12–120 hours post-transfusion.
RESULTS
Comparable changes in hemoglobin, hematocrit, reticulocyte count and hemoglobin S with transfusion were observed in all subjects. Viscosity, hematocrit and high-shear HVR increased with transfusion while low shear HVR decreased significantly.
CONCLUSION
Decreased low-shear HVR suggests impaired oxygen transport to low-flow regions and may explain why some complications of sickle cell anemia are ameliorated by chronic transfusion therapy and others may be made worse.
doi:10.1111/j.1537-2995.2012.03822.x
PMCID: PMC3510323  PMID: 22882132
sickle cell disease; chronic transfusion therapy; blood viscosity; hematocrit to viscosity ratio
14.  Autologous Stem Cell Transplant Recipients Tolerate Haploidentical Related-Donor Natural Killer Cell Enriched Infusions 
Transfusion  2012;53(2):412-418.
BACKGROUND
In the setting of allogeneic stem cell transplantation (alloSCT), infusing natural killer (NK) cells from a major histocompatibility complex (MHC) mismatched donor can mediate an anti-leukemic effect. Graft versus tumor (GvT) effect following autologous stem cell transplantation (ASCT) may result in less disease relapse.
STUDY DESIGN AND METHODS
We performed a phase I clinical trial to assess the safety and feasibility of infusing distantly processed donor NK enriched mononuclear cell (NK-MC) infusions from a MHC haplotype mismatched (haploidentical) donor to patients who recently underwent ASCT for a hematologic malignancy. On day 1, peripheral blood mononuclear cells (MC) were obtained by steady-state leukapheresis and sent from Boston to the Production Assistance for Cellular Therapies (PACT) facility at the University of Minnesota, where immunomagnetic depletion of CD3 cells was performed on day 2. NK-MC product were then returned to Boston on day 2 for infusion on day 3. Toxicity, cellular product characteristics and logistic events were monitored.
RESULTS
At a median of 90 days (range, 49–191) following ASCT, thirteen patients were treated with escalating doses of NK-MC per kg from 105 to 2 ×107. Adverse effects included grade 2 rigors and muscle aches, but no grade 3 or 4 events, and no GvHD or marrow suppression. One air courier delay occurred. NK-MC products were viable with cytotoxic activity after transport.
CONCLUSION
CD3-depleted, MHC mismatched allogeneic NK-MC infusions can be safely and feasibly administered to patients after ASCT following distant processing and transport, justifying further development of this approach.
doi:10.1111/j.1537-2995.2012.03764.x
PMCID: PMC3549470  PMID: 22738379
Natural Killer Cell; Cellular Therapy; Transplantation- Stem Cell
15.  Alterations of platelet function and clot formation kinetics following in vitro exposure to anti-A and -B antibodies 
Transfusion  2012;53(2):382-393.
Background
ABO mismatched platelets are commonly transfused despite reported complications. We hypothesized that because platelets possess A and B antigens on their surface, ABO mismatched transfused or recipient platelets could become activated and/or dysfunctional after exposure to anti-A or -B antibodies in the transfused or recipient plasma. We present here in vitro modeling data on the functional effects of exposure of platelets to ABO antibodies.
Methods
Platelet functions of normal platelets of all ABO types were assessed before and after incubation with normal saline, ABO identical plasmas, or O plasmas with varying titers of anti-A and anti-B (anti-A/B) antibodies. Assays used for this assessment include: platelet aggregation, clot kinetics, thrombin generation, platelet cytoskeletal function, and mediator release.
Results
Exposure of antigen bearing platelets to O plasma with moderate to high titers of anti-A/B antibodies significantly inhibits aggregation, prolongs PFA-100 epinephrine closure time, disrupts clot formation kinetics, accelerates thrombin generation, reduces total thrombin production, alters platelet cytoskeletal function, and influences pro-inflammatory and pro-thrombotic mediator release.
Conclusions
Our findings demonstrate a wide range of effects that anti-A/B antibodies have on platelet function, clot formation, thrombin generation, platelet cytoskeletal function, and mediator release. These data provide potential explanations for clinical observations of increased red cell utilization in trauma and surgical patients receiving ABO non-identical blood products. Impaired hemostasis caused by anti-A/B antibodies interacting with A and B antigens on platelets, soluble proteins, and perhaps even endothelial cells is a potential contributing factor to hemorrhage in patients receiving larger volumes of ABO non-identical transfusions.
doi:10.1111/j.1537-2995.2012.03718.x
PMCID: PMC3566315  PMID: 22624532
Platelet transfusion; Transfusion complications; Platelet aggregation; Thromboelastography; Thrombin generation
16.  SPRAY: Single Donor Plasma Product For Room Temperature Storage 
Transfusion  2011;52(4):828-833.
Background
Spray drying techniques are commonly utilized in the pharmaceutical, dairy and animal feed industries for processing liquids into powders but have not been applied to human blood products. Spray dried protein products are known to maintain stability during storage at room temperature.
Study design and methods
Plasma units collected at the donor facility were shipped overnight at room temperature to a processing facility where single-use spray drying occurred. After 48 hours storage at room temperature, the spray dried plasma product was split in two and rehydrated with 1.5% glycine or deionized water and assayed for chemistry analytes and coagulation factors. Matched fresh frozen plasma (FFP) was analyzed in parallel as controls.
Results
Reconstitution was achieved for both rehydration groups within five minutes (n=6). There was no statistically significant intergroup difference in recovery for total protein, albumin, IgG, IgA, and IgM (96% or higher). With the exception of factor VIII (58%), the recovery of clotting factors in the glycine reconstituted products ranged from 72% to 93%. Glycine reconstitution was superior to deionized water.
Conclusion
We documented proteins and coagulation activities were recovered in physiologic quantities in reconstituted spray dried plasma products. Further optimization of the spray drying method and reconstitution fluid may result in even better recoveries. Spray drying is a promising technique for preparing human plasma that can be easily stored at room temperature, shipped, and reconstituted. Rapid reconstitution of the microparticles results in a novel plasma product from single donors.
doi:10.1111/j.1537-2995.2011.03419.x
PMCID: PMC3891503  PMID: 22043873
17.  Transfusion of older stored blood and risk of death: a meta-analysis 
Transfusion  2011;52(6):10.1111/j.1537-2995.2011.03466.x.
BACKGROUND
Blood for transfusion is stored for up to 42 days. Older blood develops lesions and accumulates potentially injurious substances. Some studies report increasing toxicity as blood ages. We assessed the safety of transfused older versus newer stored blood.
STUDY DESIGN AND METHODS
PubMed, Scopus and Embase were searched using terms new and old and red blood cell and storage through May 6, 2011 for observational and randomized controlled studies comparing outcomes using transfused blood having longer and shorter storage times. Death was the outcome of interest.
RESULTS
Twenty-one studies were identified, predominantly in cardiac surgery (n=6) and trauma (n=6) patients, including 409,966 patients. A test for heterogeneity of these studies’ results was not significant for mortality (I2=3.7%, p=0.41). Older blood was associated with a significantly increased risk of death [odds ratio (OR) 1.16; 95% confidence interval (CI) (1.07, 1.24)]. Using available mortality data, 97 (63, 199; 95% CI) patients need to be treated with only new blood to save one life. Subgroup analysis of these trials indicated the increased risk was not restricted to a particular type of patient, size of trial, or amount of blood transfused.
CONCLUSION
Based on available data, use of older stored blood is associated with a significantly increased risk of death.
doi:10.1111/j.1537-2995.2011.03466.x
PMCID: PMC3883449  PMID: 22188419
18.  Major depression and generalized anxiety disorder among HTLV-I/II infected former blood donors 
Transfusion  2012;53(1):60-68.
Background
Other studies have reported high rates of depression and anxiety among human T-lymphotropic virus type 1 (HTLV-1) infected subjects, and have even suggested that HTLV-I causes psychiatric disease.
Study design and methods
We interviewed HTLV-I, HTLV-II and demographically similar HTLV seronegative blood donors with the Mini-International Neuropsychiatric Interview (MINI). Prevalences of major depression and generalized anxiety disorder in each group were calculated and compared to published U.S. population data. Adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) controlling for educational achievement, alcohol intake and self-reported health status were calculated with multivariate logistic regression.
Results
Major depression was diagnosed in 5 (5.4%) of 93 HTLV-I positive subjects (aOR = 2.19, 95% CI 0.63–7.55) and 17 (6.6%) of 256 HTLV-II positive subjects (aOR = 1.61, 95% CI 0.66–3.927), compared to 12 (2.1%) of 585 HTLV seronegative blood donors. The prevalence of major depression among infected subjects was comparable to the 6.7% prevalence in the U.S. general population. Generalized anxiety disorder was diagnosed in 5 (5.4%) HTLV-I positive subjects (OR= 2.32, 95% CI 0.74–7.26) and 12 (4.7%) HTLV-II positive subjects (OR = 1.65 95% CI 0.68–4.01), compared to 15 (2.6%) seronegatives and 3.1% in the U.S. general population.
Conclusion
Major depression and generalized anxiety disorder were not significantly more prevalent among HTLV-I and HTLV-II infected former blood donors after controlling for health status and other confounding variables. HTLV seronegative blood donors had lower prevalence of these conditions than the U.S. population, probably due to a “healthy blood donor effect”.
doi:10.1111/j.1537-2995.2012.03677.x
PMCID: PMC3414678  PMID: 22554308
HTLV-I Infections; HTLV-II Infections; Depression; Anxiety Disorders; Mental Disorders
20.  Race, ABO Blood Type and VTE Risk: Not Black and White 
Transfusion  2012;53(1):187-192.
The rate of venous thromboembolism (VTE) has been reported to be higher in blacks compared to whites. Non-O blood types have also been associated with a significantly higher VTE risk. Given that a higher proportion of blacks have O blood type, one might have expected that black individuals would have fewer VTE. In this study, we analyzed race, gender, age, ABO/Rh blood type and VTE risk in 60,982 black and white patients admitted over a span of 10 years. The overall occurrence of VTE was 7.6%, higher in males (8.7% males vs. 7.2% females), higher in non-O blood types (8.5% non-O vs. 6.9% O blood type), and increasing with age (5.8% <65yrs, 11.3% ≥65yrs). No difference in VTE rate was noted with Rh antigen positivity. When stratified by age, VTE rate was consistently higher in blacks and non-O blood types. No difference was detected among the various non-O blood types. To assess the potential confounder of comorbidities, we stratified patients according to Charlson comorbidity score. In a subgroup of healthy patients with age-independent Charlson comorbidity scores of 0 (N=28,387), blacks still had an increased VTE risk and this risk was still higher with increasing age and in those with non-O blood types. We conclude that black race and non-O blood types have increased VTE risk when stratified for age and that associated comorbidities do not explain these differences.
doi:10.1111/j.1537-2995.2012.03665.x
PMCID: PMC3566784  PMID: 22536799
Blood Type; Venous Thromboembolism; Thrombophilia; Race
21.  Effect of ex vivo culture duration on phenotype and cytokine production by mature dendritic cells derived from peripheral blood monocytes 
Transfusion  2009;49(3):10.1111/j.1537-2995.2008.02020.x.
Background
To generate clinical-grade dendritic cells (DCs) ex vivo for immunotherapy trials, peripheral blood monocytes are typically cultured in GM-CSF and IL-4, and then matured using one or more agents. Duration of the initial DC culture is one important variable that has not been systematically evaluated for its effect on the characteristics of the final mature DC product.
Study Design
DCs were generated from elutriated peripheral blood monocytes by incubation in medium containing 2000 units/ml each of GM-CSF and IL-4 for 3 to 7 days, followed by maturation with LPS and IFNγ. DC yield, viability, flow cytometric phenotype, and cytokine production were evaluated.
Results
The % yield and viability of mature DCs were similar after initial culture durations of 3 or 7 days. Mature DCs expressed abundant CD80, CD86, CD83, and CCR7 regardless of initial culture duration, but 3-day DCs expressed these antigens in a more consistent and homogenous manner. Mature DCs produced much more IL12 and less IL10 in response to restimulation with CD40L when the initial culture duration was 3 days, rather than 7 days. Analogous changes were observed in mature DCs prepared using lower concentrations of GM-CSF/IL4 or when the alternative maturation cocktails poly-(I:C)/IFNγ and CD40L/IFNγ were used.
Conclusion
Extended initial culture of DCs in GM-CSF/IL4 does not affect yield or viability of subsequently matured DCs, but can adversely affect their ability to homogeneously express high levels of costimulatory molecules and to produce IL12.
doi:10.1111/j.1537-2995.2008.02020.x
PMCID: PMC3859301  PMID: 19243546
Dendritic Cells; Immunotherapy; Tumor Vaccine; LPS; IL-12
22.  Nitric oxide, hemolysis, and the red blood cell storage lesion: Interactions between transfusion, donor, and recipient 
Transfusion  2012;52(7):10.1111/j.1537-2995.2012.03748.x.
doi:10.1111/j.1537-2995.2012.03748.x
PMCID: PMC3855012  PMID: 22780890
23.  Water administration and the risk of syncope and pre-syncope during blood donation: a randomized clinical trial 
Transfusion  2012;52(12):2577-2584.
Background
Blood centers rely heavily upon adolescent donors to meet blood demand, but pre-syncope and syncope are more frequent in younger donors. Studies have suggested administration of water prior to donation may reduce syncope and/or pre-syncope in this group.
Study design and methods
We conducted a randomized, controlled trial to establish the effect of pre-loading with 500ml of water on the rate of syncope and pre-syncope in adolescent donors. School collection sites in Eastern Cape Province of South Africa were randomized to receive water or not. Incidence of syncope and pre-syncope was compared between randomization groups using multivariable logistic regression.
Results
Of 2,464 study participants, 1,337 received water and 1,127 did not; groups differed slightly by gender and race. Syncope or pre-syncope was seen in 23 (1.7%) of the treatment and 18 (1.6%) of the control arm subjects. After adjusting for race, gender, age and donation history, there was no difference in outcome between the water versus no water arms (adjusted odds ratio (OR) = 0.80 (95% CI 0.42–1.53). Black donors had 7-fold lower odds of syncope or pre-syncope than their white counterparts (adjusted OR 0.14, 95% CI 0.04–0.47).
Conclusion
Preloading adolescent donors with 500ml of water did not have a major effect in reducing syncope and pre-syncope in South African adolescent donors. Our adolescent donors had a lower overall syncope and pre-syncope rate than similar populations in the USA, limiting the statistical power of the study. We confirmed much lower rates of syncope and pre-syncope among young Black donors.
doi:10.1111/j.1537-2995.2012.03631.x
PMCID: PMC3404162  PMID: 22486209
Blood Donors; Syncope; Randomized control trial; South-Africa; Adolescent
24.  DECREASING FREQUENCY OF PLASMA EXCHANGE COMPLICATIONS IN PATIENTS TREATED FOR THROMBOTIC THROMBOCYTOPENIA PURPURA – HEMOLYTIC UREMIC SYNDROME, 1996-2011 
Transfusion  2012;52(12):2525-2532.
BACKGROUND
Plasma exchange (PEX) treatment for patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has risk for major complications.
STUDY DESIGN AND METHODS
Data for PEX-related complications have been prospectively collected on all patients enrolled in the Oklahoma TTP-HUS Registry, 1996-2011. PEX-related complications have been defined as major or minor and as central venous catheter-related or plasma-related.
RESULTS
During 15 years, 1996-2011, 72 (24%) of 302 consecutive patients had major PEX-related complications. Analysis of five consecutive three-year cohorts demonstrated that there has been a significant trend for decreasing frequency of all PEX-related major complications (P=0.014) and central venous catheter-related major complications (P=0.021) but not for the less common plasma-related major complications (P=0.380). ADAMTS13 activity was measured in 288 (95%) of the 302 patients. Analysis of the 66 patients with ADAMTS13 activity <10% demonstrated a significant trend for decreasing frequency of PEX-related major complications (P=0.036); the trend for the 222 patients with ADAMTS13 activity ≥10% was not significant (P=0.118). The decreased frequency of PEX-related major complications among patients with ADAMTS13 activity <10% may be related to a significant trend for decreasing duration of PEX treatment (P=0.040) and decreasing frequency of requirement for more than one central venous catheter (P=0.044). The decreased duration of PEX treatment may be related to increased use of adjunctive treatments: corticosteroids (P<0.001) and rituximab (P<0.001).
CONCLUSIONS
The frequency of PEX-related major complications has decreased from 1996 to 2011, possibly related to increased use of corticosteroids and rituximab and the decreased duration of PEX required to achieve remission.
doi:10.1111/j.1537-2995.2012.03646.x
PMCID: PMC3402590  PMID: 22501034
25.  The Role of Complement in the Trafficking of Hematopoietic Stem/Progenitor Cells 
Transfusion  2012;52(12):2706-2716.
doi:10.1111/j.1537-2995.2012.03636.x
PMCID: PMC3402689  PMID: 22486360

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