On this page you can view articles from previous editions of the Transfusion Evidence Alert and Round-Up; use the button on the left to sign up to receive future editions direct to your inbox. The Transfusion Evidence Alert is a monthly overview of 10 selected evidence-based publications in the field of transfusion medicine, including relevant COVID-19 articles. The articles are selected by experts in the field from the Systematic Review Initiative, funded by the four UK blood services. The Transfusion Evidence Round-Up is a quarterly overview of the top 10 high quality studies about an internationally relevant subject in the field of transfusion medicine. The articles are selected by members from the International Society of Blood Transfusion and drawn from the Transfusion Evidence Library and where relevant Stem Cell Evidence.
March 2023
Transfusion Evidence Round-Up - World Haemophilia Day 2023
Hemophilia A, the most common hereditary disorder, is caused by clotting factor deficiency. Challenges encountered in the current treatment of hemophilia A [factor VIII (FVIII) replacement therapy] due to inhibitor development have caused ineffective treatment as well as morbidity and mortality among patients. However, there are no studies comparing the two types of FVIII treatments in terms of inhibitor development rate. Therefore, we conducted this systematic review to devise a better treatment option with a lower risk of inhibitor development. The systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and by searching several databases. Data extraction on study characteristics and outcomes was conducted. Reviewers also conducted a risk of bias assessment on all studies. All eligible studies for quantitative analysis were then processed using RevMan 5.4.1 and the data was extrapolated into cumulative outcomes and expressed in forest and funnel plots. Nine studies were included in the meta-analysis, involving a total of 2,531 hemophilia A patients who were followed up from birth until death. A higher incidence of inhibitor development was found to be associated with recombinant FVIII (rFVIII) [odds ratio (OR)=1.57, 95% confidence interval (CI): 0.95-2.59; hazard ratio (HR)=1.89, 95% CI: 1.15-3.12]. The same trend was also found for high-responding inhibitors (OR=1.38, 95% CI: 0.70-2.70; HR=1.42, 95% CI: 0.84-2.39). rFVIII is associated with a higher risk of overall and high-responding inhibitor development compared to plasma-derived FVIII (pdFVIII).
PICO Summary
Population
Children and adults with haemophilia A (9 studies, n= 2,531).
Intervention
Plasma-derived factor VIII.
Comparison
Recombinant factor VIII.
Outcome
Most of the included participants in the studies were children. A higher incidence of inhibitor development was found to be associated with recombinant factor VIII (odds ratio (OR)= 1.57, 95% confidence interval (CI): 0.95-2.59; hazard ratio (HR)= 1.89, 95% CI: 1.15-3.12). The same trend was also found for high-responding inhibitors (OR= 1.38, 95% CI: 0.70-2.70; HR= 1.42, 95% CI: 0.84-2.39). Recombinant factor VIII was associated with a higher risk of overall and high-responding inhibitor development compared to plasma-derived factor VIII.
Critical reviews in oncology/hematology. 2022;:103581
Editor's Choice
Abstract
One possible side effect of thrombopoietin receptor agonists in immune thrombocytopenia is thrombosis. Our aim is to systematically review whether patients with ITP that were treated with a TPO-RA have an increased risk for thrombosis as compared to ITP patients without TPO-RA. Patients in the intervention group were required to receive TPO-RA therapy. The primary outcome was the incidence of thromboembolic events. Eleven studies were included in the pooled analysis. More thromboembolic events were noted in the TPO-RA group than in the control group: 25 compared to 4. Ten out of 11 studies showed a relative risk greater than 1. However, none of these individual risk ratios was statistically significant. The meta-analysis showed a RR of 1.82 [95% CI 0.78-4.24]. Our findings indicate there is a non-significant higher chance of thrombosis in ITP patients with TPO-RA treatments versus ITP patients without TPO-RA treatment.
PICO Summary
Population
Adult patients with persistent or chronic immune thrombocytopenia patients (11 studies).
More thromboembolic events were noted in the TPO-RA group than in the control group: 25 events compared to 4 events respectively. Ten out of 11 studies showed a relative risk greater than 1. However, none of these individual risk ratios was statistically significant. The meta-analysis showed a RR of 1.82 (95 % CI: 0.78-4.24).
Immune thrombocytopenia (ITP) is the most common clinical bleeding disorder with a high mortality rate and poor long-term survival quality in severe patients. There is controversy on how to choose the appropriate treatment. We systematically reviewed 19 randomized controlled trials (including 2615 participants) from January 1, 2015, to April 20, 2021. These investigations compared multiple drugs or their combinations in the therapeutic dose range for the treatment of ITP. The primary endpoint was based on the proportion of patients who responded to these therapies. The efficacy of eltrombopag plus rituximab, avatrombopag, dexamethasone plus anti-HP, and dexamethasone plus rhTPO was significantly higher than placebo (OR: 46.66, 29.44, 2.66, 1.86) or dexamethasone alone (OR: 46.22, 29.01, 2.22, 1.40). Placebo, oral immunosuppressants, and dexamethasone plus oseltamivir were less effective than the other ITP therapies tested. Eltrombopag plus rituximab may be the best choice when starting treatment for ITP.
PICO Summary
Population
People with idiopathic thrombocytopenia purpura (ITP) enrolled in clinical trials, and identified by systematic review (n= 2,615, 19 RCTs).
Intervention
Interventions for ITP: romiplostim, eltrombopag, rituximab, prednisolone, IVIG, efgartimod, dexamethasone or avatrombopag.
Comparison
Placebo, dexamethasone, danazol or other drug interventions.
Outcome
The efficacy of eltrombopag plus rituximab, avatrombopag, dexamethasone plus anti-HP, and dexamethasone plus rhTPO was significantly higher than placebo (odds ratio [OR]: 46.66, 29.44, 2.66, 1.86) or dexamethasone alone (OR: 46.22, 29.01, 2.22, 1.40). Placebo, oral immunosuppressants, and dexamethasone plus oseltamivir were less effective than the other ITP therapies tested.
BACKGROUND Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. OBJECTIVE To compare the effects of factor replacement therapies in patients with hemophilia. METHODS We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). RESULTS Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. CONCLUSIONS Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.
PICO Summary
Population
Patients with haemophilia (9 randomised controlled trials).
Other factor replacement therapies: episodic, tailored, or other therapies.
Outcome
Six studies compared episodic with prophylactic treatment in patients with haemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means (RM): 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups. Compared to the episodic treatment, the annualized joint bleeding rate was lower in the low-dose prophylactic treatment (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates, assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration.
BACKGROUND Knowledge about the risk for bleeding in patients with hemophilia (PWH) would be relevant for patients, stakeholders, and policy makers. OBJECTIVES to perform a systematic review of the literature on risk assessment models (RAMs) and risk factors for bleeding in PWH on regular prophylaxis. METHODS We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from inception through August 2019. In duplicate, reviewers screened the articles for inclusion, extracted data, and assessed the risk for bias using the QUIPS tool. A qualitative synthesis of the results was not performed due to high heterogeneity in risk factors, outcomes definition and measurement, and statistical analysis of the results. RESULTS From 1843 search results, 10 studies met the inclusion criteria. No RAM for the risk for bleeding in PWH was found. Most studies included only PWH A or both PWH A and B and were conducted in North America or Europe. Only one study had a low risk for bias in all the domains. Eight categories of risk factors were identified. The risk for bleeding was increased when factor levels were lower and in people with a significant history of bleeding or who engaged in physical activities involving contact. CONCLUSIONS Our findings suggest that plasma factor levels, history of bleeds, and physical activity should be considered for the derivation analysis when building a RAM for bleeding in PWH, and the role of other risk factors, including antithrombotic treatment and obesity, should be explored.
PICO Summary
Population
People living with haemophilia (PWH) A and B treated with regular prophylaxis (10 studies).
Intervention
Systematic review on risk assessment models and risk factors for bleeding.
Comparison
Outcome
No risk assessment model for the risk for bleeding was found. Most studies included only PWH A or both PWH A and B and were conducted in North America or Europe. Only one study had a low risk for bias in all the domains. Eight categories of risk factors were identified. The risk for bleeding was increased when factor levels were lower and in people with a significant history of bleeding or who engaged in physical activities involving contact.
BACKGROUND In traumatic bleeding, transfusion practice has shifted toward higher doses of platelets and plasma transfusion. The aim of this systematic review was to investigate whether a higher platelet-to-red blood cell (RBC) transfusion ratio improves mortality without worsening organ failure when compared with a lower ratio of platelet-to-RBC. METHODS Pubmed, Medline, and Embase were screened for randomized controlled trials (RCTs) in bleeding trauma patients (age ≥16 years) receiving platelet transfusion between 1946 until October 2020. High platelet:RBC ratio was defined as being the highest ratio within an included study. Primary outcome was 24 hour mortality. Secondary outcomes were 30-day mortality, thromboembolic events, organ failure, and correction of coagulopathy. RESULTS In total five RCTs (n = 1757 patients) were included. A high platelet:RBC compared with a low platelet:RBC ratio significantly improved 24 hour mortality (odds ratio [OR] 0.69 [0.53-0.89]) and 30- day mortality (OR 0.78 [0.63-0.98]). There was no difference between platelet:RBC ratio groups in thromboembolic events and organ failure. Correction of coagulopathy was reported in five studies, in which platelet dose had no impact on trauma-induced coagulopathy. CONCLUSIONS In traumatic bleeding, a high platelet:RBC improves mortality as compared to low platelet:RBC ratio. The high platelet:RBC ratio does not influence thromboembolic or organ failure event rates.
A high platelet:RBC compared with a low platelet:RBC ratio significantly improved 24 hour mortality (odds ratio (OR) 0.69 (0.53-0.89)) and 30- day mortality (OR 0.78 (0.63-0.98)). There was no difference between platelet:RBC ratio groups in thromboembolic events and organ failure. Correction of coagulopathy was reported in five studies, in which platelet dose had no impact on trauma-induced coagulopathy.
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.
Thrombopoietin receptor agonists (TPO-RAs) play a crucial role in stimulating thrombopoiesis. However, conventional meta-analyses have shown inconsistent results regarding the efficacy of thrombopoietin receptor agonists versus placebo. Therefore, we performed a network meta-analysis to assess the effects of five TPO-RAs via indirect comparison. For this network meta-analysis, we considered randomized trials that included any of the following interventions: avatrombopag, lusutrombopag, eltrombopag, romiplostim, recombinant human thrombopoietin (rhTPO). We searched the Medline, PubMed, Embase, the Cochrane Library, and Web of Science databases for randomized controlled clinical trials from inception to January 31, 2021. We use randomized controlled clinical trials of TPO-RAs for treatment of immune thrombocytopenia in adults. The primary outcome was the number of patients achieving platelet response which was defined as the achievement of a platelet count of more than 30 or 50 cells × 10(9)/L in the absence of rescue therapy, and the secondary outcome was the therapy-related serious adverse events and incidence of bleeding episodes. To obtain the estimates of efficacy and safety outcomes, we performed a random-effects network meta-analysis. These estimates were presented as odds ratios with 95% confidence intervals. We use surface under the cumulative ranking probabilities to rank the comparative effects and safety of all drugs against the placebo. In total, 2,207 patients were analyzed in 20 clinical trials. All preparations improved the point estimates of platelet response when compared with the placebo. Avatrombopag and lusutrombopag had the best platelet response compared to the placebo, the former had a non-significant advantage compared to the latter [odds ratio (OR) = 1.91 (95% confidence interval: 0.52, 7.05)]. The treatments were better than eltrombopag, romiplostim, rituximab, and rhTPO + rituximab, with corresponding ORs of 3.10 (1.01, 9.51), 9.96 (2.29, 43.29), 33.09 (8.76, 125.02), and 21.31 (3.78, 119.98) for avatrombopag and 1.62 (0.63, 4.17), 5.21 (1.54, 17.62), 17.34 (5.15, 58.36), and 11.16 (2.16, 57.62) for lusutrombopag. Regarding bleeding, the placebo group had the highest probability of bleeding, whereas lusutrombopag had the lowest risk of bleeding when compared to the placebo. Adverse events were slightly higher in patients receiving rituximab than in those receiving placebo or other treatments. Overall, this meta-analysis showed that avatrombopag may yield the highest efficacy because it has the most favorable balance of benefits and acceptability.
PICO Summary
Population
Adults with thrombocytopenia (20 studies, n= 2,207).
Intervention
Thrombopoietin receptor agonists: avatrombopag, lusutrombopag, eltrombopag, romiplostim, recombinant human thrombopoietin.
Comparison
Placebo.
Outcome
All preparations improved the point estimates of platelet response when compared with the placebo. Avatrombopag and lusutrombopag had the best platelet response compared to the placebo, the former had a non-significant advantage compared to the latter [odds ratio (OR)= 1.91 (95% confidence interval: 0.52, 7.05)]. The treatments were better than eltrombopag, romiplostim, rituximab, and rhTPO + rituximab, with corresponding ORs of 3.10 (1.01, 9.51), 9.96 (2.29, 43.29), 33.09 (8.76, 125.02), and 21.31 (3.78, 119.98) for avatrombopag and 1.62 (0.63, 4.17), 5.21 (1.54, 17.62), 17.34 (5.15, 58.36), and 11.16 (2.16, 57.62) for lusutrombopag. Regarding bleeding, the placebo group had the highest probability of bleeding, whereas lusutrombopag had the lowest risk of bleeding when compared to the placebo. Adverse events were slightly higher in patients receiving rituximab than in those receiving placebo or other treatments.
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2021
Editor's Choice
Abstract
BACKGROUND Severe thrombocytopenia in cirrhosis can preclude invasive procedures. Platelet transfusion is recommended if platelet count pre-procedure is potential alternative to platelet transfusion is thrombopoietin-receptor (TPO) agonists. AIM: Evaluate TPO-agonist efficacy and safety in cirrhotic patients with severe thrombocytopenia undergoing invasive procedures. METHODS Randomized control trials (RCT) from electronic reference databases were searched from inception till December 2019. PRISMA guidelines were followed. Primary outcome was platelet transfusion avoidance. Secondary outcomes were weighted mean difference (WMD) in platelet count from baseline to pre-procedure and rates of major adverse events (AE). Pooled Odds Ratio (OR) were estimated using a random-effects model. RESULTS Six RCTs with 1,229 patients were included. All studies had low risk of bias. Compared with placebo, those treated with TPO-agonists had a pooled OR of 0.12(0.08-0.17), P<0.01 for platelet transfusion avoidance, and WMD in platelet count (x10 3 /µL) of 35.6(28.6-42.7), P<0.01. Major AE did not differ between groups [Pooled OR: 0.87(0.47-1.62), P=0.66]. CONCLUSION Compared to placebo, TPO-agonists used in cirrhotic patients with severe thrombocytopenia prior to elective invasive procedures had 88% reduced odds of requiring peri-procedural platelet transfusion and increased platelet count pre-procedure, with no difference in AE rates.
PICO Summary
Population
Adults with cirrhosis and severe thrombocytopenia undergoing elective invasive procedures (6 randomised controlled trials, n= 1,229).
All the included studies had low risk of bias. Compared with placebo, those treated with TPO-agonists had a pooled odds ratio (OR) of 0.12 (0.08-0.17) for platelet transfusion avoidance, and weighted mean difference in platelet count (x10 3 /µL) of 35.6 (28.6-42.7). Major adverse events did not differ between groups (Pooled OR: 0.87 (0.47-1.62)).
Children with immune thrombocytopenia (ITP) rarely suffer from life-threatening bleeds (eg, intracranial hemorrhage). In such settings, the combination of IV methylprednisolone (IVMP) with IV immune globulin (IVIG) is used to rapidly increase platelet counts (PCs). However, there are no controlled data to support using combination therapy over IVIG alone. We conducted a randomized, double-blind, placebo-controlled study to evaluate the rapidity of the PC increment and associated adverse events (AEs) between 2 regimens: A (IV placebo) and B (IVMP 30 mg/kg), both given over 1 hour, followed in both cases by IVIG (Gamunex 10%) 1 g/kg over 2-3 hours in children 1-17 years old with primary ITP and PCs <20 x 109/L in whom physicians had decided to treat with IVIG. Thirty-two children (ages: median, 8 years; range, 1.2-17.5 years) with a mean baseline PC of 9.2 x 109/L participated. Eighteen were randomized to regimen A and 14 to regimen B. By 8 hours after initiating therapy, 55% of all children had a PC ≥20 x 109/L (no group difference). By 24 hours, mean PCs were 76.9 x 109/L (B) vs 55 x 109/L (A) (P = .06; P = .035 when adjusted for intergroup differences in patient ages). No patient experienced severe bleeding/unexpected severe AEs. There were statistically fewer IVIG-related headaches in the group receiving combination therapy (P = .046). Our findings show a rapid response to IVIG with/without steroids and provide evidence to support the use of IVMP+IVIG in life-threatening situations. This trial was registered at www.clinicaltrials.gov as #NCT00376077.
PICO Summary
Population
Children with immune thrombocytopenia (n=32).
Intervention
IV methylprednisolone (IVMP 30 mg/kg) followed by IVIG (Gamunex 10%) 1 g/kg, (n=14).
Comparison
IV placebo followed by IVIG (Gamunex 10%) 1 g/kg, (n=18).
Outcome
By 8 hours after initiating therapy, 55% of all children had a platelet count (PC) >/=20 x 109/L (no group difference). By 24 hours, mean PCs were 76.9 x 109/L (B) vs 55 x 109/L (A). No patient experienced severe bleeding/unexpected severe associated adverse events. There were statistically fewer IVIG-related headaches in the group receiving combination therapy.
Editor's Choice