Steven R. Sloan

Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage

BACKGROUND We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)

Effects of Red-Cell Storage Duration on Patients Undergoing Cardiac Surgery

BACKGROUND Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoing cardiac surgery may be especially vulnerable to the adverse effects of transfusion. METHODS We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge. RESULTS The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group. CONCLUSIONS The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341.).

Stochastic modeling of human RBC alloimmunization: evidence for a distinct population of immunologic responders

Red blood cell (RBC) transfusion is unique as a common large-scale intravenous introduction of foreign tissue and provides a valuable opportunity to study human immunologic response to intravenous foreign antigen. Patients receiving RBC transfusions are at risk of forming alloantibodies against donor RBC antigens, and valid estimates of alloimmunization risk are clinically important, but little is known about the factors governing this risk or, more generally, about determinants of human response to intravenous antigen. Here, we mine large electronic patient databases enabling us to model RBC alloimmunization as a stochastic process. We identify a subgroup of transfusion recipients that has a dramatically increased risk of alloimmunization that appears to be genetically determined because it is independent of common disease states, patient age, or the number of alloantibodies already formed, and only weakly dependent on transfusion count.

Phosphorylation of E47 as a potential determinant of B-cell-specific activity.

The E2A gene encodes two basic helix-loop-helix proteins designated E12 and E47. Although these proteins are widely expressed, they are required only for the B-lymphocyte lineage where DNA binding is mediated distinctively by E47 homodimers. By studying the properties of deltaE47, an N-terminal truncation of E47, we provide evidence that phosphorylation may contribute to B-cell-specific DNA binding by E47. Two serines N terminal to the deltaE47 basic helix-loop-helix domain were found to be phosphorylated in a variety of cell types but were hypophosphorylated in B cells. Phosphorylating these serines in vitro inhibited DNA binding by deltaE47 homodimers but not by deltaE47-containing heterodimers, such as deltaE47:MyoD. These results argue that hypophosphorylation may be a prerequisite for activity of E47 homodimers in B cells, suggesting the use of an inductive (nonstochastic) step in early B-cell development.

The AABB recommendations for the Choosing Wisely campaign of the American Board of Internal Medicine.

C hoosing Wisely is an initiative of the American Board of Internal Medicine Foundation designed to help physicians and patients engage in conversations to reduce overuse of tests and procedures and support physician efforts to help patients make smart and effective care choices. Blood transfusion is the commonest procedure performed in the hospitalized patient. Unnecessary use of blood transfusion in the hospitalized patient is common worldwide. Overuse of blood transfusion has also been listed as a Choosing Wisely statement by the American Society of Hematology, the Society of Hospital Medicine, and the Critical Care Societies Collaborative. To support this AABB Choosing Wisely initiative, the AABB developed a set of 10 recommendations with input from AABB committees and the AABB Board of Directors. This list was vetted by numerous AABB members to select the top five statements as required by the American Board of Internal Medicine. As required, all of these statements start with “Don’t.” The development of these statements and commentaries are intended to assist you with the promotion of better patient blood management at your local institution. These statements are intended to prompt non– transfusion medicine physicians to rethink their engrained culture of liberal transfusion practice and prompt patients to question why they are being prescribed blood. 1. Don’t transfuse more units of blood than absolutely necessary A restrictive threshold (7.0-8.0g/dL) should be used for the vast majority of hospitalized, stable patients without evidence of inadequate tissue oxygenation (evidence supports a threshold of 8.0g/dL in patients with existing cardiovascular disease). Transfusion decisions should be influenced by symptoms and hemoglobin (Hb) concentration. Singleunit red blood cell (RBC) transfusions should be the standard for nonbleeding hospitalized patients. Additional units should only be prescribed after reassessment of the patient and their Hb value. A total of 13.8 million units of whole blood and RBCs were transfused in the United States in 2011 equating to 44 units per 1000 population, which is considerably higher than in other developed countries such as Australia, Canada, the Netherlands, and the United Kingdom where the rates of RBC transfusion are at least 25% lower. In common with those countries, the use of RBC units is decreasing in the United States; the rate was 48.8 per 1000 population in 2008. In 2011, there were approximately 21 million blood components transfused in the United States. Each transfusion carries risks, although the number of transfusion-related fatalities reported to the US Food and Drug Administration (58 in 2013) and the number of transfusion-related adverse reactions reported to the National Blood Collection and Utilization Survey (51,000 in 2011) remain small in comparison to the total number of transfusions. There is considerable variation in the use of blood between countries, hospitals, and even clinical teams within the same hospital. This observation has been documented over many years and in several clinical settings and probably indicates that a substantial amount of blood is being transfused inappropriately. The precise reasons for this variation are uncertain, but they include lack of knowledge about the evidence for the restrictive use of blood and inadequate feedback of comparative data on blood utilization. The number of published clinical practice guidelines for RBC transfusion including those on behalf of the AABB and the American College of Physicians attest to the interest in appropriate blood utilization. The guidelines generally acknowledge the necessity of considering ABBREVIATIONS: INR(s) = international normalized ratio(s); PCC(s) = prothrombin complex concentrate(s); RR = risk ratio.

Neutron radiation can activate K-ras via a point mutation in codon 146 and induces a different spectrum of ras mutations than does gamma radiation.

Neutron radiation is known to produce tumors in animals and cause cell transformation. We have developed a protocol to efficiently induce thymic lymphomas in RF/J mice by a single acute dose of neutron irradiation. Activated ras genes were detected in 17% (4 of 24) of the tumors analyzed. One of the tumors contained a K-ras gene activated by a point mutation in codon 146. Activating ras mutations at position 146 have not been previously detected in any known human or animal tumors. The spectrum of ras mutations detected in neutron radiation-induced thymic lymphomas was different from that seen in thymic lymphomas induced by gamma radiation in the same strain of mice. These results may have important implications for the mechanisms by which different types of radiation damage DNA.

Efficacy of transfusion with granulocytes from G-CSF/dexamethasone–treated donors in neutropenic patients with infection

High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/μL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 10(9) granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 10(9) granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393.

Bleeding risks are higher in children versus adults given prophylactic platelet transfusions for treatment-induced hypoproliferative thrombocytopenia

Age-group analyses were conducted of patients in the prophylactic platelet dose trial (PLADO), which evaluated the relation between platelet dose per transfusion and bleeding. Hospitalized patients with treatment-induced hypoproliferative thrombocytopenia were randomly assigned to 1 of 3 platelet doses: 1.1 × 10(11), 2.2 × 10(11), or 4.4 × 10(11) platelets/m(2) per transfusion, given for morning counts of ≤ 10 000 platelets/μL. Daily hemostatic assessments were performed. The primary end point (percentage of patients who developed grade 2 or higher World Health Organization bleeding) was evaluated in 198 children (0-18 years) and 1044 adults. Although platelet dose did not predict bleeding for any age group, children overall had a significantly higher risk of grade 2 or higher bleeding than adults (86%, 88%, 77% vs 67% of patients aged 0-5 years, 6-12 years, 13-18 years, vs adults, respectively) and more days with grade 2 or higher bleeding (median, 3 days in each pediatric group vs 1 day in adults; P < .001). The effect of age on bleeding differed by disease treatment category and was most pronounced among autologous transplant recipients. Pediatric subjects were at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts.

Survey of transfusion policies at US and Canadian children's hospitals in 2008 and 2009.

BACKGROUND: Previous surveys have reported variation in transfusion practice or policies in specific pediatric populations. Our objective was to determine the current transfusion policies in US and Canadian childrens hospitals for both neonatal and pediatric general populations.

The electrical capacitance of bilayer membranes: The contribution of transient aqueous pores☆

Abstract Experiments of others have demonstrated that the electrical capacitance of artificial bilayer membranes has a transmembrane potential dependence of the form C(U) = C(0)[1 + αU2] Elsewhere it is shown that a large population of transient aqueous pores in a bilayer can explain both reversible electrical breakdown and electrically assisted destructive rupture. The population of pores is attributed to thermal fluctuations, such that a bilayer membrane contains many pores which are continually expanding or contracting. Here the contribution of transient aqueous pores to capacitance is calculated. This contribution has the correct transmembrane potential dependence, and can be a significant fraction of the experimental value. An important attribute of such pores is that they are filled with water, not electrolyte. For this reason, the pores in a typical bilayer do not conduct significantly until the transmembrane potential exceeds about 300 mV. Overall, we conclude that the presence of a large population of transient aqueous pores can be consistent with the magnitude and transmembrane potential dependence of the capacitance.