Biological stratification of clinical disease courses in childhood immune thrombocytopenia
Journal of thrombosis and haemostasis : JTH. 2021
BACKGROUND In childhood immune thrombocytopenia (ITP), an autoimmune bleeding disorder, there is a need for better prediction of individual disease courses and treatment outcomes. OBJECTIVE To predict the response to intravenous Immunoglobulins (IVIg) and ITP disease course using genetic and immune markers. METHODS Children aged below seven years with newly diagnosed ITP (N = 147) from the TIKI study were included, which randomized children to an IVIg or observation group. A total of 46 variables were available: clinical characteristics, targeted genotyping, lymphocyte immune phenotyping, and platelet autoantibodies. RESULTS In the treatment arm, 48/80 children (60%) showed a complete response (platelets ≥100 x 10(9) /L) that lasted for at least one month (complete sustained response; CSR) and 32 exhibited no or a temporary response (absence of a sustained response; ASR). For a biological risk score, five variables were selected by regularized logistic regression that predicted ASR vs CSR: 1) hemoglobin; 2) platelet count; 3) genetic polymorphisms of FcγRIIc; 4) the presence of IgG anti-platelet antibodies; and 5) preceding vaccination. The ASR sensitivity was 0.91 (95% CI, 0.80 - 1.00) and specificity was 0.67 (95% CI, 0.53 - 0.80). In the 67 patients of the observation arm, this biological score was also associated with recovery during one-year follow-up. The addition of the biological score to a predefined clinical score further improved the discrimination of favorable ITP disease courses. CONCLUSIONS The prediction of disease courses and IVIg treatment responses in ITP is improved by using both clinical and biological stratification.
Incidence and mortality rates of intracranial hemorrhage in hemophilia: a systematic review and meta-analysis
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.
Expected individual benefit of prophylactic platelet transfusions in hemato-oncology patients based on bleeding risks
BACKGROUND Prophylactic platelet transfusions prevent bleeding in hemato-oncology patients, but it is unclear how any benefit varies between patients. Our aim was to assess if patients with different baseline risks for bleeding benefit differently from a prophylactic platelet transfusion strategy. STUDY DESIGN AND METHODS Using the data from the randomized controlled TOPPS trial (Trial of Platelet Prophylaxis), we developed a prediction model for World Health Organization grades 2, 3, and 4 bleeding risk (defined as at least one bleeding episode in a 30 days period) and grouped patients in four risk-quartiles based on this predicted baseline risk. Predictors in the model were baseline platelet count, age, diagnosis, disease modifying treatment, disease status, previous stem cell transplantation, and the randomization arm. RESULTS The model had a c-statistic of 0.58 (95% confidence interval [CI] 0.54-0.64). There was little variation in predicted risks (quartiles 46%, 47%, and 51%), but prophylactic platelet transfusions gave a risk reduction in all risk quartiles. The absolute risk difference (ARD) was 3.4% (CI -12.2 to 18.9) in the lowest risk quartile (quartile 1), 7.4% (95% CI -8.4 to 23.3) in quartile 2, 6.8% (95% CI -9.1 to 22.9) in quartile 3, and 12.8% (CI -3.1 to 28.7) in the highest risk quartile (quartile 4). CONCLUSION In our study, generally accepted bleeding risk predictors had limited predictive power (expressed by the low c-statistic), and, given the wide confidence intervals of predicted ARD, could not aid in identifying subgroups of patients who might benefit more (or less) from prophylactic platelet transfusion.
Haemato-oncology patients enrolled in the TOPPS trial (n= 600).
Platelet transfusions based on a threshold of 10 × 10 9/L (Prophylactic arm, n= 299).
Platelet transfusions in case of active bleeding (Therapeutic arm, n= 301).
47% of patients (279) developed at least one WHO grade 2, 3, or 4 bleeding during 30-day follow-up. The model had a c-statistic of 0.58. There was little variation in predicted risks (quartiles 46%, 47%, and 51%), but prophylactic platelet transfusions gave a risk reduction in all risk quartiles. The absolute risk difference was 3.4% in the lowest risk quartile (quartile 1), 7.4% in quartile 2, 6.8% in quartile 3, and 12.8% in the highest risk quartile (quartile 4).
Back to base pairs: What is the genetic risk for red bloodcell alloimmunization?
Blood reviews. 2021;:100794
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.
Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death
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.
Are thrombocytopenia and platelet transfusions associated with major bleeding in preterm neonates? A systematic review
Blood Reviews. 2018
Over 75% of severely thrombocytopenic preterm neonates receive platelet transfusions to prevent bleeding, but transfusion guidelines are based mainly on expert opinion. The aim of this review was to investigate whether platelet counts or transfusions are associated with major bleeding in preterm neonates. We performed a systematic search of the EMBASE and MEDLINE databases until December 2017. We included randomized trials, cohort and case control studies. (Prospero: CRD42015013399). We screened 8734 abstracts and 1225 fulltexts, identifying 36 eligible studies. In 30, timing of the platelet counts or transfusions in relation to the bleeding was unclear. Of the remaining six studies, two showed that thrombocytopenia was associated with increased risk of bleeding, two showed no such assocation, and three showed lack of an association between platelet transfusions and bleeding risk. The study results suggest that prophylactic platelet transfusions may not reduce bleeding risk in preterm neonates.
The effect of a fibrin sealant on knee function after total knee replacement surgery. Results from the FIRST trial. A multicenter randomized controlled trial
Plos One. 2018;13((7)):e0200804.
BACKGROUND Total knee replacement (TKR) is increasingly performed in short term hospital stay, making same day mobilization an important issue is after surgery. This implies little joint effusion by reducing intra-articular blood loss, which will enhance knee range of motion. The application of a topical fibrin sealant on the intraoperative bare bone and synovial tissue may contribute to better early full mobilization and thus improved functional outcomes. Since ambulation with a fully extended knee is less strenuous, we hypothesized that patients who received fibrin sealant would demonstrate improved early knee extension after six weeks compared to patients who received standard care. METHODS A multicenter randomized controlled trial in a consecutive series of osteoarthritis patients scheduled for TKR surgery. Participants were randomized to receive fibrin sealant or not before closing the knee joint capsule. Primary outcome was change in knee extension angle( degrees ) at short term (2 weeks) follow-up (cExt). Secondary outcomes were 6-week extension angle, knee flexion angle, hemoglobin loss, blood transfusion rates, complication rates, the Knee Society Score, and the KOOS and EQ5D questionnaires. RESULTS When data on primary outcome became available from 250 patients, an interim analysis was performed by an independent Data Safety Monitoring Board for safety and effectivity assessment. This analysis showed that sufficient patients were included to detect a cExt of 10 degrees between both groups. Inclusion was stopped however, all in the meantime included patients were treated according to their randomization. A total of 466 were available for analysis. Both groups were comparable in terms of baseline characteristics. The estimated mean cExt difference was 0.2 degrees (95%CI -0.5 to 0.9). No differences in secondary outcomes were found. CONCLUSIONS No beneficial effects or side effects were found of a topically applied fibrin sealant during TKR surgery. These results discourage the clinical use of a fibrin sealant in TKR. TRIAL REGISTRATION Dutch Trial Register, NTR2500.
Comparing transfusion reaction rates for various plasma types: a systematic review and meta-analysis/regression
BACKGROUND We estimated rates for common plasma-associated transfusion reactions and compared reported rates for various plasma types. STUDY DESIGN AND METHODS We performed a systematic review and meta-analysis of peer-reviewed articles that reported plasma transfusion reaction rates. Random-effects pooled rates were calculated and compared between plasma types. Meta-regression was used to compare various plasma types with regard to their reported plasma transfusion reaction rates. RESULTS Forty-eight studies reported transfusion reaction rates for fresh-frozen plasma (FFP; mixed-sex and male-only), amotosalen INTERCEPT FFP, methylene blue-treated FFP, and solvent/detergent-treated pooled plasma. Random-effects pooled average rates for FFP were: allergic reactions, 92/105 units transfused (95% confidence interval [CI], 46-184/105 units transfused); febrile nonhemolytic transfusion reactions (FNHTRs), 12/105 units transfused (95% CI, 7-22/105 units transfused); transfusion-associated circulatory overload (TACO), 6/105 units transfused (95% CI, 1-30/105 units transfused); transfusion-related acute lung injury (TRALI), 1.8/105 units transfused (95% CI, 1.2-2.7/105 units transfused); and anaphylactic reactions, 0.8/105 units transfused (95% CI, 0-45.7/105 units transfused). Risk differences between plasma types were not significant for allergic reactions, TACO, or anaphylactic reactions. Methylene blue-treated FFP led to fewer FNHTRs than FFP (risk difference = -15.3 FNHTRs/105 units transfused; 95% CI, -24.7 to -7.1 reactions/105 units transfused); and male-only FFP led to fewer cases of TRALI than mixed-sex FFP (risk difference = -0.74 TRALI/105 units transfused; 95% CI, -2.42 to -0.42 injuries/105 units transfused). CONCLUSION Meta-regression demonstrates that the rate of FNHTRs is lower for methylene blue-treated compared with FFP, and the rate of TRALI is lower for male-only than for mixed-sex FFP; whereas no significant differences are observed between plasma types for allergic reactions, TACO, or anaphylactic reactions. Reported transfusion reaction rates suffer from high heterogeneity.
Effect of storage time of platelet products on clinical outcomes after transfusion: a systematic review and meta-analyses
Vox Sanguinis. 2017;112((4):):291-300
BACKGROUND Prolonged storage improves availability of platelet products but could also influence safety and efficacy. This systematic review and meta-analyses summarize and quantify the evidence of the effect of storage time of transfused platelets on clinical outcomes. METHODS A systematic search in seven databases was performed up to February 2016. All studies reporting storage time of platelet products and clinical outcomes were included. To quantify heterogeneity, I(2) was calculated, and to assess publication bias, funnel plots were constructed. RESULTS Twenty-three studies reported safety outcomes and fifteen efficacy outcomes. The relative risk of a transfusion reaction after old platelets compared to fresh platelets was 1.53 (95% confidence interval (CI): 1.04-2.25) (12 studies). This was 2.05 (CI:1.47-2.85) before and 1.05 (CI: 0.60-1.84) after implementation of universal leucoreduction. The relative risk of bleeding was 1.13 (CI: 0.97-1.32) for old platelets compared to fresh (five studies). The transfusion interval was 0.25 days (CI: 0.13; 0.38) shorter after transfusion of old platelets (four studies). Three studies reported use of platelet products: two for haematological patients and one for trauma patients. Selecting only studies in haematological patients, the difference was 4.51 units (CI: 1.92; 7.11). CONCLUSION Old platelets increase the risk of transfusion reactions in the setting of non-leucoreduction, shorten platelet transfusion intervals, thereby increase the numbers of platelet transfusions in haematological patients, and may increase the risk of bleeding.
Effect of storage time of platelet products on clinical outcomes after transfusion: a systematic review and meta-analyses
Vox Sanguinis. 2016;111((S1)):261-2.. p-488.