Twice Weekly Vs. Thrice Weekly Low-Dose Prophylactic Factor VIII Therapy in Children with Hemophilia A: An Open Label Randomized Trial
Journal of tropical pediatrics. 2022;68(3)
INTRODUCTION Low dose factor VIII prophylactic therapy in hemophilia has not been well established till date. This randomized controlled trial compared the efficacy of twice vs. thrice weekly schedule of low dose prophylactic factor VIII in children with hemophilia A as evaluated by the bleeding rate and clinico-radiological evaluation. METHODS Thirty-three children with severe hemophilia A (≤18 years) were randomized into two groups. Baseline evaluation included detailed history, clinical (HJHS 2.1 score and FISH score) and radiological examination (Pettersson score and ultrasound score). Group 1 received twice weekly factor VIII prophylaxis while group 2 received thrice weekly factor VIII prophylaxis, the dose being 10 U/kg in both groups. All participants were followed up over next 6 months to one year. Data regarding acute bleeding episodes and repeat clinico-radiological assessment at the end of follow up were recorded. RESULTS We analyzed 14 children in twice weekly prophylaxis group and 16 children in thrice weekly prophylaxis group. Statistically insignificant difference was found between the bleeding rates in both the groups after prophylaxis with the median values of monthly bleeding rate being 0.17 and p-value of 0.79. The differences between the initial and final clinical and radiological scores within each group were found to be statistically significant. There was no significant difference in the clinical and radiological scores in between the groups. CONCLUSION Twice weekly FVIII therapy is effective, easily administered prophylactic schedule to prevent long-term complications of hemophilia A. Lay summaryHemophilia A is one of the most common congenital coagulation factor deficiencies. Low dose factor VIII prophylaxis is recommended for hemophilia in resource-poor settings to reduce the bleeding episodes and improve the quality of life, although the optimal schedule for the same has not been well established. A randomized controlled trial on 33 children with hemophilia A (≤18 years) was done to compare the efficacy of twice versus thrice weekly schedule of prophylactic factor VIII. Group 1 received twice weekly factor VIII prophylaxis while group 2 received thrice weekly factor VIII prophylaxis, the dose in both groups being 10 U/kg. They were evaluated by the bleeding rate and clinical (HJHS 2.1 score and FISH score) and radiological scores (Pettersson score and ultrasound score). All participants were followed up over next 6 months to one year. Data regarding acute bleeding episodes and repeat clinico-radiological assessment at end of follow up were recorded. When analyzed, statistically insignificant difference was found between the bleeding rates after the two prophylaxis regimes. There was a significant improvement between initial and final clinical and radiological scores in both the groups and no difference was recorded in between the groups. To conclude, twice weekly FVIII therapy is effective, easily administered prophylactic schedule to prevent long-term complications of hemophilia A.
Measuring Factor XIII Inhibitors in Patients with Factor XIII Deficiency: A Case Report and Systematic Review of Current Practices in Japan
Journal of clinical medicine. 2022;11(6)
Factor XIII (FXIII) deficiency is a rare but serious coagulopathy. FXIII is critical in blood coagulation, and FXIII deficiencies can lead to uncontrolled or spontaneous bleeding. FXIII deficiencies can be congenital or acquired; acquired FXIII deficiency can be categorized as autoimmune and non-autoimmune. Immunological tests to measure FXIII inhibitors are required to diagnose acquired FXIII deficiency; however, appropriate test facilities are limited, which increases the turnaround time of these tests. In the case of critical bleeding, delayed test results may worsen prognosis due to delayed treatment. Here, we report a case of acquired FXIII deficiency, followed by a review of FXIII deficiency cases in Japan. We performed a systematic review to investigate the present conditions of the diagnosis and treatment of FXIII deficiency, including the measurement of FXIII inhibitors in Japan. FXIII inhibitor testing was only performed in 29.7 of acquired FXIII deficiency cases. Clinical departments other than internal medicine and pediatrics were often involved in medical treatment at the time of onset. Therefore, it is important for doctors in clinical departments other than internal medicine and pediatrics to consider FXIII deficiency and perform FXIII inhibitor testing when examining patients with prolonged bleeding of unknown cause or persistent bleeding after trauma.
Adherence to Iron Chelation Therapy among Adults with Thalassemia: A Systematic Review
Iron chelation therapy (ICT) is essential to prevent complications of iron overload in patients with transfusion-dependent thalassemia. However, the role that adherence to ICT plays in health-related outcomes is less well known. Our objectives were to identify adherence rates of ICT, and to assess methods of measurement, predictors of adherence, and adherence-related health outcomes in the literature published between 1980 and 2020. Of 543 articles, 43 met the inclusion criteria. Studies measured ICT adherence, predictors, and/or outcomes associated with adherence. Most studies were across multiple countries in Europe and North America (n = 8/43, 18.6%), recruited in clinics (n = 39/43, 90.7%), and focused on β-thalassemia (β-thal) (n = 25/43, 58.1%). Common methods of assessing ICT adherence included patient self-report (n = 24/43, 55.8%), pill count (n = 9/43, 20.9%), prescription refill history (n = 3/43, 7.0%), provider scoring (n = 3/43, 7.0%), and combinations of methods (n = 4/43, 9.3%). Studies reported adherence either in 'categories' with different levels of adherence (n = 24) or 'quantitatively' as a percentage of doses of medication taken out of those prescribed (n = 17). Adherence levels varied (median 91.7%, range 42.0-99.97%). Studies varied in sample size and methods of adherence assessment and reporting, which prohibited meta-analysis. Due to a lack of consensus on how adherence is defined, it is difficult to compare ICT adherence reporting. Further research is needed to establish guidelines for assessing adherence and identifying suboptimal adherence. Behavioral digital interventions have the potential to optimize ICT adherence and health outcomes.
Efficacy of packed red blood cell transfusions based on weight versus formula in thalassemic children: An open-label randomized control trial
BACKGROUND Protocols for transfusion therapy in transfusion-dependent thalassemia (TDT) children differ among various medical centers. In India, most centers consider only the patient's weight while calculating the volume of packed red blood cells (PRBCs) to be transfused. This study aimed to compare the efficacy of PRBC transfusions of different volumes calculated either by weight or by a formula using weight and pretransfusion hemoglobin of patient and hematocrit of PRBC. STUDY DESIGN AND METHODS Sixty TDT patients in the age group of 3-9 years were enrolled and randomly allocated to two groups. Group A received PRBC transfusion volume based on the patient's weight, and Group B received PRBC volume calculated using a formula for 6 months. RESULTS Average pretransfusion hemoglobin in Group A and Group B (9 ± 0.4 vs. 8.9 ± 0.4 g/dl) was not significantly different (p = .353). Although the average number of visits in 6 months was less for Group A compared to Group B (7 ± 1 vs. 8 ± 1; p = .001); the average volume transfused per visit was more (351 ± 78 vs. 287 ± 68 ml; p = .003). The calculated average annual pure red cell requirement of the patients was 178 ml/kg/year for Group A and 154 ml/kg/year for Group B (p = .000). Total donor exposures were significantly lower in Group B than Group A (11 ± 3 vs. 14 ± 3; p = .006). CONCLUSION The number of donor exposures and annual pure red cell requirement was significantly lower in the formula-based group. Transfusions based on formula are recommended in TDT patients.
Transfusion-dependent thalassemia children (n= 60).
Packed red blood cells (PRBC) transfusion volume based on the patient’s weight (Group A, n= 30).
PRBC transfusion volume calculated according to a formula based on haematocrit of blood unit, desired rise in patient's haemoglobin, and patient's weight (Group B, n= 30).
The average number of visits in 6 months was less for Group A compared to Group B (7 ± 1 vs. 8 ± 1). The average volume transfused per visit was higher for Group A than Group B (351 ± 78 vs. 287 ± 68 ml). The calculated average annual pure red cell requirement of the patients was 178 ml/kg/year for Group A and 154 ml/kg/year for Group B. The total donor exposures were significantly lower in Group B than Group A (11 ± 3 vs. 14 ± 3).
Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia
Blood advances. 2022
We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naïve children with severe (SAA) and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin and cyclosporin A with (n=49) or without (n=49) ELTR. The primary endpoint was the overall response rate (ORR) at 4 months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR+IST and IST groups was similar (65% vs. 53%, p=0.218); however, the complete response (CR) rate was significantly higher in ELTR+IST group (31% vs. 12%, p=0.027). In severity subgroups, the ORR was 89% vs. 57% (p=0.028) in favor of IST+ELTR in SAA, but it did not differ in patients with vSAA (52% vs. 50%, p=0.902). At 6 months after the crossover, 61% of initial ELTR(-) patients achieved a response compared to 17% of initial ELTR(+) patients (p=0.016). No significant difference in ELTR+IST and IST groups was observed in the 3-year OS (89% vs. 91%, p=0.673) or the 3-year EFS (53% vs. 41%, p=0.326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA, but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(-) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. Clinicaltrials.gov #NCT03413306.
Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis
PloS one. 2022;17(1):e0262273
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.
Extramedullary haematopoiesis in patients with transfusion dependent β-thalassaemia (TDT): a systematic review
Annals of medicine. 2022;54(1):764-774
INTRODUCTION Around 5% of the world's population is expected to have some degree and type of thalassaemia. Beta thalassaemia (BT) occurs due to a deficient production of the beta-globin chain of haemoglobin. Extramedullary haematopoiesis (EMH) is one of the complications of BT, mainly observed in minor/intermedia subtypes. EMH is the production of blood cells outside the marrow as a compensatory response to longstanding hypoxia. Due to chronic transfusions, it is not expected in patients with beta-thalassaemia major (BTM). However, there are increasingly reported cases of EMH in BTM. The incidence of EMH in BTM is thought to be <1%. We aim to pool the available data and provide cumulative evidence on the occurrence of EMH in BTM patients. METHODS This is a systematic review of case reports, series, and retrospective studies that presented data on the occurrence of EMH in BTM patients. Data were recorded and analyzed in Microsoft Excel 2016 and SPSS 26. The protocol has been registered in PROSPERO CRD42021242943. RESULTS Data from 253 cases of EMH in BTM patients were extracted with a mean age of 35.3 years. Mean haemoglobin at presentation with EMH was 8.2 mg/dL. Lower limb weakness was the most common presenting feature (N = 23) (paraspinal EMH). Magnetic resonance imaging (MRI) was the most widely used diagnostic modality (226). Overall, blood transfusion was the commonest reported treatment (30), followed by radiotherapy (20), surgery (15), hydroxyurea (12), steroids (6), and exchange transfusion (2). An outcome was reported in 20% of patients, all recovered, except one who died as a result of nosocomial infection. CONCLUSION EMH is rare in BTM and can occur in any organ system with varied clinical features. MRI can effectively diagnose EMH, and conservative management has similar results compared to invasive treatments. Larger studies, focussing on outcomes may enhance guidelines on preventive and therapeutic strategies for managing EMH in BTM.KEY MESSAGESExtramedullary haematopoiesis is a rare complication in beta thalassaemia. Although it is more common in non-transfusion dependent thalassaemia, increasingly reported cases suggest a higher prevalence of EMH in TDT than what is known before.There are no clear guidelines on the management of EMH in TDT, with reported patients showing similar outcomes with conservative invasive treatment modalities.More extensive and preferably prospectively designed studies are required focussing on the management of EMH and its outcomes in patients with TDT to formulate evidence-based guidelines.
Comparative Efficacy of Rivaroxaban and Immunoglobulin Therapy in the Treatment of Livedoid Vasculopathy: A Systematic Review
Livedoid vasculopathy (LV) is an uncommon chronic coagulation disorder whose underlying etiology is not yet fully understood. It predominantly affects females, especially those in late adolescence. There is currently limited research on treatment options for those with this diagnosis. The present systematic review aims to compare the efficacy of rivaroxaban and intravenous immunoglobulin (IVIG) therapy in the treatment of livedoid vasculopathy. A detailed search was conducted from April 20, 2022, to May 1, 2022, using four databases: Elsevier, Medline Complete, Medline Ovid, and PubMed. Out of these, 20 relevant articles were used, and the data was extracted and analyzed. Both rivaroxaban and IVIG were shown to be effective treatment options with similar treatment response times. However, future large-scale clinical trials are needed to determine an established treatment regimen for these patients.
Comparative evaluation of efficacy and safety of automated versus manual red cell exchange in sickle cell disease: A systematic review and meta-analysis
Vox sanguinis. 2022
BACKGROUND AND OBJECTIVES Exchange transfusion is a valuable treatment option in sickle cell disease (SCD) and is preferred over simple transfusion as it removes abnormal haemoglobin S (HbS) levels and reduces complications. This meta-analysis aims to evaluate the efficacy and safety profile of automated red cell exchange (aRBX) procedure over manual red cell exchange transfusion (MET) in SCD patients. MATERIALS AND METHODS A standard meta-analysis protocol was developed, and after performing a comprehensive literature search in PubMed/MEDLINE, Cochrane and International Clinical Trial Registry Platform (ICTRP), reviewers assessed eligibility and extracted data from nine relevant studies. A random effects model was used to estimate the pooled effect size calculated from the mean difference in HbS percentage, serum ferritin level and risk ratio for the adverse events. Quality assessment was done using the risk-of-bias assessment tool, and a summary of observations was prepared using standard Cochrane methodology with GradePro GDT. RESULTS The random-model analysis revealed a mean difference of 4.10 (95% CI: -3.29-11.49; Z = 1.09; p = 0.28) for HbS percentage, mean difference of 435.29 (95% CI: -73.74-944.32; Z = 1.68; p = 0.09) for serum ferritin and pooled risk ratio of 1.35 (95% CI: 0.63-2.87; Z = 0.77; p = 0.44) for adverse events. CONCLUSION This meta-analysis did not reveal any significant benefit of aRBX in reducing HbS percentage and attenuating the serum ferritin level when compared with MET. There was also no significant increased risk of adverse events detected in association with aRBX.
Effect of thrombopoietin receptor agonist on health-related quality of life and platelet transfusion burden for patients with myelodysplastic syndromes: a systematic review and meta-analysis
Annals of hematology. 2022
Thrombocytopenia is a common and unsolved problem in myelodysplastic syndrome (MDS) patients; we aimed to summarize the evidence of TPO-RA treatment for heath-related quality of life (HRQoL) and platelet transfusion burden of MDS patients. We searched Pubmed, Web of Science, EMBASE, and CENTRAL for randomized clinical trials (RCTs) comparing TPO-RA to placebo in MDS published until July 31, 2021. A random-effect model was used. Eight RCTs with 908 patients were identified. Only three RCTs involving eltrombopag reported HRQoL, and all three studies treated HRQoL as a secondary outcome. In these three RCTs, the HRQoL instruments used in each study were different. However, this outcome cannot be meta-analyzed because some studies did not provide complete data. Subsequent clinical trials should pay more attention to this. Compared to placebo, TPO-RA did not affect platelet transfusion incidence 0.83 (95% CI 0.60-1.15). There was no evidence for subgroup differences in the analyses of different types of TPO-RA, different additional agent, and different types of MDS risk groups. However, platelet transfusion units (RR = 0.68, 95% CI 0.53 to 0.84) were significantly decreased. The RR of patients who did not require platelet transfusion for 56 or more consecutive days was not different between groups (RR = 0.98, 95% CI 0.41 to 2.34). TPO-RA may decrease platelet transfusion units in MDS patients with thrombocytopenia. But the significance of this finding should be interpreted with caution, because too few studies were meta-analyzed.