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1.  ABO Antibody Titers are not Predictive of Hemolytic Reactions Due to Plasma Incompatible Platelet Transfusions 
Transfusion  2012;52(10):2087-2093.
The overall risk of hemolytic transfusion reactions from plasma (minor) incompatible platelet transfusions and the role of a critical anti-A or anti-B titer in predicting/preventing these reactions has not been clearly established.
We evaluated all apheresis platelet (AP) transfusions for three months. Using the gel titer method, we determined the anti-A and/or the anti-B IgG titer for all incompatible APs. Reported febrile transfusion reactions and hemolytic transfusion reactions (HTRs) were recorded; transfusions were not prospectively evaluated by the study team. A post-transfusion DAT and eluate were performed after a reported febrile or hemolytic reaction for patients who received plasma incompatible APs.
647of 4,288 AP transfusions (15.1%) were plasma incompatible. Group O APs (N = 278) had significantly higher anti-A and anti-B titers than group A or B APs (p<0.0001). No group A or B APs had a titer >128 (0/342). For group O APs, 73 had titers ≥256 (26.3%), and 27 had titers ≥512 (9.7%). No HTRs were reported to any plasma incompatible AP transfusion during the study period. Two plasma incompatible AP transfusions were associated with fever/chills and positive DATs, of which one had a positive eluate. The incidence of a DAT and eluate positive febrile transfusion reaction in the plasma incompatible AP population is 0.15% (95% CI 0.0–0.86%).
A critical anti-A or B titer is not sufficient to predict the risk of hemolysis in patients receiving plasma incompatible APs, although underreporting of reactions to the blood bank may limit the generalizability of this study.
PMCID: PMC3360137  PMID: 22339320
platelet; apheresis; ABO; antibody titer; transfusion; incompatible; febrile transfusion reaction; hemolysis
2.  Hemoglobin Drift after Cardiac Surgery 
The Annals of thoracic surgery  2012;94(3):703-709.
Recent literature suggests that a restrictive approach to red blood cell transfusions is associated with improved outcomes in cardiac surgery (CS) patients. Even in the absence of bleeding, intravascular fluid shifts cause hemoglobin levels to drift postoperatively, possibly confounding the decision to transfuse. We undertook this study to define the natural progression of hemoglobin levels in postoperative CS patients.
We included all CS patients from 10/10-03/11 who did not receive a postoperative transfusion. Primary stratification was by intraoperative transfusion status. Change in hemoglobin was evaluated relative to the initial postoperative hemoglobin. Maximal drift was defined as the maximum minus the minimum hemoglobin for a given hospitalization. Final drift was defined as the difference between initial and discharge hemoglobin.
Our final cohort included 199 patients, 71(36%) received an intraoperative transfusion while 128(64%) did not. The average initial and final hemoglobin for all patients were 11.0±1.4g/dL and 9.9±1.3g/dL, respectively, an final drift of 1.1±1.4g/dL. The maximal drift was 1.8±1.1g/dL and was similar regardless of intraoperative transfusion status(p=0.9). Although all patients’ hemoglobin initially dropped, 79% of patients reached a nadir and experienced a mean recovery of 0.7±0.7g/dL by discharge. On multivariable analysis, increasing CPB time was significantly associated with total hemoglobin drift(Coefficient/hour: 0.3[0.1–0.5]g/dL, p=0.02).
In this first report of hemoglobin drift following CS, although all postoperative patients experienced downward hemoglobin drift, 79% of patients exhibited hemoglobin recovery prior to discharge. Physicians should consider the eventual upward hemoglobin drift prior to administering red cell transfusions.
PMCID: PMC3610599  PMID: 22609121
Blood; Blood conservation; Blood transfusion
3.  Allergic agonists in apheresis platelet products are associated with allergic transfusion reactions 
Transfusion  2011;52(3):575-581.
The mechanisms that underlie allergic transfusion reactions (ATRs) are not well characterized, but likely involve recipient, donor, and product factors. To assess product factors associated with ATRs, we investigated candidate mediators in apheresis platelet products associated with ATRs and controls.
Using bead-based and standard ELISA immunoassays, we tested supernatants from 20 consecutive apheresis platelet transfusions associated with ATRs and 30 control products for concentrations of mediators in 3 categories: acute inflammatory mediators, direct agonists of basophils and mast cells, and growth/priming factors of basophils and mast cells.
Median concentrations of the direct allergic agonists C5a, brain derived neurotrophic factor (BDNF), and CCL5 (RANTES) were 16.6%, 41.8%, and 13.9% higher, respectively, in the supernatant of apheresis platelet products that were most strongly associated with ATRs (P < 0.05 for each mediator). Other direct agonists (MIP-1α, MCP-1, eotaxin-1, IL-8) were similar between groups. Concentrations of acute inflammatory mediators and basophil growth/priming factors were also similar between groups (P > 0.2 for all associations).
The allergic agonists C5a, BDNF, and CCL5 may be mediators of ATRs in apheresis platelet products. Acute inflammatory proteins and basophil/mast cell growth and priming factors do not appear to be associated with apheresis platelet products that cause ATRs.
PMCID: PMC3711211  PMID: 21883267
allergy; transfusion reaction; IgE; platelet
4.  Atopic predisposition of recipients in allergic transfusion reactions to apheresis platelets 
Transfusion  2011;51(11):2337-2342.
The biologic mechanisms of allergic transfusion reactions (ATRs) are largely unknown. We sought to compare the atopic predisposition of platelet recipients who experienced an ATR to non-reactive control recipients.
We identified 37 consecutive apheresis platelet recipients who experienced an ATR and 26 matched controls. Total IgE and aero- and food-allergen-specific IgE were quantified in plasma by ImmunoCAP (Phadia, Phadiatop and Fx5). IgE testing of apheresis platelet supernatants was also performed.
Pruritus and urticaria were manifest in 91.9% and 83.8% of all ATRs, with more severe respiratory symptoms and angioedema occurring in <15% of cases. No subject had anaphylaxis. Sex, age, and primary diagnosis were balanced between the two groups. Total and aero-allergen specific IgE was higher among subjects experiencing an ATR in comparison to control subjects (median total IgE 55.5 kU/L vs. 8.3 kU/L, P=0.002; and median aero-allergen specific IgE 0.57 kUa/L vs. 0.36 kUa/L, P=0.046). IgE antibody levels in apheresis products associated with ATRs were similar to control products (P>0.1 for all IgE tests).
Recipient atopic predisposition, as defined by IgE sensitization, is a risk factor associated with ATRs.
PMCID: PMC3711221  PMID: 21569041
allergy; transfusion reaction; IgE; platelet
5.  The Impact of Apheresis Platelet Manipulation on Corrected Count Increment 
Transfusion  2012;52(6):1221-1227.
Concentrating and washing apheresis platelets (APs) substantially reduce the number of allergic transfusion reactions likely due to removal of plasma. However, these processes may damage platelets. This study evaluated whether concentrating or washing APs decrease the Corrected Count Increment (CCI).
Study Design and Methods
This retrospective study evaluated individuals who initially received unmanipulated APs and subsequently received concentrated and/or washed APs at a large university hospital between 1998 and 2009. Concentrated units were prepared by reducing the plasma volume of APs by a goal of >67%. Washed units were prepared by washing the APs with 1L normal saline. The CCI (plt × m2/uL) for all transfusions was calculated. Hypothesis testing was performed with Student’s t-tests for continuous variables and chi-square tests for dichotomous variables.
We evaluated 121 individuals; 46 patients who received unmanipulated, concentrated and then washed APs, 59 patients who received unmanipulated and then concentrated APs; and 16 patients who received unmanipulated and then washed APs. Patient demographics were similar among the three groups. The mean CCI for unmanipulated AP transfusions at 0–2 hours post transfusion were significantly higher than concentrated and washed platelet transfusions (p<0.001). However, when accounting for platelet loss due to manipulation, concentrating APs did not impact the CCI, but the CCI remained significantly lower for washed products at all time points post transfusion (40.7% mean reduction at 20–24 hours, p<0.001).
Washing APs significantly reduces platelet count recovery and survival, as demonstrated by a significantly reduced CCI.
PMCID: PMC3325359  PMID: 22233358
corrected count increment (CCI); allergic transfusion reaction (ATR); platelet; wash; concentrate; urticaria; hives; anaphylaxis; premedication
6.  Allergic transfusion reactions to platelets are associated more with recipient and donor factors than with product attributes 
Transfusion  2011;51(8):1716-1722.
Mechanisms of allergic transfusion reactions (ATRs) are not well understood. The aim of this study was to distinguish recipient, donor, and product-specific factors associated with ATRs.
Study Design and Methods
We conducted a retrospective cohort study of apheresis platelet (AP) products transfused from 4/2000–3/2010. The concordance rate of ATRs when split AP products were transfused to ≥2 individuals was compared to the overall ATR rate among all AP products. Per person ATR rates also were compared to the overall ATR rate.
We observed 1,616 ATRs among 93,737 transfusions, for an overall incidence of 1.72%(95%CI: 1.64–1.81%). Of the 1,616 ATRs, 630 occurred when split AP products were transfused to ≥2 recipients. Of these 630 AP products, ATRs were observed in ≥2 different recipients of the same AP collection only 6/630 times, for a concordant incidence of 0.95% (95% CI: 0.35–2.06%), which is similar to the overall ATR rate (P=0.17). On an individual level, 30.0% of recipients had ATR rates >5%, and these 30.0% accounted for 62.1% of ATRs. Donors of AP products associated with concordant ATRs donated AP products that had an ATR rate of 5.8% (95% CI 3.1–9.7%), which is higher than the overall ATR rate (P<0.001).
An observed ATR does not predict an ATR in a different recipient of a split AP product. A minority of platelet recipients accounts for the majority of ATRs. Some donors are strongly associated with ATRs. Consequently, recipient and donor factors are implicated in the mechanism of ATRs.
PMCID: PMC3137746  PMID: 21214586
Allergy; transfusion reaction; platelet
7.  Natural history of paroxysmal nocturnal hemoglobinuria clones in patients presenting as aplastic anemia 
Investigate the natural history of PNH clones in patients with acquired aplastic anemia (AA).
Patients and Methods
Twenty-seven patients with AA and a detectable PNH clone were monitored for a median of 5.7 years (range1.5 to 11.5 years). Twenty-two patients received high dose cyclophosphamide (HiCy) therapy. The erythrocyte and granulocyte PNH clone sizes were measured using flow cytometry and analyzed via CellQuest software. PE-conjugated anti-glycophorin A, anti-CD15, FITC-conjugated anti-CD59, and FLAER staining were used to define GPI-AP deficient cells.
We found a linear relationship between PNH clone size and the development of intravascular hemolysis, assessed by LDH values (Pearson Correlation Coefficient=0.80, P<0.001 for erythrocyte PNH clones; and Pearson Correlation Coefficient=0.73, P<0.0001 for granulocyte PNH clones). An erythrocyte PNH size of 3~5% and granulocyte PNH size of 23% were the thresholds to predict hemolysis as measured by an elevated LDH (ROC analyses with AUC=0.96 for erythrocyte PNH clone sizes and AUC=0.88 for granulocyte PNH clone sizes). Patients with small (≤15%) initial PNH clone sizes were less likely to develop an elevated LDH (mean±SD: 236.9±109.9 vs423.1±248.8; P=0.02). Over time, the PNH clone sizes remained stable in 25.9% of patients; 48.1% experienced a rise in the PNH clone size and 25.9% experienced a decrease.
The risk of developing clinically significant PNH after HiCy therapy appears to be low in AA patients with PNH clones, especially for those with small initial PNH clones and for those who respond to HiCy therapy.
PMCID: PMC3120909  PMID: 21447004
Aplastic Anemia (AA); Paroxysmal Nocturnal Hemoglobinuria (PNH); High dose cyclophosphamide (HiCy); Fluoresceinated Aerolysin Variant (FLAER); Lactate Dehydrogenase (LDH).
8.  Plasma Glial Fibrillary Acidic Protein Levels in a Child with Sickle Cell Disease and Stroke 
Acta Haematologica  2010;125(3):103-106.
A 12-year-old boy with HbSS sickle cell disease (SCD) was admitted with an acute febrile illness and developed overt stroke 3 days later. Plasma glial fibrillary acidic protein levels were elevated, as compared to pediatric controls, 32 h prior to the clinical diagnosis of stroke, peaked immediately prior to the exchange transfusion, and remained elevated 1 year later despite chronic transfusion therapy. Stroke in SCD can occur in the setting of acute illness, and a biomarker that could predict the onset and triage ill children to therapeutic intervention more quickly would be useful.
PMCID: PMC3202928  PMID: 21099215
Chronic transfusion; Glial fibrillary acidic protein; Sickle cell; Stroke
9.  Bacterial Culture Reduces but Does Not Eliminate the Risk of Septic Transfusion Reactions to Single Donor Platelets 
Transfusion  2009;49(12):2588-2593.
Transfusion associated bacterial sepsis has been a significant risk of morbidity and mortality related to platelet transfusion therapy. Previously we determined the rate of septic transfusion reactions (SPTRs) to single donor platelets (SDPs) in our hospital to be 1 in 15,098 transfusions. The goal of this study was to determine if there has been a reduction in the rate of SPTRs in our hospital since the implementation of bacterial testing of SDPs.
An automated microbial detection system was implemented at our regional blood supplier in February 2004. We performed a retrospective examination of the number of SPTRs that have occurred to SDPs at our hospital since that time, using the same criteria we used prior to bacterial screening. Transfusions over a three and a half year period were examined. Clinical and laboratory data were gathered and correlated from transfusion reaction files and three independent computer documentation systems.
From 3/1/04 through 8/31/07, there were 49,625 transfusions of SDP with 1,096 transfusion reactions reported. Only one reaction detected the same organism in two of three sites, meeting the criteria we set for a SPTR. Consequently we identified our rate of SPTRs in SDPs as 1 in 49,625.
Although not statistically significant we did observe in our institution a decrease in the rate of STRs to SDPs from to with the implementation of bacterial testing.
PMCID: PMC3127255  PMID: 19694995
SPTR(s) septic transfusion reaction(s); SDP(s) single donor platelet(s)
10.  Glycosylphosphatidylinositol-anchored Protein Deficiency Confers Resistance to Apoptosis in PNH 
Experimental hematology  2008;37(1):42-51.
Investigate the contribution of PIG-A mutations to clonal expansion in paroxysmal nocturnal hemoglobinuria (PNH).
Primary CD34+ hematopoietic progenitors from PNH patients were assayed for annexin V positivity by flow cytometry in a cell-mediated killing assay using autologous effectors from PNH patients or allogeneic effectors from healthy controls. To specifically assess the role of the PIG-A mutation in the development of clonal dominance and address confounders of secondary mutation and differential immune attack that can confound experiments using primary cells, we established an inducible PIG-A CD34+ myeloid cell line, TF-1. Apoptosis resistance was assessed after exposure to allogeneic effectors, NK92 cells (an IL-2 dependent cell line with the phenotype and function of activated NK cells), TNF-α, and γ-irradiation. Apoptosis was measured by annexin V staining and caspase 3/7 activity.
In PNH patients, CD34+ hematopoietic progenitors lacking GPI-anchored proteins (GPI-AP-) were less susceptible than GPI-AP+ CD34+ precursors to autologous (8% versus 49%, p<0.05) and allogeneic (28% versus 58%, p<0.05) cell-mediated killing from the same patients. In the inducible PIG-A model, GPI-AP- TF-1 cells exhibited less apoptosis than induced, GPI-AP+ TF-1 cells in response to allogeneic cell-mediated killing, NK92-mediated killing, TNF-α, and γ-irradiation. GPI-AP- TF-1 cells maintained resistance to apoptosis when effectors were raised against GPI-AP- cells, arguing against a GPI-AP being the target of immune attack in PNH. NK92 mediated killing was partially inhibited with blockade by specific antibodies to the stress-inducible GPI-AP ULBP1 and ULBP2 that activate immune effectors. Clonal competition experiments demonstrate that the mutant clone expands over time under pro-apoptotic conditions with TNF-α.
PIG-A mutations contribute to the clonal expansion in PNH by conferring a survival advantage to hematopoietic progenitors under pro-apoptotic stresses.
PMCID: PMC2628761  PMID: 19013003
paroxysmal nocturnal hemoglobinuria; PIG-A; clonal expansion

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