Therapeutic plasma exchange is feasible and tolerable in severely injured patients with trauma-induced coagulopathy.

Objectives: Trauma-induced coagulopathy (TIC) occurs in a subset of severely injured trauma patients. Despite having achieved surgical hemostasis, these individuals can have persistent bleeding, clotting, or both in conjunction with deranged coagulation parameters and typically require transfusion support with plasma, platelets, and/or cryoprecipitate. Due to the multifactorial nature of TIC, targeted interventions usually do not have significant clinical benefits. Therapeutic plasma exchange (TPE) is a non-specific modality of removing and replacing a patient's plasma in a euvolemic manner that can temporarily normalize coagulation parameters and remove deleterious substances, and may be beneficial in such patients with TIC. Methods: In a prospective case series, TPE was performed in severely injured trauma patients diagnosed with TIC and transfusion requirement. These individuals all underwent a series of at least 3 TPE procedures performed once daily with plasma as the exclusive replacement fluid. Demographic, injury, laboratory, TPE, and outcome data were collected and analyzed. Results: In total, 7 patients received 23 TPE procedures. All patients had marked improvements in routine coagulation parameters, platelet counts, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activities, inflammatory markers including interleukin-6 concentrations, and organ system injuries after completion of their TPE treatments. All-cause mortality rates at 1 day, 7 days, and 30 days were 0%, 0%, and 43%, respectively, and all patients for whom TPE was initiated within 24 hours after injury survived to the 30-day timepoint. Surgical, critical care, and apheresis nursing personnel who were surveyed were universally positive about the utilization of TPE in this patient population. These procedures were tolerated well with the most common adverse event being laboratory-diagnosed hypocalcemia. Conclusion: TPE is feasible and tolerable in severely injured trauma patients with TIC. However, many questions remain regarding the application of TPE for these critically ill patients including identification of the optimal injured population, ideal time of treatment initiation, appropriate treatment intensity, and concurrent use of adjunctive treatments. Level of evidence: Level V.

Predicting the CD34 content of mobilized peripheral blood leukapheresis products: single institution experience over 20 years.

BACKGROUND AIMS: Since the standardization of CD34 measurement by flow cytometry, predictors of leukapheresis CD34 yield have played a pivotal role in planning donor leukaphereses. We describe here a single institution's experience with a multivariate predictor that was used for 2,929 products without alteration for 20 years. METHODS: The ordinary least squares regression model variables included log peripheral CD34 count, collection duration (3- versus 4-hours), collection number, donor sex, and transplant type. RESULTS: During the study period we changed flow cytometers twice and leukapheresis instruments once. During the Cobe Spectra era the predictor explained 90% of the variability in CD34 collection yield for autologous transplants (r2 = 0.90), and 70% for allogeneic transplants with an overall sensitivity to predict a CD34 yield of ≥ 1 × 106/kg of 97.7%, and specificity of 81.4%. CONCLUSIONS: Implemented prospectively with real-time result reporting, the model allowed us to predict CD34 yield with both 3- and 4-hour collection scenarios. Given this guidance, 3-hour collections were selected by the clinical team 25% of the time, saving patient leukapheresis time and resources. When faced with a prediction of < 1 × 106 CD34/kg, the clinical team chose to defer collection 72% of the time. In instances where leukapheresis was performed despite a poor predicted outcome, 85% of patients collected on the Cobe Spectra, and 92% of patients collected on the Optia, failed to collect at least 1 × 106 CD34/kg. A revised model is tested retrospectively on Optia data, and suggestions for further improvements are discussed.

Effective peripheral blood stem cell collection in a 4.6-kg child.

BACKGROUND: Due to unique technical challenges, effective peripheral blood stem cell collections (PBSCs) have not been consistently reported in patients weighing less than 5 kg. We describe three PBSCs performed in a 4.6-kg child undergoing myeloablative chemotherapy for high-grade glioma. STUDY DESIGN AND METHODS: A multidisciplinary group representing the clinical and apheresis teams adapted a PBSC protocol to accommodate the patient's size and collection targets. Special considerations included timing of the collection relative to chemotherapy, vascular access, strategies for monitoring adverse events during collection, and contingencies. RESULTS AND DISCUSSION: The patient underwent three PBSC procedures over 2 days due to suboptimal collection after the first two procedures. For procedure 1, a conservative inlet: anticoagulant (AC) ratio and AC infusion rate of 15 and 0.6 mL/min/L total blood volume (TBV) resulted in premature discontinuation due to clotting. A ratio of 8 and AC infusion rate of 1.5-1.7 mL/min/L TBV with subsequent titration to higher levels were adopted for the second and third procedures. These changes resulted in greater acid-citrate-dextrose exposure, that was managed by continuous calcium chloride infusion. There was no hypocalcemia, hypotension, or distress during any procedure. A total of 15 × 106 CD34+ cells/kg were collected. This retrospective review illustrates that PBSC can be safely undertaken in children weighing less than 5 kg.

How do we consistently provide high-dose granulocyte products for transfusions in neutropenic patients?

BACKGROUND: The therapeutic use of granulocyte transfusions for the treatment of infections in immunocompromised patients has been a controversial practice. Randomized controlled trials suggest that benefit may be provided when a high-dose product, defined as providing a dose of at least 0.6 × 109 /kg, is offered. Here we describe the collection process and granulocyte product yield over a four-year period at a donation center supplying a large, tertiary academic medical center. METHODS: A retrospective chart review was performed for apheresis granulocyte donations collected between 2018 and 2021 following implementation of combined G-CSF and dexamethasone donor stimulation at our institution. Data collected includes donor demographics, G-CSF administration timeline, pre-collection cell counts, product yields, donor adverse events, and post-transfusion ANC increments. RESULTS: A total of 269 granulocyte units were collected from 184 unique donors. The median neutrophil yield (ANC) following G-CSF implementation was 7.5 × 1010 /unit. The proportion of granulocyte products meeting or exceeding a yield of 4.0 × 1010 per unit was 96.5%. These products resulted in measurable median ANC increment of 550/µL in transfused adult patients (n = 166 transfusions). DISCUSSION: In order to properly assess the effectiveness of granulocyte transfusions in patients, it is necessary to ensure that the products being transfused contain an adequate granulocyte dose. This study demonstrates that the combination of G-CSF and dexamethasone donor stimulation, followed by apheresis granulocyte collection, is safe and can reliably yield a high-dose product. Consistent production of high-dose units allows for better assessment of patient outcomes by reducing dosage variability.

Optimizing interpretation of survival studies of fresh and aged transfused biotin-labeled RBCs.

BACKGROUND: Ex vivo labeling with 51 chromium represents the standard method to determine red blood cell (RBC) survival after transfusion. Limitations and safety concerns spurred the development of alternative methods, including biotinylated red blood cells (BioRBC). STUDY DESIGN AND METHODS: Autologous units of whole blood were divided equally into two bags and stored under standard blood bank conditions at 2 to 6°C (N = 4 healthy adult volunteers). One bag was biotinylated (15 µg/ml) on storage days 5 to 7 (fresh) and the other was biotinylated (3 µg/ml) on days 35 to 42 (aged). The proportion of circulating BioRBC was measured serially, and cell-surface biotin was quantified with reference to molecules of equivalent soluble fluorochrome. Clearance kinetics were modeled by RBC age distribution at infusion (Gaussian vs. uniform) and decay over time (constant vs. exponential). RESULTS: Data were consistent with biphasic exponential clearance of cells of uniform age. Our best estimate of BioRBC clearance (half-life [T1/2 ]) was 49.7 ± 1.2 days initially, followed by more rapid clearance 82 days after transfusion (T1/2  = 15.6 ± 0.6 days). As BioRBC aged in vivo, molecules of equivalent soluble fluorochrome declined with a T1/2 of 122 ± 9 days, suggesting gradual biotin cleavage. There were no significant differences between the clearance of fresh and aged BioRBC. CONCLUSION: Similar clearance kinetics of fresh and aged BioRBC may be due to the extensive washing required during biotinylation. Survival kinetics consistent with cells with uniform rather than Gaussian or other non-uniform age distributions suggest that washing, and potentially RBC culling, may extend the storage life of RBC products.

Clinical Significance of Serum Albumin and Implications of FcRn Inhibitor Treatment in IgG-Mediated Autoimmune Disorders.

Serum albumin (SA), the most abundant soluble protein in the body, maintains plasma oncotic pressure and regulates the distribution of vascular fluid and has a range of other important functions. The goals of this review are to expand clinical knowledge regarding the functions of SA, elucidate effects of dysregulated SA concentration, and discuss the clinical relevance of hypoalbuminemia resulting from various diseases. We discuss potential repercussions of SA dysregulation on cholesterol levels, liver function, and other processes that rely on its homeostasis, as decreased SA concentration has been shown to be associated with increased risk for cardiovascular disease, hyperlipidemia, and mortality. We describe the anti-inflammatory and antioxidant properties of SA, as well as its ability to bind and transport a plethora of endogenous and exogenous molecules. SA is the primary serum protein involved in binding and transport of drugs and as such has the potential to affect, or be affected by, certain medications. Of current relevance are antibody-based inhibitors of the neonatal Fc receptor (FcRn), several of which are under clinical development to treat immunoglobulin G (IgG)-mediated autoimmune disorders; some have been shown to decrease SA concentration. FcRn acts as a homeostatic regulator of SA by rescuing it, as well as IgG, from intracellular degradation via a common cellular recycling mechanism. Greater clinical understanding of the multifunctional nature of SA and the potential clinical impact of decreased SA are needed; in particular, the potential for certain treatments to reduce SA concentration, which may affect efficacy and toxicity of medications and disease progression.

CD4+ T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1-Dependent.

Rationale: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. Objectives: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4+ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4+TNF-α+ T-cell responses inversely correlated with absolute CD4+ counts from patients with severe COVID-19 (n = 76; R = -0.797; P < 0.0001). In vitro TNF-α blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4+ T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. We also evaluated BAL and lung explant CD4+ T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4+ dysfunction in severe COVID-19 is TNF-α/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19.

Benchmarking the centralized urgent plasma exchange service for patients admitted with a diagnosis of suspected acquired thrombotic thrombocytopenic purpura at a large healthcare system.

BACKGROUND: Consensus guidelines recommend that therapeutic plasma exchange (TPE) should be started within 4 to 8 hours after the diagnosis of suspected acquired thrombotic thrombocytopenic purpura (aTTP). This study aimed to audit the steps from diagnosis to initiation of plasma exchange at a centralized apheresis service. METHODS: A retrospective review of the electronic medical record and laboratory information systems from January 1, 2014 to August 31, 2017 was conducted to identify all patients with suspected aTTP undergoing TPE. Demographics, comorbidities, pertinent laboratory tests, and temporal TPE procedural data were collected. RESULTS: The median (5th-95th percentile) time from request to initiation of TPE was 5.4 (3.2-10.6) hours. TPE was initiated within 8 hours in 94 of the 108 patients (87.0%). The median (5th-95th percentile) time from request to central venous access was 2.5 (0.5-6.9) hours and from request to plasma product issuance from the blood bank was 3.4 (1.6-8.1) hours. aTTP patients in whom TPE was initiated greater than 6 hours from request did not have worse outcomes compared to those with TPE initiation within 6 hours: in-hospital mortality (2/14 [14.3%] vs 2/21 [9.5%], P = 0.66), median length of stay (9.0 [4.7-44.1] vs 8.3 [3.9-27.0] days, P = 0.76), and median number of days to durable platelet count recovery (4.5 [2.0-9.0] vs 4.0 [2.0-18.0] days, P = 0.66). CONCLUSIONS: The 4 to 8-hour target window from TPE request to initiation appears feasible for a centralized apheresis program servicing a large healthcare system.

Multiple-ancestry genome-wide association study identifies 27 loci associated with measures of hemolysis following blood storage.

BackgroundThe evolutionary pressure of endemic malaria and other erythrocytic pathogens has shaped variation in genes encoding erythrocyte structural and functional proteins, influencing responses to hemolytic stress during transfusion and disease.MethodsWe sought to identify such genetic variants in blood donors by conducting a genome-wide association study (GWAS) of 12,353 volunteer donors, including 1,406 African Americans, 1,306 Asians, and 945 Hispanics, whose stored erythrocytes were characterized by quantitative assays of in vitro osmotic, oxidative, and cold-storage hemolysis.ResultsGWAS revealed 27 significant loci (P < 5 × 10-8), many in candidate genes known to modulate erythrocyte structure, metabolism, and ion channels, including SPTA1, ALDH2, ANK1, HK1, MAPKAPK5, AQP1, PIEZO1, and SLC4A1/band 3. GWAS of oxidative hemolysis identified variants in genes encoding antioxidant enzymes, including GLRX, GPX4, G6PD, and SEC14L4 (Golgi-transport protein). Genome-wide significant loci were also tested for association with the severity of steady-state (baseline) in vivo hemolytic anemia in patients with sickle cell disease, with confirmation of identified SNPs in HBA2, G6PD, PIEZO1, AQP1, and SEC14L4.ConclusionsMany of the identified variants, such as those in G6PD, have previously been shown to impair erythrocyte recovery after transfusion, associate with anemia, or cause rare Mendelian human hemolytic diseases. Candidate SNPs in these genes, especially in polygenic combinations, may affect RBC recovery after transfusion and modulate disease severity in hemolytic diseases, such as sickle cell disease and malaria.

Testosterone replacement therapy in blood donors modulates erythrocyte metabolism and susceptibility to hemolysis in cold storage.

BACKGROUND: Red blood cells (RBCs) derived from patients who receive testosterone replacement therapy (TRT) may be considered eligible for component production and transfusion. The aim of this study was to identify testosterone-dependent changes in RBC metabolism and to evaluate its impact on susceptibility to hemolysis during cold storage. STUDY DESIGN AND METHODS: We characterized stored RBCs from two cohorts of TRT patients who were matched with control donors (no TRT) based upon sex, age, and ethnicity. We further evaluated the impact of testosterone deficiency (orchiectomy) on RBC metabolism in FVB/NJ mice. RBC metabolites were quantified by ultra-high-pressure liquid chromatography-mass spectrometry. RBC storage stability was determined in RBC units from TRT and controls by quantifying storage, osmotic, and oxidative hemolysis. RESULTS: Orchiectomy in mice was associated with significant (P < 0.05) changes in RBC metabolism as compared with intact males including increased levels of acyl-carnitines, long-chain fatty acids (eg, docosapentaenoic acids), arginine, and dopamine. Stored RBCs from TRT patients exhibited higher levels of pentose phosphate pathway metabolites, glutathione, and oxidized purines (eg, hypoxanthine), suggestive of increased activation of antioxidant pathways in this group. Further analyses indicated significant changes in free fatty acids and acyl-carnitines in response to testosterone therapies. With regard to hemolysis, TRT was associated with enhanced susceptibility to osmotic hemolysis. Correlation analyses identified acyl-carnitines as significant modifiers of RBC predisposition to osmotic and oxidative hemolysis. CONCLUSIONS: These observations provide new insights into testosterone-mediated changes in RBC metabolome and biology that may impact the storage capacity and posttransfusion efficacy of RBCs from TRT donors.

Association of proton pump inhibitor and histamine H2-receptor antagonists with restless legs syndrome.

Restless legs syndrome (RLS) is a common sensorimotor disorder, which can disrupt sleep and is thought to be caused in part by low cellular iron stores. Proton pump inhibitors (PPI) and histamine H2-receptor antagonists (H2A) are among the most commonly used drugs worldwide and show evidence of causing iron deficiency. We conducted a case/non-case observational study of blood donors in the United States (N = 13,403; REDS-III) and Denmark (N = 50,323; Danish Blood Donor Study, DBDS), both of which had complete blood count measures and a completed RLS assessment via the Cambridge-Hopkins RLS questionnaire. After adjusting for age, sex, race, BMI, blood donation frequency, smoking, hormone use, and iron supplement use, PPI/H2A use was associated with RLS (odds ratio [OR] = 1.41; 95% confidence interval [CI], 1.13-1.76; p = 0.002) in REDS-III for both PPI (OR = 1.43; CI, 1.03-1.95; p = 0.03) and H2A (OR = 1.56; CI, 1.10-2.16; p = 0.01). DBDS exhibited a similar association with PPIs/H2As (OR = 1.29; CI, 1.20-1.40; p < 0.001), and for PPIs alone (OR = 1.27; CI, 1.17-1.38; p < 0.001), but not H2As alone (OR = 1.18; CI, 0.92-1.53; p = 0.2). We found no evidence of blood iron stores mediating this association. The association of PPI, and possibly H2A, consumption with RLS independent of blood iron status and other factors which contribute to RLS risk suggest the need to re-evaluate use of PPI/H2A in populations at particular risk for RLS.

Process mapping of the urgent red cell exchange procedure for patients with severe complications of sickle cell disease at a centralized hemapheresis service.

Sickle cell disease (SCD) patients require urgent red cell exchange (RCE) procedures for acute chest syndrome (ACS), demanding a coordinated effort of multiple clinical services. Execution of RCE is a multistep process from the time the procedure is requested to the time the procedure is initiated. A retrospective review of patients with SCD requiring urgent RCE for ACS and stroke from 2012 to 2017 was performed at a centralized hemapheresis service covering a multihospital healthcare system. A total of 30 urgent RCE procedures performed on 28 patients were evaluated. The time required for red blood cell (RBC) preparation was the longest step in the process (median 3.8 hours). Furthermore, RBC preparation time was longer for sickle cell patients with RBC alloimmunization compared with nonalloimmunized patients (8.6 vs 3.8 hours, P = .03). One mortality event occurred in Ab- group. This study identified potentially modifiable factors, which impact the time to implementation of RCE in one service area. It highlights the importance of a structured and coordinated approach for the efficient and timely delivery of this vital treatment modality.

Therapeutic plasma exchange and intravenous immune globulin in the treatment of heparin-induced thrombocytopenia: A systematic review.

BACKGROUND: Immunomodulatory strategies in heparin-induced thrombocytopenia (HIT) include the use of intravenous immune globulin (IVIG) and therapeutic plasma exchange (TPE). The optimal application of these therapies is unknown and outcomes data are limited. We investigated treatment categories and laboratory and clinical outcomes of IVIG and/or TPE in HIT with a systematic literature review. STUDY DESIGN AND METHODS: We searched MEDLINE, Embase, and Web of Science through December 2019 for studies combining controlled vocabulary and keywords related to thrombocytopenia, heparin, TPE, and IVIG. The primary outcome was treatment indication. Secondary outcomes were platelet recovery, HIT laboratory parameters, heparin re-exposure, and post-treatment course. Case-level data were analyzed by qualitative synthesis. RESULTS: After 4241 references were screened, we identified 60 studies with four main categories of IVIG and/or TPE use as follows: (a) treatment of refractory HIT (n = 35; 31%); (b) initial therapy (n = 45; 40%); (c) cardiopulmonary bypass surgery (CPB; n = 30; 27%); and (d) other (n = 2; 2%). IVIG was most commonly used for the treatment of refractory HIT while TPE was primarily used to facilitate heparin exposure during CPB. Both IVIG and TPE were equally used as initial therapy. Heparin re-exposure occurred without thrombotic event in 29 TPE-treated patients and three IVIG-treated patients. CONCLUSION: In patients with HIT, both TPE and IVIG are used for initial therapy or treatment of refractory HIT. However, TPE is more commonly used in patients undergoing CPB. Prospective studies may help clarify which treatment is indicated in HIT population subsets.

The benefits of iron supplementation following blood donation vary with baseline iron status.

Whole blood donation rapidly removes approximately 10% of a donor's blood volume and stimulates substantial changes in iron metabolism and erythropoiesis. We sought to identify donors who benefit from iron supplementation, describe the nature of the benefit, and define the time course for recovery from donation. Blood samples were collected over 24 weeks following whole blood donation from 193 participants, with 96 participants randomized to 37.5 mg daily oral iron. Changes in total body, red blood cell (RBC), and storage iron, hepcidin, erythropoietin, and reticulocyte count were modeled using semiparametric curves in a mixed model. and the changes were compared among six groups defined by baseline ferritin (<12; 12-50; ≥50 ng/mL) and iron supplementation. The effect of oral iron on storage and RBC iron recovery was minimal in donors with baseline ferritin ≥50 ng/mL, but sizeable when ferritin was <50 ng/mL. Iron initially absorbed went to RBC and storage iron pools when ferritin was <12 ng/mL but went mostly to RBCs when ferritin was ≥12 ng/mL. Donors with ferritin ≥12 ng/mL had a "ripple" increase in reticulocytes ~100 days after donation indicating physiological responses occur months following donation. Thus, iron supplements markedly enhance recovery from whole blood donation in donors with ferritin <50 ng/mL. However, full recovery from donation requires over 100 days when taking iron. The findings also highlight the value of the study of blood donors for understanding human hemoglobin and iron metabolism and their usefulness for future studies as additional biomarkers are discovered.

Thrombotic Thrombocytopenic Purpura, Heparin-Induced Thrombocytopenia, and Disseminated Intravascular Coagulation.

Hemostatic abnormalities are common among critically ill patients and are associated with a high risk of bleeding. The abnormalities range from isolated thrombocytopenia or prolongation of global coagulation assays to complex disease states, such as thrombotic microangiopathic syndromes, and can be associated with a wide range of conditions, including trauma, surgery, acute disease processes, cardiopulmonary bypass, and exposure to drugs and blood products. Prompt identification of underlying causes is important because treatment strategies vary. Moreover, prompt initiation of both supportive and specific treatments is vital to decrease the morbidity and mortality in the intensive care unit.

Equivalent inpatient mortality among direct-acting oral anticoagulant and warfarin users presenting with major hemorrhage.

BACKGROUND: Extrapolation of clinical trial results comparing warfarin and direct-acting oral anticoagulant (DOAC) users experiencing major hemorrhage to clinical care is challenging due to differences seen among non-randomized oral anticoagulant users, bleed location, and etiology. We hypothesized that inpatient all-cause-mortality among patients presenting with major hemorrhage differed based on the home-administered anticoagulant medication class, DOAC versus warfarin. METHODS: More than 1.5 million hospitalizations were screened and 3731 patients with major hemorrhage were identified in the REDS-III Recipient Database. Propensity score matching and stratification were used to account for potentially confounding factors. RESULTS: Inpatient all-cause-mortality was lower for DOAC (HR = 0.60, 95%CI 0.45-0.80, p = 0.0005) before accounting for confounding and competing events. Inpatient all-cause-mortality for 1266 propensity-score-matched patients compared using proportional hazards regression did not differ (HR = 0.84, 95%CI 0.58-1.22, p = 0.36). Inpatient all-cause-mortality in stratified analyses (warfarin as reference) produced: HR = 0.69 (95%CI 0.31-1.55) for traumatic head injuries; HR = 1.10 (95%CI 0.62-1.95) for non-traumatic head injuries; HR = 0.62 (95%CI 0.20-1.94) for traumatic, non-head injuries; and HR = 0.69 (95%CI 0.29-1.63) for non-traumatic, non-head injuries. Mean time to discharge was shorter for DOAC (HR = 1.17, 95%CI 1.05-1.30, p = 0.0034) in the propensity score matched analysis. Plasma transfusion occurred in 42% of warfarin hospitalizations and 11% of DOAC hospitalizations. Vitamin K was administered in 63% of warfarin hospitalizations. CONCLUSIONS: After accounting for differences in patient characteristics, location of bleed, and traumatic injury, inpatient survival was no different in patients presenting with major hemorrhage while on DOAC or warfarin.

Iron status and risk factors for iron depletion in a racially/ethnically diverse blood donor population.

BACKGROUND: The optimal approach for reducing iron depletion (ID) in blood donors may vary depending on biologic or behavioral differences across donors. STUDY DESIGN AND METHODS: More than 12,600 successful whole blood donors were enrolled from four US blood centers for ferritin testing. The study population was enriched for racial/ethnic minorities (1605 African American, 1616 Asian, 1023 Hispanic). Subjects completed questionnaires on ID risk factors. Logistic regression identified predictors of absent iron stores (AIS; ferritin <12 ng/mL) and low ferritin (LF; ferritin <26 ng/mL). RESULTS: Across all subjects, 19% had AIS and 42% had LF, with a sharp increase in risk observed with increasing donation intensity and among women a large decrease in risk in those more than 50 years old. When other factors were controlled for, African American and Asian donors showed 20% to 25% decreased risk for AIS compared to non-Hispanic Caucasian donors, while Hispanic donors had 25% higher risk. Daily iron supplementation reduced risk for LF and AIS by 30% to 40%, respectively, while the benefit from less frequent use was lower (7%-19% protection). Regular antacid use was associated with at least 20% increment to risk. Use of oral contraceptives or estrogen in females reduced risk by 16% to 22%, while males who reported supplemental testosterone use had a 50% to 125% greater risk for LF and AIS. CONCLUSIONS: This study confirms high prevalence of LF and AIS in US donors and the principal risk factors of age, sex, and donation frequency. Additional demographic and behavioral risk factors of secondary importance might allow for refinement of ID mitigation strategies.

Therapeutic plasma exchange for management of heparin-induced thrombocytopenia: Results of an international practice survey.

INTRODUCTION: Anti-heparin/platelet factor 4 antibody immune complexes resulting from heparin-induced thrombocytopenia (HIT) are removed by therapeutic plasma exchange (TPE). We sought to define TPE in HIT practice patterns using an international survey. METHODS: A 31-item online survey was disseminated through the American Society for Apheresis. After institutional duplicate responses were eliminated, a descriptive analysis was performed. RESULTS: The survey was completed by 94 respondents from 78 institutions in 18 countries. Twenty-nine institutions (37%) used TPE for HIT (YES cohort) and 49 (63%) did not (NO cohort). Most NO respondents (65%) cited "no requests received" as the most common reason for not using TPE. Of the 29 YES respondents, 10 (34%) gave incomplete information and were excluded from the final analysis, leaving 19 responses. Of these, 18 (95%) treated ≤10 HIT patients over a 2-year period. The most common indications were cardiovascular surgery (CS; 63%) and HIT-associated thrombosis (HT; 26%). The typical plasma volume processed was 1.0 (63% CS and 58% HT). For CS, the typical replacement fluid was plasma (42%) and for HT, it was determined on an individual basis (32%). For CS, patients were treated with a set number of TPE procedures (37%) or laboratory/clinical response (37%). For HT, the number of TPE procedures typically depended on laboratory/clinical response (42%). CONCLUSION: In a minority of responding institutions, TPE is most commonly used in HIT to prophylactically treat patients who will undergo heparin re-exposure during CS. Prospective studies are needed to more clearly define the role of TPE in HIT.

Current good manufacturing practices-compliant manufacture and measurement of biotin-labeled red blood cells.

BACKGROUND: Red blood cells (RBCs) can be labeled with N-hydroxysuccinimidobiotin (sulfo-NHS-biotin), which binds to cell surface proteins under aqueous conditions. Biotinylated RBCs can be safely infused and detected in peripheral blood samples using flow cytometry, using a fluorochrome-conjugated streptavidin (SA) detection reagent. Biotinylated RBCs have been used to track survival of transfused RBCs, and have applications in optimizing RBC storage and in understanding donor genetic, environmental and disease factors affecting RBC products. METHODS: We have developed a closed-system, current good manufacturing practices (cGMP)-compliant procedure for biotinylation of RBCs and a quantitative flow cytometric assay to estimate the dose of cell-bound biotin delivered to the patient. Resulting products were characterized for variability, sterility, endotoxin, hemolysis, total dose of cell-bound biotin and stability. RESULTS: The density of biotin-labeling increased as a log-linear function of sulfo-NHS-biotin-labeling concentration, with greater variability at lower concentrations. The upper estimates of biotin doses in the average product (mean RBC content = 5.55 × 1011) were 9.8 and 73.0 µg for products labeled at 3 and 15 µg sulfo-NHS-biotin/mL of total reaction mixture (27 and 135 nmol/mL packed RBCs), respectively. All products were negative for bacterial and fungal growth at 14 days and were below the limit of endotoxin detection. Biotinylated RBCs were stable in vitro for up to 50 days after labeling. DISCUSSION: We have validated a closed-system procedure for biotinylating RBCs for investigational use. A standard operating procedure is presented in sufficient detail for implementation in a cGMP-compliant cell-processing facility.

Elevated risk for iron depletion in high-school age blood donors.

BACKGROUND: High school students 16 to 18 years-old contribute 10% of the US blood supply. Mitigating iron depletion in these donors is important because they continue to undergo physical and neurocognitive development. STUDY DESIGN AND METHODS: Study objectives were to determine the prevalence of iron depletion in 16- to 18-year-old donors and whether their risk for iron depletion was greater than adult donors. Successful, age-eligible donors were enrolled from high school blood drives at two large US blood centers. Plasma ferritin testing was performed with ferritin less than 12 ng/mL as our primary measure of iron depletion and ferritin less than 26 ng/mL a secondary measure. Multivariable repeated-measures logistic regression models evaluated the role of age and other demographic/donation factors. RESULTS: Ferritin was measured from 4265 enrollment donations September to November 2015 and 1954 follow-up donations through May 2016. At enrollment, prevalence of ferritin less than 12 ng/mL in teenagers was 1% in males and 18% in females making their first blood donation, and 8% in males and 33% in females with prior donations. Adjusted odds for ferritin less than 12 ng/mL were 2.1 to 2.8 times greater in 16- to 18-year-olds than in 19- to 49-year-olds, and for ferritin less than 26 ng/mL were 3.3- to 4.7-fold higher in 16- to 18-year-olds. Progression to hemoglobin deferral was twice as likely in 16- to 18-year-old versus 19- to 49-year-old females. CONCLUSION: Age 16 to 18 years-old is an independent risk factor for iron deficiency in blood donors at any donation frequency. Blood centers should implement alternate eligibility criteria or additional safety measures to protect teenage donors from iron depletion.