Rachel S. Bercovitz

Transfusion reactions: prevention, diagnosis, and treatment

Blood transfusion is one of the most common procedures in patients in hospital so it is imperative that clinicians are knowledgeable about appropriate blood product administration, as well as the signs, symptoms, and management of transfusion reactions. In this Review, we, an international panel, provide a synopsis of the pathophysiology, treatment, and management of each diagnostic category of transfusion reaction using evidence-based recommendations whenever available.

Platelet transfusions for critically ill patients with thrombocytopenia

#### Continuing Medical Education onlinennThis activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology.nnMedscape

The pro‐inflammatory effects of platelet contamination in plasma and mitigation strategies for avoidance

Background and Objectivesu2002 Plasma and platelet concentrates are disproportionately implicated in transfusion‐related acute lung injury (TRALI). Platelet‐derived pro‐inflammatory mediators, including soluble CD40 ligand (sCD40L), accumulate during storage. We hypothesized that platelet contamination induces sCD40L generation that causes neutrophil [polymorphonuclear leucocyte (PMN)] priming and PMN‐mediated cytotoxicity.

A survey of transfusion practices in pediatric hematopoietic stem cell transplant patients.

Until recovery of hematopoiesis, pediatric hematopoietic stem cell transplant (HSCT) patients are dependent on red blood cell and platelet transfusions to avoid the complications associated with anemia and thrombocytopenia, respectively. Despite the fact that these patients are high utilizers of blood components, there are no evidence-based guidelines regarding optimal transfusion practices in this patient population. A web-based survey was designed to examine current transfusion thresholds used by institutions that perform pediatric HSCT. This survey was sent to department directors identified through the Children’s Oncology Group directory with a response rate of 69%. The majority of institutions use 8 g/dL as the hemoglobin threshold for red blood cell transfusions (60%), but a significant minority use 7 g/dL (25%). With respect to platelet transfusion thresholds, 47% of respondents report using 20×109/L and 44% use 10×109/L. Respondents were also asked about specific clinical scenarios that would prompt an increase in a patient’s threshold. This survey revealed that there is variation in transfusion practices among pediatric HSCT institutions with respect to both baseline transfusion threshold and what prompts an increase in threshold. Future clinical trials are needed to determine optimal transfusion thresholds in pediatric HSCT patients, which can lead to improved standardization in practices.

Measuring bleeding as an outcome in clinical trials of prophylactic platelet transfusions.

A 12-year-old girl with acute myeloid leukemia has completed her third cycle of chemotherapy and is in the hospital awaiting count recovery. Her platelet count today is 15 000 and, based on your institutions protocol, she should receive a prophylactic platelet transfusion. She has a history of allergic reactions to platelet transfusions and currently has no bleeding symptoms. The patients mother questions the necessity of todays transfusion and asks what her daughters risk of bleeding would be if the count is allowed to decrease lower before transfusing. You perform a literature search regarding the risk of bleeding with differing regimens for prophylactic platelet transfusions.

Tumor necrosis factor-α causes release of cytosolic interleukin-18 from human neutrophils

Neutrophils (PMNs) are a vital part of host defense and are the principal leukocyte in innate immunity. Interleukin (IL)-18 is a proinflammatory cytokine with roles in both innate and adaptive immunity. We hypothesize that PMNs contain preformed IL-18, which is released in response to specific inflammatory stimuli. Isolated PMNs were stimulated with a battery of chemoattractants (5 min to 24 h), and IL-18 release was measured. PMNs were also separated into subcellular fractions and immunoblotted with antibodies against IL-18 or were fixed and probed with antibodies to IL-18 as well as to the contents of granules, intracellular organelles, and filamentous actin (F-actin), incubated with fluorescent secondary antibodies, and examined by digital microscopy. Quiescent PMNs contained IL-18 in the cytoplasm, associated with F-actin, as determined by positive fluorescence resonance energy transfer (FRET+). In turn, TNF-alpha stimulation disrupted the association of IL-18 with F-actin, induced a FRET+ interaction of IL-18 with lipid rafts, and elicited IL-18 release. Manipulation of F-actin status confirmed the relationship between IL-18 and F-actin in resting PMNs. Consequently, incubation with monomeric IL-18 binding protein inhibited TNF-alpha-mediated priming of the PMN oxidase. We conclude that human PMNs contain IL-18 associated with F-actin in the cytoplasm and TNF-alpha stimulation causes dissociation of IL-18 from F-actin, association with lipid rafts, and extracellular release. Extracellular IL-18 participates in TNF-alpha priming of the PMN oxidase as demonstrated by inhibition with the IL-18 binding protein.

Thrombocytopenia and bleeding in pediatric oncology patients

Prophylactic platelet transfusions are the standard of care for patients with hypoproliferative thrombocytopenia after receiving chemotherapy or radiation for the treatment of malignancy, for BM replacement by leukemia or solid tumor, or in preparation for a hematopoietic stem cell transplantation.(1) During this time of thrombocytopenia, these patients may receive both prophylactic platelet transfusions, which are given to prevent potentially life-threatening bleeding when a patients platelet count drops below a predetermined threshold, and therapeutic platelet transfusions, which are given to treat active or recurrent bleeding. In the 1950s, the invention of the plastic blood bag allowed for the production and storage of platelet concentrates,(2) and in the 1960s, it was recognized that prophylactic platelet transfusions effectively reduced hemorrhagic death in patients with newly diagnosed leukemia.(3,4) In 1962, Gaydos published the paper that is frequently credited with the inception of the 20 000/μL platelet transfusion threshold.(5) Despite a half-century of experience with prophylactic platelet transfusions, there are still insufficient data to provide clinicians with evidence-based guidelines specific to pediatric oncology and hematopoietic stem cell transplantation (HSCT) patients.

Acute tumor lysis syndrome in a 7-month-old with hepatoblastoma.

Acute tumor lysis syndrome (TLS) is characterized by the triad of hyperuricemia, hyperkalemia, and hyperphosphatemia and is caused by the death of tumor cells and release of intracellular contents into the circulation. This syndrome is most frequently associated with hematopoietic malignancies with a high growth fraction, including acute leukemias and lymphomas, but can be encountered in patients with nonhematopoietic solid tumors. Acute tumor lysis is typically precipitated by chemotherapy leading to rapid cell death, but may also occur spontaneously prior to treatment. In severe cases, the metabolic abnormalities of TLS can cause renal failure, cardiac arrhythmias, and death. Standard therapies include intravenous hydration, alkalinization of the urine to increase the solubility of uric acid, and administration of allopurinol to block production of uric acid. Recombinant urate oxidase (rasburicase) is a newer agent that directly cleaves uric acid. It is important for the clinician to maintain a high level of clinical suspicion for TLS when initiating therapy in children newly diagnosed with cancer, including those with solid tumors, and to know how to prevent and treat this potentially deadly metabolic complication.

Neonatal Platelet Transfusions and Future Areas of Research

Thrombocytopenia affects approximately one fourth of neonates admitted to neonatal intensive care units, and prophylactic platelet transfusions are commonly administered to reduce bleeding risk. However, there are few evidence-based guidelines to inform clinicians decision-making process. Developmental differences in hemostasis and differences in underlying disease processes make it difficult to apply platelet transfusion practices from other patient populations to neonates. Thrombocytopenia is a risk factor for common preterm complications such as intraventricular hemorrhage; however, a causal link has not been established, and platelet transfusions have not been shown to reduce risk of developing intraventricular hemorrhage. Platelet count frequently drives the decision of whether to transfuse platelets, although there is little evidence to demonstrate what a safe platelet nadir is in preterm neonates. Current clinical assays of platelet function often require large sample volumes and are not valid in the setting of thrombocytopenia; however, evaluation of platelet function and/or global hemostasis may aid in the identification of neonates who are at the highest risk of bleeding. Although platelets primary role is in establishing hemostasis, platelets also carry pro- and antiangiogenic factors in their granules. Aberrant angiogenesis underpins common complications of prematurity including intraventricular hemorrhage and retinopathy of prematurity. In addition, platelets play an important role in host immune defenses. Infectious and inflammatory conditions such as sepsis and necrotizing enterocolitis are commonly associated with late-onset thrombocytopenia in neonates. Severity of thrombocytopenia is correlated with mortality risk. The nature of this association is unclear, but preclinical data suggest that thrombocytopenia contributes to mortality rather than simply being a proxy for disease severity. Neonates are a distinct patient population in whom thrombocytopenia is common. Their unique physiology and associated complications make the risks and benefits of platelet transfusions difficult to understand. The goal of this review was to highlight research areas that need to be addressed to better understand the risks and benefits of platelet transfusions in neonates. Specifically, it will be important to identify neonates at risk of bleeding who would benefit from a platelet transfusion and to determine whether platelet transfusions either abrogate or exacerbate common neonatal complications such as sepsis, chronic lung disease, necrotizing enterocolitis, and retinopathy of prematurity.

Effect of 22q11.2 deletion on bleeding and transfusion utilization in children with congenital heart disease undergoing cardiac surgery

Background:Postsurgical bleeding causes significant morbidity and mortality in children undergoing surgery for congenital heart defects (CHD). 22q11.2 deletion syndrome (DS) is the second most common genetic risk factor for CHD. The deleted segment of chromosome 22q11.2 encompasses the gene encoding glycoprotein (GP) Ibβ, which is required for expression of the GPIb-V-IX complex on the platelet surface, where it functions as the receptor for von Willebrand factor (VWF). Binding of GPIb-V-IX to VWF is important for platelets to initiate hemostasis. It is not known whether hemizygosity for the gene encoding GPIbβ increases the risk for bleeding following cardiac surgery for patients with 22q11.2 DS.Methods:We performed a case–control study of 91 pediatric patients who underwent cardiac surgery with cardiopulmonary bypass from 2004 to 2012 at Children’s Hospital of Wisconsin.Results:Patients with 22q11.2 DS had larger platelets and lower platelet counts, bled more excessively, and received more transfusion support with packed red blood cells in the early postoperative period relative to control patients.Conclusion:Presurgical genetic testing for 22q11.2 DS may help to identify a subset of pediatric cardiac surgery patients who are at increased risk for excessive bleeding and who may require more transfusion support in the postoperative period.