Garrett S. Booth

Red blood cell alloimmunization is influenced by recipient inflammatory state at time of transfusion in patients with sickle cell disease.

Sickle cell disease (SCD) patients are at increased risk of red blood cell (RBC) alloimmunization. Recipient inflammatory state at time of transfusion has been shown to regulate alloimmunization in murine models, but evidence is lacking in SCD patients. We retrospectively studied a cohort of alloimmunized SCD patients to determine the influence of pro‐inflammatory SCD‐related complications at time of transfusion on alloimmunization. For each transfusion, the presence of pro‐inflammatory state, degree of RBC antigen matching, unit age, storage solution and alloantibody detection date were ascertained. Transfusion‐associated pro‐inflammatory events were compared between transfusions resulting and not resulting in new alloantibodies. Univariate analysis and multivariate logistic regression were performed. Fifty‐two patients received 3166 pre‐storage leuco‐reduced transfusions of which 128 resulted in alloantibodies. Transfusions during inflammatory events were associated with increased alloantibody risk on univariate and multivariate analysis; acute chest syndrome and vaso‐occlusive crisis showed strongest associations with alloimmunization. Increased antigen matching demonstrated a protective effect on alloimmunization (univariate and multivariate analysis). Although an association was seen between citrate‐phosphate‐dextrose (adenine) stored units and alloimmunization on univariate analysis, no effect was found on multivariate analysis. Identifying recipient pro‐inflammatory states at time of transfusion that promote alloimmunization can impact RBC unit selection decisions for SCD patients at risk for alloimmunization.

Clinical guide to ABO-incompatible allogeneic stem cell transplantation.

The independent genomic inheritance of the human leukocyte antigen (HLA) and the ABO-blood group system allows for HLA-matched hematopoietic progenitor cell transplantation (HCT) to occur in donors who are not matched for ABO blood groups. In fact, nearly one-half of all HCT will involve recipient-donor ABO incompatibility. This places the recipient at increased risk for acute and delayed hemolytic reactions, delayed RBC engraftment, and pure red blood cell aplasia. Additionally, clinical and laboratory evaluation for potential non-ABO, minor RBC antigen-antibody discrepancies may be beneficial to facilitate safe transfusions before, during, and after transplantation. In addition to posing potential clinical risks, analyses of outcomes in ABO-incompatible HCT have yielded inconsistent results with respect to overall survival, relapse risk, incidence of acute or chronic graft-versus-host disease, and engraftment of platelets and granulocytes. As such, pretransplantation donor-recipient evaluation and management for ABO-incompatible HCT requires adopting unique strategies when major, minor, and bidirectional differences exist. These strategies have the potential to improve patient outcomes and allow for effective management of the blood bank inventory. The purpose of this article is to describe practical approaches to screening for and managing ABO-incompatible HCT, with the goal of reducing preventable morbidity and mortality after transplantation.

Peripheral blood stem cell transplant-related Plasmodium falciparum infection in a patient with sickle cell disease.

BACKGROUND: Although transmission of Plasmodium falciparum (Pf) infection during red blood cell (RBC) transfusion from an infected donor has been well documented, malaria parasites are not known to infect hematopoietic stem cells. We report a case of Pf infection in a patient 11 days after peripheral blood stem cell transplant for sickle cell disease.

A perfect storm: Tumor lysis syndrome with rasburicase-induced methemoglobinemia in a G6PD deficient adult.

To the Editor: Methemoglobinemia is a rare but serious complication of rasburicase administration, occurring in <1% of patients [1]. There is a paucity of cases wherein automated red blood cell exchange is used for rasburicaseinduced methemoglobinemia in an adult patient [2]. A 50-year-old African-American male newly diagnosed with T lymphoblastic leukemia presented with spontaneous tumor lysis syndrome, a blood uric acid concentration of 13.3 mg/dL (ref: 3.5–7.2 mg/dL), and evidence of acute kidney injury. Per protocol, the patient received 600 mg PO allopurinol and 7.5 mg IV rasburicase, which decreased his uric acid to 2.1 mg/dL over a period of 10 h. Six hours after rasburicase administration, the patient became dyspneic with persistent percent oxygen saturation in the 70s–80s by pulse oximetry, despite supplemental oxygen. Co-oximetry subsequently revealed a blood methemoglobin level of 10.3% (ref: <2.9%). As the patient was symptomatic, a single dose of 132 mg IV methylene blue was administered. Methemoglobin level subsequently increased to 14.6% over the next 8 h, with no clinical improvement. Additionally, the patient’s hemoglobin decreased from 14.5 to 7.7 mg/dL over the five days following rasburicase and methylene blue administration. The patient was found to be glucose-6-phosphate dehydrogenase (G6PD) deficient and methylene blue was discontinued. Continuous ascorbic acid treatment was initiated, but methemoglobin remained persistently elevated (12.9–14.6%) over the next 48 h. The transfusion medicine service was consulted to assess the patient for possible red cell exchange. The American Society for Apheresis (ASFA) 2013 guidelines regarding the use of therapeutic apheresis do not address refractory methemoglobinemia [3], but transfusion exchange has been performed successfully in at least three cases [4–6]. The decision was made to perform a 1600 mL (1 red cell volume) automated red cell exchange via right internal jugular central venous catheter, resulting in a decrease in the patient’s methemoglobin to 8.0%, a 45% reduction. The end hematocrit was 30%. This marked decrease further aides in reducing hemolysis by replacing G6PD deficient RBCs with normal RBCs. The patient saw only modest improvement (O2% saturation in the 80s, with continued subjective dyspnea), but also suffered from concurrent bilateral pleural effusions. The patient’s methemoglobin fluctuated between 7.5 and 11.0% in the 36 h following exchange, and he was discharged on room air on hospital Day 30 after completing induction chemotherapy. Rasburicase is contraindicated by an FDA black box warning in patients with G6PD deficiency, as the increased oxidative stress can cause methemoglobinemia and hemolysis [prescribing information]. In cases of severe tumor lysis syndrome, it may not be practical or possible to test for the condition prior to drug administration, as the patient may experience kidney damage in the interim, and the test has a high false negative rate during acute hemolysis [7]. However, examination of a peripheral blood smear may reveal characteristic “bite” and “blister” cells in these patients, even in the setting of a falsely normal G6PD level. Of the reported cases of rasburicase-induced methemoglobinemia, 11 of the 15 patients tested for G6PD were found deficient (73%) [8–14]; however, this may be an underestimate, as some patients were only tested for the condition in the acute phase of illness. G6PD deficiency is a relative contraindication for methylene blue therapy; like rasburicase, it may exacerbate methemoglobinemia

Brodifacoum Inhalation and its Clinical Manifestations in a 21-Year-Old Caucasian Man.

Exposure to brodifacoum, a superwarfarin substance, can lead to severe coagulopathic manifestations. Brodifacoum is a lipophilic, vitamin K antagonist with a long half-life. Clinical manifestations are challenging to diagnose if the patient cannot provide information regarding exposure. Herein, we report the first case in the literature, to our knowledge, of a patient who had intentionally inhaled brodifacoum. We performed coagulation studies such as prothrombin time (PT) and international normalized ratio (INR) to monitor vitamin K dependent coagulation factors in the patient, a 21-year-old Caucasian man. On admission to the hospital, the INR of the patient was 12.9; a computed tomography (CT) angiogram detected a mediastinal hemorrhage. In the absence of 4-factor PCC, the patient received 30 plasma transfusions during a 4-day period due to persistent left pleural effusions, along with vitamin K therapy to normalize his coagulation factors. His high-performance liquid chromatography (HPLC) results on hospital day 3 and day 26 confirmed the presence of brodifacoum in his body. We believe that inhalation led the poison to bypass the initial metabolism process of the liver, resulting in rapid anticoagulation and subsequent bleeding diathesis. Management of brodifacoum poisoning is case dependent on the amount of exposure and INR status. Constant INR monitoring, large dose vitamin K therapy and initial plasma transfusions (in the absence of PCC) were able to prevent severe internal bleeding in the patient.

Minor RBC Ab and allo-SCT.

Nearly half of all SCTs hematopoietic progenitor cell (HPC) contain some degree of ABO blood group incompatibility. ABO blood group is an important consideration in HPC because donor Abs incompatible with the recipient major RBC Ags (A and B) may result in acute hemolysis in the peri-transplant period, whereas recipient Abs to incompatible donor major RBC Ags may cause hemolysis and/or delayed RBC engraftment and prolonged RBC transfusion dependence. Non-ABO blood group Abs, also called minor blood group Abs, can cause similar complications. As a result, even in the setting of an autologous HPC, all previously identified minor RBC Abs must be accounted for in the selection of RBC units for transfusion. Although the increased level of immunosuppression during transplant can reduce the detection of previously detectable Abs, failure to provide Ag negative, crossmatchcompatible units of RBCs may reactivate the immune response and result in hemolysis. Accordingly, current Foundation for the Accreditation of Cellular Therapy (FACT) standards require the performance of ABO group and Rh typing as well as a red blood cell Ab screen before HCT (for specific standards, please see FACT standards B6.4.1, B6.4.2, D6.20.1 and D6.20.2 available at http:// www.factweb.org). Abs to various minor RBC Ags have been reported in the context of HPC, including Abs to Jk, Jk, M, Le, Di, D, E and K Ags. The incidence of minor RBC Abs complicating HPC is low, with reports ranging from 1 to 8.6%. Once such an Ab has been identified, transfusion with Ag-negative units (or, in severe cases, RBC exchange) is required to prevent hemolysis. Depending on the number of Abs and the degree of ABO incompatibility during the transplant, identifying Ag negative, crossmatch-compatible units may require an extensive search. The etiology of Abs to minor blood group Ags can be difficult to determine in patients undergoing HPC. In some cases, the Abs are believed to be due to passenger lymphocytes adoptively transferred during the stem cell infusion. In other cases, it is believed that the Abs are produced by recipient B-cells that persist after myeloablation. A third possibility is a primary immune response to minor Ag-mismatched RBCs that were transfused in the posttransplant period. Other than careful monitoring for hemolysis, there are very few measures that could be taken to avoid hemolysis arising from passenger lymphocytes or myeloablation-resistent B-cells. However, adopting a transfusion policy limiting minor Ag mismatches between RBC donors and HPC recipients could prevent post-transplant sensitization to minor RBC Ags. Opponents to the concept of minor Ag matching between RBC transfusions and HPC recipients would be correct to point out that HPC transplant recipients are profoundly immunosuppressed, and therefore have an impaired capacity to mount an immune response to minor RBC Ags. Although alloimmunization rates to the highly immunogenic D Ag are reported to be greater than 80% among healthy people, the rate of alloimmunization to the D Ag is estimated to be only B20% among general hospital patients and is exceedingly low among immunosuppressed patients undergoing liver transplantation (see Table 1). Patients undergoing HPC would be expected to be comparatively more immunosuppressed than patients undergoing liver transplantation, but D Ag alloimmunization in HPC patients may still occur, particularly in Rh-negative recipients with pre-transplant history of D Ag alloimmunization receiving Rh-positive grafts. These factors, in combination with the substantial transfusion needs of the HPC population, may make minor Ag matching seem like an ineffective use of scarce resources. However, there are convincing arguments in favor of minor RBC Ag matching between RBC transfusions and HPC recipients. First,

Primary prevention of pediatric lead exposure requires new approaches to transfusion screening.

OBJECTIVE To facilitate further assessment of transfusion-associated lead exposure by designing a procedure to test packed red blood cells (pRBCs) prepared for transfusion. STUDY DESIGN The relationship between pRBCs and whole blood lead concentration was investigated in 27 samples using a modified clinical assay. Lead concentrations were measured in 100 pRBC units. RESULTS Our sample preparation method demonstrated a correlation between whole blood lead and pRBC lead concentrations (R(2) = 0.82). In addition, all 100 pRBC units tested had detectable lead levels. The median pRBC lead concentration was 0.8 μg/dL, with an SD of 0.8 μg/dL and a range of 0.2-4.1 μg/dL. In addition, after only a few days of storage, approximately 25% of whole blood lead was found in the supernatant plasma. CONCLUSION Transfusion of pRBCs is a source of lead exposure. Here we report the quantification of lead concentration in pRBCs. We found a >20-fold range of lead concentrations in the samples tested. Pretransfusion testing of pRBC units according to our proposed approach or donor screening of whole blood lead and selection of below-average units for transfusion to children would diminish an easily overlooked source of pediatric lead exposure.

Ten-year retrospective review of transfusion practices in beating-heart organ donors.

Recent studies suggest that restrictive transfusion strategies are equivocal or noninferior to liberal strategies in various patient populations; however, evidence for the optimal transfusion threshold or current transfusion practice in beating‐heart organ donors is lacking. A 10‐year retrospective analysis of blood product utilization in beating‐heart organ donors was performed to determine current transfusion practice.

Reducing intraoperative red blood cell unit wastage in a large academic medical center.

The wastage of red blood cell (RBC) units within the operative setting results in significant direct costs to health care organizations. Previous education‐based efforts to reduce wastage were unsuccessful at our institution. We hypothesized that a quality and process improvement approach would result in sustained reductions in intraoperative RBC wastage in a large academic medical center.

Warm autoimmune hemolytic anemia secondary to Plasmodium ovale infection: A case report and review of the literature

A three year old male from the Democratic Republic of the Congo was admitted to Monroe Carell Jr. Childrens Hospital at Vanderbilt with a 10-day history of fever, emesis, and diarrhea. Examination demonstrated scleral icterus, splenomegaly, and anemia. By peripheral blood smear, the patient was diagnosed with Plasmodium ovale. Immunohematology demonstrated a positive direct antiglobulin test (DAT) for IgG and C3d with pan-agglutination on eluate. These findings, in combination with hemolytic labs, signified presence of an autoimmune hemolytic anemia (AIHA). We believe this to be the first reported case of P. ovale infection-mediated AIHA.