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Two-year outcomes following a randomised platelet transfusion trial in preterm infants
Moore CM, D'Amore A, Fustolo-Gunnink S, Hudson C, Newton A, Santamaria BL, Deary A, Hodge R, Hopkins V, Mora A, et al
Archives of disease in childhood. Fetal and neonatal edition. 2023
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Editor's Choice
Abstract
OBJECTIVE Assess mortality and neurodevelopmental outcomes at 2 years of corrected age in children who participated in the PlaNeT-2/MATISSE (Platelets for Neonatal Transfusion - 2/Management of Thrombocytopenia in Special Subgroup) study, which reported that a higher platelet transfusion threshold was associated with significantly increased mortality or major bleeding compared to a lower one. DESIGN Randomised clinical trial, enrolling from June 2011 to August 2017. Follow-up was complete by January 2020. Caregivers were not blinded; however, outcome assessors were blinded to treatment group. SETTING 43 level II/III/IV neonatal intensive care units (NICUs) across UK, Netherlands and Ireland. PATIENTS 660 infants born at less than 34 weeks' gestation with platelet counts less than 50×10(9)/L. INTERVENTIONS Infants were randomised to undergo a platelet transfusion at platelet count thresholds of 50×10(9)/L (higher threshold group) or 25×10(9)/L (lower threshold group). MAIN OUTCOMES MEASURES Our prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age. RESULTS Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR 1.54, 95% CI 1.09 to 2.17, p=0.017). CONCLUSIONS Infants randomised to a higher platelet transfusion threshold of 50×10(9)/L compared with 25×10(9)/L had a higher rate of death or significant neurodevelopmental impairment at a corrected age of 2 years. This further supports evidence of harm caused by high prophylactic platelet transfusion thresholds in preterm infants. TRIAL REGISTRATION NUMBER ISRCTN87736839.
PICO Summary
Population
Preterm infants enrolled in the PlaNeT-2/MATISSE trial, at 43 neonatal intensive care units across UK, Netherlands and Ireland (n= 660).
Intervention
Higher platelet transfusion threshold (n= 296).
Comparison
Lower platelet transfusion threshold (n= 305).
Outcome
The prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age. Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR: 1.54; 95% CI [1.09, 2.17]).
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Determinants of successful immune tolerance induction in hemophilia A: systematic review and meta-analysis
Oomen I, Camelo RM, Rezende SM, Voorberg J, Mancuso ME, Oldenburg J, Carcao M, Matino D, Lillicrap D, Fischer K, et al
Research and practice in thrombosis and haemostasis. 2023;7(1):100020
Abstract
BACKGROUND Immune tolerance induction (ITI) aims to eradicate anti-factor VIII (FVIII) antibodies (inhibitors) in persons with hemophilia A. However, this burdensome treatment fails in 10% to 40%. To estimate the chance of ITI success in clinical decision making, it is important to identify the predictors of ITI success. OBJECTIVES We performed a systematic review and meta-analysis to summarize the current evidence on determinants of ITI outcome in persons with hemophilia A. METHODS A literature search was conducted to identify randomized controlled trials, cohort, or case-control studies reporting on the predictors for ITI outcome in persons with hemophilia A. The main outcome was ITI success. Methodological quality was assessed using an adapted Joanna Briggs Institute checklist, rating as high if ≥11 of 13 criteria were met. Pooled odds ratios (ORs) for ITI success were calculated for each determinant. ITI success was defined as negative inhibitor titer (<0.6 BU/mL), FVIII recovery ≥66% of expected, and FVIII half-life ≥6 hours in 16 (59.3%) studies. RESULTS We included 27 studies, involving 1,734 participants. Methodological quality of 6 (22.2%) studies (418 participants) was rated as high. Twenty different determinants were assessed. Historical peak titer ≤100 BU/mL (compared with >100 BU/mL, OR, 1.7; 95% CI, 1.4-2.1), pre-ITI titer ≤10 BU/mL (compared with >10 BU/mL, OR, 1.8; 95% CI, 1.4-2.3), and peak titer during ITI ≤100 BU/mL (compared with >100 BU/mL, OR, 2.7; 95% CI, 1.9-3.8) were associated with a higher chance of ITI success. CONCLUSION Our results suggest that determinants related to the inhibitor titer are associated with ITI success.
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Incidence and mortality rates of intracranial hemorrhage in hemophilia: a systematic review and meta-analysis
Zwagemaker AF, Gouw SC, Jansen JJ, Vuong C, Coppens M, Hu Q, Feng XQ, Kim SK, van der Bom JG, Fijnvandraat K
Blood. 2021
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Full text
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Editor's Choice
Abstract
Intracranial hemorrhage (ICH) is a severe complication that is relatively common among hemophilia patients. This systematic review aimed to obtain more precise estimates of ICH incidence and mortality in hemophilia, which may be important for patients, caregivers, researchers and health policy-makers. PubMed and EMBASE were systematically searched using terms related to "hemophilia" and "intracranial hemorrhage" or "mortality". Studies that allowed calculation of ICH incidence or mortality rates in a hemophilia population of at least 50 patients were included. We summarized evidence on ICH incidence and calculated pooled ICH incidence and mortality in three age groups: (1) persons of all ages with hemophilia, (2) children and young adults below 25 years of age with hemophilia and (3) neonates with hemophilia. Incidence and mortality were pooled with a Poisson-Normal model or a Binomial-Normal model. We included 45 studies that represented 54 470 patients, 809 151 person-years and 5326 live births of hemophilia patients. In persons of all ages, the pooled ICH incidence and mortality rates were 2.3 (95% CI 1.2-4.8) and 0.8 (95% CI 0.5-1.2) per 1000 person-years, respectively. In children and young adults, the pooled ICH incidence and mortality rates were 7.4 (95% CI 4.9-11.1) and 0.5 (95% CI 0.3-0.9) per 1000 person-years, respectively. In neonates, the pooled cumulative ICH incidence was 2.1% (95% CI 1.5-2.8) per 100 live births. ICH was classified as spontaneous in 35-58% of cases. Our findings suggest that ICH is an important problem in hemophilia that occurs among all ages, requiring adequate preventive strategies.
PICO Summary
Population
Persons with haemophilia of all ages (45 studies, n= 54,470).
Intervention
Summarized evidence on intracranial haemorrhage (ICH) incidence and calculated pooled ICH incidence and mortality with a systematic review and meta-analysis.
Comparison
Outcome
Incidence and mortality were pooled with a Poisson-normal model or a binomial-normal model. The included studies represented 54,470 patients, 809,151 person-years, and 5,326 live births of patients with haemophilia. In persons of all ages, the pooled ICH incidence and mortality rates were 2.3 (95% confidence interval (CI): 1.2-4.8) and 0.8 (95% CI: 0.5-1.2) per 1,000 person-years, respectively. In children and young adults, the pooled ICH incidence and mortality rates were 7.4 (95% CI: 4.9-11.1) and 0.5 (95% CI: 0.3-0.9) per 1,000 person-years, respectively. In neonates, the pooled cumulative ICH incidence was 2.1% (95% CI: 1.5-2.8) per 100 live births. ICH was classified as spontaneous in 35% to 58% of cases.
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Back to base pairs: What is the genetic risk for red bloodcell alloimmunization?
Gerritsma JJ, Oomen I, Meinderts S, van der Schoot CE, Biemond BJ, van der Bom JG, Fijnvandraat K
Blood reviews. 2021;:100794
Abstract
Red blood cell (RBC) alloimmunization is a serious complication of blood transfusions, challenging selection of compatible units for future transfusions. Genetic characteristics may be associated with the risk of RBC alloimmunization and may therefore serve to identify high-risk patients. The aim of this systematic review was to summarize the available evidence on genetic risk factors for RBC alloimmunization. Electronic databases were searched up to April 2020 for studies (Search terms included transfusion, alloimmunization and genetic). A total of 2581 alloimmunized cases and 26,558 controls were derived from 24 studies. The alleles that were most frequently studied and that demonstrated significant associations in a meta-analysis with alloimmunization to the Duffy(a) antigen were HLA-DRB1*04 (Odds Ratio 7.80 (95%CI 4.57-13.33)), HLA-DRB1*15 (OR 3.76 (95%CI 2.14-6.59)), and HLA-DRB1*03 (OR 0.12 (95%CI 0.05-0.29)). Furthermore, significant associations with anti-K formation was found for the alleles HLA-DRB1*10 (OR 2.64 (95%CI 1.41-4.95)), HLA*DRB1*11 (OR 2.11, (95%CI 1.34-3.32)), and HLA-DRB1*13 (OR 1.71 (95%CI 1.26-2.33)). Overall, the available evidence was of moderate to low quality, hampering interpretation of reported results. There is an urgent need for high quality evidence on genetic risk factors for RBC alloimmunization.
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Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death
Fustolo-Gunnink SF, Fijnvandraat K, van Klaveren D, Stanworth S, Curley AE, Onland W, Steyerberg EW, de Kort E, d'Haens E, Hulzebos C, et al
Blood. 2019
Abstract
The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25x109/L compared to 50x109/L for major bleeding and/or mortality in preterm neonates (7% absolute risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25x109/L threshold. We aimed to assess this heterogeneity of treatment effect in the PlaNet-2 trial, in order to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariable logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into four risk quartiles. Within these quartiles we assessed absolute risk difference between the 50x109/L and 25x109/L threshold group. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval 0.58 - 0.68). The 25x109/L threshold was associated with absolute risk reduction in all risk groups, varying from 4.9% in the lowest to 12.3% in the highest risk group. These results suggest that a 25x109/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. Current Controlled Trials number ISRCTN87736839.
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Effect of von Willebrand factor on inhibitor eradication in patients with severe haemophilia A: a systematic review
van Velzen AS, Peters M, van der Bom JG, Fijnvandraat K
British Journal of Haematology. 2014;166((4):):485-95.
Abstract
This systematic review was designed to summarize the reported valid quantitative evidence on the association between use of von Willebrand factor (VWF)-containing Factor VIII (FVIII) concentrates and successful immune tolerance induction (ITI) in patients with severe haemophilia A. The primary outcome was successful ITI; secondary outcomes were time to success, complications of the inhibitor or ITI and relapse of the inhibitor. A systematic literature search identified 26 randomized controlled trials, registries and cohort studies, evaluating a total of 1284 patients. For a pooled meta-analysis, 13 studies evaluating 382 patients were included. Due to incomplete data we were not able to assign pre-ITI risk categories to all patients for risk factor analysis. The meta-analysis did not demonstrate a difference in the proportion of patients with successful inhibitor eradication between those treated with VWF-containing products and those treated with FVIII concentrates devoid of VWF (relative risk [RR] 070 (95% confidence interval [CI] 052-089) and 084 (95% CI 075-093) respectively). Bleeding rate during ITI ranged from 000 to 085 bleeding episodes per year. The proportion of patients with a relapse of the inhibitor (range 0-20%) was mentioned in four studies that were included in the meta-analysis. The results of this systematic review do not support the idea of a positive effect of VWF-containing products in ITI. 2014 John Wiley & Sons Ltd.
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Cost-effectiveness analysis of preoperative transfusion in patients with sickle cell disease using evidence from the TAPS trial
Spackman E, Sculpher M, Howard J, Malfroy M, Llewelyn C, Choo L, Hodge R, Johnson T, Rees DC, Fijnvandraat K, et al
European Journal of Haematology. 2014;92((3):):249-55.
Abstract
The study's objective was to assess the cost-effectiveness of preoperative transfusion compared with no preoperative transfusion in patients with sickle cell disease undergoing low- or medium-risk surgery. Seventy patients with sickle cell disease (HbSS/Ss(0) thal genotypes) undergoing elective surgery participated in a multicentre randomised trial, Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS). Here, a cost-effectiveness analysis based on evidence from that trial is presented. A decision-analytic model is used to incorporate long-term consequences of transfusions and acute chest syndrome. Costs and health benefits, expressed as quality-adjusted life years (QALYs), are reported from the 'within-trial' analysis and for the decision-analytic model. The probability of cost-effectiveness for each form of management is calculated taking into account the small sample size and other sources of uncertainty. In the range of scenarios considered in the analysis, preoperative transfusion was more effective, with the mean improvement in QALYs ranging from 0.018 to 0.206 per patient, and also less costly in all but one scenario, with the mean cost difference ranging from -813 to 26. All scenarios suggested preoperative transfusion had a probability of cost-effectiveness >0.79 at a cost-effectiveness threshold of 20 000 per QALY. 2013 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.
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Surgery and inhibitor development in hemophilia A: a systematic review
Eckhardt CL, van der Bom JG, van der Naald M, Peters M, Kamphuisen PW, Fijnvandraat K
Journal of Thrombosis & Haemostasis. 2011;9((10):):1948-58.
Abstract
BACKGROUND Although the association between intensive treatment and the formation of inhibiting antibodies towards factor VIII (FVIII) in hemophilia A has been demonstrated, the contributing effect of surgery is presently unclear. The release of immunological danger signals resulting from tissue damage during surgery in the presence of a high FVIII antigen load may elicit the formation of FVIII antibodies. The aim of this systematic review was to investigate the role of surgery in the inhibitor risk associated with intensive treatment as compared with treatment for bleeding and prophylactic administration of FVIII. METHODS A comprehensive literature search was performed that identified four cohort studies and three case control studies, comprising 342 inhibitor patients among a total of 957 hemophilia A patients. RESULTS Intensive treatment increased the inhibitor risk, most pronounced with intensive treatment of >= 5 exposure days (EDs) compared with < 3 EDs (OR, 4.1; 95% confidence interval, 2.6-6.5). Pooled odds ratio for inhibitor development in severe hemophilia patients that received intensive treatment for surgery at first exposure was 4.1 (95% confidence interval, 2.0-8.4) compared with treatment for bleeding or prophylaxis. Information on continuous infusion, previously treated patients and non-severe hemophilia A was insufficient for valid meta-analyses. CONCLUSIONS Intensive FVIII treatment for surgery at first exposure leads to a higher inhibitor risk in hemophilia A patients compared with intensive treatment for bleeding.