Publications by authors named "Julie Carruthers"

14 Publications

  • Page 1 of 1

Cost-effectiveness of eltrombopag versus intravenous immunoglobulin for the perioperative management of immune thrombocytopenia.

Blood Adv 2021 Nov 15. Epub 2021 Nov 15.

McMaster University, Hamilton, Canada.

Eltrombopag has been shown to be non-inferior to intravenous immunoglobulin (IVIG) for improving perioperative platelet counts in patients with immune thrombocytopenia (ITP) in a randomized trial; thus, cost is an important factor for treatment and policy decisions. We used patient-level data from the trial to conduct a cost-effectiveness analysis comparing perioperative eltrombopag 50mg daily starting dose, with IVIG 1 or 2g/kg (according to local practice) from a Canadian public healthcare payer's perspective over the observation period, from preoperative day 21 to postoperative day 28. Resource utilization data were obtained from the trial data (eltrombopag, n=38; IVIG, n=36) and unit costs were collected from the Ontario Schedule of Benefits, Ontario Drug Formulary, and secondary sources. All costs were adjusted to 2020 Canadian dollars. We calculated the incremental cost per patient for all patients randomized. Uncertainty was addressed using non-parametric bootstrapping. The use of perioperative eltrombopag for patients with ITP resulted in a cost-saving of $413 Canadian dollars per patient. Compared with IVIG, the probability of eltrombopag being cost-effective was 70% even with zero willingness to pay. In a sensitivity analysis based on IVIG dose, we found that with the higher dose of IVIG (2g/kg), eltrombopag saved $2,714 per patient; whereas with the lower dose of IVIG (1g/kg), eltrombopag had a higher mean cost of $562 per patient. In summary, based on data from the randomized trial that demonstrated non-inferiority, the use of eltrombopag for the management of ITP in the perioperative setting was less costly than IVIG.
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http://dx.doi.org/10.1182/bloodadvances.2021005627DOI Listing
November 2021

Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial.

Trials 2021 May 4;22(1):323. Epub 2021 May 4.

McMaster Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada.

Background: Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection.

Methods: CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n = 600).

Discussion: This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification.

Trial Registration: Clinicaltrials.gov NCT04348656 . Registered on 16 April 2020.
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http://dx.doi.org/10.1186/s13063-021-05235-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094980PMC
May 2021

Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia: a non-inferiority, multicentre, randomised trial.

Lancet Haematol 2020 Sep;7(9):e640-e648

Michael G DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada; McMaster Centre for Transfusion Research, Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.

Background: Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin.

Methods: We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 10 cells per L before major surgery or less than 50 × 10 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 10 cells per L before major surgery or 45 × 10 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov, NCT01621204.

Findings: Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49-55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; p=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI -2·1%; p=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred.

Interpretation: Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles.

Funding: GlaxoSmithKline and Novartis.
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http://dx.doi.org/10.1016/S2352-3026(20)30227-1DOI Listing
September 2020

Peri-Operative Eltrombopag or Immune Globulin for Patients with Immune Thrombocytopaenia (The Bridging ITP Trial): Methods and Rationale.

Thromb Haemost 2019 Mar 27;119(3):500-507. Epub 2019 Jan 27.

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.

Background:  The Bridging ITP Trial is an open-label randomized trial designed to compare the oral thrombopoietin receptor agonist eltrombopag and intravenous immune globulin (IVIG) for patients with immune thrombocytopaenia (ITP) who require an increase in platelet count before elective surgery. Here, we report the study methods and rationale.

Methods:  We designed a multi-centre, non-inferiority randomized trial comparing daily oral eltrombopag starting 3 weeks pre-operatively, and IVIG administered 1 week pre-operatively for patients with ITP requiring a platelet count increase prior to surgery. Starting dose of eltrombopag is 50 mg daily with a weekly pre-operative dose titration schedule, and treatment is continued for 1 week after surgical haemostasis is achieved. IVIG is administered at a dose of 1 to 2 g/kg 1 week pre-operatively with the allowance for a second dose within 1 week after surgical haemostasis. The objective of the study is to demonstrate non-inferiority of eltrombopag for the primary endpoint of achieving the pre-operative platelet count threshold (50 × 10/L for minor surgery; or 100 × 10/L for major surgery) and sustaining platelet count levels above the threshold for 1 week after surgical haemostasis is achieved, without the use of rescue treatment. Secondary endpoints include thrombosis, bleeding and patient satisfaction.

Conclusion:  The Bridging ITP Trial will evaluate the efficacy and safety of eltrombopag as an alternative to IVIG in the peri-operative setting for patients with ITP. The protocol was designed to provide a management strategy that can be applied in clinical practice. CLINICALTRIALS.

Gov Identifier:  NCT01621204.
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http://dx.doi.org/10.1055/s-0038-1677531DOI Listing
March 2019

Effect of a thrombopoietin receptor agonist on use of intravenous immune globulin in patients with immune thrombocytopenia.

Transfusion 2016 Jan 24;56(1):73-9. Epub 2015 Sep 24.

Department of Medicine Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario.

Background: Thrombopoietin receptor agonists are new treatments for patients with chronic immune thrombocytopenia (ITP). How one of these agent, romiplostim, has impacted practice patterns, especially the use of intravenous immune globulin (IVIG), has not been evaluated outside of clinical trials.

Study Design And Methods: This was a retrospective cohort study of adult ITP patients treated with romiplostim in four Canadian centers. Patients had primary or secondary ITP and were followed for 1 year before starting weekly romiplostim treatment. We compared IVIG use, clinical outcomes, and cost before and after romiplostim.

Results: Twenty-nine patients with ITP received romiplostim. Median age was 54 years (interquartile range [IQR], 45-63 years) and patients had a median of two prior ITP treatments (IQR, 1-4) including splenectomy (n = 7). Median platelet (PLT) count was 23 × 10(9) before and 124 × 10(9) after romiplostim. Median duration of romiplostim treatment was 3.7 months. Patients used a median of two IVIG infusions per year before and 0.7 per year after starting romiplostim (p = 0.16). For patients who received weekly romiplostim for at least 1 month (n = 19), IVIG infusions were three (IQR, 1-5) per year before and 0.7 (IQR, 0.4-1.6) per year after romiplostim. Results were squewed by two high IVIG users. Nineteen (66%) patients discontinued romiplostim treatment during follow-up because of lack of response (n = 8), sustained response (n = 5), toxicities (n = 4), or response to splenectomy (n = 2). Overall health care costs were similar before and after romiplostim when concomitant treatments, nursing resources, and hospitalizations were considered.

Conclusions: Romiplostim was associated with improved PLT counts and fewer IVIG infusions for most ITP patients. In practice, romiplostim was generally not continued long term and was cost neutral for overall ITP management.
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http://dx.doi.org/10.1111/trf.13336DOI Listing
January 2016

A new tool to assess bleeding severity in patients with chemotherapy-induced thrombocytopenia.

Transfusion 2012 Nov 9;52(11):2466-74; quiz 2465. Epub 2012 Apr 9.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Background: Current scales to measure bleeding in clinical trials are inadequate. The aim of this study was to develop a simple, valid, and reliable measurement tool to categorize the severity of bleeding in patients with chemotherapy-induced thrombocytopenia (CIT).

Study Design And Methods: Measurement theory was used to develop the Bleeding Severity Measurement Scale (BSMS) in four steps: 1) identification of the patient population, 2) item generation and reduction, 3) reviewing the items and formatting the scale, and 4) evaluation of psychometric properties. Feasibility was tested in a pilot study. Content and face validity were assessed by expert review. Psychometric evaluation included determination of intra- and interrater reliability and construct and criterion validity.

Results: The final BSMS defined two grades of bleeding: not clinically significant (Grade 1) and clinically significant (Grade 2). Grade 2 bleeds were defined as bleeds resulting in morbidity, requiring interventions, or directly causing death. The BSMS had excellent interrater (intraclass correlation coefficient [ICC], 0.80) and intrarater (ICC, 1.0) reliability and good construct and criterion validity. The BSMS distinguished between patients with different bleeding severities.

Conclusion: Using rigorous methods, we designed a simple bleeding assessment tool with excellent psychometric properties for patients with CIT. Use of this scale in clinical trials should provide valid and reliable assessments of bleeding.
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http://dx.doi.org/10.1111/j.1537-2995.2012.03634.xDOI Listing
November 2012

A pilot randomized trial of adjuvant rituximab or placebo for nonsplenectomized patients with immune thrombocytopenia.

Blood 2012 Feb 5;119(6):1356-62. Epub 2012 Jan 5.

Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.

The benefit of adding rituximab to standard treatment in nonsplenectomized patients with primary immune thrombocytopenia (ITP) is uncertain. We performed a pilot randomized trial to determine the feasibility of recruitment, protocol adherence, and blinding of a larger trial of rituximab versus placebo; and to evaluate the potential efficacy of adjuvant rituximab in ITP. Nonsplenectomized adults with newly diagnosed or relapsed ITP who were receiving standard ITP therapy for a platelet count below 30 × 10(9)/L were randomly allocated to receive 4 weekly infusions of 375 mg/m(2) rituximab or saline placebo. Sixty patients were recruited over 46 months, which was slower than anticipated. Protocol adherence and follow-up targets were achieved, and blinding was successful for research staff but not for patients. After 6 months, there was no difference between rituximab and placebo groups for the composite outcome of any platelet count below 50 × 10(9)/L, significant bleeding or rescue treatment once standard treatment was stopped (21/32 [65.6%] vs 21/26 [80.8%]; relative risk = 0.81, 95% confidence intervals, 0.59%-1.11%). Timely accrual poses a challenge to the conduct of a large randomized trial of rituximab for presplenectomy ITP. No difference in the frequency of the composite outcome was observed in this pilot trial (registered at www.clinicaltrials.gov NCT00372892).
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http://dx.doi.org/10.1182/blood-2011-08-374777DOI Listing
February 2012

Misleading hepatitis B test results due to intravenous immunoglobulin administration: implications for a clinical trial of rituximab in immune thrombocytopenia.

Transfusion 2010 Dec;50(12):2577-81

Department of Medicine, Michael DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.

Background: Rituximab may cause reactivation of hepatitis B virus (HBV) even in patients with remote HBV infection. Thus, the presence of hepatitis B core antibodies (anti-HBc) was an exclusion criterion for a randomized trial of rituximab for patients with immune thrombocytopenia. A high seroprevalence of anti-HBc observed among patients screened for the trial prompted this substudy to investigate for an association between anti-HBc seropositivity and exposure to intravenous immunoglobulin (IVIG).

Study Design And Methods: This was a retrospective case-control study that was a substudy of a randomized controlled trial.

Results: Of 24 trial participants screened at one center, 11 (45.8%) were anti-HBc positive and of those, 10 (90.0%) had received IVIG in the preceding 4 weeks. Of 13 seronegative patients screened, five (38.5%) had received IVIG (odds ratio, 16; 95% confidence interval, 1.5-166.1). Seven (70%) of 10 seropositive participants subsequently reverted to negative upon repeat testing. Serial testing before and after IVIG (n = 2) demonstrated transient anti-HBc that lasted for up to 11 weeks after the last dose of IVIG. Samples from three of five different IVIG products were found to contain anti-HBc.

Conclusions: Passive transfer of anti-HBc from certain IVIG products may lead to misinterpretation of hepatitis test results with implications for treatment and clinical trial eligibility. To avoid misleading test results, anti-HBc should be measured before or 3 months after IVIG administration; alternatively an IVIG product known to be free of anti-HBc should be used.
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http://dx.doi.org/10.1111/j.1537-2995.2010.02766.xDOI Listing
December 2010

A multicenter pilot-randomized controlled trial of the feasibility of an augmented red blood cell transfusion strategy for patients treated with induction chemotherapy for acute leukemia or stem cell transplantation.

Transfusion 2008 Jan 24;48(1):81-91. Epub 2007 Sep 24.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Background: Anemia may be an important factor contributing to an increased risk of bleeding, particularly in patients with thrombocytopenia.

Study Design And Methods: A multicenter, single-blinded pilot randomized controlled trial (RCT) was performed to evaluate the feasibility of conducting a larger RCT to determine the effect of the hemoglobin (Hb) concentration on bleeding risk. Patients with acute leukemia receiving induction chemotherapy or those undergoing stem cell transplantation were assigned to one of two treatment groups: standard transfusion strategy (transfusion of 2 units of red blood cells [RBCs] when their Hb level was less than 80 g/L) or an augmented transfusion strategy (transfusion of 2 units of RBCs when their Hb level was less than 120 g/L).

Results: Sixty patients were enrolled: 29 in the control group and 31 in the experimental group. The proportions of patients experiencing clinically significant bleeding and the time to first bleed were not significantly different between the control and experimental groups. The experimental group received more RBC transfusions (transfusions/patient-day) than the control group (0.233 vs. 0.151; relative risk, 1.56; 95% confidence interval, 1.16-2.10; p = 0.003). The proportion of patient-days with platelet (PLT) transfusions was not different between the experimental and control groups. The mean number of donor exposures (PLT and RBC transfusions) was not different between experimental and control groups. Bleeding symptoms were systematically documented.

Conclusion: This pilot study thus indicated that it would be feasible to enroll the required number of patients to enable the performance of a large RCT to investigate the effect of Hb on bleeding risk in thrombocytopenic patients.
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http://dx.doi.org/10.1111/j.1537-2995.2007.01485.xDOI Listing
January 2008

A study of the agreement between patient self-assessment and study personnel assessment of bleeding symptoms.

Transfusion 2006 Nov;46(11):1926-33

McMaster University, Hamilton, Ontario, Canada.

Background: Clinical trials investigating new platelet transfusion therapies frequently require the assessment of bleeding for the study outcome. These assessments are commonly performed by study personnel and can be time-consuming. The purpose of this study was to assess whether patients were able to reliably assess their bleeding status on a daily basis.

Study Design And Methods: Patients admitted to hospital to receive chemotherapy for acute leukemia or to undergo allogeneic peripheral blood progenitor cell transplant were included. Patients were given an introduction to a form for documenting the occurrence of 16 bleeding symptoms. Patients completed this form and were examined daily by a study assessor. A weekly health record review was also performed by a study assessor. The agreement between raters was determined by calculating the raw agreement, chance-corrected agreement, and chance-independent agreement.

Results: Thirty-five patients completed 458 assessment forms that were paired with 559 forms completed by a study assessor with 450 matched forms available for analysis (mean, 12.86 per patient). Agreement for most individual bleeding symptoms was high. Thirteen items had agreement greater than 90 percent and all items had agreement greater than 77 percent. The lowest agreement was seen for skin symptoms: petechiae (89.2%), purpura (80.9%), and ecchymosis (77.6%). The negative predictive value of patient self-assessment was high (range, 71.1%-100%) whereas the positive predictive value was lower (range, 0%-86.5%).

Conclusion: The reliability was very good between patients and study assessors with the patients reporting excellent negative predictive value and variable positive predictive value.
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http://dx.doi.org/10.1111/j.1537-2995.2006.00999.xDOI Listing
November 2006

In vivo recovery and survival of apheresis and whole blood-derived platelets: a paired comparison in healthy volunteers.

Transfusion 2006 Feb;46(2):257-64

Canadian Blood Services, Hamilton, Ontario, Canada.

Background: Methods of platelet preparation may alter the recovery and survival characteristics of platelets following transfusion. As suggested by a recent clinical trial, platelet recovery may be better preserved with apheresis platelet preparations than with platelets prepared from whole blood by the platelet-rich plasma (PRP) method.

Study Design And Methods: In vivo platelet recovery and survival of autologous leukoreduced (LR) apheresis platelets and autologous filter-LR PRP platelets were compared in 22 healthy volunteers using a paired crossover design. On the same day, each participant gave one apheresis platelet donation and one whole blood donation from which platelets were recovered from the PRP. The sequence of donations was randomly assigned for each participant. Following 5 days of storage and bacterial screening, a sample from each platelet product was labeled with either (51)chromium or (111)indium (randomly assigned) and both samples were simultaneously re-infused into the original donor. Recovery and gamma-function platelet survival were calculated for each platelet product using the multiple hit mathematical model.

Results: Five day stored LR-apheresis platelets had 18.8 percent better recovery, and 32.9 percent longer gamma-survival than filter-LR PRP platelets. Stored apheresis platelets had lower p-selectin expression and higher morphology scores than stored PRP platelets.

Conclusions: Filter-LR PRP platelet preparation appears to adversely affect platelet recovery and survival characteristics. The reasons for this effect are not clear. These results may not apply to all apheresis and PRP methods of platelet preparation.
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http://dx.doi.org/10.1111/j.1537-2995.2006.00709.xDOI Listing
February 2006

Developing a tracking system for coagulation factor concentrates in southern Ontario.

Transfusion 2003 May;43(5):556-62

McMaster University Medical Center, 1200 Main St. West, Hamilton, Ontario, Canada, L8N 3Z5, USA.

Background: In response to the transfusion- transmitted AIDS epidemic, Canadian authorities recommended the development of tracking systems and improved reporting of adverse events. This study describes the development of a verifiable and comprehensive regional tracking system for coagulation factor concentrates.

Study Design And Methods: The Hamilton- Niagara Regional Hemophilia Program received distribution and utilization data from Canadian Blood Services, 26 regional hospitals, and 70 individuals with bleeding disorders on home-based therapy. Purpose-specific software, the Canadian Hemophilia Assessment and Resource Management System (CHARMS), was used to store, monitor, analyze, and validate data.

Results: During a 1-year period (2001), all factor concentrates distributed in this region were accounted for. A higher proportion of FVIII and FIX concentrates (88 vs. 12%) was infused at home than in hospitals, and a higher proportion (63 vs. 28%) was used to prevent than to treat bleeds. During a period of shortage, a 5-percent reduction in utilization of both FVIII and FIX concentrates was documented. One recall was managed swiftly and efficiently. Two patients reported allergic skin reactions.

Conclusion: A verifiable tracking system has been developed that can provide ongoing data for both clinical and administrative purposes. Data collection from patients needs to be made more efficient and real-time recording is an important future objective. Such a system can be instituted locally for less than 1.5 percent of the cost of the factor concentrate used.
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http://dx.doi.org/10.1046/j.1537-2995.2003.00387.xDOI Listing
May 2003

Platelet transfusions in children: results of a randomized, prospective, crossover trial of plasma removal and a prospective audit of WBC reduction.

Transfusion 2002 Jun;42(6):753-8

Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

Background: Febrile nonhemolytic transfusion reactions (FNHTRs) complicate 2 to 37 percent of platelet transfusions in adults, but the incidence of such reactions in children is not known. The effectiveness of plasma reduction after storage and WBC reduction of platelet concentrates before storage was studied in pediatric recipients of platelet transfusions.

Study Design And Methods: In the first study, a prospective randomized crossover design was used in which patients received either unmodified whole-blood-derived or apheresis platelets or platelets from which most of the plasma supernatant had been removed just before transfusion. The second study was a prospective audit of recipients of prestorage WBC-reduced platelets. Children between 3 months and 17 years of age were eligible for both studies. Patients were assessed for signs and symptoms that are characteristic of a reaction during, immediately after, and 2 hours following transfusion.

Results: There were 226 platelet transfusions administered to 66 children. One hundred and sixty transfusions were given to 35 children enrolled in the randomized study, and 66 transfusions were given to 33 children during the audit. In the randomized study, nine of the 75 transfusions of unmodified platelets (12%) and six of 85 transfusions of poststorage plasma-removed platelets (7%) were associated with an FNHTR (p=0.42). In the audit, three of 66 transfusions of prestorage WBC-reduced platelets (5%) were associated with an FNHTR. Allergic reactions occurred with 5 percent (4 of 75), 6 percent (5 of 85), and 6 percent (4 of 66) of platelet transfusions, respectively.

Conclusion: FNHTRs appear to be less common among pediatric recipients of platelet transfusions than in adults. In our two studies, there was a trend toward a lower frequency of FNHTRs with poststorage plasma removal and prestorage WBC reduction than with standard platelets, but this was not significant.
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http://dx.doi.org/10.1046/j.1537-2995.2002.00070.xDOI Listing
June 2002

Unique Catalysis and Regioselectivity Observed in the Poly(C)-Directed RNA Dimer Formation from 2-MeImpG: Kinetic Analysis as a Function of Monomer and Polymer Concentration.

J Org Chem 1999 Oct;64(22):8323-8333

Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064.

Polycytidylate, poly(C), serves as a scaffold or template to direct and catalyze the synthesis of long oligoguanylates from guanosine 5'-phosphate 2-methylimidazolide, 2-MeImpG. In the absence of poly(C), small amounts of three isomeric dimers, i.e., the 2'-5'-, the 3'-5'-, and the pyrophosphate-linked, are formed slowly. In the presence of poly(C) oligomers that are primarily 3'-5'-linked are formed quickly and in high yield. Product analysis suggests that the oligomers are elongation products of the 3'-5'-linked dimer, abbreviated D. Assuming that D is formed slowly from two molecules of 2-MeImpG (Scheme 1) and elongates relatively fast, the initial rate of dimerization, d[D]/dt in M h(-1), was determined using two independent methods. The first method is based on the approximation that at the onset of the reaction the substrate is consumed only via hydrolysis and dimerization, and thus elongation can be neglected. The second, more accurate, method exploits the assertion that every oligomer was once a 3'-5'-linked dimer. Hence the concentration of D was obtained indirectly from the concentration of the oligomer products. These two methods gave comparable results. Experiments were run in aqueous solution in the presence of 1.0 M NaCl, 0.2 M MgCl(2) at pH 7.9 +/- 0.1 and 23 degrees C. Controls were run in the absence of poly(C) and in the presence of other polynucleotides. The kinetics were determined as a function of both monomer and polymer concentration the latter expressed in C equivalents. The kinetic data obtained in the presence of poly(C) confirmed an earlier conclusion regarding the remarkable effect of poly(C) on the formation of the 3'-5'-linked diguanylate. Initial dimerization rates were quantitatively correlated using a simple template-directed (TD) model that presumes cooperative binding (two association constants) of 2-MeImpG on poly(C) and reaction between adjacent template-bound molecules. The model allows for the estimation of the association constants and the intrinsic rate constant of dimerization, k(2). Insights into the detailed mechanism are also gained from this analysis. The fact that the proposed model can successfully correlate kinetic data that vary by more than 5000-fold between the slowest and the fastest reaction adds confidence and suggests the suitability of this model for describing TD reactions in general. It is anticipated that similar analysis of other known TD reactions may lead to clues that will facilitate the design of more efficient polynucleotide-synthesizing systems.
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http://dx.doi.org/10.1021/jo991216qDOI Listing
October 1999
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