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Background Hemolysis following the administration of intravenous immunoglobulin (IVIG) is an important adverse event (AE). While the monocyte monolayer assay (MMA) has been used to predict in vivo hemolysis when serologically incompatible blood may be transfused, it has also been shown to correlate with IVIG-associated hemolysis. In this study, the MMA was examined for its utility in assessing the risk of hemolysis after IVIG. Study design and methods Forty-two non-blood group O patients receiving high-dose IVIG (≥2 g/kg) were examined using an autologous and allogeneic MMA. Hemolysis was defined by a drop in hemoglobin of ≥1 g/L, a positive direct antiglobulin test (DAT) and eluate, and a decrease in haptoglobin or increase in lactate dehydrogenase and/or reticulocytes. Results Forty-two patients provided 50 assessable postinfusion samples, with hemolysis observed in 20 (40%) of cases. Autologous MMA using post-IVIG red blood cells significantly correlated with clinical outcomes when compared to allogeneic MMA (P = .0320 vs .5806, t test). No significant difference in receiver operating characteristics was observed when comparing autologous MMA testing against DAT for the diagnosis of IVIG-associated hemolysis. However, when using samples collected 5 to 10 days after receipt of high-dose IVIG, the autologous MMA had higher sensitivity than the DAT. Conclusion MMA testing with autologous monocytes collected 5 to 10 days after receipt of high-dose IVIG can be used for the diagnosis of IVIG-associated hemolysis and may be of particular value in cases in which the Day 5 to 10 DAT is negative.

Background Platelet transfusions are used to prevent or control bleeding in patients with thrombocytopenia or platelet dysfunction. The pretransfusion platelet count threshold has been studied extensively in multiple patient settings yielding high-quality evidence that has been summarized in several comprehensive evidence-based platelet guidelines. Study design and methods A prospective 12-week audit of consecutive platelet transfusions using validated and evidence-based adjudication criteria was conducted. Patient demographic, laboratory, and transfusion details were collected with an electronic audit tool. Each order was adjudicated either electronically or independently by two transfusion medicine physicians. The aim was to determine platelet transfusion appropriateness and common scenarios with deviations from guidelines. Results Fifty-seven (38%) of 150 hospitals provided data on 1903 platelet orders, representing 90% of platelet usage in the region during the time period. Overall, 702 of 1693 adult (41.5%) and 133 of 210 pediatric orders (63.3%) were deemed inappropriate. The most common inappropriate platelet order was for prophylaxis in the absence of bleeding or planned procedure in patients with hypoproliferative thrombocytopenia and a platelet count over 10 x 109 /L (53% of inappropriate orders in adults and 45% in pediatrics). Platelet transfusions ordered with either a preprinted transfusion order set (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.44-2.73) or technologist prospective screening (OR, 1.40; 95% CI, 1.10-1.78) were more likely to be appropriate. Conclusion There is a discrepancy between clinical practice and evidence-based platelet guidelines. Broad educational and system changes will be needed to align platelet transfusion practice with guideline recommendations.

In this study, we assessed the association between preoperative hemoglobin and red blood cell transfusion in children undergoing spine surgery after the implementation of our preoperative iron supplementation protocol.We performed a retrospective analysis of patients who underwent posterior spinal fusion surgery between January 2013 and December 2017 and received preoperative iron supplementation. We used uni- and multivariable logistic regression to determine the association between preoperative hemoglobin level and red blood cell transfusion in patients receiving iron supplementation.A total of 382 patients treated with preoperative oral iron were included. Of these, 175 (45.5%) patients were transfused intraoperatively. Multivariable logistic regression analysis revealed nonidiopathic etiology of the scoliosis (OR 4.178 [95% CI: 2.277-7.668], P .001), the Cobb angle (OR 1.025 [95% CI: 1.010-1.040], P = .001), and number of vertebrae fused (OR 1.169 [95% CI: 1.042-1.312], P = .008) were associated with red blood cell transfusion. In addition, patients with a preoperative hemoglobin ≥ 140 g/L (OR 0.157 [95% CI: 0.046-0.540], P = .003), and hemoglobin between 130 and 140 g/L (OR 0.195 [95% CI: 0.057-0.669], P = .009) were less likely to be transfused compared with patients with preoperative hemoglobin between 120 and 130 g/L (OR 0.294 [95% CI: 0.780-1.082], P = .066) or120 g/L (reference).Our study suggests that higher preoperative hemoglobin levels (130 g/L) are associated with a reduced need for red blood cell transfusion in pediatric patients who have received iron supplementation before undergoing posterior spinal fusion in our institution. The effect of iron supplementation, the optimal dosing, and duration of supplemental iron therapy remains unclear at this time.

Hemolytic anemia resulting from IV Immunoglobulin (IVIG) treatment can be a serious complication, especially for those with underlying conditions with a high level of inflammation and after administration of high IVIG dosages, such as Kawasaki disease (KD), a multisystem vasculitis affecting young children. This hemolysis is caused by antibodies against blood groups A and B, but the precise mechanism for hemolysis is not known. We performed a single center, partly retrospective, partly prospective study of a cohort of 581 patients who received IVIG for treatment of KD from 2006 to 2013. Factors associated with hemolysis were identified through univariable and multivariable logistic regression. Six IVIG preparations were assayed for their hemolytic effect with serological and cellular assays to clarify the mechanism of red cell destruction. During the study period, a sudden increase in the incidence of hemolysis was observed, which coincided with the introduction of new IVIG preparations in North America that contained relatively high titers of anti-A and anti-B. These blood-group–specific antibodies were of the immunoglobulin G2 (IgG2) subclass and resulted in phagocytosis by monocyte-derived macrophages in an FcγRIIa-dependent manner. Phagocytosis was increased in the presence of proinflammatory mediators that mimicked the inflammatory state of KD. An increased frequency of severe hemolysis following IVIG administration was caused by ABO blood-group–specific IgG2 antibodies leading to FcγRIIa-dependent clearance of erythrocytes. This increase in adverse events necessitates a reconsideration of the criteria for maximum titer (1:64) of anti-A and anti-B in IVIG preparations.

Background Intravenous Immune Globulin (IVIG) is used to treat numerous immune-mediated and inflammatory conditions. There is growing awareness of hemolysis, occasionally severe, as a side-effect of this therapy. While most cases are associated with anti-A and/or anti-B isoagglutinins, the frequency and mechanism of hemolysis remain poorly characterized. Study design and methods A prospective observational study was conducted to determine incidence, natural history and risk factors for IVIG-mediated hemolysis. A total of 99 infusions of high-dose IVIG (2 g/kg or higher) administered to 78 non-group O patients were monitored and graded according to Canadian IVIG Hemolysis Pharmacovigilance Group. Serum ferritin and C3/C4 levels were monitored as indicators of macrophage activation and complement consumption, respectively. Supplementary investigations included assessment for ABO zygosity, Secretor status, FcR polymorphisms, eluate IgG subclass, monocyte monolayer assay, and a panel of cytokines. Results Hemolysis was observed in 32 of 99 (32%) of infusions, with 19 of 99 (19%) grade 2 or higher. Hemolysis was only apparent 5-10 days after a completed IVIG infusion in 84% of cases and was associated with increases in serum ferritin without complement-consumption. In univariate analysis, increased risk was observed in group AB patients, first-time IVIG recipients, those not taking immuosuppressive medications, or patients treated with a specific IVIG brand; however, in multivariate analysis, product association was no longer observed. No other patient- or practice-related risk factors were identified. Conclusion IVIG-mediated hemolysis is common and frequently severe. Monitoring for 5-10 days following an infusion should be considered in non-O patients receiving high-dose IVIG with known risk factors.

BACKGROUND Alloantibodies to the low-frequency antigen Scianna-2 (Sc2) have been implicated in cases of hemolytic disease of the fetus and newborn but never in hemolytic transfusion reactions (HTRs); thus, the clinical significance of anti-Sc2 has yet to be fully addressed. STUDY DESIGN AND METHODS A 26-year-old woman with thalassemia presented rigors, fever, nausea, abdominal pain, and hemolytic biochemistry after exposure to 75 mL of plasma-reduced red blood cells (RBCs). The RBC unit was issued by electronic crossmatch but was 3+ incompatible on recrossmatch by gel indirect antiglobulin test (IAT). The patient had anti-Sc2 previously identified, but considered to be clinically insignificant. The transfusion history was reviewed and a monocyte monolayer assay (MMA) was performed. RESULTS The patient was investigated for a RBC reaction 9 years prior, when she developed symptoms of HTR. The RBC unit was crossmatched by immediate spin due to consistent screen negativity. Full crossmatch found the RBC 1+ incompatible by gel IAT with both pre/post samples, while direct antiglobulin test was negative (pre) and 1+ immunoglobulin G positive (post). The antibody remained unidentified and she was committed to gel IAT crossmatch. Two-years later, the specificity to Sc2 was deduced when one RBC unit was found 3+ incompatible. Finally, the transfusion reaction reported herein occurred when she received by happenstance RBCs from the same donor who was associated with the remote reaction 9 years earlier. MMA yielded highly positive phagocytic indices only for Sc2+ RBCs, including the donor's RBCs that triggered the severe HTR. CONCLUSION This is the first case of HTR caused by anti-Sc2 confirmed by clinical findings and MMA.

TO THE EDITOR: Although frequently effective[1][1],[2][2] and usually benign, high-dose (2 g/kg) intravenous immunoglobulin (IVIG) therapy can result in marked red blood cell (RBC) hemolysis, which in some cases is life threatening in severity.[3][3][⇓][4]-[5][5] The mechanism by which this

BACKGROUND The optimal method of providing transfusion medicine (TM) education has not been determined. Transfusion Camp was established in 2012 at the University of Toronto as a centrally delivered TM education program for postgraduate trainees. The impact of Transfusion Camp on knowledge, attitudes, and self-reported behavior was evaluated. METHODS Didactic lectures (delivered locally, by webinar, or recorded) and locally facilitated team-based learning seminars were delivered over 5 days during the academic year to 8 sites: 7 in Canada and 1 in the United Kingdom. Knowledge assessment using a validated 20-question multiple-choice exam was conducted before and after Transfusion Camp. Attitudes and self-reported behavior were collected through a survey. RESULTS Over 2 academic years (July 2016 to June 2018), 390 trainees from 16 different specialties (predominantly anesthesia, 41%; hematology, 14%; and critical care, 7%) attended at least 1 day of Transfusion Camp. The mean pretest score was 10.3 of 20 (±2.9; n = 286) compared with posttest score of 13.0 (±2.8; n = 194; p < 0.0001). Lower pretest score and greater attendance (4-5 days compared with 1-3 days) were associated with larger improvement in posttest score; delivery format, specialty, and postgraduate year were not. Trainees reported an improvement in self-rated abilities to manage TM scenarios; 95% rated TM knowledge as very or extremely important in providing patient care; and 81% indicated that they had applied learning from Transfusion Camp into clinical practice. CONCLUSIONS Transfusion Camp increased TM knowledge, fostered a positive attitude toward TM, and enabled a self-reported positive impact on transfusion practice in postgraduate trainees. It is a novel and scalable approach to delivering TM education.

Aim To quantify circulating fibroblast activation protein (cFAP) and dipeptidyl peptidase 4 (cDPP4) protease activities in patients with rheumatoid arthritis (RA), systemic sclerosis (SSc), and a control group with mechanical back pain and to correlate plasma levels with disease characteristics. Methods Plasma was collected from patients with RA (n = 73), SSc (n = 37) and control subjects (n = 26). DPP4 and FAP were quantified using specific enzyme activity assays. Results Median cDPP4 was significantly lower in the RA group (P = 0.02), and SSc group (P = 0.002) compared with controls. There were no significant differences in median cFAP between the three groups. DPP4 and FAP demonstrated a negative correlation with inflammatory markers and duration of disease. There were no associations with disease subtypes in RA, including seropositive and erosive disease. Decreased cDPP4 was found in SSc patients with myositis. Plasma FAP was lower in RA patients receiving prednisone (P = 0.001) or leflunomide (P = 0.04), but higher with biologic agents (P = 0.01). RA patients receiving leflunomide also had decreased cDPP4 (P = 0.014). SSc patients receiving prednisone (P = 0.02) had lower cDPP4 but there was no association with cFAP. Conclusions No association was found between cFAP and RA or SSc. Plasma DPP4 was decreased in RA and SSc when compared with controls. cDPP4 and cFAP correlated negatively with inflammatory markers and there were no significant correlations with disease characteristics in this RA cohort.

In a failure event, circuit schematic analysis usually follows after fault isolation to increase the success rate. However, analyzing an extracted netlist of the isolated sub-circuit can be messy. Manual circuit translation from layout where the analyst is in control of the cell instance placement is one way to overcome this challenge. Although it is neater and intuitive for analysis, it can be time consuming to create the schematic. To analyze circuits in a systematic manner, cross-mapping between layout and schematic contents is the most commonly recognized approach. However, at times, cross-mapping alone is insufficient and some further simplification procedures are favorable. This paper describes the challenges and illustrates using real case studies, how schematics re-ordering and substitutions can be useful to simplify and enhance circuit analysis. These procedures can be implemented in an automated manner to enhance turnaround time for analysis.

BACKGROUND Blood transfusions and fractionated products are not without risk and may lead to acute and long-term adverse events. The objective of this study was to evaluate the appropriateness of usage of frozen plasma (FP), cryoprecipitate (CRYO), and recombinant factor VIIa (rVIIa) in a pediatric setting. METHODS All orders for FP, CRYO, and rVIIa were prospectively audited over 6 weeks. Data collected included demographics, laboratory values, indication, and adverse reactions. The appropriateness of each order was independently evaluated using adjudication criteria rated by two hematologists. RESULTS Two hundred sixty-five products were ordered; 67% of the orders were issued to operating rooms or intensive care units. The most common indication for all products was cardiac surgery. FP was ordered as fluid replacement (15/215; 7%) to correct abnormal coagulation tests (23/215; 11%) and for patients with minor or no bleeding (111/242; 46%). FP was more likely to alter the international normalized ratio (INR) if the INR was over 2.0 (P

Hyperleukocytosis in children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is associated with early morbidity and mortality. The benefit from leukapheresis is controversial, and its complications are not well defined. We analyzed the frequency of early complications in children with ALL and AML presenting with white blood cell (WBC) count >100 × 10(9)/L, and the type and frequency of complications related to leukapheresis. During a 12-year period, 84 of 634 (13%) ALL and 18 of 143 (12.5%) AML patients presented with hyperleukocytosis. Leukapheresis was performed in 18 ALL and 12 AML patients. The median initial WBC was 474 × 10(9)/L in the leukapheresis group compared with 175 × 10(9)/L in the nonleukapheresis group. Neurological leukostasis occurred in 6 ALL (7.1%) and 4 AML (22.2%) patients. Pulmonary leukostasis occurred in 16 ALL (19%) and 4 AML patients (22.2%). Neurological symptoms improved in few patients after leukapheresis, except in patients with very high WBC (>650 × 10(9)/L in ALL and >400 × 10(9)/L in AML). Leukapheresis improved respiratory symptoms in some patients but caused worsening symptoms in others. Early death was associated with neurological complications, AML diagnosis, and coagulopathy. Leukapheresis did not delay initiation of chemotherapy, nor did it impact early response to chemotherapy or long-term survival. Complications included femoral vein thrombosis, electrolyte imbalances, and hemodynamic instability, which were all reversible. The role of leukapheresis as a cytoreductive procedure in childhood hyperleukocytic leukemia remains to be well defined.

Background: Intravenous immunoglobulin (IVIG) is the mainstay of treatment for Kawasaki Disease (KD). Due to the consolidation of IVIG manufacturers in 2008, different preparations of IVIG are currently available in Canada. An increase in adverse effects, especially hemolytic anemia, has been observed. Objective: To characterize the natural history of IVIG-associated hemolytic anemia in KD. Methods: A single-centre retrospective study was conducted at Toronto’s SickKids Hospital between January 2002 and December 2012. Medical records of all KD patients were reviewed and hemolytic anemia identified (drop in hemoglobin ≥20mg/dl post-IVIG treatment with 2 or more of the following criteria: reticulocytosis, positive direct anti-globulin test (DAT), and morphological changes on blood film). For statistical analysis, Chi-square tests and ANOVA with Tukey’s post-hoc correction for multiple comparisons were utilized. Results: Between 2002 and 2008, 2 of 370 patients diagnosed with KD who received Iveegam had hemolytic anemia (0.5%). After 2008, the rates of IVIG-associated hemolysis were as follows: Privigen 17% (8/48, p5) in the hemolysis group (17% vs. 5.3%). All patients who hemolyzed had non-O+ blood types. Out of the 17 patients with hemolysis, 9 required red cell transfusions (60%). Starting in 2012, a detailed hemolysis work-up was included as standard protocol for all KD patients. Hemolysis was mediated by anti-blood group A & B antibodies resulting in DAT positivity, but no complement fixation. This extravascular hemolysis was maximal at 72 hours post-IVIG infusion and appeared to be dose dependent. Conclusions: Hemolysis is seen in up to 17% of those receiving new IVIG preparations, which also appear to be less efficacious - associated with treatment failure and, possibly, poor coronary outcome. There are important implications for patient safety. Further study is required to develop evidence-based guidelines to improve our management of these children.

An 8-year-old boy with no history of allergies received craniospinal radiation and cycles of autologous transplantations, which included chemotherapy and blood product support, for the treatment of medulloblastoma. A few weeks after his third cycle, he experienced anaphylaxis within 10 minutes after