Sickle cell disease is associated with extensive healthcare utilization; estimated lifetime costs exceed $460,000 per patient. Approximately 30% of chronically transfused sickle cell patients become alloimmunized to red cell antigens, but these patients cannot be identified a priori. Prospective antigen-matching can prevent alloimmunization, but is costly and may not benefit most patients.
Study Design and Methods
A Markov-based model was constructed to compare the health and financial implications of four alternative antigen-matching strategies for chronically transfused sickle cell patients. The strategies varied by the selection method of patients receiving matched blood (contingent on prior alloimmunization or prospectively for all patients) and the extent of antigen-matching (limited or extensive). Direct medical costs and alloimmunization events were assessed over 10 and 20-year periods, for a hypothetical cohort of initially transfusion-naïve patients and for a dynamic population.
Within a hypothetical cohort of initially transfusion-naïve patients, implementing prophylactic limited matching for chronically transfused patients instead of history-based limited matching is expected to cost an additional $766 million over 10 years, but result in 2,072 fewer alloimmunization events. Within the same cohort, implementing prospective extensive matching is expected to cost $1.86 billion more than history-based extensive matching, but result in 2,424 fewer alloimmunization events. Averting a single alloimmunization event using prospective matching would cost $369,482–769,284. Among a dynamic population over 10 years, prospective limited matching is expected to cost $358 million more than history-based limited matching.
While prospective matching for all transfused patients would reduce alloimmunization, this benefit requires considerable expenditure.
cost-effectiveness; delayed hemolytic transfusion reaction (DHTR); red blood cells; transfusion; alloimmunization; phenotype matching; sickle cell disease; Markov model; decision-tree
Allergic transfusion reactions (ATRs) are among the most common complications of transfusion. Storage in platelet additive solution (PAS) has been shown to reduce ATRs from apheresis platelets (APs). This study evaluated the cost-effectiveness of using PAS storage as an alternative method to reduce ATRs.
Study Design and Methods
A Markov-based decision tree was constructed to compare ATR rates and associated costs expected from current practice and from alternative strategies of using APs stored in PAS. The potential use of premedication was also incorporated. Using a hospital perspective and including direct medical expenses only (US$2012), Monte Carlo microsimulations were run to evaluate outcomes under a base-case analysis. One-way and probabilistic sensitivity analyses were used to assess outcome uncertainty.
Under base-case parameters, using APs stored in PAS for all patients as an initial transfusion protocol is expected to avert ATRs and associated costs, as compared to current practice. Using PAS for all patients along with premedication would be cost-saving only when the additional cost of PAS is below $9.14. If PAS storage could eliminate premedication use, it is expected to result in cost savings when the additional unit cost of PAS is under $11.90. At a PAS cost of $15, averting 1 ATR would cost $701.95. Using PAS storage only in response to recurring mild ATRs is associated with cost savings under all costs of PAS evaluated.
Using PAS storage for all AP transfusions to prevent ATRs may be financially and clinically beneficial, as compared to current practice.
allergic transfusion reaction (ATR); platelet additive solution (PAS); platelet; plasma; urticaria; hives; anaphylaxis; hypersensitivity; Markov model; decision-tree
Thirty percent of chronically transfused patients with sickle cell disease (SCD) become alloimmunized. Antigen-matching reduces alloimmunization. Matching may be prospective (for all patients) or based on history (only for patients with an alloimmunization history). We assessed the clinical and financial value of a potential assay to identify at-risk patients to guide antigen-matching.
A Markov-based model evaluated direct medical costs and alloimmunization events over 10 to 20 years for a cohort of initially transfusion-naïve patients with SCD receiving simple or exchange transfusion. Four strategies were evaluated: prospective matching, history-based matching, perfectly-informed matching (assay with 100% sensitivity, 100% specificity), and imperfectly-informed matching (reduced accuracy). RBCs were matched for C, E, K and any additional alloantibodies present. A hospital perspective was adopted, with costs (2012US$) and events discounted (3%).
Perfectly-informed antigen-matching using a $1000 assay is expected to save $82,334 per patient over 10 years, as compared to prospective matching. Perfectly-informed antigen-matching is more costly than history-based matching, but reduces alloimmunization events by 45.6% over 10 years. Averting each alloimmunization event using perfectly-informed matching would cost an additional $10,934 per patient. Imperfectly-informed antigen-matching using an assay with 75% specificity and 75% sensitivity is less costly than prospective matching, but increases alloimmunization events. Compared to history-based matching, imperfectly-informed matching would decrease alloimmunization events by 32.61%, at an additional cost of $147,915 per patient over 10 years. Cost-effectiveness of informed antigen-matching is largely driven by assay specificity.
A sufficiently specific assay to inform antigen-matching may be cost-effective in reducing alloimmunization among transfused patients with SCD.
sickle cell; alloimmunization; assay; economic evaluation; cost-effectiveness; antigen-matching
Iron overload is an inevitable consequence of chronic red cell transfusions without erythrocytapheresis or chelation therapy. The effectiveness of partial manual exchange, a technique used to slow iron loading, has not been evaluated. We evaluated all children with sickle cell disease (SCD) receiving chronic transfusion to identify chelation naïve subjects who had quantitative liver iron concentration (LIC) studies. Seventeen chelation naïve children with SCD received a median of 29 transfusions prior to first LIC determination. Serum ferritin concentrations were assessed prior to each transfusion. The mean volume of blood phlebotomized prior to each transfusion was 5.1±1.8 cc/kg, which cumulatively resulted in a calculated median 35.0 mg/kg removal of iron. Using linear regression, pretransfusion phlebotomy resulted in a statistically significant reduction in ferritin (-8.8 ng/mL of ferritin for each mg/kg of iron phlebotomized, P = 0.02). A reduction in LIC from pretransfusion phlebotomy could not be established (P =0.4). Partial manual exchanges appear to be an effective strategy for slowing the pace of iron loading in the setting of chronic transfusion for SCD.
Sickle cell; iron loading; transfusion; iron; ferritin
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.
allergy; transfusion reaction; platelets; plasma; red cell; hypersensitivity; urticaria; pruritus
GFAP is specific to astrocytes in the central nervous system. We hypothesized that serum GFAP would be increased in neonates with hypoxic-ischemic encephalopathy (HIE) treated with whole body cooling.
We measured GFAP at birth and daily for up to 7 days for neonates in the intensive care unit. We compared neonates with HIE treated with whole body cooling to gestational age matched controls without neurologic injury and neonates with HIE by brain abnormalities on MRI.
Neonates with HIE had increased GFAP levels compared to controls. Neonates with HIE and abnormal brain imaging had elevated GFAP levels compared to neonates with HIE and normal imaging.
Serum GFAP levels during the first week of life were increased in neonates with HIE and were predictive of brain injury on MRI. Biomarkers like GFAP could help triage neonates with HIE to treatment, measure treatment efficacy and provide prognostic information.
fetal acidosis; glial fibrillary acidic protein; hypoxic-ischemic encephalopathy; neonatal seizures; whole body cooling
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.
platelet; apheresis; ABO; antibody titer; transfusion; incompatible; febrile transfusion reaction; hemolysis
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.
Blood; Blood conservation; Blood transfusion
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.
STUDY DESIGN AND METHODS
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.
allergy; transfusion reaction; IgE; platelet
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.
STUDY DESIGN AND METHODS
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.
allergy; transfusion reaction; IgE; platelet
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.
Chronic transfusion; Glial fibrillary acidic protein; Sickle cell; Stroke
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.
corrected count increment (CCI); allergic transfusion reaction (ATR); platelet; wash; concentrate; urticaria; hives; anaphylaxis; premedication
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.
Allergy; transfusion reaction; platelet
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.
Aplastic Anemia (AA); Paroxysmal Nocturnal Hemoglobinuria (PNH); High dose cyclophosphamide (HiCy); Fluoresceinated Aerolysin Variant (FLAER); Lactate Dehydrogenase (LDH).
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.
STUDY DESIGN AND METHODS
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.
SPTR(s) septic transfusion reaction(s); SDP(s) single donor platelet(s)
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.
paroxysmal nocturnal hemoglobinuria; PIG-A; clonal expansion