Abstract

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).

Abstract

Due to several issues, standard treatments are not recommended for asymptomatic patients with moderate immune thrombocytopenia (ITP). Since platelet responses are reported in some patients with Helicobacter pylori (H. pylori)-positive ITP after eradication, we conducted a multicenter, phase 3 study to evaluate the safety and efficacy of recently established sequential eradication for these patients having moderate thrombocytopenia. Persistent or chronic ITP patients with platelet count (30 × 10(3) ~ 80 × 10(3)/μL) and confirmed active H. pylori infection were randomly assigned to a treatment and a control group. The former received 10-day sequential treatment. Eradication was assessed by urea breath test at 3 months after treatment. Primary endpoint was the overall platelet response rate at 3 months in successfully eradicated treatment group and control group. Secondary endpoints were platelet response time, H. pylori eradication success rate, etc. The patient enrollment terminated early because of the change of national insurance and treatment guideline for H. pylori-positive patients in Korea during the study. Of the 28 H. pylori-positive ITP patients, 17 were randomized to the treatment group, and eradication was achieved for 15 (88.2%) at 3 months, and seven in control group after withdrawal. Statistically, significant difference in platelet response rates between the two groups were observed (p = 0.017). Our study verifies that H. pylori eradication was an effective ITP treatment for patients with H. pylori-associated moderate ITP. This sequential eradication regimen showed not only a high H. pylori eradication rate, but also a remarkable platelet response for ITP patients. Trial registration number and date of registration for these prospectively registered trials is ClinicalTrials.gov number, NCT03177629 and June 6, 2017.

Abstract

The Kasabach-Merritt phenomenon (KMP) in kaposiform hemangioendothelioma (KHE) is characterized by life-threatening thrombocytopenia and consumptive coagulopathy. This study compared the efficacy and safety of sirolimus plus prednisolone versus sirolimus monotherapy as treatment strategies for KHE with KMP in the largest cohort to date. Participants were randomized to receive either sirolimus in combination with a short course of prednisolone or sirolimus monotherapy for at least 12 months. The primary outcome was defined as achievement of a durable platelet response (platelet count >100×109/L) at week 4. Participants completed efficacy assessments 2 years after the initial treatment. At week 4, a durable platelet response was achieved by 35 of 37 patients given sirolimus and prednisolone compared with 24 of 36 patients given sirolimus monotherapy (difference 27.9%; 95% CI, 10.0% to 44.7%). Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in terms of measures of durable platelet responses at all points during the initial 3-week treatment period, median platelet counts during weeks 1 to 4, increased numbers of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at month 12. Patients receiving combination therapy had fewer blood transfusions and a lower total incidence of disease sequelae than patients receiving sirolimus alone. The frequencies of total adverse events and grade 3-4 adverse events during treatment were similar in both groups. The responses seen in patients with KHE with KMP were profound and encouraging, suggesting that sirolimus plus prednisolone should be considered a valid treatment for KHE with KMP. ClinicalTrial.gov, number NCT03188068.

Abstract

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.

Abstract

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.

Abstract

BACKGROUND To account for interindividual variability in the pharmacokinetics (PK) of factor concentrates, PK-guided dosing is increasingly implemented in haemophilia patients. Calculations are based on provided label potency, but legislation allows a potency difference of ±20% between label and actual potency. It is unknown if these differences affect PK guidance. AIM: Explore the effects of potency differences on individual factor VIII (FVIII) PK parameters and the prediction of FVIII trough levels of dosing regimens. METHODS We analyzed individual preoperative PK profiling data from severe and moderate haemophilia A patients included in the OPTI-CLOT randomized controlled trial. Label and actual potency were compared, with data on potency provided by pharmaceutical companies. For both potencies, individual PK parameters were estimated and concentration-time curves were constructed by nonlinear mixed-effects modelling. Finally, we explored the effect of both the identified and the maximum legislated potency difference on predicted FVIII trough levels infused in a low and high dose regimen. RESULTS In 45/50 included patients, actual potency was higher than its label potency. The median potency difference was 6.0% (range -9.2% to 18.4%) and resulted in varying individual PK parameter estimates but practically identical FVIII concentration-time curves. As expected, predicted FVIII trough levels were linearly correlated to the actual dose. CONCLUSION It is not necessary to take potency differences into account when applying PK guidance of FVIII concentrates in haemophilia A patients. However, when the patient is switched to another FVIII batch after PK-guided dosing, trough levels may deviate ±20% from calculations based on label dose.

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.

Abstract

OBJECTIVES Hereditary hemorrhagic telangiectasia (HHT) is a common inherited condition characterized by mucosal telangiectasias, recurrent epistaxis, and arteriovenous malformations. HHT results in detriment to quality of life. Morbidity and mortality result from severe anemia. Conventional interventions for HHT-related epistaxis include nasal packing, diathermy, lasers, coblation, microdebridement, bevacizumab (topical and systemic), as well as septodermoplasty and nasal closure. Sclerotherapy has been recently described in the literature as a novel approach to HHT-related epistaxis. We hypothesize that sclerotherapy is an effective treatment for HHT-related epistaxis and improves upon the current standard of care for this disease. METHODS A systematic review was conducted to study sclerotherapy for treating HHT-related epistaxis. Ovid MEDLINE, Ovid EMBASE, Scopus, and Web of Science were searched. Articles were evaluated and excluded according to PRISMA guidelines and reviewed by 2 authors. Reported variables included number of injections, months of follow up, changes in Epistaxis Severity Score, previous treatments used to control epistaxis, and post-injection side effects. RESULTS Seven studies with a total of 196 patients met inclusion criteria. Three studies reported significant improvement as measured by the Epistaxis Severity Score scale. One reported improvement through subjective patient surveys and others used the Bergler-Sadick scale to measure frequency and intensity of epistaxis. All studies reported improvement in HHT-related epistaxis. The lack of uniform reporting measures however precluded formal meta-analysis. CONCLUSIONS Based on limited data, sclerotherapy appears to be effective for treating HHT-related epistaxis and offers promise for treating this recalcitrant condition. However, larger, prospective, multi-centered studies using universally validated instruments for epistaxis are needed to definitively evaluate outcomes from sclerotherapy.

Abstract

OBJECTIVE To evaluate the efficacy and safety of recombinant human thrombopoietin (rhTPO) combined with glucocorticoid in treatment of newly diagnosed adult primary immune thrombocytopenia (ITP). METHODS Eleven male and 23 female patients with the diagnosis of primary ITP in our hospital from November 2018 to October 2019 were enrolled and randomly divided into test group (17 cases) and control group (17 cases), the median age was 52 years old (range: 20-76 years old). The patients in test group were treated with rhTPO 300 IU/(kg·d) combined with glucocorticoid , while the patients in control group were treated with rhTPO (15 000 IU/d) combined with glucocorticoid. Platelet count, platelet increase, as well as the overall response rate were compared. At the same time, the drug tolerance and any adverse drug reactions were observed. RESULTS The platelet counts and platelet increase of the patients in the test group were significantly higher than those in control group (P<0.05). There was no significant difference in platelet counts and platelet increase between the patients in the test group and control group at day 3, 7 after treatment. There was no significant difference in overall response rates and complete response rates at day 7, 14 between the two groups either. In test group, there were 13 cases received platelet transfusion, while 12 cases in control group. The muscle aches occurred in one patient, and mild aminotransferase increased in another patient in test group which was self-recovery without treatment. CONCLUSION RhTPO 300 U/(kg·d) combined with glucocorticoid could rapidly increase the platelet count with a low incidence of tolerable adverse events compared with conventional dose rhTPO with glucocorticoid.

Abstract

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.